JP2006028108A - Suspensible pharmaceutical composition containing tranilast or pharmacologically acceptable salt thereof - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a tranilast-containing pharmaceutical composition having high safety and extremely excellent absorption of an active ingredient from the digestive tract and the skin (eyes), and good stability to light and scarcely causing irritation. <P>SOLUTION: The purpose is achieved by an aqueous suspension agent, containing tranilast or its pharmacologically acceptable salt as an active ingredient, in which pH of the base is 3-7 and the center of the particle diameter distribution is 0.005 μm to 5 μm and 90% median diameter of the particle diameter distribution is ≤10 μm. The aqueous suspension agent can be applied to e.g. an eye drop, a nasal drop, an oral medicine, a lotion or an ointment. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a suspension pharmaceutical composition containing tranilast or a pharmacologically acceptable salt thereof as an active ingredient, having high stability and pharmacological effect, and less irritation.

  Tranilast (3,4-dimethoxycinnamoyl anthranilic acid) has an inhibitory action on the release of chemical mediators from mast cells and various inflammatory cells. Useful as. This therapeutic agent is used in the field of medicine as an oral agent such as a capsule, a tablet, a dry syrup, or a fine granule, or an eye drop.

  In general, when an orally administered drug is sparingly soluble, the absorption rate from the digestive tract is low, and the bioavailability decreases. In this regard, tranilast also shows the same tendency, and tranilast contained in a commercially available preparation is extremely difficult to dissolve in water, so that the absorption rate from the digestive tract is low. In addition, since the center of the particle size distribution of the tranilast preparation currently on the market is coarse particles of 80 μm to 100 μm, the absorption rate from the digestive tract is further reduced. For this reason, in order to maintain the effective blood drug concentration, a large amount of drug is administered, which imposes a burden on the patient and often causes side effects such as gastric disorder and liver disorder. Therefore, development and research of a tranilast preparation with improved absorbability in oral administration is desired.

  Tranilast is administered orally as a treatment for keloids and hypertrophic scars, but it is being developed as an ideal dosage form because local administration can reduce the side effects associated with oral administration. Various proposals have been made. For example, a tranilast transdermal absorption patch (Japanese Patent Laid-Open No. 2003-119132) characterized in that an acrylic pressure-sensitive adhesive layer containing tranilast as an active ingredient is provided on a support, a state of being uniformly dissolved by a dissolution aid After externally contained in the plaster base (Japanese Patent Laid-Open No. 2001-131064), tranilast is heated and dissolved in a basic aqueous solution, a surfactant, suspending agent, stabilizer, preservative, Proposals have been made for a method of adding other pharmaceutical additives and kneading with an ointment base to make an ointment (Japanese Patent Laid-Open No. 6-128153). However, in addition to the problems that the blending amount of fatty acid esters and alcohols of absorption aids is large, and that basic substances are used as absorption aids, skin irritation is a concern. Formulation is difficult.

  In addition, eye drops as a therapeutic agent for diseases caused by allergies are ideal preparations for topical administration, and various proposals for solubilization have been made. For example, a method of adding polyvinyl pyrrolidone as a solubilizing agent and a basic substance as necessary to tranilast (Japanese Patent Laid-Open No. 1-294620), a method of containing a nonionic surfactant or an amphoteric surfactant of HLB 10-16 ( Japanese Patent Publication No. 7-116029), aqueous preparations containing organic amines such as monoethanolamine and trometamol (Japanese Patent Laid-Open No. 11-302162) have been proposed. However, the solubilization technique using a solubilizing agent has not yet solved the problem of essentially precipitating crystals during low-temperature storage or being easily decomposed by light.

  In the above-described solubilization technique, since the carboxylic acid group is dissociated into an ionic form and dissolved in combination with a base, ionic drugs are generally absorbed from the digestive tract, skin or eyes. bad.

The present invention has been made in view of the above-described problems, and its purpose is high in safety, extremely excellent in the absorption of active ingredients from the digestive tract and skin (eye), and has good stability, and It is to provide a pharmaceutical composition containing tranilast with less irritation.
JP 2003-119132 A Japanese Patent Laid-Open No. 2001-131064 JP-A-6-128153 JP-A-1-294620 Japanese Patent Publication No.7-116029 Japanese Patent Laid-Open No. 11-302162

  In order to increase the absorption of tranilast from the digestive tract and skin, it is necessary to make the region of pH 3-7 where tranilast exists in a molecular form. However, the presence of tranilast in molecular form means that it does not dissolve in water. As a result of intensive investigations to solve such problems, the inventors have reversely utilized the feature that tranilast does not dissolve in water in the region of pH 3 to 7 where the molecular form exists. The inventors have found that the particle size of tranilast is made ultrafine to obtain an aqueous suspension, and the present invention has been basically completed.

  Thus, the aqueous suspension according to the present invention contains tranilast or a pharmacologically acceptable salt thereof as an active ingredient, and the center of the particle size distribution is 0.005 μm to 5 μm, preferably 0.005 μm to 2 μm. The 90% median diameter of the particle size distribution is 10 μm or less, and the pH of the base is in the range of 3 to 7.

  According to the present invention, there is provided a tranilast-containing pharmaceutical composition that is highly safe, has excellent absorbability of active ingredients from the digestive tract and skin (including the eyes), has good stability, and is less irritating. can do. In the present invention, “skin” means “single or multi-layered tissue covering the surface of metazoans” (Ojirin (second edition), Sanseido (1995-11-3)), retina, cornea It is a concept that also includes the cells that make up the isoeye.

Next, the best mode for carrying out the present invention will be described in detail, but the technical scope of the present invention is not limited by the following embodiments or examples, and without changing the gist thereof, Various modifications can be made. Further, the technical scope of the present invention extends to an equivalent range.
Tranilast or a pharmacologically acceptable salt thereof used in the present invention has a pH of the base in the range of 3 to 7, is suspended in this base, and the center of the particle size distribution of tranilast is at the center. It is preferably 0.005 μm to 5 μm, and the 90% median diameter of the particle size distribution is preferably 10 μm or less. However, the center of the particle size distribution is 0.005 μm to 5 μm, 0.005 μm to 2 μm, 0.005 μm to 0.5 μm, 0.01 μm to 5 μm, 0.01 μm to 2 μm, 0.01 μm to 0.5 μm, It is preferable that the particle size distribution is 0.05 μm to 5 μm, 0.05 μm to 2 μm, 0.05 μm to 0.5 μm, or 0.05 μm to 0.1 μm, and the 90% median diameter of the particle size distribution is 10 μm or less, 8 μm or less, 6 μm Below, it is preferable that it is 4 micrometers or less and 2 micrometers or less. The numerical range relating to the center of the particle size distribution and the 90% median size of the particle size distribution can be set in any combination according to the purpose.

Tranilast is suspended in the base if the pH of the base is in the range of 3-7. However, when the pH of the base rises above 7 and becomes an alkaline region, tranilast apparently dissolves, and tranilast in the dissolved solution is easily hydrolyzed and decomposed by water. On the other hand, when the pH is lower than 3, the acidity of the base becomes strong, and irritation to the digestive tract and skin by the base, not tranilast, is not preferable.
The particle size distribution of the powder generally shows a distribution having a certain spread approximated to a normal distribution when the logarithm of the particle diameter is taken on the horizontal axis and the frequency% is taken on the vertical axis. For this reason, even if the center of the particle size distribution is 0.005 μm to 5 μm, the distribution is wide, so that particles of 5 μm or more are included. In the present invention, the 90% median diameter of the tranilast particle size distribution is 10 μm or less with respect to the spread of the particle size distribution (in other words, the proportion of particles having a particle size larger than 10 μm is 10% Is less important).

By setting it as such conditions, the suspended particle of tranilast carries out Brownian motion, and the sedimentation by secondary aggregation is suppressed. Further, the area of contact with the gastrointestinal tract, skin and mucous membrane can be increased and the cell space can be passed through, so that the absorbability is increased. Furthermore, in the present invention, in addition to improving the stability of tranilast to light, it is possible to reduce irritation.
The increase in absorption and the reduction in light stability and irritation are correlated with the size of the particles. When the center of the particle size distribution is 5 μm or more, or when the 90% median diameter exceeds 10 μm, absorption from the digestive tract and skin is low, light is unstable, and irritation is high.

  The aqueous suspension in the present invention has an effect of suppressing secondary aggregation only by the energy with which the fine particles undergo Brownian motion because the particle size is too small, and further, a surfactant and / or a water-soluble polymer is added, By making the absolute value of the zeta potential of the tranilast particles in the range of 20 mV to 150 mV, the redispersibility can be improved. The type of surfactant, the type of water-soluble polymer, and the amount of drug used to adjust the zeta potential vary depending on the pH, but are preferably in the range of 0.05% to 3%.

  Surfactants include quaternary amine surfactants such as benzethonium chloride and benzalkonium chloride, polyoxyethylene higher alcohol ethers, polyoxyethylene sorbitan fatty acid esters, glycerin fatty acid esters, polyoxyethylene hydrogenated castor oil , Polyoxyethylene fatty acid ester, polyoxyethylene nonyl phenyl ether, polyoxyethylene octyl phenyl ether, sorbitan fatty acid ester, propylene glycol fatty acid ester, fatty acid polyethylene glycol, polyglycerin fatty acid ester, sucrose fatty acid ester, etc. And the like.

Examples of the water-soluble polymer include methyl cellulose, ethyl cellulose, propyl methyl cellulose, propyl cellulose, carboxymethyl cellulose, polyvinyl alcohol, and polyvinyl pyrrolidone.
The tranilast content in the present invention is not particularly limited. Usually, the concentration is 0.5% to 10%, which is the same as the content of the formulation actually used. However, a higher concentration tranilast suspension should be prepared and diluted to the concentration to be used. Is also possible.
In addition, excipients, bases, stabilizers, preservatives, pH adjusters, ointment bases, etc. that are widely used in pharmacology are added, oral preparations, eye drops, nasal drops, ointments, lotions It can be used as an agent. Examples of such components that are widely used in pharmacology include the following components.

Examples of excipients include lactose, sucrose, sucrose, starch, and crystalline cellulose.
Examples of isotonic agents include sodium chloride, potassium chloride, calcium chloride, mannitol and the like.
Base ingredients include glycerin, butylene glycol, dipropylene glycol, propylene glycol, ethanol, isopropanol, butylene glycol, water, sorbitol, mannitol, xylitol, glucose, epsilon aminocaproic acid, glycine, glutamate, sodium hyaluronate, glyceryl stearate , Polyethylene glycols, carboxyvinyl polymers, polyvinylpyrrolidone, polyvinyl alcohol, cetyl alcohol, isostearyl alcohol, stearyl alcohol, hexyl decanol, octyldodecanol and other alcohols, methylpolysiloxane, methylphenylpolysiloxane, dodecamethylpolysiloxane, etc. Silicone oil, avocado oil, almond oil, olive oil, cacao Oils such as beef tallow, sesame oil, wheat germ oil, safflower oil, turtle oil, persimmon oil, persic oil, castor oil, grape oil, macadamia nut oil, mink oil, yellow egg oil, safflower oil, molasses, palm oil, rosehip oil , Liquid waxes such as orange luffy oil and jojoba oil, liquid hydrocarbons such as liquid paraffin, liquid petrolatum, squalane and squalene, higher fatty acids such as lauric acid, myristic acid and oleic acid, ethyl linoleate and isopropyl myristate And fatty acid esters such as hexyl laurate, octyldodecyl myristate, decyl oleate, octyldodecyl oleate, and hexyldecyl dimethyloctanoate.

Examples of the stabilizer include sodium edetate, sodium sulfite, sodium hydrogen sulfite, sodium thiosulfate, dibutylhydroxytoluene, tocopherol and the like.
Examples of the refreshing agent include menthol, mint oil, camphor, and eucalyptus oil.
Examples of the preservative include paraoxybenzoic acid ester, chlorobutanol, phenylethyl alcohol, benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, alkylpolyaminoethylglycines, and sorbic acid.

Examples of pH adjusters include hydrochloric acid, sulfuric acid, acetic acid, lactic acid, citric acid, tartaric acid, malic acid, phosphoric acid, boric acid, sodium hydroxide, potassium hydroxide, calcium hydroxide, monoethanolamine, diethanolamine, diethylamine, ammonia and These salts can be mentioned.
Ointment base: Vaseline, paraffin, plastic base, silicone, lard, wax, single ointment, single lead plaster, hydrophilic ointment, hydrophilic petrolatum, purified lanolin, aquahole, euselin, neoserin, water-absorbing ointment, hydrous lanolin, hydrophilic plastin base , Macrogols, sol base, gel hydrocarbon, and the like.

  In the present invention, the above-mentioned aqueous suspension is dehydrated, and the above-described excipients, bases, stabilizers, preservatives, pH adjusters, ointment bases and the like that are widely used in pharmacology are added, and oral It can be an agent or an external preparation. When these preparations are dispersed and suspended in water (dry syrups, powders, etc.) or taken simultaneously with water (tablets, capsules, etc.), tranilast is suspended in water in the stomach and intestines. It becomes a state. In addition, the preparation of the present invention can be applied to the skin after being suspended in use.

Next, representative examples of the method for producing the preparation of the present invention will be described below, but the technical scope of the present invention is not limited by these examples.
Tranilast can be purchased with a particle size distribution center of 80 μm to 100 μm. By applying this to various pulverizers / dispersers, tranilast having a predetermined particle size can be obtained. Examples of pulverizers include ball mills, vibrating ball mills, centrifugal ball mills, rod mills, micron mills, jet mills, centrifugal fluidized ball mills, hammer mills, pin mills, administers, various homogenizers, mixers, ultrasonic waves, high-pressure homogenizers, and ultra-thin film high-speed rotation. A pulverizer can be exemplified, and tranilast can be refined by using one or two or more of these pulverizers and dispersers. Among these, an ultra-thin film type high-speed rotary pulverizer can be preferably used.

As a manufacturing method of this product, when necessary for tranilast, after adding water whose pH is adjusted with a pH adjuster, it is pulverized and dispersed using an ultra-thin film type high-speed rotary pulverizer to obtain a desired particle size distribution. A refined product having
A surfactant and / or a water-soluble polymer is added as necessary to obtain a suspendable pharmaceutical composition in which the absolute value of the zeta potential of the tranilast particles is in the range of 20 mV to 150 mV.
Furthermore, after dehydrating using an evaporator, spray dryer, vacuum dryer or freeze dryer, adding lactose and kneading, it is made into granules or powder. It can also be tableted into tablets.

Next, the present invention will be specifically described with reference to examples.
As for tranilast, a commercial product of bulk powder having a particle diameter center of about 500 μm and a 90% median diameter of 800 μm was purchased. Each component was weighed in accordance with the amount of components in Table 1 below, and preliminarily pulverized and dispersed with a homogenizer (CLEAMIX 2.2S, manufactured by M Technique Co., Ltd.) at 9000 rpm for 30 minutes. Furthermore, in Examples 1-3, it refined | miniaturized with the ultra-thin film type high speed rotary crusher (SS-5-100 type | mold, the product made from M technique Co., Ltd.), and was disperse | distributed. On the other hand, in Comparative Examples 1 and 3, only the homogenizer treatment was performed, and the treatment with the high-speed rotary pulverizer was not performed. In Comparative Example 2, neither the homogenizer treatment nor the treatment with a high-speed rotary pulverizer was performed.

実施例１〜３、又は比較例１〜３に従って得られた各試験液につき、ｐＨ、中心粒子径（粒子径分布の中心）、及び９０％メジアン径を測定した。ｐＨは、各試験液中にｐＨメーター（堀場製作所製）のプローブを浸漬することで測定した。中心粒子径、及び９０％メジアン径は、粒度分布測定装置（ＳＡＬＤ−７０００、島津製作所製）のフローセルを使用して求めた。なお、循環液として、ｐＨ３の水溶液を用いた。表２には、各パラメータの測定結果を示した。

About each test liquid obtained according to Examples 1-3 or Comparative Examples 1-3, pH, center particle diameter (center of particle diameter distribution), and 90% median diameter were measured. The pH was measured by immersing a probe of a pH meter (Horiba Seisakusho) in each test solution. The central particle diameter and 90% median diameter were determined using a flow cell of a particle size distribution measuring device (SALD-7000, manufactured by Shimadzu Corporation). In addition, pH3 aqueous solution was used as a circulating liquid. Table 2 shows the measurement results for each parameter.

In Examples 1 to 3, the pH was 3.0 to 7.0, the center particle size was 0.05 to 4.8 μm, and the 90% median diameter was 0.8 to 9.0 μm. On the other hand, in Comparative Example 1, since the pH was as high as 8.0 and the tranilast particles were dissolved, the particles could not be detected. In Comparative Examples 2 and 3, although tranilast particles were confirmed, the center particle diameter and 90% median diameter were larger than the range of the present invention.
The following tests related to absorbency were performed on the samples of Examples 1 to 3 and Comparative Examples 1 to 3.

<Skin permeability test>
Human artificial cultured skin (Test Skin Hi, manufactured by Toyobo Co., Ltd.) was fixed to a vertical Franz cell (effective area 0.035 cm ² , reservoir volume 15 mL) so that the dermis layer was on the donor side. The reservoir solution was a 20% polyethylene glycol solution. On the donor side, 1.0 mL of each solution of Examples 1 to 3 and Comparative Examples 1 to 3 was added. The time when the solution was added to the donor side was regarded as zero time, and the reservoir solution was sampled over time. The concentration of tranilast in the sampling solution was measured by HPLC, and tranilast transferred from the dermis side to the donor side was evaluated.

  The results are shown in FIG. As shown in the figure, Comparative Examples 1 to 3 had low skin permeability, and the maximum value (Comparative Example 3) did not exceed 100 μg / mL even after 7 hours. Among them, Comparative Example 1 had the lowest skin permeability. In Comparative Example 1, it was considered that tranilast was dissolved and the ionic drug was poor in skin permeation. From this, in tranilast, it was shown that the pH (3 ≦ pH ≦ 7) of the molecular type is higher in the skin transferability than the ionic type.

On the other hand, in Examples 1 to 3, the tranilast concentration gradually increased from the start of the test, and increased remarkably after the third hour, and after 7 hours, all showed high values of 1100 μg / mL or higher. It was. Moreover, in Examples 1-3, the pH dependence that the permeability of skin was so high that pH was low was shown.
Comparing Comparative Example 3 and Example 3, it was revealed that the center of the particle size distribution is 5 μm or less and the 90% median diameter is 10 μm or less is a factor that greatly increases the absorption of tranilast. .

<Comparison of absorbability by oral administration>
5 mL (50 mg as tranilast) of each test solution of Examples 1 to 3 and Comparative Examples 1 to 3 was administered to Japanese white male rabbits using an intragastric sonde. About 1 mL of blood was collected from the ear vein over time up to the 8th hour, starting at the start of administration, and the unchanged concentration of tranilast in plasma was measured by HPLC.
The results are shown in Table 3 and FIG.

比較例１〜３では、Ｃｍａｘ（血漿中トラニラスト濃度の最大値）は、３０μｇ／ｍＬ〜５０μｇ／ｍＬであり、Ｔｍａｘ（最大濃度に達したときの時間）は、３時間〜４時間であった。また、ＡＵＣ（曲線下面積）は、１２３μｇ／ｍＬ・ｈｒ〜１６１μｇ／ｍＬ・ｈｒであった。

In Comparative Examples 1 to 3, Cmax (maximum value of plasma tranilast concentration) was 30 μg / mL to 50 μg / mL, and Tmax (time when maximum concentration was reached) was 3 hours to 4 hours. . The AUC (area under the curve) was 123 μg / mL · hr to 161 μg / mL · hr.

On the other hand, in Examples 1 to 3, Cmax was 80 μg / mL to 95 μg / mL, Tmax was 1.5 hours to 2 hours, and AUC was 212 μg / mL · hr to 231 μg / mL · hr.
From these results, Examples 1-3 showed that Cmax and AUC were about twice as high as those of Comparative Examples 1-3, indicating that the absorption rate from the gastrointestinal tract was improved. . Moreover, in Examples 1-3, Tmax was shortened to the short time, and it was shown that the absorption rate becomes high.

<Light stability test>
10 mL of each test solution of Examples 1 to 3 and Comparative Examples 1 to 3 was placed in a glass transparent vial, and irradiated with light from a light source of 2000 Lux · hr with a light irradiation tester. The test solution in each vial was sampled over time, the tranilast concentration was measured by HPLC, and the remaining ratio (%) of tranilast was evaluated.
The results are shown in FIG. As is clear from the figure, in Comparative Example 1, the degradation of tranilast was recognized immediately after the start of the test, and on the second day, almost all of the tranilast was degraded and the residual rate was 0%. Also in Comparative Examples 2 and 3, rapid degradation of tranilast was observed after the start of the test, and the residual rate on the 25th day (1.2 × 10 ⁶ Lux · hr) was about 20% in Comparative Example 2, and Comparative Example 3 was about 65%. From these facts, in Comparative Examples 1 to 3, tranilast was significantly degradable with respect to light.

On the other hand, in Test Examples 1 to 3, the stability of tranilast was extremely high, and the remaining rate on the 25th day from the start of the test was a high value of 90% or more.
Comparison of Comparative Examples 2 and 3 with Examples 1 to 3 showed that the stability to light increased as the particle size of tranilast decreased. Thus, it was shown that in the suspension of tranilast, the center particle diameter is 5 μm or less and the 90% median diameter is 10 μm or less, so that the stability to light is high.

<Skin irritation test>
The back of the SD rat was shaved, and 0.5 mL of each test solution of Examples 1 to 3 and Comparative Examples 1 to 3 was applied once. After 24 hours, 48 hours and 72 hours, inflammation and The state of damage was examined with the naked eye. In the case of inflammation or damage, the irritation score is “0” in the case of normal skin, the irritation score is “1” if redness is clearly recognized, and the irritation score is 1 if redness is clearly observed “2”, those in which inflammation was observed were evaluated as 4 levels, with an irritation score “3”.
The results are shown in Table 4.

比較例１〜３においては、２４時間目では０.７〜１.７、４８時間目では１.０〜１.７、７２時間目では１.０〜２.３の刺激性スコアが観察された。一方、実施例１〜３においては、２４時間目〜７２時間目の全例において、刺激性スコアは「０」であり、刺激性は観察されなかった。

In Comparative Examples 1 to 3, an irritancy score of 0.7 to 1.7 at 24 hours, 1.0 to 1.7 at 48 hours, and 1.0 to 2.3 at 72 hours was observed. It was. On the other hand, in Examples 1 to 3, in all cases from 24 hours to 72 hours, the irritation score was “0” and no irritation was observed.

From these results, it was found that the product of this example was a hypoallergenic tranilast preparation.
From the above test results, the product of the present invention is highly safe, has excellent absorption of active ingredients from the digestive tract and skin (including the eyes), has good light stability, and has little irritation. It has been found to provide a pharmaceutical composition containing tranilast.

It is a graph which shows a result when a skin penetration test is done using the tranilast formulations of Examples 1 to 3 and Comparative Examples 1 to 3. It is a graph which shows the tranilast concentration change in plasma with time when the tranilast formulations of Examples 1 to 3 and Comparative Examples 1 to 3 were orally administered to rabbits. It is a graph which shows the residual rate change of the tranilast over time when the tranilast formulation of Examples 1-3 and Comparative Examples 1-3 is applied to a light irradiation tester.

Claims (8)

It contains tranilast or a pharmacologically acceptable salt thereof as an active ingredient, the center of the particle size distribution is 0.005 μm to 5 μm, the 90% median diameter of the particle size distribution is 10 μm or less, and the pH is An aqueous suspension characterized by being 3-7. The aqueous suspension according to claim 1, wherein the center of the particle size distribution is from 0.005 µm to 2 µm. The aqueous suspension according to claim 1 or 2, which is an eye drop. The aqueous suspension according to claim 1 or 2, which is a nasal drop. The aqueous suspension according to claim 1 or 2, which is an oral preparation. The aqueous suspension according to claim 1 or 2, which is a lotion. The aqueous suspension according to claim 1 or 2, which is an ointment. A pharmaceutical composition comprising the dehydrated aqueous suspension according to claim 1 or 2 and a pharmaceutically acceptable ingredient.

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