JP4817562B2 - Long-lasting nifedipine dry-coated tablets - Google Patents

Description

【００３１】
条件：特開平９−１４３０７３号記載の条件に準ずる。
１．第２法溶出試験法
試験液：ポリソルベート８０の１％水溶液
温度：３７℃
ハンギングシンカー使用、回転数１００ｒｐｍ
２．崩壊試験装置法
試験液：ポリソルベート８０の１％水溶液
温度：３７℃
補助盤使用
【００３２】
表１に示すように、第２法溶出試験法に比較して崩壊試験法における溶出率は、実施例の有核錠にあっては１２０分において１．４倍未満に加速されるに過ぎないが、比較例の有核錠にあっては２倍以上に加速されることがわかる。これは、本発明によるニフエジピン有核錠の外殻部は、芯部が消化管下部の標的部位へ到達する以前に一挙にまたは急速に機械的ストレスによって崩壊することなしに、長時間にわたって徐々に侵食され、ニフエジピンを放出し続けることを意味している。さらに実施例１対比較例１、および実施例３対比較例２のデータの比較により、同量のＥＣまたはリン酸水素カルシウムを含んでいても、それらの平均粒子径が７５μｍ未満であれば満足な効果を示さず、水不溶性粒子の粒子径がこれに関係していることが明らかである。なお１２０分において比較するのは、錠剤のヒト小腸通過時間を考慮し、消化管下部（大腸）における芯部からの薬物の放出に影響されない溶出率を表すものと考えられるからである。[0001]
【Technical field】
The present invention relates to a long-lasting type, for example, a nifedipine dry-coated tablet whose effective blood concentration is sustained by administration once or twice a day.
[0002]
[Prior art and issues]
As one of the preparation techniques for achieving sustained release of a drug over a long period of time, a dry-coated tablet is known in which an immediate-release part is a core part and an outer shell is a sustained-release part. This type of dry-coated tablet is designed so that the outer shell is gradually eroded in the gastrointestinal tract to release the drug, and the remaining drug is released from the exposed core that reaches the lower part of the gastrointestinal tract.
[0003]
This type of sustained-release preparation contains a hydrophilic high-molecular substance that gels by water absorption, unlike a preparation with an enteric high-molecular substance coating whose solubility depends on the pH of the digestive fluid. The outer shell forms a gel matrix containing the drug in the digestive tract. Obviously, this gel matrix must collapse at once by peristaltic movement of the intestine before reaching the lower digestive tract, and the drug release from the fast dissolving part of the core must not end upstream of the target site. . For this reason, the gel matrix needs to have an appropriate mechanical strength that is gradually eroded in the digestive tract but does not collapse at once.
[0004]
Japanese Examined Patent Publication No. 6-11699 describes a dry tablet of nifedipine using a hydrophilic gel-forming polymer in the outer shell. Japanese Patent Laid-Open No. 9-143073 describes a nifedipine dry-coated tablet using a hydrophilic gel-forming polymer and an acrylic acid / methacrylic acid / methacrylic acid trimethylammoniumethyl terpolymer as an outer shell. The terpolymer is a substance used to improve the mechanical strength or disintegration property of the gel matrix of the hydrophilic polymer, but the outer shell is formed by using a more commonly available substance in the pharmaceutical technology. It is preferable to reinforce the gel matrix.
[0005]
[Solution]
In the present invention, the core and the outer shell both contain nifedipine and HPC-L or a combination of HPC-L and HPC-M, and the outer shell further contains water-insoluble particles having an average particle diameter of 75 to 150 μm. Alternatively, a long-lasting type nifedipine dry-coated tablet comprising a granulated product is provided .
[0006]
The main benefit of the present invention is that it uses more readily available materials that are more commonly used in the pharmaceutical industry, without the use of special polymeric materials such as the acrylic terpolymers described above. It is possible to reinforce the mechanical strength of the gel matrix of the shell. These substances can be formed into granules together with nifedipine and a water-soluble polymer substance that forms a gel, and the outer shell can be tableted, but granules containing no water-insoluble particles or granules are prepared. The outer shell portion can be tableted by mixing these particles or granulated product into the granule. This simplifies the formulation process.
[0007]
[Preferred embodiment]
The Nifedipine dry-coated tablet of the present invention comprises a core part and an outer shell part. Both the core part and the outer shell part contain nifedipine and a water-soluble organic polymer substance that forms a gel. Examples of water-soluble organic polymeric substances that form gels include water-soluble cellulose derivatives such as hydroxypropylcellulose (HPC), methylcellulose (MC), hydroxypropylmethylcellulose (HPMC), sodium carboxymethylcellulose (CMC), and polyvinyl alcohol Water-soluble vinyl polymers such as (PVA). Among them, HPC is preferable, and it is preferable to use low-viscosity HPC (HPC-L) alone for the core. In addition to nifedipine and a water-soluble polymer substance, the core can optionally contain auxiliary components such as conventional excipients, disintegrants, and solubilizing agents. In order to tablet into tablets, the above ingredients are granulated by a known technique, mixed with a lubricant and compressed into tablets with a diameter of about 3 to 7 mm. In order for the core part to form a gel matrix, the water-soluble organic polymer substance preferably accounts for 15 to 40% by weight of the core tablet.
[0008]
The outer shell can generally contain the same components as the core, except for particles or granules that enhance the mechanical strength of the gel matrix. That is, it can contain nifedipine, a water-soluble polymeric substance that forms a gel, and optionally auxiliary components such as excipients, disintegrants, and solubilizers. HPC is also preferable as the water-soluble polymer substance in the outer shell, and in this case, HPC-L alone or a mixture containing HPC-L as a main component and medium viscosity HPC (HPC-M) in a small proportion may be used. good. The ratio of the water-soluble polymer substance in the outer shell is preferably 30 to 70% by weight, particularly 40 to 60% by weight.
[0009]
According to the present invention, it has been found that the mechanical strength of the outer shell gel matrix is enhanced by water-insoluble particles or granules having a relatively large average particle size in a certain range. Such particles and granulates have an average particle size of 75 μm to 500 μm, examples of which are cellulose and water-insoluble cellulose derivatives such as ethyl cellulose, cellulose acetate and crystalline cellulose, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate Inorganic particles such as calcium citrate, magnesium aluminum metasilicate, calcium sulfate, aluminum silicate and magnesium silicate. Even particles having an average particle size of less than 75 μm can be coated with a wax that is solid at room temperature, or bonded to form a particle size in the above range. Particularly preferred such particles or granules are those obtained by melt coating sucrose fatty acid esters on ethyl cellulose (EC), calcium hydrogen phosphate, and talc (magnesium silicate) and calcium hydrogen phosphate. is there. Other examples of waxes that can be used for this purpose are higher fatty acids such as stearic acid and palmitic acid, hardened oils, their glycerin esters such as beef tallow, higher fatty alcohols such as stearyl alcohol and cetyl alcohol, tree waxes, Natural waxes such as refined beeswax and mineral oil-based waxes represented by paraffin wax are included. Waxes can be used in coatings that further enhance the gel matrix reinforcing effect of particles having a particle size in the range of 75-500 μm.
[0010]
The outer shell can be formed by granulating all of the ingredients described above into a granule, mixing a lubricant with this, and compressing it into a dry-coated tablet. Instead, after the above-mentioned water-insoluble particles or components excluding the granulated product are granulated into granules, the particles or granulated products are mixed with this, and a lubricant is further mixed into a dry-coated tablet. Can be tableted.
[0011]
In order for the gel matrix of the absorbed outer shell portion to exhibit sufficient strength to withstand mechanical stress in the digestive tract, the reinforcing particles or granules blended according to the present invention have a weight of 1 to 50 of the outer shell portion weight. % Is appropriate. The weight ratio of the core part to the outer shell part is suitably 1: 3 to 1: 6, and 50 to 75% of the total nifedipine content is suitably present in the outer shell part.
[0012]
The effect of the particles or granules used in accordance with the present invention for reinforcing the gel matrix of the outer shell is based on the pharmacopeia method 2 dissolution test method (using sinker) and the pharmacopeia test device It can be confirmed by measuring the elution rate of nifedipine by each method according to the method (using an auxiliary board) and comparing the obtained data. Since the dissolution rate by the local disintegration test method is accelerated by mechanical stress than the dissolution rate by the second method dissolution test method, the greater the degree of this acceleration, the lower the mechanical strength of the gel matrix. Means that. According to the present invention, this degree of acceleration can be kept below 200%, preferably below 150%, most preferably below 120%.
[0013]
【Example】
The following examples illustrate the invention without intending to be limiting.
[0014]
Example 1
1. Manufacture of the core 375 g of niphedipine crystals (average particle diameter 5 μm, the same applies hereinafter), 800 g of lactose, 100 g of crystalline cellulose, and HPC-L685 g were mixed uniformly using a fluidized bed granulator, and 500 g of polyvinylpyrrolidone was added to ethanol (95% The solution dissolved in (1) was used as a binding solution, and fluidized and granulated. The obtained granulated product was dried using a fluidized bed dryer and then sized using a power mill. 40 g of magnesium stearate was mixed with 2460 g of the obtained sized powder, and tableted into tablets having a weight of 50 mg and a diameter of 5 mm by a conventional method. This tablet was used as a core tablet in all examples and comparative examples.
[0015]
2. Production of outer shell portion 125 g of Nifedipine and 2100 g of HPC-L were mixed uniformly using a fluidized bed granulator, and fluidized granulated using ethanol (95%) as a binding liquid. The obtained granulated product was sized using a power mill, 245 g of EC (average particle size of about 150 μm) was added thereto, and mixed together using a Boule mixer. To 2470 g of this mixture, 30 g of magnesium stearate was added, 250 mg of this mixture was coated on the outside of the core tablet using a dry tableting machine, and tableted into dry tablets having a diameter of 9 mm and a weight of 300 mg.
[0016]
Example 2
125 g of Nifedipine, 1420 g of HPC-L, and 470 g of HPL-M were uniformly mixed using a fluidized bed granulator, and fluidized and granulated using ethanol (95%) as a binder solution. The obtained granulated product was sized using a power mill, 455 g of EC (average particle size of about 150 μm) was added thereto, and the mixture was mixed using a Boule mixer. To 2470 g of this mixture, 30 g of magnesium stearate was mixed. 250 mg of this mixture was coated on the outside of the core tablet obtained in Example 1 using a dry tableting machine to produce a dry tablet having a diameter of 9 mm and a weight of 300 mg.
[0017]
Example 3
125 g of Nifedipine, 1420 g of HPC-L, and 470 g of HPC-M were uniformly mixed using a fluidized bed granulator, and fluidized granulated using ethanol (95%) as a binding liquid. The obtained granulated product was sized with a power mill, and 455 g of calcium hydrogen phosphate (average particle diameter of about 150 μm) was added thereto and mixed using a Boule mixer. To 2470 g of this mixture, 30 g of magnesium stearate was mixed. 250 mg of this mixture was coated on the outside of the core tablet obtained in Example 1 using a dry tableting machine to produce a dry tablet having a diameter of 9 mm and a weight of 300 mg.
[0018]
Example 4
125 g of Nifedipine, 1420 g of HPC-L, 470 g of HPC-M and 655 g of EC (average particle diameter of about 150 μm) were mixed uniformly using a fluidized bed granulator, and fluidized granulated using ethanol (95%) as a binding liquid. The obtained granulated product was sized using a power mill. 3070 g of magnesium stearate was mixed with 2670 g of the obtained sized product, and 270 mg of this mixture was coated on the outside of the core tablet obtained in Example 1 using a dry tableting machine, and had a diameter of 9 mm and a weight of 320 mg. A nuclear tablet was produced.
[0019]
Example 5
Nifujipin 125g, HPC-L1420g and HPC-M470g are mixed uniformly using a fluidized bed granulator, fluidized granulation using ethanol (95%) as a binding liquid, and the resulting granulated product is sized using a power mill To obtain granules containing nifedipine.
[0020]
Separately, 100 g of sucrose fatty acid ester was added to 655 g of calcium hydrogen phosphate (average particle size of about 150 μm) and melt-coated to obtain a granulated product having an average particle size of about 250 μm.
[0021]
Example 1 Example: Using granulated tablet press, 2015 g of granulated nifedipine-containing granule and 755 g of calcium hydrogen phosphate granulate were uniformly mixed with a Boule mixer, and 30 g of magnesium stearate was added thereto. The core tablet obtained in 1 was coated on the outside to produce a dry-coated tablet having a diameter of 9 mm and a weight of 330 mg.
[0022]
Example 6
Nifujipin 125g, HPC-L1420g and HPC-M470g are mixed uniformly using a fluidized bed granulator, fluidized granulation using ethanol (95%) as a binding liquid, and the resulting granulated product is sized using a power mill To obtain granules containing nifedipine.
[0023]
Separately, 100 g of sucrose fatty acid ester was added to 655 g of talc (200 mesh pass) and melt-coated to obtain a granulated product having an average particle size of about 150 μm.
[0024]
The granulated nifedipine-containing granules (2015 g) and talc granulated product (755 g) were uniformly mixed with a Boule mixer, to which 30 g of magnesium stearate was added, and 280 mg of this mixture was obtained in Example 1 using a dry tableting machine. The core tablet was coated on the outside to produce a dry-coated tablet having a diameter of 9 mm and a weight of 330 mg.
[0025]
Example 7
Nifujipin 125g, HPC-L1420g and HPC-M470g are mixed uniformly using a fluidized bed granulator, fluidized granulation using ethanol (95%) as a binding liquid, and the resulting granulated product is sized using a power mill Then, 955 g of EC (average particle diameter of about 75 μm) was added thereto, and the mixture was uniformly mixed with a Boule mixer. 2970 g of this mixture was mixed with 30 g of magnesium stearate, and 300 mg of the mixture was coated on the outside of the core tablet of Example 1 using a dry tableting machine to produce dry tablets with a diameter of 9 mm and a weight of 350 mg.
[0026]
Example 8
Nifujipin 125g, HPC-L1420g and HPC-M470g are mixed uniformly using a fluidized bed granulator, fluidized granulation using ethanol (95%) as a binding liquid, and the resulting granulated product is sized using a power mill did. 155 g of EC (average particle diameter of about 75 μm) was added to the obtained granule, and the mixture was uniformly mixed with a Boule mixer. 2170 g of this mixture was mixed with 30 g of magnesium stearate, and 220 mg of the mixture was coated on the outside of the core tablet of Example 1 using a dry tableting machine to produce dry tablets having a diameter of 9 mm and a weight of 270 mg.
[0027]
Comparative Example 1
125 g of Nifedipine and 2100 g of HPC-L were uniformly mixed using a fluidized bed granulator, and fluidized granulation was performed using ethanol (95%) as a binder, and the resulting granulated product was sized with a power mill. To the obtained granules, 245 g of EC (average particle size of about 10 μm) was added and mixed uniformly with a Boule mixer. 30 g of magnesium stearate was added to 2470 g of the obtained mixture, and 250 mg of this mixture was coated on the outside of the core tablet of Example 1 using a dry tableting machine to produce dry tablets having a diameter of 9 mm and a weight of 300 mg. did.
[0028]
Comparative Example 2
Nifujipin 125g, HPC-L1420g and HPC-M470g are mixed uniformly using a fluidized bed granulator, fluidized granulation using ethanol (95%) as a binding liquid, and the resulting granulated product is sized using a power mill did. To the obtained granules, 455 g of calcium hydrogen phosphate (200 mesh pass) was added and mixed uniformly with a Boule mixer. 30 g of magnesium stearate was mixed with 2470 g of the obtained mixture, and 250 mg of the mixture was coated on the outside of the core tablet of Example 1 using a dry tableting machine to produce dry tablets with a diameter of 9 mm and a weight of 300 mg. .
[0029]
Dissolution test For the dry-coated tablets obtained in the examples and comparative examples, the dissolution within a predetermined time according to the pharmacopoeia second method dissolution test method (using sinker) and the pharmacopecial disintegration test method (using auxiliary board), respectively. The dissolution rate of nifedipine was measured. The measurement results are shown in Table 1.
[0030]
[Table 1]

[0031]
Conditions: According to the conditions described in JP-A-9-143073.
1. Second Method Dissolution Test Method Test solution: 1% aqueous solution of polysorbate 80 Temperature: 37 ° C
Using hanging sinker, rotation speed 100rpm
2. Disintegration test apparatus test solution: 1% aqueous solution of polysorbate 80 Temperature: 37 ° C.
Use auxiliary panel [0032]
As shown in Table 1, the dissolution rate in the disintegration test method compared with the second method dissolution test method is only accelerated to less than 1.4 times in 120 minutes in the dry coated tablets of the examples. However, in the dry-coated tablet of the comparative example, it can be seen that the acceleration is twice or more. This is because the outer shell of the Nifedipine dry-coated tablet according to the present invention is gradually extended over a long period of time without collapsing at once or rapidly by mechanical stress before the core reaches the target site in the lower digestive tract. It means being eroded and keeps releasing nifedipine. Furthermore, by comparing the data of Example 1 vs. Comparative Example 1 and Example 3 vs. Comparative Example 2, even if the same amount of EC or calcium hydrogen phosphate is included, the average particle diameter is less than 75 μm, which is satisfactory. It is clear that the particle size of the water-insoluble particles is related to this. The reason for comparison at 120 minutes is that it is considered that the dissolution rate is not affected by the release of the drug from the core in the lower digestive tract (large intestine) in consideration of the passage time of the tablet through the human small intestine.

Claims (4)

The core contains nifedipine and low-viscosity hydroxypropylcellulose,
The outer shell contains nifedipine and low-viscosity hydroxypropylcellulose, or a combination of low-viscosity hydroxypropylcellulose and medium-viscosity hydroxypropylcellulose , and the outer shell further contains water-insoluble particles having an average particle size of 75 to 150 μm. Or a long-lasting type nifedipine dry-coated tablet characterized by containing a granulated product. Water-insoluble particles having an average particle diameter of 75 to 150 μm are ethyl cellulose, cellulose acetate, crystalline cellulose, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, calcium citrate, magnesium aluminum metasilicate, calcium sulfate, aluminum silicate or silica. The nifedipine dry-coated tablet according to claim 1, which is magnesium acid particles or a granulated product of these substances. Rights Hitoshitsubu径75 to 0.99 [mu] m of the water-insoluble particles or granulated product of claim 1 wherein the particles or talc granulated product ethylcellulose or calcium hydrogen phosphate Nifuejipin dry-coated tablet. The nifedipine dry-coated tablet according to claim 1, wherein water-insoluble particles or granules having an average particle diameter of 75 to 150 µm in the outer shell part account for 1 to 50% of the weight of the outer shell part.