JP2014224087A - Telmisartan-containing solid formulation with improved photostability - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a product which is a telmisartan-containing solid formulation readily producible by a conventional method, for medical treatments, having a color tone which does not change for a long period of time even if it is stored in a distribution process or unpacked condition.SOLUTION: There is provided a solid formulation containing telmisartan, polyethylene glycol, a basic compound, and also at least one additives. A polyethylene glycol having a molecular weight of 4,000-20,000 is preferable, particularly a polyethylene glycol having a molecular weight of 6,000 is especially preferable, and meglumine is especially preferable as a basic compound.

Description

  The present invention relates to 4 ′-[[2-n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) -benzimidazol-1-yl] -methyl] -biphenyl-2 as an active ingredient. -It relates to a solid preparation containing carboxylic acid, that is, telmisartan (general name of Japanese pharmaceuticals) and having improved light stability.

Telmisartan is an angiotensin II receptor antagonist developed for the treatment of hypertension and other indications, as disclosed in EP 0502314 (A1).
In order to develop high-quality telmisartan tablets, the inventors manufactured tablets by conventional methods using general-purpose additives (excipients, disintegrants, binders, lubricants, etc.). When light was irradiated, it was found that the color turned yellow over time.
As a method for preventing coloration of pharmaceutical preparations by light, there is generally a method of coating a solid preparation such as a tablet with a polymer base material containing a light-shielding agent such as titanium oxide. Telmisartan and a coating polymer Considering the interaction with the base material and the like, development of a method for suppressing coloring by light in an uncoated state such as an uncoated tablet is desired.

EP0502314 (A1) publication

  An object of the present invention is to produce an uncoated solid preparation containing telmisartan by a simple method, and to provide a solid preparation that does not change in color for a long time even when stored in a distribution process or in an unwrapped state for medical use. .

The present inventors diligently studied to solve the above problems. During the process, the color tone after light irradiation on the tablet was examined for combinations with various additives, but no significant effect was obtained depending on the type of additive. However, as a result of subsequent studies, it was surprisingly found that the change in color tone after light irradiation was remarkably suppressed in tablets made by adding polyethylene glycol 6000.
Therefore, the present inventors have made further studies based on the findings and have completed the present invention.

That is, the present invention relates to the following inventions (1) to (5).
(1) A solid preparation containing telmisartan, polyethylene glycol, a basic compound, and at least one additive.
(2) The solid preparation according to (1), wherein the polyethylene glycol has an average molecular weight of 4000 to 20000.
(3) The solid preparation according to (1), wherein the ratio of the weight of telmisartan to the weight of polyethylene glycol is 1: 0.05 to 1: 1.
(4) The solid preparation according to (1), wherein the basic compound is meglumine.
(5) The solid preparation according to (1), wherein the ratio of the weight of telmisartan to the weight of the basic compound is 1: 0.1 to 1: 1.

  In the solid preparation of the present invention containing telmisartan, by containing polyethylene glycol as an additive, color change can be suppressed for a long time even when stored in a distribution process or in an unwrapped state. And the solid formulation which concerns on this invention does not require any special operation on a formulation, and can be manufactured by a simple method.

FIG. 1 shows the color tone (L * a * b * color system) before and after light irradiation for each tablet of Examples 1 to 5 and Comparative Examples 1 and 2, and before and after light irradiation. The color difference (ΔE * ab) is calculated and the result is displayed in a graph.

In the present invention, the solid preparation refers to a preparation using a granulated product obtained by a spray drying method, a fluidized bed granulation method or the like, and examples thereof include granules, tablets, capsules and the like.
The average particle size (measured by light scattering method) of telmisartan used in the present invention is preferably 10 μm or less, more preferably 0.1 to 5 μm. If necessary, dry or wet pulverization can be appropriately performed to adjust the particle size to an arbitrary value.

Preferred polyethylene glycols used in the present invention are commercially available polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 1000, polyethylene glycol 1500, polyethylene glycol 1540, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 20000 and polyethylene. Any of glycol 35000 can be suitably used. Preferred are polyethylene glycol 4000, polyethylene glycol 6000 and polyethylene glycol 20000, and most preferred is polyethylene glycol 6000.
Moreover, the preferable weight ratio which uses telmisartan and polyethyleneglycol is 0.05-1 with respect to the former 1, More preferably, it is 0.1-0.5, More preferably, it is 0.15-0.3.

  The basic compound used in the present invention is not particularly limited as long as it is pharmacologically acceptable and can be dissolved in water. Preferred bases include sodium hydroxide, L-arginine, meglumine, potassium hydroxide. More preferred is meglumine.

As additives in the preparation, commonly used excipients, binders, disintegrants, surfactants, lubricants, light-shielding agents and the like can be used.
Examples of excipients include lactose, crystalline cellulose, corn starch, potato starch, D-mannitol, erythritol, xylitol, sorbitol, isomalt, maltitol, sucrose, sucrose, glucose and the like.
Examples of the binder include hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, povidone, ethylcellulose, pregelatinized starch, polyvinyl alcohol, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, and the like.
Examples of the disintegrant include corn starch, low-substituted hydroxypropyl cellulose, carmellose, carmellose calcium, carmellose sodium, carboxymethyl starch sodium, crospovidone, agar powder and the like.
Examples of the surfactant include polysorbate, sucrose fatty acid ester, sodium lauryl sulfate and the like.
Examples of the lubricant include plasma anhydrous silicic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, and hardened oil.
As the light-shielding agent, titanium oxide, talc, yellow ferric oxide, ferric oxide and the like are preferable.

There is no difficulty in the operation method of the manufacturing method of the solid formulation which concerns on this invention, and the target solid formulation can be manufactured easily according to a conventional method.
In addition, as a stirring mixer used when implementing this invention, a common paddle type stirring mixer, a homogenizer (made by TOKYU KIKA: ROBOMICS), etc. can be used.

160.8 g of D-mannitol and 0.2 g of light anhydrous silicic acid were charged into a fluidized bed granulator (manufactured by POWREC: MP-01 type), 80.0 g of telmisartan, 80.0 g of meglumine, and 16.0 g of polyethylene glycol 6000. The solution in 180 g of purified water was sprayed and granulated. The obtained granules were dried and sieved with a JIS 30 mesh sieve. To 168.5 g of the obtained sized product, 1.5 g of magnesium stearate was added and mixed in a polyethylene bag. Subsequently, this mixture was compression-molded to a diameter of 8 mm using a rotary tableting machine (manufactured by Kikusui Seisakusho: VELA type 5) to obtain tablets having the following composition.
[Components] [Weight per tablet (mg)]
Telmisartan 40.0
D-mannitol 80.4
Meglumine 40.0
Polyethylene glycol 6000 8.0
Light anhydrous silicic acid 0.1
Magnesium stearate 1.5

160.8 g of D-mannitol and 0.2 g of light anhydrous silicic acid were charged into a fluidized bed granulator (manufactured by Paul Wrec Inc .: MP-01 type), telmisartan 80.0 g, meglumine 80.0 g, and polyethylene glycol 4000 16.0 g. The solution in 180 g of purified water was sprayed and granulated. The obtained granules were dried and sieved with a JIS 30 mesh sieve. To 168.5 g of the obtained sized product, 1.5 g of magnesium stearate was added and mixed in a polyethylene bag. Next, this mixture was compression molded to a diameter of 8 mm using a rotary tableting machine (manufactured by Kikusui Seisakusho: VELA5 type) to obtain tablets having the following composition.
[Components] [Weight per tablet (mg)]
Telmisartan 40.0
D-mannitol 80.4
Meglumine 40.0
Polyethylene glycol 4000 8.0
Light anhydrous silicic acid 0.1
Magnesium stearate 1.5

160.8 g of D-mannitol and 0.2 g of light anhydrous silicic acid were charged into a fluidized bed granulator (manufactured by Paulek: MP-01 type), telmisartan 80.0 g, meglumine 80.0 g, and polyethylene glycol 20000 16.0 g. The solution in 180 g of purified water was sprayed and granulated. The obtained granules were dried and sieved with a JIS 30 mesh sieve. To 168.5 g of the obtained sized product, 1.5 g of magnesium stearate was added and mixed in a polyethylene bag. Next, this mixture was compression molded to a diameter of 8 mm using a rotary tableting machine (manufactured by Kikusui Seisakusho: VELA5 type) to obtain tablets having the following composition.
[Components] [Weight per tablet (mg)]
Telmisartan 40.0
D-mannitol 80.4
Meglumine 40.0
Polyethylene glycol 20000 8.0
Light anhydrous silicic acid 0.1
Magnesium stearate 1.5

303.6 g of D-mannitol and 2.0 g of light anhydrous silicic acid were charged into a fluidized bed granulator (manufactured by Paulek, Inc .: MP-01 type), telmisartan 160.0 g, meglumine 160.0 g, polysorbate 0.4 g and polyethylene A solution prepared by dissolving 32.0 g of glycol 6000 in 360 g of purified water was sprayed and granulated. The obtained granules were dried and sieved with a JIS 30 mesh sieve. 12.0 g of sucrose fatty acid ester was added to 493.5 g of the obtained sized product, and mixed in a polyethylene bag. Furthermore, 4.5 g of magnesium stearate was added and mixed in a polyethylene bag. Next, this mixture was compression molded to a diameter of 8 mm using a rotary tableting machine (manufactured by Kikusui Seisakusho: VELA5 type) to obtain tablets having the following composition.
[Components] [Weight per tablet (mg)]
Telmisartan 40.0
D-mannitol 75.9
Meglumine 40.0
Polyethylene glycol 6000 8.0
Polysorbate 0.1
Light anhydrous silicic acid 0.5
Sucrose fatty acid ester 4.0
Magnesium stearate 1.5

270.0 g of D-mannitol and 16.0 g of light anhydrous silicic acid were charged into a fluidized bed granulator (manufactured by Paulek, Inc .: MP-01 type), 160.0 g of telmisartan, 160.0 g of meglumine, 16.0 g of polysorbate and polyethylene A solution prepared by dissolving 32.0 g of glycol 6000 in 360 g of purified water was sprayed and granulated. The obtained granules were dried and sieved with a JIS 30 mesh sieve. To 490.5 g of the obtained sized product, 6.0 g of sucrose fatty acid ester was added and mixed in a polyethylene bag. Further, 6.0 g of magnesium stearate was added and mixed in a polyethylene bag. Subsequently, this mixture was compression-molded to a diameter of 10 mm using a rotary tableting machine (manufactured by Kikusui Seisakusho: VELA5 type) to obtain tablets having the following composition.
[Components] [Weight per tablet (mg)]
Telmisartan 80.0
D-mannitol 135.0
Meglumine 80.0
Polyethylene glycol 6000 16.0
Polysorbate 8.0
Light anhydrous silicic acid 8.0
Sucrose fatty acid ester 4.0
Magnesium stearate 4.0

[Comparative Example 1]
176.8 g of D-mannitol and 0.2 g of light anhydrous silicic acid were charged into a fluidized bed granulator (manufactured by Paulek: MP-01 type), and 80.0 g of telmisartan and 80.0 g of meglumine were dissolved in 180 g of purified water. The liquid was sprayed and granulated. The obtained granules were dried and sieved with a JIS 30 mesh sieve. To 168.5 g of the obtained sized product, 1.5 g of magnesium stearate was added and mixed in a polyethylene bag. Next, this mixture was compression-molded to a diameter of 8 mm using a rotary tableting machine (manufactured by Kikusui Seisakusho: VELA type 5) to obtain tablets having the following composition.
[Components] [Weight per tablet (mg)]
Telmisartan 40.0
D-mannitol 88.4
Meglumine 40.0
Light anhydrous silicic acid 0.1
Magnesium stearate 1.5

[Comparative Example 2]
168.8 g of D-mannitol and 0.2 g of light anhydrous silicic acid were charged into a fluidized bed granulator (manufactured by Paulek: MP-01 type), 80.0 g of telmisartan, 80.0 g of meglumine, 2.0 g of polysorbate and hydroxy A solution obtained by dissolving 6.0 g of propylcellulose in 180 g of purified water was sprayed and granulated. The obtained granules were dried and sieved with a JIS 30 mesh sieve. To 168.5 g of the obtained sized product, 1.5 g of magnesium stearate was added and mixed in a polyethylene bag. Next, this mixture was compression-molded to a diameter of 8 mm using a rotary tableting machine (manufactured by Kikusui Seisakusho: VELA type 5) to obtain tablets having the following composition.
[Components] [Weight per tablet (mg)]
Telmisartan 40.0
D-mannitol 84.4
Meglumine 40.0
Hydroxypropyl cellulose 3.0
Polysorbate 1.0
Light anhydrous silicic acid 0.1
Magnesium stearate 1.5

[Test Example 1]
For each of the tablets obtained in Examples 1 to 5 and Comparative Examples 1 and 2, a spectrocolorimeter (Nippon Denshoku Kogyo Co., Ltd .: SE6000) was used for the sample after irradiation with 3000 lux incandescent light for 400 hours and the sample before irradiation. Type) was used to measure the color tone (L * a * b * color system). The measurement results and the following formula (Nippon Denko Kogyo Co., Ltd., Spectrophotometer
Color difference (ΔE * ab) before and after light irradiation was calculated for each tablet from SE6000 type, instruction manual, page 54), and the results are shown in Table 1 and FIG.
ΔE * ab = {square of (ΔL *) + (square of (Δa *) + square of (Δb *)}}, where ΔL *, Δa *, and Δb * are The difference between the tablet brightness index L *, the color coordinate a *, and the color coordinate b * before and after light irradiation is shown.
From Table 1 and FIG. 1, in the tablet of Example 1-Example 5 which concerns on this invention, compared with the tablet of the comparative example 1 and the comparative example 2, it is that the color tone change before and behind light irradiation is suppressed notably. I understand.

According to the present invention, a telmisartan-containing solid preparation that can be easily produced by a conventional method, and a product whose color tone does not change for a long time even when stored in a distribution process or in a non-packaging state, can be used for medical treatment.

Claims (5)

A solid preparation containing telmisartan, polyethylene glycol, a basic compound, and at least one additive. The solid preparation according to claim 1, wherein the polyethylene glycol has an average molecular weight of 4,000 to 20,000. The solid preparation according to claim 1, wherein the ratio of the weight of telmisartan to the weight of polyethylene glycol is 1: 0.05 to 1: 1. The solid preparation according to claim 1, wherein the basic compound is meglumine. The solid preparation according to claim 1, wherein the ratio of the weight of telmisartan to the weight of the basic compound is 1: 0.1 to 1: 1.