JP2016216409A - Orally disintegrating tablet comprising triptan compound - Google Patents

Abstract

An object of the present invention is to provide an orally disintegrating tablet containing a triptan compound excellent in stability of the triptan compound in a tablet. An orally disintegrating tablet comprising a triptan-based compound and a starch-derived disintegrant and not containing crospovidone. [Selection] Figure 1

Description

  The present invention relates to an orally disintegrating tablet containing a triptan compound.

  One of the most common symptoms of headache is migraine. Symptoms of migraine may be painful for a long time with pulsation on one or both sides of the head, and may be accompanied by nausea and vomiting when severe. The cause of such a migraine is not clearly known, but it is thought that a migraine is caused by the expansion of blood vessels in the head due to a loss of hormonal balance or the like.

Regarding the treatment and prevention of migraine, triptan compounds such as zolmitriptan, rizatriptan, eletriptan and sumatriptan are known as effective active ingredients for effective migraine treatment and prevention (for example, Patent Document 1). . A triptan compound spreads blood vessels by acting on serotonin receptors (5-HT receptors), in particular, two receptors, 5-HT _1B receptors and 5-HT _1D receptors present in cerebral blood vessels. It is thought to improve the state of migraine.

  In addition, because triptan compounds have many opportunities to be taken when migraine begins, oral dosage forms of pharmaceutical preparations containing triptan compounds are easy to carry and can be taken as soon as migraine begins. A lock is desired. For example, Patent Documents 2 and 3 disclose orally disintegrating tablets containing a triptan-based compound such as sumatriptan succinate or zolmitriptan (see Example 3 in Patent Document 2 and Example 26 in Patent Document 3). ).

  An orally disintegrating tablet is a tablet that can be rapidly dissolved or disintegrated in the oral cavity and taken and must have an appropriate disintegrating property. Therefore, in the orally disintegrating tablet containing the triptan compound disclosed in Patent Documents 2 and 3, appropriate disintegration property in the oral cavity is ensured by containing crospovidone as a disintegrant.

Japanese National Patent Publication No. 05-502679 Special table 2010-540588 gazette JP 2009-114113 A

  However, the orally disintegrating tablets containing the triptan compounds disclosed in Patent Documents 2 and 3 have a problem that related substances (N-oxides) are generated from the triptan compounds in the tablets.

  For this reason, in the orally disintegrating tablet containing a triptan compound, it is desired to suppress the production of a related substance of the triptan compound in the tablet.

  This invention is made | formed in view of said point, and it aims at providing the orally disintegrating tablet containing the triptan type compound excellent in the stability of the triptan type compound in a tablet conventionally.

  As a result of intensive investigations in view of the above problems, the present inventors have found that crospopidone conventionally used as a disintegrant in an orally disintegrating tablet containing a triptan-based compound produces a related substance (N-oxide). By identifying the cause, using a disintegrant derived from starch and not containing crospovidone, appropriate disintegration as an orally disintegrating tablet is ensured and a related substance (N-oxide) It was found that the production of (body) was suppressed.

  That is, the orally disintegrating tablet according to one embodiment of the present invention includes a triptan compound and a starch-derived disintegrant and does not contain crospovidone.

  Moreover, in the orally disintegrating tablet, it is preferable that the starch-derived disintegrant is at least one selected from partially pregelatinized starch and corn starch.

  Furthermore, in the orally disintegrating tablet, the content rate of the starch-derived disintegrant is preferably in the range of 5 to 40% by mass in the orally disintegrating tablet.

  The orally disintegrating tablet preferably contains 1 to 20% by mass of partially pregelatinized starch as the starch-derived disintegrant.

  Furthermore, the orally disintegrating tablet preferably contains partially pregelatinized starch and corn starch in a mass ratio of 1: 1 to 1:20 as the starch-derived disintegrant.

  In the orally disintegrating tablet, the triptan compound is preferably a compound selected from the group consisting of zolmitriptan, rizatriptan, eletriptan, sumatriptan, and pharmaceutically acceptable salts thereof.

  ADVANTAGE OF THE INVENTION According to this invention, the orally disintegrating tablet containing the triptan type compound excellent in the stability of the triptan type compound in a tablet can be provided.

It is a figure which shows the time-dependent change of the production amount (%) of the related substance (N-oxide body) of zolmitriptan in the tablet concerning Examples 1, 2 and Comparative Example 1. It is a figure which shows a time-dependent change of the production amount (%) of the related substance (N-oxide body) of the rizatriptan benzoate salt in the tablet concerning Example 3, 4 and the comparative example 2. FIG.

  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 is characterized by containing a triptan compound and a starch-derived disintegrant and not containing crospovidone.

  With such a configuration, an orally disintegrating tablet containing a triptan-based compound, which is stable as a preparation, can be obtained by suppressing the production of an N-oxide compound that is a related substance. Therefore, the orally disintegrating tablet of this embodiment is very useful for industrial use because it can keep the active ingredient stable even when stored for a relatively long period of time.

  The triptan compound used as an active ingredient in the orally disintegrating tablet of the present embodiment is a known compound known as an active ingredient for treatment / prevention of migraine and the like.

  Among these, in the orally disintegrating tablet of the present embodiment, a compound selected from the group consisting of zolmitriptan, rizatriptan, eletriptan, sumatriptan, and pharmaceutically acceptable salts thereof as the active agent (active ingredient) Is preferably used. When these triptan compounds are used, it is considered that the effects of the present invention are more exhibited.

  Zolmitriptan is the chemical name (S) -4-[[3- [2- (dimethylaminoethyl)]-1H-indol-5-yl] methyl] -2-oxazolidinone, and Rizatriptan is the chemical name. 3- [2- (dimethylamino) ethyl] -5- (1H-1,2,4-triazol-1-ylmethyl) indole, and eletriptan has the chemical name: (+)-(R) -3- (1-methylpyrrolidone-2-ylmethyl) -5- (2-phenylsulfonylethyl) -1H-indole, sumatriptan is the chemical name: 3- [2- (dimethylamino) ethyl] -N-methylindole -5-methanesulfonamide.

  Examples of pharmaceutically acceptable salts of these triptan compounds include pharmaceutically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts, and the like.

  The compounding amount of the triptan compound in the orally disintegrating tablet of the present embodiment is such that the daily dose of the triptan compound for a human patient is usually about 1 to 70 mg (once or divided). It is preferable to do.

  Therefore, the orally disintegrating tablet of the triptan compound of the present embodiment contains 1 to 20 mg of the main drug, which can be administered to a human patient one or more tablets at a time as needed. Note that the actual dose appropriate for each patient can be appropriately set depending on the age, weight and symptoms of the patient.

  Next, in the present embodiment, “not containing crospovidone” means that the orally disintegrating tablet is substantially free of crospovidone, and more specifically, containing crospovidone. The rate refers to 0.1% by mass or less in the tablet. When crospovidone is contained (when crospovidone is contained in the tablet in an amount of more than 0.1% by mass), an analogous substance (N-oxide) of the triptan compound as the active ingredient of the present embodiment is produced, The stability of the amount of triptan compound in the orally disintegrating tablet is deteriorated. If the content of crospovidone is 0.1% by mass or less in the tablet and is not substantially contained, the production of the related substances is suppressed, and the stability of the triptan compound is good even after long-term storage. It is possible to obtain an orally disintegrating tablet.

  Moreover, the orally disintegrating tablet of this embodiment is characterized by containing a starch-derived disintegrant as a disintegrant. Although it can be used without any limitation as long as it can be used as a disintegrant for a pharmaceutical preparation derived from starch, specifically, for example, partially pregelatinized starch, corn starch, pregelatinized starch, potato starch, hydroxypropyl starch, etc. Is mentioned.

  Especially, it is preferable to contain at least one of partially pregelatinized starch or corn starch as a starch-derived disintegrant.

  Thereby, there exists an advantage that the effect of the stability improvement of the triptan type compound in the tablet in this embodiment can be acquired more reliably.

  The content (mixing ratio) of the starch-derived disintegrant in the orally disintegrating tablet of this embodiment is preferably in the range of 5 to 40% by mass in the orally disintegrating tablet, and is 15 to 30% by mass. More preferably, it is within the range. If the content rate of the disintegrant derived from starch is in the range of 5 to 40% by mass, there is an advantage of having excellent disintegration properties and hardness. When the content of the disintegrant derived from starch is less than 5% by mass, there is a risk of causing disintegration delay and hardness reduction, and disintegration delay under heating / humidification conditions. On the other hand, when the content rate of the starch-derived disintegrant exceeds 40% by mass, the hardness may be lowered under heating / humidification conditions.

  As a more preferred embodiment, the orally disintegrating tablet preferably contains 1 to 20% by mass of partially pregelatinized starch as the starch-derived disintegrant, and more preferably 2 to 10% by mass. Thereby, it is thought that it is excellent by the disintegration property and hardness in an orally disintegrating tablet.

  As another preferred embodiment, in the orally disintegrating tablet, the starch-derived disintegrant contains both partially pregelatinized starch and corn starch, and the blending ratio of partially pregelatinized starch and corn starch is: A mass ratio of 1: 1 to 1:20 is desirable, and a mass ratio of 1: 2 to 1:10 is more desirable. Thereby, it is considered that excellent disintegration and hardness in the orally disintegrating tablet can be obtained more reliably.

  In the orally disintegrating tablet of the present embodiment, in addition to the above components, pharmaceutically acceptable additives can be appropriately blended as necessary within the range not impairing the effects of the present invention.

  Specific additives include, for example, excipients such as lactose, D-mannitol, ethyl cellulose, light anhydrous silicic acid, microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine; Disintegrants (excluding crospovidone); sweeteners such as aster palm; fragrances such as I-menthol, yogurt micron, pineapple micron, peppermint micron, lemon micron; yellow ferric oxide, titanium oxide, ferric oxide, etc. Colorants and light-shielding agents; Lubricants such as magnesium stearate, glyceryl behenate and talc; water-soluble polymers such as polyvinylpyrrolidone, hydroxypropylcellulose and hydroxypropylmethylcellulose; granulating binders such as sucrose and gelatin Can be blended.

The orally disintegrating tablet containing the triptan compound of the present embodiment is effective for the treatment and / or prevention of diseases relating to 5-HT ₁ receptor, and particularly selective agonists of 5-HT _{1B / 1D} receptor. Can be used. Such diseases include migraine, recurrent migraine, hypertension, depression, vomiting, anxiety, eating disorders, obesity, substance abuse, cluster headache, pain, chronic paroxysmal migraine and headache associated with vascular disorders. Is included.

  Next, it does not specifically limit as a manufacturing method of the orally disintegrating tablet containing the triptan-type compound of this embodiment, A well-known method can be utilized, for example, each which comprises the orally disintegrating tablet mentioned above. The method of shape | molding as a tablet after mixing an ingredient is mentioned.

  As a specific example, an orally disintegrating tablet can be produced by the following method. First, a granulated product (granule) is obtained by a known fluidized bed granulation method using granule components including a disintegrant, an excipient, a colorant, a light shielding agent and the like. And the obtained granule is sized using a sizing machine etc., and a sized powder is obtained. Next, a tableting component containing excipients, sweeteners, flavors, colorants, light-shielding agents, lubricants, etc., a triptan compound as a drug substance, and the above sized powder, a Bole container mixer, etc. To obtain granule powder for tableting. Then, the granule powder for tableting is tableted to obtain a tablet.

  Tableting is preferably performed by compression molding. For example, a tableting die used for tableting, an upper punch and a lower punch for tableting, a hydraulic hand press machine, a single-shot tableting machine, or a rotary tableting machine is used. A lock machine or the like can be used. The tableting pressure can be appropriately set according to the tablet weight as the orally disintegrating tablet to be produced.

  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 orally disintegrating tablet of this embodiment obtained as described above has a disintegration time within 60 seconds, further within 30 seconds, according to the disintegration test method (16th revised Japanese Pharmacopoeia), and It is preferable that the hardness measured by the tablet hardness tester is 20N or more, more preferably 40N or more. The orally disintegrating tablet referred to in the present invention includes not only an orally disintegrating tablet that can be rapidly dissolved or disintegrated in the oral cavity described in the 16th revised Japanese Pharmacopoeia, but also a rapidly disintegrating tablet. .

  The disintegration test method can be performed in accordance with the disintegration test method described in the 16th revision Japanese Pharmacopoeia. The hardness can be measured using, for example, a tablet hardness meter TBH425 manufactured by ERWEKA.

  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.

(Examples 1-6, Comparative Examples 1 and 2)
Table 1 below shows the formulations of the tablets shown in Examples 1 to 6 and Comparative Examples 1 and 2. As shown in Table 1, in Examples 1, 2, 5, and 6 and Comparative Example 1, zolmitriptan was used as the triptan compound as the drug substance, and in Examples 3 and 4 and Comparative Example 2, Rizatriptan benzoate was used as the triptan compound as the drug substance.

  The tablets of Examples 1 to 6 and Comparative Examples 1 and 2 were produced by the following method. That is, first, granulated materials (granules) were obtained by the fluidized bed granulation method using the granule components shown in Table 1. Next, the obtained granule was sized using a sizing machine (wet dry type sizing machine (Quadrocor mill) “QC-197S” manufactured by POWREC Co., Ltd.) to obtain a sized powder. And the said granulated powder, an active ingredient, and the component for tableting were mixed using the Boule container mixer ("LM-20" by Kotobuki Giken Co., Ltd.), and the granule powder for tableting was obtained. And the said granule for tableting was tableted using the rotary type tableting machine ("VIRG0512SS2AZ" by Kikusui Seisakusho Co., Ltd.), and the target tablet was obtained.

  In Examples 1 and 2 and Comparative Example 1, tableting was performed at a tableting pressure of 78.5 MPa so that the diameter was 7.0 mm and the weight of one tablet was 135 mg. In Example 3, 98.1 MPa was used. The tableting pressure was 8.0 mm in diameter and 1 tablet weight was 180 mg. In Example 4 and Comparative Example 2, the tableting pressure was 117.7 MPa, the diameter was 9.0 mm, Tablets were tableted to a weight of 270 mg, and the stability tests of the triptan compounds were performed on the tablets of Examples 1 to 4 and Comparative Examples 1 and 2 obtained as described below.

(Stability test 1)
The tablets of Examples 1 and 2 and Comparative Example 1 containing zolmitriptan obtained above were stored in PE bottles (open) for a certain period in an environment of a temperature of 40 ° C. and a humidity of 75%.

  And in the tablet of Example 1, the production | generation amount of the N-oxide body which is a related substance was investigated about the tablet after progress of 0 month, 0.25 month, 1 month, and 1.5 month, respectively. In Example 2, about 0 month, 0.125 month, 0.25 month, 0.5 month, and 2 months after the tablet, in Comparative Example 1, 0 month, 0.25 month, 0.5 month, 1 month The amount of N-oxide produced in each tablet after the passage of months was examined.

  The amount of zolmitriptan-related substance (N-oxide) produced was measured by UPLC analysis. The amount of zolmitriptan-related substance produced was expressed as the percentage (%) of the peak area of the related substance in the total peak area derived from UPLC zolmitriptan. The sample solution used for this measurement and the UPLC measurement conditions are as follows.

[Sample solution]:
To a 50 mL brown centrifuge tube charged with 1 tablet, 2.5 mL of water was added to disintegrate the tablet, and then 2.5 mL of acetonitrile was further added and shaken for 10 minutes. The liquid in the brown centrifuge tube was filtered with DISMIC (registered trademark) 25HP manufactured by ADVANTEC, and the remaining filtrate except 1 mL of the initial flow was used as a sample solution.

[UPLC measurement conditions]:
Measurement wavelength: 225 nm (detector: UV-visible spectrophotometer)
Column: A stainless steel tube having an inner diameter of 2.1 mm and a length of 100 mm packed with 1.7 μm of octadecyl silica gel for liquid chromatography.

Column temperature: 30 ° C
Mobile phase A: A solution obtained by adding 1.26 g of ammonium formate to 1000 mL of water and adding 1 mL of n-propylamine.

Mobile phase B: Acetonitrile Injection volume: 2 μL
Flow rate: 0.4 mL / min

  The above results are shown in Table 2 and FIG. The unit of each numerical value in Table 2 is (%).

  As shown in FIG. 1 and Table 2, the tablets of Examples 1 and 2 containing a starch-derived disintegrant (partially pregelatinized starch and / or corn starch) and no crospovidone disintegrate crospovidone. Compared with the tablet of Comparative Example 1 included as an agent, the amount of related substances produced over time was extremely small, and it was confirmed that the stability of the triptan-based compound (zolmitriptan) was excellent.

(Stability test 2)
The tablets of Examples 3 and 4 and Comparative Example 2 containing rizatriptan benzoate obtained above were stored in PE bottles (sealed) for a certain period in an environment of 70 ° C. and humidity.

  In each tablet, the amount of N-oxide produced as a related substance was examined for the tablets after 0 days, 3 days, 6 days, and 9 days.

  The amount of Rizatriptan-related substance (N-oxide) produced was measured by HPLC analysis. The amount of Rizatriptan-related substance produced was expressed as a percentage of the peak area of the related substance in the total peak area derived from HPLC Rizatriptan. The sample solution used for this measurement and the measurement conditions of HPLC are as follows.

[Sample solution]:
A water / acetonitrile / trifluoroacetic acid mixture (840: 160: 1) was added to a 10 mL brown centrifuge tube containing 1 tablet, and the tablet was disintegrated by shaking for 10 minutes. The liquid in the brown centrifuge tube was filtered through Millex-LH manufactured by MERCK having a pore diameter of 0.45 μm, and the remaining filtrate except 5 mL of the initial flow was used as a sample solution.

[HPLC measurement conditions]:
Measurement wavelength: 280 nm (detector: ultraviolet absorption photometer)
Column: A stainless tube having an inner diameter of 4.6 mm and a length of 25 cm packed with 5 μm of octadecyl silica gel for liquid chromatography.

Column temperature: 30 ° C
Mobile phase A: water / acetonitrile / trifluoroacetic acid (840: 160: 1)
Mobile phase B: acetonitrile / trifluoroacetic acid (1000: 1)
Injection volume: 20 μL
Flow rate: 1 mL / min

  The above results are shown in Table 3 and FIG. The unit of each numerical value in Table 3 is (%).

  As shown in Table 3 and FIG. 2, the tablets of Examples 3 and 4 containing starch-derived disintegrants (partially pregelatinized starch and corn starch) and no crospovidone were used with crospovidone as the disintegrant. Compared with the tablet of Comparative Example 2 containing, the production amount of the related substance over time was extremely small, and it was confirmed that the stability of the triptan-based compound (Rizatriptan) was excellent.

(Tablet hardness and disintegration test)
The tablets obtained in Examples 1, 5 and 6 were tested for hardness and disintegration. Specifically, for Examples 1, 5, and 6, the hardness (N) of each tablet obtained by tableting at a tableting pressure (compression pressure) of 58.8 MPa, 68.6 MPa, and 78.5 MPa, The decay time (sec) was measured. About hardness, it measured by n = 5 using the tablet hardness meter (Erweka company tablet hardness meter TBH425), and employ | adopted the average value. About disintegration, based on the disintegration test method (16th revision Japanese Pharmacopoeia), it measured by n = 3 and employ | adopted the average value.

  Table 4 shows the results.

  As shown in Table 4, all of the tablets of Examples 1, 5, and 6 have a content of partially pregelatinized starch of 1 to 5% by mass within a content of starch-derived disintegrant. Within the range of ˜20% by weight, the weight ratio of partially pregelatinized starch and corn starch is within the range of 1: 1 to 1:20. All of the tablets of Examples 1, 5, and 6 have a high hardness of 40 N or more, disintegrate in a short time of 30 seconds or less, and have excellent characteristics as orally disintegrating tablets. Admitted.

  In addition, the tablets of Examples 2 to 4 contain 5 to 40% by mass of a starch-derived disintegrant as in the tablets of Examples 1, 5, and 6, and have appropriate hardness and an orally disintegrating tablet. Has disintegration.

(Discussion)
As is clear from the above results, the orally disintegrating tablet of the present invention was shown to have very good stability of the triptan compound in the tablet. On the other hand, in the comparative example using crospovidone conventionally used as a disintegrant, an N-oxide form, which is a related substance of a triptan compound, is generated at a relatively early stage, and the stability of the triptan compound is improved. It was an inferior tablet.

  Furthermore, by making the content ratio of the disintegrant derived from starch, in particular, the blending ratio of partially pregelatinized starch and / or the mass ratio of partially pregelatinized starch and corn starch, more excellent disintegration and hardness It was also confirmed that an orally disintegrating tablet having

Claims (6)

  An orally disintegrating tablet comprising a triptan compound and a starch-derived disintegrant and not containing crospovidone.   The orally disintegrating tablet according to claim 1, wherein the disintegrant derived from starch is at least one selected from partially pregelatinized starch and corn starch.   The orally disintegrating tablet according to claim 1 or 2, wherein the content of the disintegrant derived from starch is in the range of 5 to 40% by mass in the orally disintegrating tablet.   The orally disintegrating tablet according to any one of claims 1 to 3, comprising 1 to 20 mass% of partially pregelatinized starch as the disintegrant derived from starch.   The orally disintegrating tablet according to any one of claims 2 to 4, comprising partially pregelatinized starch and corn starch in a mass ratio of 1: 1 to 1:20 as the disintegrant derived from starch. The said triptan-type compound is a compound selected from the group which consists of zolmitriptan, rizatriptan, eletriptan, sumatriptan, and these pharmaceutically acceptable salts. Orally disintegrating tablets.

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