JP6037687B2 - Orally disintegrating tablets containing glimepiride - Google Patents

Description

  The present invention relates to an orally disintegrating tablet which is taken orally for the purpose of treating diabetes and contains glimepiride as an active ingredient.

  Glimepiride has the chemical name 1- [4- [2- (3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) ethyl] phenylsulfonyl] -3- (trans-4-methylcyclohexyl). ) Urea is a sulfonylurea oral hypoglycemic agent useful for type 2 diabetic patients.

  Tablets containing glimepiride as an active ingredient have already been approved and sold in over 100 countries around the world, including the first marketed Amalil (registered trademark), and its effectiveness in treating type 2 diabetes is well known. It has been.

  On the other hand, with the progress of an aging society, the number of elderly type 2 diabetic patients who are treated with sulfonylurea oral hypoglycemic agents such as glimepiride is also increasing. In such elderly patients, the swallowing function of swallowing things from the mouth is often reduced, and conventional regular tablets may not always be easy to take. In addition, non-elderly patients often experience difficulty in taking tablets in the case of pediatric patients and patients with reduced swallowing function due to various causes.

  Therefore, in order to facilitate administration even in patients with such a swallowing function, various improvements such as downsizing of tablets and introduction of orally disintegrating tablets have been made even in the case of glimepiride tablets. Has been considered.

Patent Document 1 describes an oral disintegrating tablet of glimepiride containing polyvinyl alcohols and water-soluble polyoxyethylenes. This intraoral quick disintegrating tablet further requires a disintegrating agent. In Examples 1 to 3, a known crospovidone or a large amount of corn starch is used as a super disintegrating agent.
Patent Document 2 describes an orally disintegrating tablet containing a powder having an average particle size of 40 μm or more and / or a granulated sugar alcohol, celluloses, and a disintegrant. Example 15 contains glimepiride as a pharmaceutically active ingredient, As a disintegrant, a crospovidone-containing orally disintegrating tablet known as a super disintegrant is disclosed.

  On the other hand, as a completely different direction, Patent Document 3 is a miniaturized tablet that contains glimepiride finely pulverized so as to have an average particle size of 10 μm or less as an active ingredient and can be taken even by patients with reduced swallowing function. Glimepiride-containing tablets are described.

  However, all of the conventional glimepiride tablets described in the above-mentioned patent documents use a specific component to make an orally disintegrating tablet, or finely pulverized glimepiride as an active ingredient.

JP 2010-53043 A JP 2009-114113 A JP 2007-31377 A

Amariru (registered trademark) pharmaceutical interview form (revised 13th edition)

  Even in patients with reduced swallowing function, such as elderly patients, it has a disintegrating property that quickly disintegrates in the oral cavity without water so that convenience in taking is high, and at the same time the patient is storing tablets The present invention also provides an orally disintegrating tablet of glimepiride, which has the advantage of maintaining a sufficient hardness, and does not add a disintegrant separately and does not change the components of a conventional formulation.

The present inventors have changed the amount and amount of each additive component of the conventional glimepiride tablet almost without changing the amount of magnesium stearate, which is a lubricant, to a minute amount of 0.1% by mass or less. In addition, the magnesium stearate is not added to the tableting granules, but is adhered to the tableting mill of the tableting machine, and the tableting is performed with a lower tableting pressure. The present invention was completed by finding that an orally disintegrating tablet having both oral disintegration property and sufficient tablet hardness and having high patient convenience can be obtained.
In addition, the expression of the content of “0.1 mass% or less” of a small amount of magnesium stearate is “0.15 mass%” such as 0.149... Content of “less than%” and is understood as such to those skilled in the art of pharmaceutical formulation.

Therefore,
(1) The present invention includes glimepiride, and crystalline cellulose as an additive, lactose hydrate, positive bi Don, sodium starch glycolate and magnesium stearate as an active ingredient, the content of magnesium stearate 0.15% by weight It is a glimepiride-containing orally disintegrating tablet that is less than.
(2) The present invention is a glimepiride-containing orally disintegrating tablet produced by tableting without adding magnesium stearate into the tableting granules, and attaching to a tableting tablet of a tableting machine. .
(3) The present invention relates to a method for producing an orally disintegrating tablet containing glimepiride, comprising the steps of tableting by adding magnesium stearate to a tableting tablet of a tableting machine without adding magnesium stearate into the tableting tablet. It is.

  The orally disintegrating tablet of the present invention is a type 2 diabetic patient with reduced swallowing function due to superior disintegration in the oral cavity as compared with glimepiride-containing tablets such as Amarille (registered trademark) tablets. It is easy to take, and the tablet hardness is maintained at the same level as conventional glimepiride-containing tablets, is not easily broken, and has excellent stability during storage.

  Because of such convenience, the orally disintegrating tablet of the present invention has high stability and does not have a decrease in hardness. Can withstand packaging. In particular, elderly patients often take a plurality of tablets at the same time, and in that case, a plurality of tablets for a single dose are often packaged and stored. Even in such a case, the orally disintegrating tablet of the present invention is an orally disintegrating tablet having sufficient hardness for handling.

  Furthermore, in the orally disintegrating tablet of the present invention, the additive components and content other than magnesium stearate are the same as those of commercially available glimepiride-containing tablets, for example, Amalil (registered trademark) tablets, and the production method is mostly common. Therefore, there are great manufacturing advantages.

  According to the present invention, in order to improve the convenience of patients using glimepiride as an oral preparation, it has a disintegrating property that disintegrates quickly in the oral cavity without water, and at the same time has sufficient hardness in storage of tablets by patients. Thus, an orally disintegrating tablet containing glimepiride is provided.

The changes in tablet hardness of a 1 mg tablet of glimepiride orally disintegrating tablet under storage at 25 ° C. and 60% were compared with the orally disintegrating tablet (saKK) of the present invention and four commercially available glimepiride orally disintegrating tablets (AD). The result measured in comparison between. The vertical axis represents tablet hardness (kg), and the horizontal axis represents storage period (days). The changes in tablet hardness of 1 mg tablet of glimepiride orally disintegrating tablet under storage at 30 ° C. and 80% were compared with the orally disintegrating tablet (saKK) of the present invention and four commercially available glimepiride orally disintegrating tablets (AD). The result measured in comparison between. The vertical axis represents tablet hardness (kg), and the horizontal axis represents storage period (hours).

Hereinafter, the present invention will be described in detail according to embodiments.
The orally disintegrating tablet of the present invention is a tablet containing 0.2 to 12 mg, preferably 0.5 to 6 mg, particularly preferably 1 to 3 mg of the active ingredient glimepiride in one tablet.
Weight of the oral disintegrating tablet of the tablet of the present invention is usually 20Mg～300mg, preferably 40～200Mg, as a blending component in addition to the active ingredient, crystalline cellulose, lactose hydrate, positive bi pyrrolidone, sodium starch glycolate and Magnesium stearate is included. Crystalline cellulose, lactose hydrate, positive bi pyrrolidone and blending ratio of sodium starch glycolate is in the range usually used in the field of preparation is not particularly limited. For example, crystalline cellulose 2 to 20% by weight, preferably in the range of 5 to 15 wt%, lactose hydrate from 50 to 90 wt%, preferably in the range of 65 to 85 wt%, positive bi Dong 0. 1 to 5% by mass, preferably 0.5 to 3% by mass, and sodium starch glycolate can be used in the range of 1 to 15% by mass, preferably 3 to 10% by mass, respectively. Magnesium stearate can be used in the range of 0.005 to less than 0.15% by mass, preferably 0.01 to less than 0.15% by mass. As these components, those described in Japanese Pharmacopoeia 16th revision can be used.
Furthermore, when it is necessary to identify the tablet, an appropriate amount of pigment, for example, iron sesquioxide, yellow iron sesquioxide, etc. is 0.001 to 0.1% by mass, preferably 0.003 to 0.05% by mass. Can be used in a range.

The orally disintegrating tablet of the present invention is preferably the same as the conventional commercially available tablet in the types and ratios of the components other than magnesium stearate. For example, the orally disintegrating tablet of the present invention can include conventional Amaryl (R) in the same content ratio as tablets glimepiride, crystalline cellulose, lactose hydrate, a port bi pyrrolidone and sodium starch glycolate.

Magnesium stearate is not added to the tableting granules, but is attached to the tableting punch side. As a result, tableting at a low tableting pressure is possible without impairing the compression moldability to tableting granules, and as a result, it is possible to produce an orally disintegrating agent with low tablet density and good disintegration.
More specifically, in the production of conventional tablets, for example, when tablet hardness of about 30 to 40 N or more or 3 to 4 kg or more is required, for example, a tableting pressure of about 6 to 8 kN or more is required. However, the orally disintegrating tablet of the present invention can produce tablets having the required tablet hardness with a tableting pressure 20-30% lower than that. Even when other tablet hardness is obtained, the oral disintegration of the present invention can produce a tablet having the required tablet hardness with a tableting pressure 20-30% lower.
Moreover, ELS-P1 made from Kikusui Seisakusho can be used for the apparatus for tableting, for example.

  The orally disintegrating tablet of the present invention uses almost the same formulation as that of a conventional Amarille (registered trademark) tablet. However, since it can be molded even when the tableting pressure is lowered as described above, the tablet diameter can be made larger than that of conventional tablets, and the effect of enhancing the discrimination between these two types of dosage forms can be obtained.

  The orally disintegrating tablet of the present invention is used for the treatment of type 2 diabetes. This is particularly effective when dietary / exercise therapy alone is not sufficient.

  The orally disintegrating tablet of the present invention is preferably used in the same usage and dosage as conventional glimepiride-containing tablets, for example, Amalil (registered trademark) tablets. Currently, Amalyl® tablets are usually administered orally as glimepiride starting at 0.5 to 1 mg per day, once or twice a day in the morning or morning and evening, before or after a meal. The maintenance amount is usually 0.5 to 4 mg per day, and may be increased or decreased as needed. The maximum daily dose is up to 6 mg.

  EXAMPLES Next, although an Example is shown and this invention is demonstrated further more concretely, this invention is not limited to these Examples.

[Preparation example] Formulation example of glimepiride orally disintegrating tablet A formulation example of white pigment tablet of glimepiride orally disintegrating tablet 0.5 mg tablet is shown below.

[Example 1] Production of 0.5 mg tablet of glimepiride orally disintegrating tablet 1) Preparation of glimepiride as an active ingredient, and lactose hydrate, sodium starch glycolate, crystalline cellulose and povidone as an additive according to the above formulation And mixed in a high speed mixer.
2) An appropriate amount of purified water was further added to the above mixture and kneaded in a high-speed mixer to obtain a granular drug.
3) The size of the granules was adjusted by a sieving device in a wet manner.
4) The wet-prepared granules were dried with a fluidized bed dryer.
5) Appropriate amounts of crystalline cellulose, sodium starch glycolate and pigment were added again to the granules.
6) Further, the size of the granules was adjusted by a sieving device.
7) The above materials were mixed using a Boule type mixer (PM1000, 1200 L) to obtain tablets for tableting.
8) Magnesium stearate less than 0.15% by mass of the whole tablet is attached to a tableting punch and mortar using a tablet manufacturing machine (Kikusui Seisakusho ELS-P1), and the tableting granules are compressed into tablets. Thus, a 0.5 mg tablet of the desired glimepiride orally disintegrating tablet was produced.

Example 2 Production of Glimepiride Orally Disintegrating Tablets 1 mg Tablet and 3 mg Tablets In the same manner as in Example 1, glimepiride orally disintegrating tablet 1 mg tablets and 3 mg tablets were produced. These orally disintegrating 1 mg tablets and 3 mg tablets of glimepiride are prepared using the same content ratios as those of conventional Amaryl 1 mg tablets and 3 mg tablets, respectively, except that the magnesium stearate content is less than 0.15% by mass. did.

[Example 3] Disintegration test: comparison between glimepiride orally disintegrating tablet of the present invention and conventional Amalil tablet The disintegration property and tablet hardness of glimepiride orally disintegrating tablet of the present invention and the conventional Amaryl tablet are as follows. Measurement was performed by two methods, that is, a method using an orally disintegrating tablet disintegration tester and a disintegration test method (without an auxiliary plate) described in Japanese Pharmacopoeia 15th revision. The results are shown in Table 1 and Table 2, respectively. Each numerical value represents a disintegration time (unit: second), and six tests were performed. Further, the tablet hardness (unit: kgf) of each tablet was measured using a tablet hardness meter (TS-75N, manufactured by Okada Seiko).

  In both of these two disintegration confirmation tests, it was found that the orally disintegrating tablet of the present invention disintegrated in a shorter time than the conventional tablet, and at the same time, a tablet having almost the same tablet hardness was obtained.

[Example 4] Testing of tablet hardness change during storage: Comparison of glimepiride orally disintegrating tablet of the present invention and commercially available glimepiride orally disintegrating tablet 1 mg tablet (sakk) of glimepiride orally disintegrating tablet of the present invention Tablet hardness (kg) during storage under conditions of 25 ° C. and 60% humidity simulating storage at room temperature for each 1 mg tablet of all four types of glimepiride orally disintegrating tablets (AD) currently on the market And changes in tablet hardness (kg) during storage under more severe conditions of 30 ° C. and humidity 80% were compared.
The tablet hardness (unit: kg) of each tablet was measured using a tablet hardness meter (TS-75N, manufactured by Okada Seiko). Each test is performed 10 times, and the result represents the average value.

As a result, as shown in FIG. 1, when stored under conditions of 25 ° C. and 60% humidity simulating storage at room temperature, the glimepiride orally disintegrating tablet of the present invention has a change in tablet hardness over the storage period of 7 days. The hardness was almost constant at ± 0 to + 6%, and the hardness was maintained.
On the other hand, in all commercially available glimepiride orally disintegrating tablets (A to D), the tablet hardness sharply decreased by 13 to 33% on the first day after storage, and decreased by 22 to 36% after 7 days. It was.

  In addition, as shown in FIG. 2, in storage under more severe conditions of 30 ° C. and humidity 80%, all orally disintegrating tablets showed a sharp decrease in tablet hardness after 30 minutes. The degree of change was 51-64% for the commercially available glimepiride orally disintegrating tablets (AD), while the glimepiride orally disintegrating tablet of the present invention was only 22%. Furthermore, even after 24 hours of storage under the harsh conditions, the commercially available glimepiride orally disintegrating tablets (AD) decreased by 67 to 76%, whereas the glimepiride orally disintegrating tablet of the present invention was 43%. Stayed in decline.

  As described above, the glimepiride orally disintegrating tablet of the present invention is superior in tablet hardness under both storage conditions at room temperature and severe conditions as compared with any of the commercially available glimepiride orally disintegrating tablets. It was shown to have

Claims (4)

Glimepiride, crystalline cellulose, include lactose hydrate, positive bi Don, sodium starch glycolate and magnesium stearate, wherein the wherein the content of magnesium stearate is less than 0.15 wt%, glimepiride-containing oral Inner disintegrating tablet.   Glimepiride-containing oral cavity comprising glimepiride, crystalline cellulose, lactose hydrate, povidone, sodium starch glycolate, and magnesium stearate, wherein the magnesium stearate content is less than 0.15% by mass Disintegrating tablets. Consists of glimepiride, crystalline cellulose, lactose hydrate, povidone, sodium starch glycolate, magnesium stearate, and a pharmaceutically acceptable pigment to identify tablets, where the magnesium stearate content is 0.15 mass An orally disintegrating tablet containing glimepiride, characterized by being less than%. A glimepiride-containing oral cavity according to any one of claims 1 to 3, comprising a step of tableting by adding magnesium stearate to a tableting milling die of a tableting machine without adding magnesium stearate to the tableting tablet. A method for producing an internally disintegrating tablet.

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