JP2013064025A - Orally disintegrating tablet - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an orally disintegrating tablet that has tablet hardness, with which extremely few cracks and chips are brought about during a production process and transportation, and is excellent, and to provide an orally disintegrating tablet, by an extremely simple production method and at low cost.SOLUTION: The orally disintegrating tablet contains a base compound with water solubility of 100 mg/mL or more. In addition, the method for producing the orally disintegrating tablet includes: tableting a mixture of a base compound with water solubility of at least 100 mg/mL or more and an excipient; and subsequently merely storing the tablet, especially storing it at about room temperature.

Description

The present invention relates to an orally disintegrating tablet in which hardness is remarkably increased by simply storing the tablet after tablet formation and disintegration is maintained, and a method for producing the orally disintegrating tablet.

In recent years, the significance of orally disintegrating tablets that can be taken without water has become important for the arrival of an aging society and the improvement of patient compliance. Known orally disintegrating tablets include those formed by freeze-drying in a container using a carrier substance such as gelatin, and those obtained by wet compression of a wet powder or granulated product. However, such tablets often break and chip during transportation, and it is difficult to say that they have sufficient hardness, and the manufacturing method is complicated. Various studies have been made to eliminate these drawbacks. For example, the following techniques have been proposed in the literature.

Patent Document 1 discloses an orally disintegrating tablet produced by mixing a drug and a wet substance, humidifying before or after tableting, and then drying.
Patent Document 2 discloses a fast-dissolving tablet produced by tableting at a low pressure, followed by moisture absorption and drying.
Although these documents describe that tablet hardness increases by humidifying and drying before and after tableting, the number of production steps is still large and complicated.

Various studies have also been made on tablets produced by a simple production method, and examples thereof include the following documents. However, these techniques are not applicable to orally disintegrating tablets.

Patent Document 3 discloses a pharmaceutical agent for oral administration containing an active substance and at least one cyclodextrin. However, no consideration has been given to tablet hardness.

Patent Document 4 is characterized in that the coated tablet is allowed to stand in the air having a relative humidity of 30 to 95% and absorbs moisture to reduce tablet hardness, thereby improving tablet splitting properties at the time of taking. A method for producing coated tablets is disclosed. This method is naturally expected to rather enhance the disadvantage of orally disintegrating tablets due to cracking and chipping of tablets due to moisture absorption during manufacture and / or storage, and is therefore applicable to orally disintegrating tablets. Is hard to think.

Patent Document 5 discloses a chewable tablet having a good taste, containing cetirizine, a sweetener, and an excipient. Since the tablet described in the only example does not contain a disintegrant or a binder and is produced by a direct compression method, although it is a slightly simplified production method compared to the conventional method, the active layer and Since it is described that each placebo layer is prepared separately and then compressed by a special machine called a double-layer tablet press, it is difficult to say that it can be easily manufactured using ordinary equipment for pharmaceutical production. Moreover, there is no description about the hardness of a tablet in this literature.

Therefore, in the prior art, an orally disintegrating tablet having high hardness and a simple manufacturing method has not been known.
Furthermore, even if the conventional orally disintegrating tablet has good tablet hardness immediately after production, it absorbs moisture during storage and the hardness decreases, and cracks and chipping occur when taking out tablets from PTP packaging. Problems were also prone to occur.

JP-A-9-48726 JP-A-8-291051 Japanese translation of PCT publication No. 2002-508773 Japanese Patent Laid-Open No. 10-57449 JP 2005-526104 A

An object of the present invention is to provide a highly water-soluble base-containing orally disintegrating tablet that can be produced by a simple process and has good tablet hardness.

As a result of intensive studies to solve the above-mentioned problems, the present inventors have surprisingly found an orally disintegrating tablet containing a main agent having a water solubility of 100 mg / mL or more and a water-soluble excipient. However, after the preparation of the tablet, the tablet hardness was increased simply by storage, and after the increase in hardness reached saturation, it was found that a high hardness state could be maintained, and the present invention was completed.

That is, the features of the present invention are as follows.
[1] An orally disintegrating tablet containing a main agent having a water solubility of 100 mg / mL or more and substantially not containing a binder.
[2] The orally disintegrating tablet according to [1], substantially free of a disintegrant.
[3] A method for producing an orally disintegrating tablet, comprising compressing and storing a mixture containing a main agent having a water solubility of at least 100 mg / mL and substantially not containing a binder.
[4] The production method according to [3], wherein the storage is for 3 days or more.
[5] The production method according to [3] or [4], wherein the storage temperature is room temperature.

According to the present invention, there is provided an excellent orally disintegrating orally disintegrating tablet that has a tablet hardness that is practically sufficient and that has extremely few cracks and chips during the production process and during transportation. Moreover, since the orally disintegrating tablet of the present invention can be produced by a very simple production method, it can be produced at low cost.

(Components of orally disintegrating tablets)
The water solubility in the “main agent having a water solubility of 100 mg / mL or more” used in the present invention is the solubility in water at 20 ° C., measured according to the 15th revision Japanese Pharmacopoeia, As the main agent, those having a solubility of 1000 mg / mL or more described as being easily soluble and those having a solubility of 100 to 1000 mg / mL being described as being easily soluble are suitable.
The main agent only needs to have the above-described solubility, and includes, for example, medicinal ingredients and food ingredients. For example, antiallergic drugs (such as suplatast tosylate, cetirizine hydrochloride, epinastine hydrochloride), antihistamines (such as diphenhydramine, hydroxyzine), gastrointestinal function regulators (itopride hydrochloride, acratonium napadisylate), peptic ulcer drugs (atropine sulfate) , Ranitidine hydrochloride, etc.), psychotropic drugs (milnacipran hydrochloride, hydroxyzine hydrochloride, etc.) antidiabetic drugs (buformin hydrochloride, acarbose, etc.), antihypertensive drugs (betaxolol hydrochloride, lisinopril, metoprolol tartrate, etc.), vitamins (dicetiamine hydrochloride) , Pyridoxine hydrochloride, etc.). These can be used as pharmaceutically acceptable salts as long as they have the above-mentioned solubility.

In the present invention, the excipient is not particularly limited, but is preferably water-soluble or water-compatible in consideration of mouthfeel and the like.
For example, lactose, mannitol, sorbitol, xylitol, trehalose, cyclodextrin, corn starch, sucrose, crystalline cellulose, anhydrous calcium hydrogen phosphate, calcium carbonate and the like can be used in appropriate combination.

In the present invention, it is possible to add a disintegrant within a range that does not impair the effects of the present invention. However, since a problem such as a decrease in tablet hardness occurs when added in a large amount, the orally disintegrating tablet of the present invention is preferably Contains no disintegrant.
Examples of the disintegrant include crystalline cellulose, crospovidone, carmellose, low-substituted hydroxypropylcellulose, carmellose calcium, croscarmellose sodium, carboxymethyl starch sodium, partially pregelatinized starch, and hydroxypropyl starch.

The orally disintegrating tablet of the present invention does not substantially contain a binder, and more preferably does not contain at all.

The orally disintegrating tablet of the present invention contains, in addition to the main agent and excipients, sweeteners, flavoring agents, fluidizing agents, lubricants, fragrances, coloring agents and the like that are generally used in the manufacture of pharmaceuticals and foods. Furthermore, you may contain.
Examples of sweeteners include, for example, mannitol, starch sugar, reduced maltose starch syrup, sorbit, sugar, fructose, lactose, honey, xylitol, erythritol, sorbitol, saccharin, licorice and extracts thereof, glycyrrhizic acid, sweet tea, aspartame, stevia , Thaumatin, acesulfame K, sodium citrate, sucralose and the like.
Examples of the corrigent include citric acid, sodium citrate, tartaric acid, DL-malic acid, glycine, and DL-alanine.
Examples of the fluidizing agent include hydrous silicon dioxide, light anhydrous silicic acid, synthetic aluminum silicate, synthetic hydrotalcite, dry aluminum hydroxide gel, kaolin, calcium silicate, magnesium metasilicate aluminate, and talc. .
Examples of the lubricant include magnesium stearate, calcium stearate, stearic acid, talc, sodium lauryl sulfate, hydrogenated vegetable oil, microcrystalline wax, sucrose fatty acid ester, polyethylene glycol and the like.
Examples of the fragrances include strawberry, lemon, lemon lime, orange, l-menthol and mint oil.
Examples of the colorant include yellow iron sesquioxide, iron sesquioxide, edible tar dye, and natural dye.

The orally disintegrating tablet of the present invention may be an orally disintegrating agent for any use as long as it contains a main ingredient or ingredient having a water solubility of 100 mg / mL or more. For example, pharmaceuticals, foods (confectionery) Functional food, health food, etc.).

(Method for producing orally disintegrating tablets)
In the present invention, the orally disintegrating tablet can be produced by a conventional method using the above components. For example, it is manufactured by tableting a powder mixture of the constituents of an orally disintegrating tablet as it is or through a process such as granulation and sizing as required. The tableting machine is not particularly limited as long as it can be used for the production of pharmaceuticals. For example, a rotary tableting machine or a single-shot tableting machine is used.

(Change during storage)
By storing the tablet produced as described above at room temperature, it is possible to remarkably increase only the tablet hardness while maintaining the disintegration characteristics immediately after production. The storage conditions may be room temperature, but more specifically 1 to 30 ° C, preferably 15 to 25 ° C. The increase in tablet hardness starts immediately after tableting and varies depending on the main agent. However, since the tablet hardness is generally constant in about 3 days to 2 weeks, the tablet storage period is preferably 3 days or more. However, since the tablet hardness is maintained after the increase in hardness reaches saturation, there is no problem even if the storage period of the tablet is further extended.
The container used for storage is not particularly limited, and any container that can be used for production of pharmaceuticals can be used.
Further, there is no correlation between the tablet hardness increase and the ambient humidity condition in the range of relative humidity of about 0 to 60%. The orally disintegrating tablet of the present invention produces an increase in tablet hardness even at an environmental humidity of 0%.
Even if the orally disintegrating tablet thus obtained is molded at a low pressure of about 500 kg or less in order to improve disintegration and the tablet hardness immediately after tableting is low, the tablet diameter is 10 mm. A tablet with a thickness of 5 to 6 mm has a tablet hardness of about 3 to 10 kg and practically sufficient, and cracks and chips are hardly generated. Moreover, the orally disintegrating tablet of the present invention exhibits good disintegration characteristics.

Hereinafter, the present invention will be described in more detail based on examples, but the present invention is not limited to these examples.

Example 1
10 parts by weight of cetirizine hydrochloride, 358.8 parts by weight of lactic acid, 5 parts by weight of sodium citrate, 4 parts by weight of aspartame, and 4 parts by weight of acesulfame K (Sanet (registered trademark)) were mixed and crushed, and then they were mixed with a 5% aqueous solution of thaumatin. (Solid content of thaumatin was 0.6 parts by weight), dried and sized. To the sized product, 12 parts by weight of crystalline cellulose, 1.6 parts by weight of a fragrance, and 4 parts by weight of magnesium stearate were added and mixed to obtain a tableting composition. This composition was tableted using a single tableting machine (model: No. 2B Kikusui Seisakusho Co., Ltd.) at tableting pressures of 100 kg, 300 kg and 500 kg to prepare tablets with a diameter of 10 mm and a weight of 400 mg. The tablet thickness of the obtained tablets was 5.9 mm at a tableting pressure of 100 kg, 5.6 mm at 300 kg, and 5.4 mm at 500 kg. Each of these tablets was placed in a petri dish at 25 ° C. and 50% RH and allowed to stand, and the change in tablet hardness was observed. The tablet hardness was measured using a Schleunigel tablet hardness tester (MODEL 6D). The results are shown in FIG. The hardness and oral disintegration time after storage of the obtained tablets for 48 hours are 2.4 kg hardness when the tableting pressure is 100 kg and 9 seconds oral disintegration time, and the hardness is 3.6 kg when the tableting pressure is 300 kg. The internal disintegration time was 20 seconds, the hardness was 9.1 kg when the tableting pressure was 500 kg, and the oral disintegration time was 35 seconds.
From the above results, the tablet hardness of each tablet increased with the passage of storage time, and after about 48 hours, it reached about twice that immediately after production, whereas the oral disintegration time had the highest hardness. The tablet was also found to be as good as 35 seconds.

Example 2
10 parts by weight of cetirizine hydrochloride, 353.4 parts by weight of lactose, 10 parts by weight of sodium citrate, 4 parts by weight of aspartame, and 4 parts by weight of acesulfame K (Sanet (registered trademark)) were mixed and pulverized, and then 5% aqueous solution of thaumatin (The solid content of thaumatin was 1 part by weight), dried and sized. To this sized product, 12 parts by weight of crystalline cellulose, 1.6 parts by weight of fragrance, and 4 parts by weight of magnesium stearate were added and mixed to obtain a tableting composition, which was converted into a single tableting machine (model: No. 2B). Kikusui Seisakusho Co., Ltd.) was tableted with 600 kg to obtain a tablet having a diameter of 10 mm, a tablet thickness of 5.3 mm, and a weight of 400 mg. The obtained tablets were placed in a petri dish at 25 ° C. and 50% RH and allowed to stand, and changes in tablet hardness and tablet disintegration time according to the 15th revised Japanese Pharmacopoeia disintegration test method were confirmed. The results regarding tablet hardness are shown in FIG. 2, and the results regarding disintegration time are shown in FIG. The tablet hardness immediately after production was 4.2 kg, but after 72 hours the tablet hardness increased to 8.9 kg. On the other hand, the disintegration time of the tablets according to the 15th revised Japanese Pharmacopoeia disintegration test method was almost constant at 2.5 to 2.8 minutes throughout the entire storage time.
From the above results, the tablet hardness increases with the lapse of storage time, but there is no change in the disintegration time of the tablet according to the 15th revision Japanese Pharmacopoeia Disintegration Test Method, and the disintegration characteristics of the tablet remain as it is immediately after production. It turns out that it has not changed.

Example 3
5 parts by weight of cetirizine hydrochloride, 177.2 parts by weight of lactose, 5 parts by weight of sodium citrate, 1.5 parts by weight of sucralose, and 2 parts by weight of acesulfame K (Sanet (registered trademark)) were mixed and pulverized. The mixture was kneaded with a% aqueous solution (the solid content of thaumatin was 0.5 parts by weight), dried and sized. To the sized product, 6 parts by weight of crystalline cellulose, 0.8 part by weight of a fragrance, and 2 parts by weight of magnesium stearate were added and mixed to obtain a tableting composition. This was tableted with a rotary tableting machine (model: VIRGO-512 Kikusui Seisakusho Co., Ltd.) at 500 kg to obtain a tablet having a diameter of 8 mm, a tablet thickness of 4.0 mm, and a weight of 200 mg. The obtained tablets were placed in a petri dish at 25 ° C. and 50% RH and allowed to stand, and the transition of tablet hardness was confirmed. The results are shown in FIG.
The tablet hardness increased with the passage of storage time, and reached a steady state in 1 to 2 weeks. The tablet after storage for 30 days had a hardness of 5.2 kg and an oral disintegration time of 30 seconds.

Example 4
10 parts by weight of cetirizine hydrochloride, 380 parts by weight of lactose and 10 parts by weight of magnesium stearate were added and mixed to obtain a tableting powder. This powder was directly compressed with a single tableting machine (model: No. 2B Kikusui Seisakusho Co., Ltd.) at 500 kg to obtain a tablet having a diameter of 10 mm, a tablet thickness of 5.4 mm, and a weight of 400 mg, which was obtained at 25 ° C. and 50% RH. The sample was placed in a petri dish and allowed to stand, and the change in tablet hardness was observed. The results are shown in FIG. As for the tablets produced by this direct hitting method, the hardness increasing phenomenon was observed as in the tablets of Examples 1 to 3 produced through the granulation process. The tablet hardness after 7 days from the start of storage was 4.7 kg.
From the above, it was found that the method for producing a tableting composition does not affect the tablet hardness increase phenomenon of the present invention.

Example 5
After mixing 10 parts by weight of various main ingredients and 380 parts by weight of lactose, purified water was added, the mixture was kneaded in a mortar, dried, and sieved with sieve No. 22. To the sized product, 10 parts by weight of magnesium stearate was added and mixed to obtain a tableting composition. This was tableted with a single tableting machine (model: No. 2B Kikusui Seisakusho Co., Ltd.) to obtain a tablet having a diameter of 10 mm and a weight of 400 mg. The obtained tablet was placed in a petri dish at 25 ° C. and 50% RH and allowed to stand, and the change in tablet hardness was observed.
The results are shown in Table 1 below.

From the above, an increase in hardness was observed with the main agent having a solubility of 100 mg / mL or more. In the main agent having low solubility, the hardness increase phenomenon was not observed. In the placebo formulation without the base agent, no increase in hardness was observed.

Comparative Example 1
After pulverizing 363 parts by weight of lactose, 10 parts by weight of sodium citrate, 0.2 parts by weight of sucralose, and 1.6 parts by weight of acesulfame K (Sanet (registered trademark)), they were kneaded with purified water, dried and conditioned. Grained. To this sized product, 20 parts by weight of crystalline cellulose, 1.2 parts by weight of fragrance, and 4 parts by weight of magnesium stearate were added and mixed to obtain a tableting composition. This was tableted with a single tableting machine (model: No. 2B Kikusui Seisakusho Co., Ltd.) to obtain a tablet having a diameter of 10 mm, a tablet thickness of 5.4 mm, and a weight of 400 mg. The tablet was petri dished at 25 ° C. and 50% RH. The tablet hardness was observed after standing. The results are shown in FIG. No significant increase in hardness was observed with placebo tablets without the main agent.

Test example 1
Cetirizine hydrochloride 10.0 parts by weight, lactose 354.4 parts by weight, sodium citrate 10.0 parts by weight, and sucralose 3 parts by weight were added to a high-speed agitation granulator (Fukae Pautech Co., Ltd.) and mixed and ground. The mixture was kneaded with a 5% aqueous solution of thaumatin (the solid content of thaumatin was 1.0 part by weight), dried and sized. To the sized product, 12.0 parts by weight of crystalline cellulose, 4.0 parts by weight of acesulfame K (Sanet (registered trademark)), 1.6 parts by weight of fragrance, and 4 parts by weight of magnesium stearate are added and mixed, and the composition for tableting is added. I got a thing. This was tableted with 500 kg with a single tableting machine (model: No. 2B Kikusui Seisakusho) to obtain a tablet having a diameter of 10 mm, a tablet thickness of 5.4 mm, and a weight of 400 mg. The obtained tablets were placed in a petri dish under 25 ° C., 0, 20, and 50% RH, and allowed to stand, and the transition of tablet hardness was confirmed for each.
The results are shown in Table 2 below.

From the above results, the tablet hardness increased even in a low humidity environment, regardless of the humidity during storage. It is clear that it is based on a completely different mechanism from the ascending method.

ADVANTAGE OF THE INVENTION According to this invention, since it has practically sufficient tablet hardness, the outstanding orally disintegrating tablet in which there are very few cracks and chippings during a manufacturing process or at the time of transportation is provided. And since the orally disintegrating tablet of this invention can be manufactured with a very simple manufacturing method, it can be manufactured at low cost.

1 is a graph showing the transition of tablet hardness in Example 1. FIG. FIG. 2 is a graph showing the transition of tablet hardness in Example 2. FIG. 3 is a graph showing the transition of the decay time in Example 2. FIG. 4 is a graph showing the transition of tablet hardness in Example 3. FIG. 5 is a graph showing changes in tablet hardness in Example 4. FIG. 6 is a graph showing the transition of tablet hardness in Comparative Example 1.

Claims (5)

An orally disintegrating tablet containing a main ingredient having a water solubility of 100 mg / mL or more and substantially not containing a binder. The orally disintegrating tablet according to claim 1, which contains substantially no disintegrant. A method for producing an orally disintegrating tablet, comprising compressing a mixture containing a main ingredient having a water solubility of at least 100 mg / mL and substantially not containing a binder and then storing the mixture. The production method according to claim 3, wherein the storage is 3 days or more. The production method according to claim 3 or 4, wherein the storage temperature is room temperature.