KR101877868B1 - Coated preparation containing azosemide as active ingredient - Google Patents

Abstract

(assignment)
(2H-tetrazol-5-yl) -4 - [(thiophen-2-ylmethyl) amino] benzenesulfonamide which is stable against external factors regardless of its packaging form, or its pharmacological A salt thereof, or a hydrate thereof as an active ingredient.
(Solution)
(2-chloro-5- (2H-tetrazol-5-yl) -4 - [(thiophen-2- ylmethyl) amino] benzenesulfonamide, or a pharmacologically acceptable salt thereof, And a coating layer formed on the surface of the active ingredient-containing portion, wherein the coating layer contains rutile titanium dioxide.

Description

TECHNICAL FIELD [0001] The present invention relates to a coating agent containing azosemide as an active ingredient,

The present invention relates to a process for the preparation of 2-chloro-5- (2H-tetrazol-5-yl) -4 - [(thiophen-2- ylmethyl) amino] benzenesulfonamide, 5-yl) -4 - [(thiophene-2-ylmethyl) amino] benzenesulfonamide, or a pharmacologically acceptable salt thereof, or a hydrate thereof To a coating agent.

(2-chloro-5- (2H-tetrazol-5-yl) -4 - [(thiophen-2- ylmethyl) amino] benzenesulfonamide, or a pharmacologically acceptable salt thereof, (Hereinafter referred to as azosemide) is a compound described in Patent Document 1, and is known as a sustained loop diuretic. Its pharmacological action is to inhibit reabsorption of sodium and chloride ions in the ascending limb of the renal tubules, mainly the henle loop (henle loop) , And is thought to exert diuretic action. [0002] Oral medicines and injecting agents (Patent Document 2) are known as medicines prepared by using as a single active ingredient azosemide. Oral medicines have been manufactured and sold in Japan since 1993 have.

It is known that the above azosemide is slowly decomposed by light to be colored in yellow. For this reason, for the purpose of protecting from light irradiation, conventionally, researches such as a light-shielding coating and a light-shielding packaging have been conducted.

In the case of a light-shielding coating, in order to improve the stability of the drug against light, it has been used as a general technique to form titanium dioxide in the coating layer. Among the titanium dioxide, there are crystal polymorphisms (crystal polymorphism). Among them, titanium dioxide of an anatase type is known to have high light shielding ability and whitening ability. Therefore, in order to improve the stability of the drug against light, anatase type titanium dioxide is generally used.

In the case of a light-shielding package, a package that can protect the preparation from the influence of light by preventing transmission of light or a visible blue region (visible blue region) from ultraviolet rays (ultraviolet rays) PTP packaging or the like is used in which a colored or translucent wrapping sheet which does not transmit light having a wavelength ranging from 0 to 100 nm is used to photostabilize the inner preparation. However, a package for preventing transmission of light by a method such as sandwiching a metal foil such as aluminum with an alkene polymer or the like to prevent transmission of light is a package made of only an alkene polymer or the like And a package sheet which does not allow light of a wavelength ranging from ultraviolet rays to visible blue regions to pass therethrough is more expensive than a package sheet that transmits light of wavelengths ranging from ultraviolet to visible blue.

Recently, in hospitals and dispensing pharmacies, there is a case where a service called "Hanbonggi" is performed in which several types of medicines are packed into one unit for each unit of taking into account convenience of patients. At this time, generally used is a package which transmits light or moisture in the air. For this reason, the medical preparations which are encapsulated are liable to be influenced by the influence of light, temperature or humidity due to climatic conditions during storage. It is required to be stable not only in terms of light but also in temperature or humidity in order to prepare a medicinal preparation suitable for unification.

: United States Patent No. 3665002 Publication Specification : WO 94/05286 Pamphlet

The inventors of the present invention have conducted studies to make a coating agent containing azosemide as an active ingredient as a stable pharmaceutical preparation without using a package, and as a result, it has been found that an agent containing an azide-type titanium dioxide- However, I realized that there are cases where the appearance changes due to temperature or humidity. SUMMARY OF THE INVENTION Accordingly, it is an object of the present invention to provide a formulation containing azosemide as an active ingredient, which is stable regardless of external factors such as temperature or humidity, without depending on the package.

The inventors of the present invention have carefully studied the cause of change in the appearance of a coating agent comprising azosemide as an active ingredient by temperature or humidity. And that azosemide reacts with anatase-type titanium dioxide under certain conditions to cause a change in formulation. Further, when the shading coating is applied to the preparation containing azosemide as an active ingredient, the use of rutile type titanium dioxide finds that the preparation becomes stable not only against light but also against temperature or humidity, and completes the present invention .

The main structure of the present invention is as follows.

(1) 2-Chloro-5- (2H-tetrazol-5-yl) -4 - [(thiophen-2- ylmethyl) amino] benzenesulfonamide, or a pharmacologically acceptable salt thereof, And a coating layer formed on the surface of the active ingredient-containing portion, wherein the coating layer contains titanium dioxide in the form of a rutile.

(2) The coating agent according to (1), wherein the content of the rutile type titanium dioxide is 0.2% by mass or more based on the content of the active ingredient.

(3) The coating agent according to (2), wherein the content of the rutile type titanium dioxide is 0.2 to 8 mass% with respect to the active ingredient-containing part.

(4) The coating agent according to (3), wherein the content of the rutile-type titanium dioxide is 0.4 to 4% by mass with respect to the content of the active ingredient.

(5) The toner according to any one of (1) to (4), wherein the rutile type titanium dioxide has a 50% particle diameter of 0.1 to 10 m when powder particle size measurement (powder particle size measurement) is performed by laser diffraction method ). ≪ / RTI >

(6) The coating agent according to any one of (1) to (5), wherein the coating layer comprises a water-soluble polymer (water-soluble polymer).

(7) A coating composition comprising, in a coating layer, at least one coloring agent selected from the group consisting of talc, calcium carbonate, magnesium oxide, kaolin and iron trioxide, A coating agent according to any one of (1) to (6).

(8) The coating layer is composed of (i) 8 to 50 mass% of rutile titanium dioxide, (ii) 40 to 85 mass% of water-soluble polymer, and (iii) talc, calcium carbonate, magnesium oxide, (1) to (7), wherein the composition contains 0 to 15 mass% of at least one coloring agent selected from the group consisting of kaolin and ferric oxide, and (iv) 0 to 20 mass% ). ≪ / RTI >

(9) The coating agent according to any one of (1) to (8), wherein part of the coating agent is colorless and transparent and the contents are visible in a package.

(10) The coating agent according to any one of (1) to (9), wherein the color difference? E is 3.0 or less under the conditions of (a), (b), (c) or (d) below.

(a) Temperature 60 ° C, relative humidity 75%, shading, preservation for 3 weeks

(b) Temperature 25 ° C, relative humidity 75%, shading, preservation for 3 months

(c) preserved until a temperature of 25 ° C, a relative humidity of 30%, an illuminance of 2000 lx / hr, and a total illuminance of 1.2 million lx

(d) Preserved until a temperature of 25 ° C, a relative humidity of 75%, an illuminance of 2000 lx / hr, and a total illuminance of 1.2 million lx

(11) 2-Chloro-5- (2H-tetrazol-5-yl) -4 - [(thiophen-2- ylmethyl) amino] benzenesulfonamide, or a pharmacologically acceptable salt thereof, Is coated with a coating agent containing at least a rutile type titanium dioxide, characterized in that the effective component-containing portion containing, as an effective component, at least a rutile type titanium dioxide is coated.

INDUSTRIAL APPLICABILITY According to the present invention, it is possible to provide a formulation containing azosemide as an active ingredient which is stable regardless of external factors, regardless of the packaging form.

Hereinafter, embodiments of the present invention will be described in more detail. However, the present invention is not limited to the following embodiments.

The coating agent composition of the present invention is a coating agent composition comprising 2-chloro-5- (2H-tetrazol-5-yl) -4 - [(thiophen-2- ylmethyl) amino] benzenesulfonamide or a pharmacologically acceptable salt thereof , Or hydrates thereof as an active ingredient. The general name (generic name) is called azoside, but the term " azoxime " is used herein to refer to 2-chloro-5- (2H-tetrazol-5-yl) The above salts are collectively referred to as " azosemide ". The agent containing the azosemide is a loop diuretic and is used as an effective agent for the treatment of heart edema (congestive heart failure), renal edema (renal edema) and hepatic edema (hepatic edema). The azosemide can be produced according to the synthesis method described in the specification of US-A-3665002.

The pharmacologically acceptable salts of the above 2-chloro-5- (2H-tetrazol-5-yl) -4 - [(thiophen-2- ylmethyl) amino] benzenesulfonamide, A pharmaceutically acceptable salt is preferable. Specifically, pharmacologically acceptable inorganic (inorganic) substances such as sodium, lithium, potassium, magnesium, ammonium, quaternary ammonium salts, hydrochloride salts, diethylamine and diethanolamine, Organic base salts (organic base salts). These pharmacologically acceptable salts can be obtained by known methods. The hydrate of the present invention is not limited to the hydrate of 2-chloro-5- (2H-tetrazol-5-yl) -4 - [(thiophen-2- ylmethyl) amino] benzenesulfonamide, The present invention also includes a hydrate of an acceptable salt, which can be obtained by a known method.

The content (ratio) of the active ingredient azosemide is preferably 10 to 70% by mass, more preferably 20 to 40% by mass as a whole preparation. The content of azosemide can be set to an appropriate amount for practical use, and it is appropriate to set the amount of azosemide in the range of 10 mg to 200 mg in one preparation, but generally, the content of azoside in one tablet is 30 mg or 60 mg Therefore, it is practically preferable to use a content based on these.

The coating agent of the present invention can be produced by coating the surface of an active ingredient-containing part containing an azo compound (hereinafter referred to as an azo compound-containing part) with a coating layer containing a rutile type titanium dioxide have. And a predetermined (basic) tablet containing an azosemide-containing porogen, for example, azosemide. It is also possible to use a coated tablet instead of a predetermined tablet. In addition, the nucleus portion may be made into an acetamide-containing portion by using a manufacturing technique of a cupric tablets described in International Publication WO01 / 98067 brochure or the like.

The above-mentioned predetermined means generally a tablet before coating. The predetermined production method is not particularly limited, and can be produced by a commonly used method. For example, a drug, a binder and a disintegrant are mixed and kneaded, and after the kneading, the kneaded product is sized and kneaded, and the kneaded product is mixed with the kneaded product, Followed by tableting.

In general, in the case of pharmaceutical preparations requiring light shielding, titanium dioxide is mainly used for the coating layer. Titanium dioxide is classified into three types of rutile type (R type), anatase type (A type) and brookite type (brookite type) (B type) due to difference in crystal structure and properties. Titanium dioxide of rutile type of tetragonal system and titanium dioxide of brutate type of orthorhombic system have low effect of light shielding and whitening and titanium tetrahedral of anatase type of tetragonal system, Shielding ability and whiteness are known to be high. Therefore, when the stability of the drug to light is improved, titanium dioxide containing a large amount of anatase-type crystals tends to be firstly selected.

However, the inventors of the present invention found that, in the coating agent containing azosemide as an active ingredient, titanium dioxide in the coating layer preferably contains a large amount of rutile crystals. This is because the tablets containing the azoside are subjected to influences such as temperature or humidity, and the mixture of the active ingredient and the anatase type titanium dioxide causes a change in the color of the preparation surface, thereby deteriorating the stability. It has also been found by the present inventors that azosemide and anatase-type titanium dioxide cause a change in composition due to the influence of temperature or humidity.

Rutile titanium dioxide is available as a commercial product. Further, it can be obtained by heating the anatase type crystal to 900 DEG C or more, or by heating the brookite type crystal to 650 DEG C or more. Therefore, other crystal systems may be mixed in rutile titanium dioxide. In that case, it is preferable that the ratio of the content of titanium dioxide other than the rutile type titanium dioxide: rutile type is in the range of 100: 0 to 90: 10. That is, titanium dioxide containing more than 90% of rutile type titanium dioxide is preferable. Also, rutile type titanium dioxide in which the surface of rutile type titanium dioxide is chemically modified with another additive is also included in the rutile type titanium dioxide of the present invention.

The X-ray diffraction pattern of the rutile titanium dioxide in the coating layer was 27.5 ± 0.5 °, 36.0 ± 0.5 °, and 54.3 ± 0.5 ° in the measurement conditions described in Table 1, using powder X-ray diffraction by Cu-K? The diffraction angle 2 &thetas; More specifically, it has a characteristic peak of diffraction angle 2? At 41.4 ± 0.5 °, 56.7 ± 0.5 °, 63.1 ± 0.5 °, 69.3 ± 0.5 ° and 140.3 ± 0.5 °.

The particle size of the rutile titanium dioxide is preferably from 0.1 to 10 μm, more preferably from 0.5 μm to 5 μm, with a 50% particle diameter when the powder particle size measured by the laser diffraction method is measured. Generally, when a material having a high refractive index such as titanium dioxide has a particle diameter of about 1/2 of the wavelength of the incident light, the ability of the incident light not to be transmitted by the diffuse reflection becomes large (Japanese Patent No. 2525192, Patent Publication No. 6-2562). Also, in order to maintain a uniform dispersion state in the coating liquid, it is preferable that the particle diameter is small. Therefore, when the particle size of 50% when the powder particle size is measured by the laser diffraction method becomes larger than 10 μm, the light shielding ability tends to be lowered, and it becomes difficult to maintain a uniform dispersion state in the coating liquid. On the contrary, when the particle size of 50% when the powder particle size measured by the laser diffraction method is measured is smaller than 0.1 占 퐉, the ability of not to transmit the incident light in the visible light region of a large wavelength becomes small and the function as a coloring agent (Japanese Patent No. 2525192, Japanese Patent Publication No. Hei 6-2562, Japanese Patent No. 4464356).

The content (ratio) of the rutile type titanium dioxide is preferably 0.2% by mass or more based on the total mass of the azo compound-containing part. When the content of the rutile titanium dioxide in the azosemide-containing portion is less than 0.2 mass%, it is not sufficient to prevent the discoloration of the active ingredient due to light. Those skilled in the art can implement the present invention by setting the optimum range of the titanium dioxide content of the rutile type. For reference, the content (ratio) of the rutile type titanium dioxide is preferably 8% by mass or less with respect to the content of the azo compound. The content (ratio) of the rutile type titanium dioxide to the azo compound-containing portion is preferably from 0.2 to 8 mass%, more preferably from 0.3 to 6 mass%, and the upper limit is more preferably 5% or less. More preferably from 0.4 to 4% by mass. Generally, a sufficient amount of titanium dioxide is known to be 1 to 5% by mass with respect to the tablets before coating. In the present invention, however, even in a smaller amount than usual, Can be provided. If the content of the rutile titanium dioxide in the azo compound-containing portion is too large, the dispersion state of the titanium dioxide in the coating liquid may deteriorate, the strength of the coating film after coating may decrease, do. The content of the rutile titanium dioxide in the coating layer can not be uniformly defined by the thickness of the coating layer, but is preferably from 8 to 50 mass%, more preferably from 9 to 40 mass% By mass to 10% by mass to 25% by mass.

In the present invention, various coating agents may be used for the coating layer in accordance with the technical knowledge in the art. Among them, water-soluble polymers are generally used. Examples of the water-soluble polymer include hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose acetate succinate, Methyl vinyl ether maleic anhydride copolymer, sodium carboxymethyl cellulose, cellulose acetate phthalate, xanthan gum, tragacanth gum, arabic acid, It is also possible to use gum arabic, agar, gelatine, sodium alginate, polyethylene oxide, polyvinylpyrrolidone, aminoalkyl methacrylate copolymer ) Methacrylic acid copolymer, carboxyvinyl polymer, polyvinyl alcohol, Macrogol, and the like. Among these, hydroxypropylmethylcellulose, hydroxypropylcellulose and macrogol are preferably used. The water-soluble polymer may be used singly or in a suitable combination of at least one selected from these. The content of the water-soluble polymer is generally 40 to 85 mass%, preferably 45 to 70 mass%, with respect to the whole coating layer.

The coating layer may contain at least one selected from the group consisting of talc, calcium carbonate, magnesium oxide, kaolin, low substituted hydroxypropylcellulose (L-HPC), calcium hydrogen phosphate, magnesium aluminometasilicate, At least one colorant selected from the group consisting of synthetic aluminum silicate, copper chlorophyll, sodium copper chlorophyllin, ferric oxide, and edible colorants may be further added. The content of these coloring agents is generally 0 to 15 mass%, preferably 0 to 5 mass%, based on the entire coating layer.

The coating layer may further contain at least one light-shielding agent other than rutile titanium dioxide. Examples of such a light-shielding agent include talc, calcium carbonate, magnesium oxide, kaolin, low-substituted hydroxypropylcellulose (L-HPC), calcium hydrogen phosphate, magnesium metasilicate aluminate and synthetic aluminum silicate. Also, classification of additives such as coloring agents and shading agents is not strict. Talc, calcium carbonate, magnesium oxide, kaolin, low-substituted hydroxypropyl cellulose (L-HPC), calcium hydrogen phosphate, magnesium metasilicate aluminate and synthetic aluminum silicate may be used as a colorant or as a light shielding agent .

In addition, known components used in pharmaceuticals can be appropriately added to the coating layer. For example, a sweetening agent, a dispersing agent, an excipient, a plasticizer, a flavoring agent, a brightening agent, an anti-adhesion agent, a preservative (Preservative), a preservative (preservative), and a pH adjuster (pH adjuster).

The coating layer in the present invention means to protect the azo compounds from external factors such as temperature and humidity, and includes not only a uniformly coated state as a whole but also an unevenly coated state as a whole. Those skilled in the art can appropriately set the coating state. For example, when the azosemide-containing portion is predetermined, it is preferable that the coating layer is formed so as to completely cover the predetermined portion. In the case of an agent coated with an azosemide-containing portion, the coating layer may be entirely in an uneven coating state. The thickness ratio of the coating layer can be appropriately set by a known method. For example, it is preferably 2% by mass to 20% by mass, more preferably 2% by mass to 15% by mass, And more preferably 3% by mass to 8% by mass.

The method of coating the azosemide-containing part is not particularly limited, but it can be coated by a generally known method. For example, a coating pan method, a fluidized bed coating method (fluidized bed coating method), and an electric coating method (rotating coating method). Here, the coating pan method is a method in which an azoside-containing portion is put into a rotary drum (pan), spraying (spraying) the coating solution to the azoside-containing portion rotating in the fan, and drying and coating. The fluidized bed coating method is a method in which an azo compound containing portion is floated or flowed by an air flow, and the coating solution is sprayed onto the suspended suspension state to coat the coating solution. The electric coating method is a method in which a coating liquid is sprayed on an azomethyl-containing part which rotates on a top surface of a disk by rotating a horizontal disk, and is coated by drying. When the coating layer is formed, a manufacturing apparatus such as a flow granulator, a transfer granulator, or the like can be used. In addition, the nucleus portion may be made into an acetamide-containing portion and the outer layer portion may be made into a coating layer by using a manufacturing technique of a press-coated tablet described in WO 01/98067.

The coating agent of the present invention can be obtained, for example, by preparing a coating containing azosemide and then coating the coating with the coating liquid prepared by dissolving the additives shown in Table 2 in water. The mass% of each additive in Table 2 represents the mass% with respect to the azo-containing-containing part (predetermined). In addition, those skilled in the art can appropriately set the content of each additive in the coating layer in addition to those shown in Table 2.

The coating agent containing the azo compounds of the present invention can be enclosed in a package which is colorless and transparent in part and whose contents are visible. A package whose contents are visible refers to a package that is provided with a transparent portion on a part of the package to check the color change of the contents. In the present invention, since the discoloration of the pharmaceutical preparation due to the external environment can be suppressed even in the non-packaging state, as compared with the conventional preparation, the packaging body itself has an advantage of not having a shading function or a moisture-proof function.

(Example)

Hereinafter, the present invention will be described in detail by way of examples, but they should not be construed as limiting the scope of the present invention.

<Color difference measurement>

The color difference was evaluated using a spectrocolorimeter (spectrocolorimeter) (CM-3500d, manufactured by Konica Minolta). D65 was used as a reference light source for measurement, and the color of the object was measured with an L * a * b * colorimetric system (L * a * b * colorimetric system) DELTA E was calculated by the following equation (1). If ΔE exceeds 3.0, the color change can be identified by naked eye (naked eye).

&Lt; Test 1 > Test of mixing change of mixed powder (mixed powder)

Way

A mixture of azosemide alone, a mixture of azosemide and rutile type titanium dioxide, and a mixture of azoside and anatase type titanium dioxide. Each mixed powder was stored under the following condition (a) in an open state or in an airtight container (glass bottle) for 3 weeks. Containment in the airtight container means that the glass bottle is capped with a cap made of polypropylene to indicate that it has been preserved and that the gas is allowed to enter the container by the Japan Pharmacopoeia, But does not reach the sealed container defined in the present invention, but means a preserved state in which the influence of humidity or the like is very small. The color difference changes of the respective powdery powders at the first week, the second week and the third week were measured by the color difference measurement method. The rutile type titanium dioxide used in the following examples was purchased from Toho Titanium Co., Ltd., and the anatase type titanium dioxide was purchased from Wako Junyaku Kogyo Co., Ltd.

Condition (a): temperature 60 ° C, relative humidity 75%, shading, preservation for 3 weeks

result

Table 3 shows the color difference (? E) of each mixed powder after storage. In the case of using only azosemide, both the state of being put in an airtight container and the state of opening were stable with respect to temperature and humidity, and the color difference? E of all the week 1 to week 3 was 3.0 or less.

When azosemide and anatase type titanium dioxide were mixed, the color difference ΔE from the 1st week to the 3rd week greatly exceeded 3.0, and the color change of the powder surface was visually confirmed. On the other hand, when azosemide and rutile titanium dioxide were mixed, the color difference? E was 3.0 or less even after three weeks in the airtight container, and the color change could not be visually confirmed. The degree of discoloration in the open state was about 1/2 as compared with? E in the case of mixing azosemide and anatase type titanium dioxide under the same conditions. That is, the use of rutile type titanium dioxide showed an improvement effect of reducing the discoloration to about 1/2 to 1/5 as compared with the case of using anatase type titanium dioxide.

From the above results, it can be seen that when anatase-type titanium dioxide causes a change in composition with azoside when it is stored for a certain period of time under the influence of temperature and humidity, the rutile-type titanium dioxide is hardly caused to change with azoside , Even if the same titanium dioxide is used, the stability of the mixed powder is remarkably different due to the difference in crystal form.

Further, when the activation energy of the chemical reaction involved in the above discoloration is assumed to be 22.4 kJ / mol, the reaction progress amount is calculated using the Arrhenius equation, The amount of progress of the reaction in the case of preservation for 3 weeks corresponds to the amount of progress of the reaction at a temperature of 25 占 폚 for 36 months or at a temperature of 40 占 폚 for 6 months.

<Test 2> Stability against high temperature and high humidity

Way

The present invention relates to a process for the preparation of a medicament for the preparation of a medicament for the preparation of a medicament for the preparation of a medicament for the preparation of a medicament for the preparation of a medicament for the preparation of a medicament for the preparation of a medicament for the preparation of medicament, ), And the mixture was kneaded with ethanol. This kneaded product was placed in a wet type sizing machine (wet type sizing machine), wet-set, and dried using a direct heating fluidized bed dryer (direct heating fluidized bed dryer). Finally, the dried product and magnesium stearate were mixed using a diffusive mixer, and the mixture was tableted using a press-type tableting machine to give 180 mg / tablet as defined (containing azoesteride). The additives shown in Table 4 were dissolved in water to prepare a coating solution, and the coating solution was applied to the above-mentioned predetermined portion using a fluidized bed granulator to obtain the respective preparations of Example 1 and Comparative Example 1. The mass% of each additive in Table 4 represents the mass% with respect to the azosamide-containing portion (predetermined). Each preparation was stored under the condition (a) in an open state or in an airtight container (vial) for 3 weeks. The change in color of the preparation surface at 1 week, 2 weeks and 3 weeks, respectively, was measured by the above colorimetric method.

Condition (a): temperature 60 ° C, relative humidity 75%, shading, preservation for 3 weeks

result

Table 4 shows the color difference (? E) of each preparation after storage. When the rutile type titanium dioxide was added and the titanium oxide was added in a large amount under a high temperature (high humidity) environment, the color difference? E in the first week to the third week was 3.0 or less in the light shielding state. When the anatase type was added as the titanium dioxide, the color difference? E at the third week under the open condition under the condition (a) greatly exceeded 3.0, and the color change of the surface of the tablet could be confirmed visually.

From the above results, it can be seen that the preparation in which the anatase type titanium dioxide is added to the coating layer undergoes a change in color tone under high temperature and high humidity conditions, while the tablet in which rutile type titanium dioxide is added to the coating layer, It was found that even when added, it was difficult to cause a change in color tone. Even with the same titanium dioxide, the stability of the preparation was remarkably different due to the difference in crystal form.

<Test 3> Long term stability against temperature and humidity (long term stability)

Way

In the same manner as in Example 1, a predetermined amount of 180 mg / tablet or 125 mg / tablet of azoside was prepared, and then the coating solution prepared by dissolving the additive shown in Table 5 in water was used to coat the above- Respectively. The mass% of each additive in Table 5 represents the mass% with respect to the azoside-containing portion. Each of the preparations of Example 1 and Example 2 was stored under the following condition (b) for 3 months in an open state or in an airtight container (vial). The change in color of the preparation surface at 1 month, 2 months and 3 months after storage was measured by the above color difference measurement method.

Condition (b): temperature 25 ° C, relative humidity 75%, shading, preservation for 3 months

result

Table 5 shows the color difference (? E) of each preparation after storage. The color difference? E of Example 1 and Example 2 was about 0.2 to 0.7, which was significantly lower (lower) than 3.0 at which color change can be visually recognized. That is, the azosemide preparation containing rutile titanium dioxide in the coating layer has an effect that it is stable even after long-term storage under high humidity.

<Test 4> Stability against temperature, humidity and light

Way

The procedure of Example 1 was repeated to prepare a coating solution containing 180 mg / well of the azo compound in the same manner as in Example 1, using the coating solution prepared by dissolving the additive shown in Table 6 in water, . The mass% of each additive in Table 6 represents the mass% with respect to the azoside-containing moiety. Example 3 and Comparative Example 2 are all the same prescription except that the crystal form of titanium dioxide is different. Each of these formulations was stored under the following condition (c) until the total illuminance reached 1.2 million lx in an open state or in an airtight container (glass bottle), and then the color difference change of the preparation surface was measured . The period until the total illuminance reaches 1.2 million lx is about 25 days.

Condition (c): Preserved until a temperature of 25 ° C, a relative humidity of 30%, an illuminance of 2000 lx / hr, and a total illuminance of 1.2 million lx

result

Table 6 shows the color difference E of each preparation after storage. Example 3 in which a rutile type titanium dioxide-containing coating was applied showed that the color difference? E was significantly lower than 3.0 under any condition and was sufficiently stable for light. On the other hand, in Comparative Example 2 in which an anatase type titanium dioxide was contained in the coating layer, the color difference? E was considerably lower than 3.0 in the case of storing in an airtight container with little influence of humidity or the like, , And the color difference? E in the open state under the influence of the humidity exceeded 3.0. This indicates that it is important to coat with rutile type titanium dioxide in order to make the formulation stable against humidity as well as light and temperature.

<Test 5> Stability against high humidity (high humidity)

Way

The procedure of Example 1 was repeated to prepare 180 mg / defined azoside-containing preparations, and then the coating solution prepared by dissolving the additive shown in Table 7 in water was used to prepare a coating solution in Examples 4 and 5. The mass% of each additive in Table 7 represents the mass% with respect to the azoside-containing part. After each preparation was stored under condition (c) or condition (d), the color difference change on the preparation surface was measured by the color difference measurement method. The period until the total illuminance reaches 1.2 million lx is about 25 days.

Condition (c): Preserved until a temperature of 25 ° C, a relative humidity of 30%, an illuminance of 2000 lx / hr, and a total illuminance of 1.2 million lx

Condition (d): Preserved until a temperature of 25 ° C, a relative humidity of 75%, an illuminance of 2000 lx / hr, and a total illuminance of 1.2 million lx

result

Table 7 shows the color difference DELTA E values of each preparation after storage. The color differences? E of Example 4 and Example 5 were all less than 3.0. This indicates that the formulation of the present invention coated with rutile type titanium dioxide is stable even after storage at high humidity (75% RH).

&Lt; Test 6 > Particle diameter of titanium dioxide

Way

The particle diameter of the rutile titanium dioxide used in the coating of the examples was measured by laser diffraction method. Water was used as a dispersion medium and the refractive index of the rutile type titanium dioxide was set to 2.7 and the refractive index was measured using a laser diffraction particle size distribution analyzer (Mastersizer 2000, Malvern Instruments) I made a measurement. The results are shown in Table 8.

Claims (11)

2-chloro-5- (2H-tetrazol-5-yl) -4 - [(thiophen-2- ylmethyl) amino] benzenesulfonamide (Active ingredient-containing portion) containing, as an active ingredient, an effective amount of 4 - [(thiophene-2-ylmethyl) amino] benzenesulfonamide or a pharmacologically acceptable salt thereof or a hydrate thereof, , And a coating layer formed on the surface of the active ingredient-containing portion, wherein the coating layer contains rutile type titanium dioxide.
The method according to claim 1,
Wherein the content of the rutile titanium dioxide is 0.2% by mass or more based on the content of the active ingredient.
3. The method of claim 2,
Wherein the content of the rutile titanium dioxide is 0.2 to 8% by mass with respect to the content of the active ingredient.
The method of claim 3,
Wherein the content of the rutile titanium dioxide is 0.4 to 4% by mass relative to the content of the active ingredient.
The method according to claim 1,
Wherein the rutile type titanium dioxide has a 50% particle diameter of 0.1 to 10 m when powder particle size measurement (powder particle size measurement) is performed by laser diffraction method.
The method according to claim 1,
Wherein the coating layer comprises a water-soluble polymer (water-soluble polymer).
The method according to claim 6,
Wherein the coating layer further contains at least one coloring agent selected from the group consisting of talc, calcium carbonate, magnesium oxide, kaolin and iron trioxide.
8. The method according to any one of claims 1 to 7,
(Ii) 40 to 85 mass% of water-soluble polymer, and (iii) at least one of talc, calcium carbonate, magnesium oxide, kaolin and 0 to 15% by mass of at least one coloring agent selected from the group consisting of iron oxide and iron oxide; and (iv) 0 to 20% by mass of additives other than the above, which are acceptable as pharmaceutical preparations.
8. The method according to any one of claims 1 to 7,
A coating agent encapsulated in a package which is partially colorless transparent (colorless transparent) and whose contents are visible.
8. The method according to any one of claims 1 to 7,
Wherein the color difference? E is 3.0 or less under the conditions of (a), (b), (c), or (d) below.
(a) Temperature 60 ° C, relative humidity 75%, shading, preservation for 3 weeks
(b) Temperature 25 ° C, relative humidity 75%, shading, preservation for 3 months
(c) preserved until a temperature of 25 ° C, a relative humidity of 30%, an illuminance of 2000 lx / hr, and a total illuminance of 1.2 million lx
(d) Preserved until a temperature of 25 ° C, a relative humidity of 75%, an illuminance of 2000 lx / hr, and a total illuminance of 1.2 million lx
(2-chloro-5- (2H-tetrazol-5-yl) -4 - [(thiophen-2- ylmethyl) amino] benzenesulfonamide, or a pharmacologically acceptable salt thereof, Is coated with a coating agent containing at least rutile type titanium dioxide (method for inhibiting discoloration) during preservation of a preparation.