JP2003261446A - Tablet containing pravastatin sodium and method for producing the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a tablet containing pravastatin sodium as an active component, keeping the aging stability of pravastatin sodium in the tablet without adding a strongly basic compound and having excellent elution property of the active component. <P>SOLUTION: This pravastatin sodium tablet contains pravastatin sodium, calcium citrate and an excipient. <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a pravastatin sodium-containing tablet useful as a therapeutic drug for hyperlipidemia and a method for producing the same.

[0002]

2. Description of the Related Art Conventionally, pravastatin sodium is known to gradually decompose under neutral to acidic conditions, resulting in a decrease in drug content during storage. In order to solve this problem, a method has been proposed in which a pravastatin sodium preparation contains a basic compound that imparts a pH of 9 or more (Japanese Patent No. 2935220). However, the inclusion of an additive that imparts a pH of 9 or higher is likely to adversely affect workers in industrial production, and a formulation containing the additive has a problem of discoloration over time. is there.

In order to solve such a problem, tablets in which a mixture of pravastatin sodium and excipients having a pH of less than 9 such as calcium hydrogen phosphate and magnesium aluminometasilicate are directly tableted have been proposed. (Unexamined-Japanese-Patent No. 2000-229855). However, in the case of direct tableting, not only attention must be paid to the fluidity of the powder and the occurrence of tableting failure, but there is a possibility that the dissolution of pravastatin sodium, which is an active ingredient, may be reduced.

In this respect, in order to exert the therapeutic effect equivalent to that of the pravastatin sodium preparation currently on the market, not only the stability of the active ingredient but also the dissolution rate thereof must be equal.

The present invention has been made in view of the above circumstances and is capable of maintaining the stability of pravastatin sodium in a tablet over time without blending a strongly basic compound and improving the dissolution of an active ingredient. An object is to provide an excellent pravastatin sodium-containing tablet and a simple and efficient production method thereof.

[0006]

Means for Solving the Problems and Embodiments of the Invention
The present inventors blended pravastatin sodium and various general-purpose pharmaceutical additives to achieve the above object, and after diligently studying the storage stability of pravastatin sodium, as a result, blended pravastatin sodium with calcium citrate. In the tablet obtained as a result, it was found that the stability of the active ingredient is improved, and pravastatin sodium and crystalline cellulose were previously kneaded with a solvent and then other additives such as calcium citrate were added,
By formulating this, it was found that the dissolution property of pravastatin sodium was improved, and the present invention was completed.

That is, the present invention is as follows: 1. Pravastatin sodium-containing tablet, characterized in that it contains pravastatin sodium, calcium citrate and excipients; 2. Pravastatin sodium-containing tablet according to 1, characterized in that the excipient comprises anhydrous lactose and / or microcrystalline cellulose. 3. The tablet containing pravastatin sodium according to 1 or 2, which contains a binder, a disintegrant, and a lubricant. 4. Pravastatin sodium-containing tablet characterized in that a kneaded product obtained by kneading pravastatin sodium and crystalline cellulose in a solvent in advance is dried and sized, and then tableted by adding an additive containing calcium citrate. 4. Manufacturing method of A method for producing a pravastatin sodium-containing tablet according to 4, wherein the additive contains anhydrous lactose.

The present invention will be described in more detail below. The pravastatin sodium-containing tablet according to the present invention is characterized by containing pravastatin sodium, calcium citrate and an excipient as described above. Pravastatin sodium in the present invention is
There is no particular limitation as long as it is generally used for formulation. Also, the average particle size may be within the range acceptable for formulation, for example, 1 to 100 μm.
It is preferable to use a resin having a particle size of 10 to 50 μm from the viewpoint that it can be used and the preparation can be carried out efficiently.

In the present invention, calcium citrate is added in order to improve the stability of the active ingredient without blending a strongly basic compound. The blending amount is, for example, pravastatin sodium. It may be 50 to 200% by weight, and considering that the stability and dissolution of pravastatin sodium are further improved, the compounding amount is preferably 80 to 120% by weight. In addition,
As the calcium citrate, those generally commercially available can be appropriately used. As the above-mentioned excipient, those used in ordinary preparations such as lactose, anhydrous lactose, mannitol, crystalline cellulose, starch and the like can be used, but the water content is reduced, the tablet hardness is optimized, and the tableting is performed. In order to improve the properties, it is particularly preferable to use an excipient containing anhydrous lactose. Further, as described below, in consideration of obtaining a tablet having excellent dissolution of the active ingredient by a method of tableting after kneading pravastatin sodium and crystalline cellulose in advance, it may contain crystalline cellulose as an excipient. preferable.

The pravastatin sodium-containing tablet of the present invention may contain, in addition to the above-mentioned components, a binder, a disintegrating agent, and a lubricant which are usually used for formulation. Here, the binder is not particularly limited,
For example, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, povidone and the like can be mentioned. The disintegrant is not particularly limited, and examples thereof include carmellose calcium, crospovidone, low-substituted hydroxypropyl cellulose and the like. The lubricant is not particularly limited, and examples thereof include magnesium stearate, light anhydrous silicic acid, talc, and sucrose fatty acid ester. In addition to the above-mentioned additives, other components such as a fragrance and a coloring agent may be blended, if necessary.

The pravastatin sodium-containing tablet of the present invention can be produced by a conventional method using a dry method or a wet method. However, due to the fluidity of the tableting powder at the time of production, tableting obstacles such as capping, and variation in mixing Considering the non-uniformity of the content and the dependence of the dissolution rate on the physical properties of the raw materials, it is preferable to use the wet method rather than the dry method such as direct compression.

[0012] In particular, a method is used in which pravastatin sodium and crystalline cellulose are kneaded in a solvent in advance, the kneaded product is dried and sized, and then an additive containing calcium citrate is added to form a tablet. Is preferred. By adopting such a method, the dissolution of the active ingredient in the tablet can be improved while improving the stability of the active ingredient. That is, the dissolution rate can be increased to 85% or more in 15 minutes, and the dissolution performance equivalent to that of the existing preparation can be exhibited.

When the pravastatin sodium and crystalline cellulose are kneaded in advance, the mixing ratio of both is not particularly limited, but pravastatin sodium: crystalline cellulose = 1: 1 to 1: 5 may be blended. From the viewpoint of further enhancing the dissolution property, it is preferable to mix them in a ratio of 1: 1 to 1: 2. The solvent used for the above kneading is not particularly limited as long as it is a solvent that is usually used for formulation by a wet method, and anhydrous ethanol, isopropyl alcohol, methanol or the like can be used. The amount used may be any amount as long as pravastatin sodium and crystalline cellulose can be kneaded, and for example, it is 5 with respect to the total amount of both components.
It can be set to 10% by weight.

The drying temperature is not particularly limited as long as it is a temperature at which the active ingredient does not deteriorate during drying, but it is usually 20 to 4
It is about 0 ° C. The average particle size at the time of sizing is also not particularly limited, and can be, for example, 100 to 500 μm, and in view of suppressing variation in mixing with an excipient or the like, particularly 300 to 400 μm. Preferably there is.

Further, the above additives may be those containing the above-mentioned excipients, binders, disintegrating agents, lubricants and the like, but for the same reason as described above, excipients containing anhydrous lactose. Is preferably used.

[0016]

EXAMPLES The present invention will be described in more detail with reference to examples and comparative examples, but the present invention is not limited to the following examples.

[Example 1] Pravastatin sodium 5
g and crystalline cellulose 5 g were mixed, and 0.7 g of anhydrous ethanol was added and kneaded. 4 of the obtained kneaded product
After drying at 0 ° C. and sizing with a 355 μm sieve, 5 g of calcium citrate, 53 g of anhydrous lactose, crystalline cellulose 15
g, hydroxypropyl cellulose 4 g, low-substituted hydroxypropyl cellulose 4 g, light anhydrous silicic acid 2 g and magnesium stearate 2 g were added and mixed to obtain a white tablet having a diameter of 6 mm and a tablet weight of 95 mg. The pH of this aqueous dispersion was 6.6.

Example 2 Pravastatin sodium 5
g, crystalline cellulose 20 g, calcium citrate 5 g,
53 g anhydrous lactose, 4 g hydroxypropyl cellulose,
Low-substituted hydroxypropylcellulose (4 g), light anhydrous silicic acid (2 g) and magnesium stearate (2 g) were added and mixed to give a white tablet having a diameter of 6 mm and a tablet weight of 95 mg (direct compression). The pH of this aqueous dispersion was 6.6.

[Comparative Example 1] Pravastatin sodium 5
g, lactose 64 g, calcium hydrogen phosphate 15 g, carboxymethyl cellulose calcium 5 g, hydroxypropyl cellulose 2 g and magnesium stearate 1
g was added and mixed to give a white tablet with a tablet weight of 92 mg (direct compression).

Comparative Example 2 Pravastatin sodium 5
g, lactose 64 g, magnesium aluminometasilicate 1
5 g, carboxymethyl cellulose calcium 5 g, hydroxypropyl cellulose 2 g and magnesium stearate 1 g were added and mixed to give a white tablet with a tablet weight of 92 mg (direct compression).

Comparative Example 3 Pravastatin sodium 5
g, mannitol (85 g) and magnesium stearate (1 g) were added and mixed to give a white tablet having a tablet weight of 91 mg (direct compression).

[Comparative Example 4] Pravastatin sodium 5
g, mannitol 80 g, crystalline cellulose 5 g and magnesium stearate 1 g were added and mixed to give a white tablet having a tablet weight of 91 mg (direct compression).

[Comparative Example 5] Pravastatin sodium 5
g, mannitol 75 g, crystalline cellulose 10 g and magnesium stearate 1 g were added and mixed to give a white tablet having a tablet weight of 91 mg (direct compression).

In the above-mentioned Examples and Comparative Examples, the tableting properties when formulating a mixture of the respective components were as shown in Table 1 below. As shown in Table 1 below, Example 1,
In No. 2, since anhydrous lactose is used as the excipient, it is found that the tableting property is superior to that of each comparative example using mannitol or lactose as the excipient.

[0025]

[Table 1]

A stability test was conducted on the tablets obtained in Example 1 and a dissolution test was conducted on the tablets obtained in Examples 1 and 2, and these results are shown in Tables 2 and 3, respectively.
It was shown to. The pravastatin sodium-containing preparation currently on the market was used as a control preparation.

[0027]

[Table 2]

Here, the stability test was carried out by storing tablets containing pravastatin sodium at 40 ° C. for one month, and the content of the active ingredient after storage was taken as the residual rate (%), and the increased amount of impurities was also measured as impurities. The amount of increase (%) is shown in Table 2. As can be seen from Table 2, the pravastatin sodium-containing tablet of Example 1 containing calcium citrate is presently present despite the pH of the aqueous dispersion being 6.6, which is almost neutral as described above. It can be seen that it has stability equal to or higher than that of the commercially available control formulation.

[0029]

[Table 3]

Here, in the dissolution test, 900 mL of water at 37 ° C. was used as the test solution, the paddle rotation speed was 50 rpm, and J
It carried out by the method based on P13 2nd method. As shown in Table 3, it can be seen that the tablets obtained in Example 1 have an elution rate of 85% or more after 15 minutes, and have an elution rate that can be regarded as equivalent to the control preparation. Further, from the results of Examples 1 and 2, compared to Example 2 in which direct compression was performed,
It can be seen that Example 1 in which kneading and granulation and then tableting had better dissolution behavior.

[0031]

As described above, according to the present invention,
Since pravastatin sodium preparation contains calcium citrate, it is possible to provide tablets that can stabilize the active ingredient for a long period of time without adding a strongly basic compound, and knead and granulate in advance. By adopting the manufacturing method, tablets with similar dissolution properties to commercial preparations can be obtained.
It can be manufactured simply and industrially.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁷ Identification code FI Theme Coat (reference) A61P 3/06 A61P 3/06 (72) Inventor Yu Mizuno 3697, Hagishima No.8, Fuchu-cho, Niseji-gun, Toyama Prefecture Ceremony company Yoshindo F term (reference) 4C076 AA36 BB01 CC11 DD27 DD43Q EE30A EE31A EE32A FF63 4C206 AA01 AA02 DB03 DB51 KA01 MA02 MA03 MA05 MA11 MA55 MA72 NA03 ZC20 ZC35

Claims (5)

[Claims] 1. A tablet containing pravastatin sodium, which comprises pravastatin sodium, calcium citrate and an excipient. 2. The tablet containing pravastatin sodium according to claim 1, wherein the excipient contains anhydrous lactose and / or crystalline cellulose. 3. The pravastatin sodium-containing tablet according to claim 1, which contains a binder, a disintegrant, and a lubricant. 4. A kneaded product obtained by previously kneading pravastatin sodium and crystalline cellulose in a solvent is dried,
A method for producing a pravastatin sodium-containing tablet, which comprises granulating and then tableting by adding an additive containing calcium citrate. 5. The method for producing a pravastatin sodium-containing tablet according to claim 4, wherein the additive contains anhydrous lactose.