JP4959991B2 - Suspension pharmaceutical composition containing tranilast or a pharmacologically acceptable salt thereof - Google Patents

Description

  The present invention relates to an external pharmaceutical composition containing tranilast or a pharmacologically acceptable salt thereof as an active ingredient.

  Tranilast (3,4-dimethoxycinnamoyl anthranilic acid) has an inhibitory action on the release of chemical mediators from mast cells or various inflammatory cells, and is known to be useful as a therapeutic agent for keloid / hypertrophic scars. In addition, preparations such as capsules, tablets, dry syrups, and fine granules are used in the field of medicine as oral preparations.

  However, since tranilast is a poorly soluble substance, it has a feature of low absorption. Therefore, for example, when tranilast is administered as an oral preparation in order to treat keloid / hypertrophic scar generated on the body surface, a large amount of drug is administered in order to maintain an effective blood drug concentration. Large amounts of tranilast are burdensome to the patient and often have side effects such as gastric and liver damage. For this reason, development and research of external preparations that can be applied locally to keloids are desired, and various proposals have been made as external preparations to date.

  For example, a tranilast transdermal absorption patch (JP-A No. 2003-119132) characterized by providing an acrylic pressure-sensitive adhesive layer containing tranilast as an active ingredient on a support, in a state of being uniformly dissolved by a solubilizing agent An external preparation (JP-A-2001-131664) tranilast contained in a plaster base is dissolved in a basic aqueous solution by heating, and then a surfactant, a suspending agent, a stabilizer, an antiseptic, and other pharmaceuticals as required. There have been proposals such as a method of adding an additive and kneading with an ointment base to make an ointment (Japanese Patent Laid-Open No. 6-128153). However, there are problems that the blending amount of fatty acid ester and alcohol as an absorption aid is large, and skin irritation is a concern because a basic substance is used as an absorption aid. Furthermore, development of a high concentration tranilast formulation has become difficult.

The present invention has been made in view of the above problems, and its object is to provide a new form of preparation containing tranilast as an active ingredient, which is highly safe and absorbs the active ingredient from the skin. It is to provide a tranilast-containing pharmaceutical composition that is extremely excellent in stability, has good stability, and is less irritating.
JP 2003-119132 A Japanese Patent Laid-Open No. 2001-131064 JP-A-6-128153

  In order to increase the absorption of tranilast from the skin, it is preferable 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. It was found that the particle size of tranilast was made ultrafine to make an aqueous suspension. Furthermore, it has been found that the absorbability of tranilast from the skin can be dramatically increased by using an appropriate permeation enhancer together, and the present invention has been basically completed.

Thus, in the aqueous suspension according to the first invention, particles containing tranilast or a pharmacologically acceptable salt thereof as an active ingredient are suspended in a pH range of 3 to 7, and 0.5% by mass to It contains 4% by mass of menthol.
At this time, the center of the particle size distribution of the particles is preferably in the range of 0.005 μm to 5 μm (more preferably 0.005 μm to 2 μm), and the 90% median diameter of the particle size distribution is preferably 10 μm or less.

  The method for enhancing the skin permeability of tranilast according to the second invention comprises 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, A menthol of 0.5 mass% to 4 mass% is added to a suspension having a 90% median diameter of a diameter distribution of 10 μm or less and a pH of 3 to 7. In the present invention, the center of the particle size distribution is preferably 0.005 μm to 2 μm.

  According to the present invention, an agent containing tranilast can be applied directly to keloid and treated locally, so that the drug containing tranilast is highly safe for patients and has an excellent ability to absorb active ingredients from the skin. A composition can be provided.

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 is suspended in a base having a pH in the range of 3 to 7, and the center of the particle size distribution of tranilast is 0.005 μm to 5 μm. The 90% median diameter of the particle size distribution is preferably 10 μm or less, more preferably 0.005 μm to 2 μm, and the 90% median diameter of the particle size distribution is more preferably 10 μm 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 when the pH of the base is in the range of 3 to 7 (preferably pH 4 to 6.5, more preferably pH 5 to 6). 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 skin by the base rather than tranilast increases, which is not preferable.

  The particle size distribution of a powder generally shows a distribution having a certain spread approximated to a normal distribution when the logarithm of the particle size 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).

Menthol can be purchased and used commercially. The blending amount of menthol is preferably 0.5% by mass to 4% by mass, and more preferably 0.5% by mass to 2% by mass. If it is 0.5% by mass or less, the skin permeability is low, and if it is 4% by mass or more, the menthol irritation is too strong.
In order to suppress secondary aggregation, the aqueous suspension in the present invention is further added with a surfactant and / or a water-soluble polymer, and the absolute value of the zeta potential of the tranilast particles is set 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, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl 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.
Further, excipients, bases, stabilizers, preservatives, pH adjusters, ointment bases, and the like that are widely used in pharmacology can be added to obtain ointments, lotions, and the like. Examples of such components that are widely used in pharmacology include the following components.

  Base ingredients include glycerin, butylene glycol, dipropylene glycol, propylene glycol, ethanol, isopropanol, water, sorbitol, mannitol, xylitol, glucose, epsilon aminocaproic acid, glycine, glutamate, sodium hyaluronate, glycerin stearate, polyethylene glycol , Carboxyvinyl polymer, polyvinylpyrrolidone, polyvinyl alcohol, cetyl alcohol, isostearyl alcohol, stearyl alcohol, hexyl decanol, octyldodecanol and other alcohols, silicone oils such as methylpolysiloxane, methylphenylpolysiloxane, dodecamethylpolysiloxane , Avocado oil, almond oil, olive oil, cacao butter, beef tallow, sesame oil, small 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, coconut oil, rosehip oil and other oils, orange luffy oil, Liquid waxes such as jojoba oil, liquid hydrocarbons such as liquid paraffin, liquid petrolatum, squalane, squalene, higher fatty acids such as lauric acid, myristic acid, oleic acid, ethyl linoleate, isopropyl myristate, hexyl laurate, myristin Examples thereof include fatty acid esters such as octyl dodecyl acid, decyl oleate, octyl dodecyl oleate, and hexyl decyl 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 p-hydroxybenzoates, chlorobutanol, phenylethyl alcohol, benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, alkylpolyaminoethylglycines, sorbic acid, and the like.
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.

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, atomizers, various homogenizers, mixers, ultrasonic waves, high-pressure homogenizers, and ultra-thin film type 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.

Next, the present invention will be specifically described with reference to examples.
<1. Skin Permeability Test of Tranilast Refinement>
Human artificial cultured skin (test skin LSE-high, manufactured by Toyobo Co., Ltd.) was fixed to a vertical Franz cell (effective area 0.035 cm ² , reservoir capacity 15 mL) so that the dermis layer was on the reservoir side. The reservoir solution was a 20% polyethylene glycol solution.
As the tranilast, a commercially available bulk powder having a particle diameter center of about 50 μm and a 90% median diameter of 80 μm was purchased and used. Tranilast was dispersed in the bulk powder itself or citric acid and an appropriate amount of purified water, and then finely pulverized and pulverized with an ultra-thin film type high-speed rotary crusher (SS-5-100, manufactured by M Technique Co., Ltd.). A refined product was used.

On the donor side, 1.0 mL of each solution of bulk powder (1%) (Comparative Example 1), bulk powder (10%) (Comparative Example 10), or refined product (1%) (Comparative Example 2) was added. . The time at which the solution was added to the donor side was set as the zero hour, and the reservoir solution was sampled over time until the eighth hour. The concentration of tranilast in the sampling solution was measured by HPLC, and tranilast that migrated from the stratum corneum to the dermis was evaluated.
The results are shown in FIG. 1 and FIG. Data are shown as the mean of three times ± SD. As is clear from the figure, it was found that the permeability to the skin increased by about 3 times compared to the bulk powder by making the tranilast bulk powder finer. In addition, even when 10% bulk powder, which is the practical concentration limit of tranilast, is used, there is no significant difference in permeability from 1% bulk powder. It did not reach greatly.

<2. Skin Permeation Test of Tranilast-Containing Cream>
In the tranilast molecule, a carboxyl group is present and dissolves in an ionic form in the presence of a cation. Therefore, a cream in which tranilast was dissolved using an organic amine was prepared, and the skin permeability of the preparation was confirmed.
Tranilast powder was dissolved in monoethanolamine and contained in a cream to prepare a tranilast-containing cream (tranilast concentration 1%) (Comparative Example 9). Further, when the solubility of the tranilast particles due to the pH change was evaluated, when the pH was 3, 4.55, 6, and 7, the tranilast was not dissolved but existed as particles. On the other hand, at pH 7.2 and 7.5, tranilast was dissolved and was not present as particles.
Moreover, since tranilast shows high solubility with respect to polyethylene glycol (PEG), tranilast-containing macrogol ointment having the same concentration as above was prepared using PEG (trade name: Macrogol) (Comparative Example 6). .

Using these two types of cream, the same operation as in the above 1 was performed, and the skin permeability of tranilast was confirmed.
The results are shown in FIGS. In the cream formulation using monoethanolamine (Comparative Example 9), although higher skin permeability was observed than when the tranilast bulk powder was used as it was, the permeability did not reach that of the refined tranilast. In addition, as for macrogol ointment (Comparative Example 6), the affinity of tranilast for the base was too high, and the permeability of tranilast to the skin was hardly recognized.
Moreover, the cream which melt | dissolved the tranilast which adjusted pH to weak alkalinity has lower permeability than using the tranilast bulk powder, and when it became more alkaline, the permeability further decreased (FIG. 5. Comparative Example 7 and comparison) (See Tables 1 to 4 for the composition of Example 8.)

<3. Comparative evaluation with various miniaturized tranilast preparations>
As the tranilast, a commercially available bulk powder having a particle diameter center of about 50 μm and a 90% median diameter of 80 μm was purchased and used. Tranilast was dispersed in the bulk powder itself or citric acid and an appropriate amount of purified water, and then finely pulverized and pulverized with an ultra-thin film type high-speed rotary crusher (SS-5-100, manufactured by M Technique Co., Ltd.). A refined product was used. The ingredients listed in Tables 1 to 4 were added to the dispersion, heated gently and stirred to obtain an ointment base.

For each test solution obtained according to Examples 1 to 7 and Comparative Examples 1 to 8, the center particle size (center of particle size distribution) and 90% median size were measured. 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). Moreover, pH3 aqueous solution was used as a circulating liquid. Each table shows the measurement results of each parameter. The unit of the central particle diameter (D ₅₀ ) and the 90% median diameter (D ₉₀ ) is “μm”.
In Comparative Examples 6 to 9, since the tranilast was dissolved in the base material, the particle diameter could not be measured.

<4. Skin permeability test of menthol-containing tranilast preparation (1)>
Next, using the three types of creams of Example 4, Example 7, and Comparative Example 2, the same operation as 1 was performed, and the skin permeability of tranilast was confirmed.
The results are shown in FIGS. The drug skin permeability of Comparative Example 2 was the lowest among the three creams. The drug skin permeability of Example 4 was about 2.5 times that of Comparative Example 2, but it was not sufficient. On the other hand, since the skin permeability of Example 7 was increased by about 2.5 times compared to Example 4, it was considered that the effect of refinement and the effect of l-menthol acted synergistically. It was.

<5. Skin permeability test of menthol-containing tranilast preparation (2)>
Next, the concentration of menthol was changed to confirm the effect of tranilast on skin permeability. Using nine types of creams of Examples 1 to 7, Comparative Example 1 and Comparative Example 2, the same operation as in the above 1 was performed, and the skin permeability of tranilast was confirmed.

The results are shown in FIGS. When tranilast bulk powder was used (Examples 1 to 4 and Comparative Example 1), the amount of tranilast permeated increased depending on the concentration of l-menthol up to 2%. However, since there was almost no change in the amount of tranilast permeated between 4% l-menthol and 2% l-menthol, it was found that there was an upper limit on the skin permeation promoting effect. When the menthol concentration was 2%, the amount of tranilast permeated was 15 μg or more after 6 hours, and the permeability was about 8 times that of Comparative Example 1.
When tranilast refined cream was used (Examples 5 to 7 and Comparative Example 2), the amount of tranilast permeated through the skin increased depending on the concentration of l-menthol, and the menthol concentration was 2%. An increase was also observed between -4%. The total permeation amount increased about twice as compared with the case where the bulk powder was used. An increase in the amount of tranilast permeation was observed between 4% l-menthol and 2% l-menthol.

<6. Skin permeability test of menthol-containing tranilast preparation (3)>
Next, the pH of the menthol-containing tranilast refined cream was changed to confirm the effect of tranilast on the skin permeability. Using the three types of creams of Example 8, Example 9, and Comparative Example 13, the same operation as in the above 1 was performed, and the skin permeability of tranilast was confirmed. The results are shown in FIG. In the range of pH 4 to 6.5 where the tranilast particles are not dissolved, the same effect was obtained regardless of the pH. However, the permeation of tranilast was greatly reduced at the pH at which tranilast was dissolved.

<7. Test to confirm the effect of other permeation enhancers on the skin permeability of tranilast preparations>
Next, the effect of permeation enhancers other than 1-menthol on the skin permeability of tranilast was confirmed. The skin permeation promoting effect of tranilast was confirmed for two types of isopropyl myristate (IPM) (Comparative Example 4) and benzyl alcohol (Comparative Example 5), which showed the skin permeation promoting effect of Tranilast bulk powder.
About Comparative Example 1- Comparative Example 5, Comparative Example 11, Comparative Example 12, and Example 7, operation similar to said 1 was performed and the skin permeability of tranilast was confirmed. In addition, about IPM and benzyl alcohol, it replaced with the tranilast bulk powder of the comparative example 4 and the comparative example 5, and confirmed the skin permeability | transmittance of what prescribed the same cream using the refinement | miniaturization thing.

The results are shown in FIGS. As for the cream to which 2% IPP was added, the skin permeability was not improved as compared with the tranilast bulk powder (Comparative Example 1), and the cream to which 2% benzyl alcohol and 2% IPM were added showed little skin. Although an improvement in permeability was observed, the effect was similar to that of the refined tranilast (Comparative Example 2), and the maximum value (Comparative Example 4) was 5 μg / day even after 6 hours even when using IPM. It did not exceed mL (Figure 12). Moreover, even when the refined tranilast was used, the effect of 4% l-menthol was not reached at all (FIGS. 13 and 14).
From this result, it was found that the permeation enhancer added to improve the skin permeability of the refined tranilast-containing cream has a high degree of selectivity. In particular, it has been found that l-menthol is selected as an effective permeation enhancer.

<8. Skin permeability test using rats>
Rats were anesthetized with ether, then the abdomen was shaved, a glass ring with an inner diameter of 20 mm was fixed, and air was not caught on the inner surface of the ring. Example 5, Example 6, Example 7 and comparison After applying 2 g of the plaster of Example 1, Comparative Example 2 and Comparative Example 9, and leaving it to stand for 5 hours, the ring and the plaster were removed, and the skin was removed. The extracted skin was thoroughly washed with purified water, weighed accurately, and purified water was added and homogenized. Ethyl acetate was added to this solution and stirred vigorously, and then the ethyl acetate was accurately measured and evaporated to dryness, and then the drug concentration was measured using HPLC.
The results are shown in FIG. Compared with Comparative Examples 1, 2, and 9, in Examples 5, 6, and 7, the drug concentration in the skin tissue was about 8 to 13 times higher.

  As described above, according to the present embodiment, it is possible to provide a tranilast-containing pharmaceutical composition that has high safety, is extremely excellent in absorbability of active ingredients from the skin, has good stability, and has little irritation. .

It is a graph which shows the test result which confirms skin permeability when tranilast is refined | miniaturized. The horizontal axis represents time (hr), and the vertical axis represents cumulative skin permeation (μg / cm ² ). It is a graph which shows the test result which confirms skin permeability when tranilast is refined | miniaturized. The cumulative amount after 6 hours from the start of the test is compared. It is a graph which shows the test result which confirms the skin permeability | transmittance of tranilast when what was dissolved with monoethanolamine and macrogol ointment was used. The horizontal axis represents time (hr), and the vertical axis represents cumulative skin permeation (μg / cm ² ). It is a graph which shows the test result which confirms the skin permeability | transmittance of tranilast when what was dissolved with monoethanolamine and macrogol ointment was used. The cumulative amount after 6 hours from the start of the test is compared. It is a graph which shows the test result which confirms the influence which pH has on the skin permeability of tranilast. The horizontal axis represents time (hr), and the vertical axis represents cumulative skin permeation (μg / cm ² ). It is a graph which shows the test result which confirms refinement | miniaturization of tranilast and skin permeability when using menthol. The horizontal axis represents time (hr), and the vertical axis represents cumulative skin permeation (μg / cm ² ). It is a graph which shows the test result which confirms refinement | miniaturization of tranilast and skin permeability when using menthol. The cumulative amount after 6 hours from the start of the test is compared. It is a graph which shows the test result which confirms skin permeability when menthol is added to the refined tranilast. The horizontal axis represents time (hr), and the vertical axis represents cumulative skin permeation (μg / cm ² ). It is a graph which shows the test result which confirms skin permeability when menthol is added to tranilast bulk powder. The horizontal axis represents time (hr), and the vertical axis represents cumulative skin permeation (μg / cm ² ). It is a graph which shows the test result which confirms skin permeability when menthol is added to the refined tranilast and the bulk powder. The cumulative amount after 6 hours from the start of the test is compared. It is a graph which shows the test result which confirms the influence which pH has on the skin permeability of tranilast. The cumulative amount after 6 hours from the start of the test is compared. It is a graph which shows the test result which confirms skin permeability when IPP, IPM, or benzyl alcohol is added to the tranilast bulk powder. The horizontal axis represents time (hr), and the vertical axis represents cumulative skin permeation (μg / cm ² ). It is a graph which shows the test result which confirms skin permeability when IPM or benzyl alcohol is added to tranilast bulk powder cream or refined cream. The horizontal axis represents time (hr), and the vertical axis represents cumulative skin permeation (μg / cm ² ). It is a graph which shows the test result which confirms skin permeability when IPM or benzyl alcohol is added to the tranilast refinement | purification product cream. The cumulative amount after 6 hours from the start of the test is compared. It is a graph which shows the result of the skin permeability test using a rat about an aqueous suspension containing tranilast.

Claims (4)

Particles containing tranilast or a pharmacologically acceptable salt thereof as an active ingredient are suspended in a pH range of 3 to 7, and contain 0.5% to 4% by weight of menthol . An aqueous suspension having a particle size distribution center of 0.005 μm to 5 μm and a 90% median diameter of the particle size distribution of 10 μm or less . Aqueous suspensions according to claim 1, wherein the center is a 0.005μm~2μm particle size distribution of the particles. The aqueous suspension according to claim 1 or 2 , which is an ointment. 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 3 to 7 A method for enhancing the skin permeability of tranilast, which comprises adding 0.5% to 4% by weight of menthol to the suspension.

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