JP5280420B2 - Method for producing a pharmaceutical containing naphthopidyl - Google Patents

Description

  The present invention relates to a method for producing a medicament containing naphthopidyl and having excellent photostability.

  Naphtopidil ([4- (2-methoxyphenyl) piperazinyl] -3- (1-naphthyloxy) propan-2-ol) is a substance disclosed in Japanese Patent Publication No. 60-29712, It is disclosed that naphthopidyl or a salt thereof is useful for treatment of difficulty in urination in prostatic hypertrophy. Naftopidil has been shown to improve dysuria associated with prostate enlargement in numerous clinical studies, and has already been released as an oral tablet (Naftopidil Tablet, “Frivus”, manufactured and sold by Asahi Kasei Pharma Corporation) Has been. Naftopidil tablets are administered as naphthopidil once daily to adults with dysuria due to benign prostatic hyperplasia from 25 mg once a day, and gradually increase to 50 to 75 mg at intervals of 1 to 2 weeks if the effect is insufficient. Taking once a day is set based on clinical test results. Examples of naphthopidyl preparations and component amounts are described in Example 12 of JP-B-60-29712 and JP-A-2001-288115.

Japanese Patent Publication No. 60-29712 Japanese Patent Publication No.6-2673 JP 2001-288115 A

The present inventors examined the stability of the naphthopidyl formulation disclosed in Japanese Patent Publication No. 60-29712 and JP-A-2001-288115. However, it was confirmed that the color was slightly changed by light.
Accordingly, an object of the present invention is to provide a stable naphthopidyl preparation which is not discolored by light.

  Conventionally, since the above problems are not known to those skilled in the art, the present inventors have intensively studied the cause of coloring by light. As a result, it was newly confirmed that discoloration due to light occurs due to the coexistence of naphthopidyl and lactose, and it was found that coloring due to light can be avoided by eliminating lactose from the additive for preparation used for preparation of the preparation. In addition, as a result of further research based on the above knowledge, the present inventors have found that when a sugar alcohol or a saccharide other than lactose is used as an additive for preparation, a preparation without coloring by light can be provided. I found it. The present invention has been completed based on these findings.

That is, the following inventions are provided by the present invention.
(1) A pharmaceutical composition comprising naphthopidyl or a physiologically acceptable salt thereof as an active ingredient and one or more pharmaceutical additives, wherein the pharmaceutical additive comes into contact with naphthopidil among the pharmaceutical additives A pharmaceutical composition characterized by not containing lactose.
(2) A pharmaceutical composition comprising naphthopidyl or a physiologically acceptable salt thereof as an active ingredient and one or more pharmaceutical additives, wherein the pharmaceutical additive does not contain lactose as the pharmaceutical additive Composition.
(3) The pharmaceutical composition according to (1) or (2) above, which is in the form of a solid preparation.
(4) The pharmaceutical composition according to the above (3), which is in the form of a tablet.
(5) The pharmaceutical composition according to the above (4), wherein the tablet hardness is 1 kg or more.

(6) The pharmaceutical composition according to any one of (1) to (5), wherein the entire pharmaceutical composition is composed of a continuous phase containing naphthopidyl.
(7) The pharmaceutical composition according to any one of (3) to (6) above, which is a compression-type orally disintegrating preparation.
(8) The pharmaceutical composition according to any one of (3) to (7), wherein the disintegration time is within 1 minute.
Naftopidil formulation.
(9) The pharmaceutical composition according to any one of (1) to (8) above, which contains sugar alcohols as an additive for preparation.
(10) The pharmaceutical composition according to any one of the above (1) to (9), which contains a saccharide other than lactose as an additive for preparation.

(11) As a pharmaceutical additive, 1 selected from the group consisting of sucrose, glucose, D-mannitol, erythritol, xylitol, maltitol, hydroxypropylcellulose, povidone, hydroxypropylmethylcellulose, magnesium stearate, and sodium stearyl fumarate Or the pharmaceutical composition in any one of said (1) thru | or (10) containing 2 or more additives for a formulation.
(12) Pharmaceutical additives include sucrose, glucose, D-mannitol, erythritol, xylitol, maltitol, crystalline cellulose, anhydrous calcium hydrogen phosphate, precipitated calcium carbonate, magnesium oxide, synthetic aluminum silicate, hydrous silicon dioxide, metasilica The above (including one or more pharmaceutical additives selected from the group consisting of magnesium aluminate, synthetic hydrotalcite, talc, hydroxypropylcellulose, povidone, hydroxypropylmethylcellulose, magnesium stearate, and sodium stearyl fumarate ( The pharmaceutical composition according to any one of 1) to (11).
(13) The pharmaceutical composition according to any one of (1) to (12), wherein the content ratio of naphthopidyl is 3 to 60% by weight based on the total weight of the pharmaceutical composition.
(14) The pharmaceutical composition according to any one of (1) to (13), wherein the pharmaceutical additive is erythritol, and the content ratio of the erythritol is 20 to 80% by weight with respect to the total weight of the pharmaceutical composition. object.

(15) The pharmaceutical composition is a compression-type orally disintegrating tablet, and the tablet comprises the following steps:
(A) a step of granulating naphthopidyl or a physiologically acceptable salt thereof and the additive for formulation using a water-soluble polymer binder and drying to obtain a granulated product; and (b) the above The pharmaceutical composition according to any one of the above (7) to (14), which is a tablet obtainable by a step of compressing and molding the granulated product obtained in the step (a) and further drying.
(16) The pharmaceutical composition according to the above (15), wherein the pharmaceutical additive is a sugar alcohol.
(17) The pharmaceutical composition according to the above (16), wherein the pharmaceutical additive is erythritol.

(18) The pharmaceutical composition is a compression-type orally disintegrating tablet, and the tablet comprises the following steps:
(A) a step of granulating a mixture containing naphthopidyl and a sugar alcohol using a water-soluble polymer binder;
(B) a step of adding a sugar alcohol to the granulated product obtained in the step (a) and granulating and drying to obtain a granulated product; and (c) obtained in the step (b). Pharmaceutical composition in any one of said (7) thru | or (14) which is a tablet which can be obtained by the process of compressing and molding a granulated material, and also drying.
(19) The pharmaceutical composition according to the above (18), wherein the sugar alcohol is erythritol.
(20) The pharmaceutical composition is a compression-type orally disintegrating tablet, and the tablet comprises the following steps:
(A) a step of granulating a mixture containing naphthopidyl and sugar alcohols using a water-soluble polymer binder and drying to obtain a granulated product;
(B) a step of granulating erythritol using a water-soluble polymer binder and drying to obtain a granulated product (wherein the granulated product is a granulated product not containing naphthopidyl), and (c) the above The granulated product obtained in the step (a), the granulated product obtained in the step (b), and the lubricant are mixed and compression-molded and then humidified and further dried. The pharmaceutical composition according to any one of (7) to (14), which is a tablet.
(21) The pharmaceutical composition according to the above (20), wherein the sugar alcohol is erythritol.
(22) The content of the granulated product obtained in the step (a) with respect to the total weight of the granulated product obtained in the step (a) and the granulated product obtained in the step (b) is 5%. % Or more and less than 100 weight%, The pharmaceutical composition as described in said (20) or (21).

(23) The pharmaceutical composition is a compression-type orally disintegrating tablet, and the tablet comprises the following steps:
(A) a step of granulating a mixture containing naphthopidyl and erythritol using a water-soluble polymer binder and drying to obtain a granulated product; and (b) a granulated product obtained in step (a) above. A step of mixing a granulated product containing D-mannitol, celluloses, crospovidone and a lubricant, and compression-molding the resulting mixture;
The pharmaceutical composition according to any one of the above (7) to (14), which is a tablet obtainable by
(24) The pharmaceutical composition is a compression-type orally disintegrating tablet, and the tablet comprises the following steps:
(A) a step of granulating a mixture containing naphthopidyl and D-mannitol using a water-soluble polymer binder and drying to obtain a granulated product; and (b) a step of obtaining the granulated product obtained in step (a) above. A step of mixing granules with a granulated product containing D-mannitol, celluloses, crospovidone, and a lubricant, and compressing the resulting mixture;
The pharmaceutical composition according to any one of the above (7) to (14), which is a tablet obtainable by
(25) The pharmaceutical composition according to the above (23) or (24), wherein the cellulose is crystalline cellulose.
(26) The pharmaceutical composition according to any one of (1) to (25), wherein coloring by light is reduced or eliminated.

(27) A method for producing a pharmaceutical composition comprising, as an active ingredient, naphthopidyl or a physiologically acceptable salt thereof and one or more pharmaceutical additives, which is described in any one of (15) to (25) above Comprising the steps of:
(28) A method for preventing coloration of a pharmaceutical composition comprising naphthopidyl or a physiologically acceptable salt thereof and one or more pharmaceutical additives as an active ingredient, wherein naphthopidyl among the pharmaceutical additives A method comprising the step of preparing the pharmaceutical composition without using lactose as a pharmaceutical additive present in contact with the pharmaceutical composition.
(29) A method for preventing coloring of a pharmaceutical composition containing naphthopidyl or a physiologically acceptable salt thereof and one or more pharmaceutical additives as an active ingredient, wherein lactose is used as the pharmaceutical additive A method comprising the step of preparing the pharmaceutical composition without use.

  The pharmaceutical composition of the present invention is characterized by having extremely high stability regardless of storage conditions because it is stable in normal storage conditions and does not cause coloring by light.

  The pharmaceutical composition of the present invention is a pharmaceutical composition comprising naphthopidyl or a physiologically acceptable salt thereof as an active ingredient and one or more pharmaceutical additives. Naphtopidil ([4- (2-methoxyphenyl) piperazinyl] -3- (1-naphthyloxy) propan-2-ol) is a substance described in Japanese Patent Publication No. 60-29712 and can be easily used by those skilled in the art. It is a substance that can be obtained. As an active ingredient of the medicament of the present invention, a physiologically acceptable salt of naphthopidyl (for example, hydrochloride) may be used, but a free form substance can be preferably used. A hydrate or solvate of naphthopidyl or a physiologically acceptable salt thereof can also be used as an active ingredient of the pharmaceutical composition of the present invention.

  The pharmaceutical composition of the present invention may be either a liquid form pharmaceutical composition or a solid form pharmaceutical composition. The liquid form of the pharmaceutical composition may be, for example, either in a solution state or in a suspended state, and can be used for injection, infusion, internal use, eye drops, or the like. Examples of solid form pharmaceutical compositions include tablets, fine granules, granules, dry syrups, powders, capsules, pills, poultices, and the like. The pharmaceutical composition of the present invention is preferably a solid form pharmaceutical composition. In normal cases, it is preferred that the solid form pharmaceutical composition be provided in a dry state. For example, the water content (water content) in the pharmaceutical composition is 20% or less, preferably 15% or less, more preferably 12 or less, and particularly preferably 10% or less.

  In the present specification, when the pharmaceutical additive is in contact with naphthopidyl, it is a liquid pharmaceutical composition, for example, the pharmaceutical additive present in solution or suspension is dissolved or suspended in naphthopidyl. In the case of a pharmaceutical composition in a solid state, for example, in a mixture containing naphthopidyl and a pharmaceutical additive, the above-mentioned pharmaceutical additive contained in the mixture It means that the powder or granulated product comes into contact with the powder or granulated product of naphthopidyl. The pharmaceutical composition of the present invention is characterized by not containing lactose as a pharmaceutical additive that comes into contact with naphthopidil among one or more pharmaceutical additives used in the preparation of the pharmaceutical composition. The pharmaceutical composition of the present invention preferably contains no lactose as a pharmaceutical additive.

  In this specification, compression molding means giving a certain shape to a powder or a granulated product by applying pressure. A typical example is a tablet obtained by compressing a powder or granulated product with a tableting machine. The hardness of the tablet and the degree of compression during production can be appropriately determined according to the shape of the tablet and the like. As the pharmaceutical composition of the present invention, a tablet is particularly preferable. Tablets can be classified according to use, but the term “tablet” used in this specification includes, for example, oral tablets (troches) that are dissolved in the mouth and applied to the oral mucosa and pharyngeal mucosa, and dissolved in the mouth from the oral mucosa. Oral tablets that absorb drugs (buccal tablets, sublingual tablets), orally disintegrating tablets that disintegrate tablets in the mouth, swallow with water or saliva, and absorb drugs from the digestive organs, implanted tablets that are implanted subcutaneously Also included are dissolved tablets that take a liquid in which tablets are dissolved or are used for external use.

  Moreover, a tablet can be classify | categorized into a plain tablet and a coated tablet from a structural viewpoint, for example. The uncoated tablet means a tablet in which the surface of the tablet obtained by compression molding is not coated. Typically, the whole tablet is a tablet composed of a continuous phase containing naphthopidyl. Usually, it can be understood that it is a tablet itself obtained by compressing a powder or granulated product containing a drug with a tableting machine. The coated tablet means a tablet in which a coating layer containing no drug is formed on the surface of the uncoated tablet. Examples of the coated tablet include a film-coated tablet, a sugar-coated tablet, and a dry-coated tablet. Furthermore, the multilayer tablet which forms the layer which does not contain a drug in a part of tablet is illustrated. It goes without saying that these tablets are included in the term “tablet” as used herein.

  The pharmaceutical composition of the present invention provided in the form of a tablet preferably has sufficient tablet hardness so that the tablet does not break during the production process, distribution process, or removal from the PTP package. The tablet hardness is not particularly limited, but the lower limit is usually about 1 kg or more, preferably about 2 kg or more, more preferably 3 kg or more, and particularly preferably 4 kg or more. In some cases, it is about 1.5 kg or more, preferably 2.5 kg or more, more preferably 3.5 kg or more, and particularly preferably about 4.5 kg or more. Furthermore, depending on the case, it can also be mentioned as a very preferable example that it is about 5 kg or more. The upper limit of tablet strength is not particularly limited, but it is usually preferably about 20 kg or less, particularly preferably about 15 kg or less, and more preferably about 10 kg or less.

  An orally disintegrating tablet is, for example, an active ingredient in which a formed tablet disintegrates rapidly in the oral cavity and is suspended and dispersed into fine particles, or a part or all of the tablet components are dissolved and then swallowed. Is a tablet absorbed from the digestive tract. As the disintegration time of the orally disintegrating tablet provided by the present invention, for example, the disintegration time due to saliva can be measured in the oral cavity, but as a simpler method, as described in the examples of the present specification, It can be measured by a measurement method according to the Japanese Pharmacopoeia disintegration test method (using water as a test solution). The disintegration time is not particularly limited, but is, for example, within 3 minutes, usually within 1 minute, preferably within 40 seconds, more preferably within 30 seconds, and particularly preferably within 20 seconds. Orally disintegrating tablets can also be classified by manufacturing method, more specifically, non-compressible type orally disintegrating that can be manufactured using a freeze-drying method after filling a suspension-dispersed solution in a mold It can be classified into tablets and compression-type orally disintegrating tablets that can be produced by compressing powder using a tableting machine or the like. In the present invention, a compression type orally disintegrating tablet is a preferred example.

  The pharmaceutical additive used in the production of the pharmaceutical composition of the present invention provides functions such as a shaping effect, a coating effect, a binding effect, a disintegration effect, and a lubrication effect when preparing the pharmaceutical composition. It is a substance added for this purpose, and includes all substances except the active ingredient among the ingredients contained in the pharmaceutical composition. Additives for pharmaceutical preparation can be classified according to the purpose of use, for example, excipients if it has a shaping effect, coating agents if it has a coating effect, binders if it has a binding effect, disintegration A substance having an effect can be classified as a disintegrant, and a substance having a lubrication effect can be classified as a lubricant. As the additive for preparation used in the present specification, a substance listed in “Pharmaceutical Additives Dictionary 2000” (edited by the Japan Pharmaceutical Additives Association, Yakuji Nippo) can be used, preferably other than lactose Substances can be used.

  For example, sugar alcohols and / or saccharides other than lactose can be used as pharmaceutical additives. Sugar alcohols are polyhydric alcohols obtained by reducing carbonyl groups of saccharides, such as glycerin, D-sorbitol, D-mannitol, erythritol, maltitol, xylitol, and D-mannitol, erythritol, Tolu and xylitol are preferable examples. One type or two or more types may be selected as sugar alcohols. Examples of saccharides other than lactose include glucose, sucrose, fructose, maltose, and candy powder obtained by saccharifying starch with an enzyme. Glucose and sucrose are preferable examples.

  For the preparation of the pharmaceutical composition of the present invention, a water-soluble polymer binder can be used. The water-soluble polymer binder is an additive for pharmaceutical preparations composed of a water-soluble polymer that exhibits viscosity by dissolving in water and exhibits adhesive properties such as glue. A water-soluble polymer binder is used when granulating a powder mixture using this property. Although the addition method is not particularly limited, for example, it can be added as a solution at the time of granulation or can be added as a powder. Examples of the water-soluble polymer binder include hydroxypropylcellulose, methylcellulose, povidone, polyvinyl alcohol, hydroxypropylmethylcellulose, pregelatinized starch, gelatin, pullulan, sodium carboxymethylcellulose, gum arabic powder and the like. As the water-soluble polymer binder, one type or two or more types may be selected. Of these, hydroxypropylcellulose, povidone, and hydroxypropylmethylcellulose are particularly preferred examples.

  In preparing the pharmaceutical composition of the present invention, a binder other than the water-soluble polymer binder may be used. Examples of such binders include crystalline cellulose, corn starch, anhydrous precipitated calcium carbonate, synthetic aluminum silicate, magnesium aluminate metasilicate, and the like. Of these, one type or two or more types may be selected. Lubricants used to avoid the phenomenon that the compression molded product adheres to the tableting parts and is difficult to be discharged (sticking: generated during tableting) include, for example, magnesium stearate and stearyl fumarate. Examples include sodium, talc, sucrose fatty acid ester, calcium stearate, stearic acid, L-leucine and the like. Of these, one type or two or more types may be selected. As the lubricant, magnesium stearate and sodium stearyl fumarate are particularly preferable. Disintegrants for rapidly disintegrating compressed tablets in saliva and gastric juice include low-substituted hydroxypropylcellulose, carmellose, carmellose calcium, croscarmellose calcium, partially pregelatinized starch, and light anhydrous silica. Examples thereof include acid, magnesium carbonate, calcium hydrogen phosphate, and synthetic hydrotalcite. Of these, one type or two or more types may be selected. A sweetener may be used to impart sweetness to the tablet and improve the dosage. Examples of the sweetener include saccharin, sodium saccharin, aspartame, monoammonium glycyrrhizinate, reduced maltose water candy, purified honey, and the like. Of these, one type or two or more types may be selected. A fragrance may be used to impart a good odor to the tablet and improve the dosage. Examples of the fragrance include L-menthol, vanillin, mint oil, lemon oil, vanilla flavor, fruit flavor, mint flavor and the like.

  The manufacturing method and manufacturing apparatus of a tablet are not specifically limited, The method and apparatus normally used in this industry can be used. More specifically, in the mixing step, a V-type mixer, a cross rotary mixer, or the like is used. In the granulation step, a fluidized bed granulator / dryer, a tumbling fluidized granulation coating apparatus, a stirring granulator, a cylindrical extrusion granulator, or the like is used. A compression molding (tablet) machine is an apparatus generally used for producing tablets, and examples thereof include a single-shot tablet machine.

  In the orally disintegrating tablet provided by the present invention, the disintegration time for achieving rapid disintegration in the oral cavity, and the destruction of the tablet in the manufacturing process, during removal from the PTP package, or in the distribution process are prevented. Therefore, it is desirable that the production conditions be more strictly limited as compared with ordinary tablets. For example, the pressure at the time of compression molding can be made smaller than the molding pressure for molding a normal tablet, thereby increasing the gap inside the tablet. Although it varies depending on the composition of the powder to be tableted and the granulated product, the lower limit of the molding pressure is preferably about 1 kg / kg or more, particularly preferably about 5 kg / kg or more, more preferably 10 kg / kg. More than about. The upper limit of the molding pressure is preferably about 1500 kg / kg or less, particularly preferably about 1000 kg / kg or less, and more preferably about 800 kg / kg or less.

  An orally disintegrating tablet having a good balance between tablet hardness and disintegration time can be prepared, for example, by compressing a powder containing naphthopidil at the above-mentioned tableting pressure, but the balance between tablet hardness and disintegration time is also possible. In some cases, the range of the tableting pressure to maintain the pressure becomes narrow. In order to widen the tableting pressure range so as to maintain a balance between tablet hardness and disintegration time, it is desirable to employ, for example, means for concealing the water repellency of naphthopidyl itself. For example, a method of obtaining a granulated product by producing a granulated product containing naphthopidyl, and further adding a pharmaceutical additive to the granulated product containing naphthopidyl and then re-granulating it is exemplified. Further, a method of preparing a granulated product containing naphthopidyl and a granulated product not containing naphthopidil in advance and mixing these two types of granulated product with a lubricant and compressing them is exemplified. The upper limit of the content ratio of the former granulated product (naphthopidyl-containing granulated product) with respect to the total weight of the granulated product containing naphthopidyl and the granulated product not containing naphthopidyl is not particularly limited. 90% by weight or less, or 80% by weight or less is preferable, 70% by weight or less is more preferable, and in some cases, 60% by weight or less can be given as a preferable example. Further, the lower limit of the content ratio is not particularly limited, but is usually 5% by weight or more, more preferably 10% by weight or more, particularly preferably 30% by weight or more, and particularly preferably 50% by weight or more. Can be mentioned. Moreover, depending on the case, 20 weight% or more is more preferable, 40 weight% or more is especially preferable, and 60 weight% or more can be mentioned as a very preferable example.

  The tablet hardness can be supplemented by carrying out a production method in which the molded product is humidified after compression molding to wet the tablet surface and then dried immediately. This means can generally be achieved by three processes including a tableting process, a humidification process, and a subsequent drying process. Although the apparatus used for a humidification process is not specifically limited, For example, a microwave humidifier or a heating steam type humidifier is illustrated. Although the apparatus used for a drying process is not specifically limited, For example, a ventilation dryer, a vacuum dryer, a far-infrared dryer, a microwave dryer etc. are illustrated. The step of drying after humidification is not particularly limited as long as the tablet surface is once wetted and then can be dried, but in industrial production, it is desirable to perform an efficient treatment in a short time. For example, it is also preferable to use the manufacturing apparatus described in FIG. 1 of Japanese Patent Application Laid-Open No. 2000-95674.

  For example, the lower limit of the temperature is preferably 40 ° C. or higher, particularly preferably 43 ° C. or higher, and more preferably 45 ° C. or higher. The upper limit of the temperature is preferably 65 ° C. or less, more preferably 63 ° C. or less, and particularly preferably 60 ° C. or less. Further, the lower limit of the humidity is preferably 75% RH or more, more preferably 78% RH or more, and particularly preferably 80% RH or more. The upper limit of humidity is preferably 100% RH or less, more preferably 99% RH or less, and particularly preferably 98% RH or less. The lower limit of the humidifying time is preferably 100 seconds or more, more preferably 110 seconds or more, and particularly preferably 120 seconds or more. The upper limit value of the humidifying time is preferably 300 seconds or less, more preferably 240 seconds or less, and particularly preferably 180 seconds or less. As for the drying conditions after humidification, the lower limit of the temperature is preferably 50 ° C. or higher, more preferably 53 ° C. or higher, and particularly preferably 55 ° C. or higher. The upper limit of the temperature is preferably 80 ° C. or less, more preferably 75 ° C. or less, and particularly preferably 70 ° C. or less. The lower limit of the drying time is preferably 5 minutes or more, more preferably 7 minutes or more, and particularly preferably 10 minutes or more. The upper limit of the humidifying time is preferably 20 minutes or less, more preferably 17 minutes or less, and particularly preferably 15 minutes or less.

  In addition, as another means for expanding the tableting pressure range so as to maintain a balance between tablet hardness and disintegration time, a granulated product containing sugar alcohols, a highly water-soluble product, and a granulated product containing naphthopidyl. A means for obtaining a desired orally disintegrating tablet by mixing a binder other than a molecule, a disintegrant, and a lubricant and compression-molding the obtained mixture can be employed. Examples of the granulated product containing sugar alcohols include granulated D-mannitol that can be produced by a spray drying method. Moreover, as binders other than water-soluble polymer, the cellulose of the property which is not soluble in water is illustrated, for example. More specifically, crystalline cellulose and low-substituted hydroxypropyl cellulose are exemplified. In particular, crystalline cellulose having an average particle diameter of 38 to 75 μm and an average major axis / minor axis ratio (L / D) of particles in particles passing through a sieve having an aperture of 75 μm is 2.0 to 4.5. It is preferable to use commercially available Theolas KG-802 (Asahi Kasei Chemicals).

  The content of the granulated product containing sugar alcohols, preferably the granulated D-mannitol content is preferably 15% or more, more preferably 17% or more, more preferably 20% or more, based on the total weight of the pharmaceutical composition. Particularly preferred. As an upper limit of the said content rate, 90% or less is preferable, for example, 85% or less is more preferable, and it is especially preferable that it is 80% or less. The granulated product containing sugar alcohols, preferably the mixing ratio of the granulated D-mannitol and crystalline cellulose is, for example, when the cellulose, preferably crystalline cellulose is 1 part by weight, the granulated D- The amount of mannitol added is usually 4 parts by weight or less, preferably 3 parts by weight or less, more preferably 2 parts by weight or less, and particularly preferably 1 part by weight or less. As the disintegrant and lubricant, the above-described additives for pharmaceutical preparation can be used. In particular, crospovidone is preferable as the disintegrant, and specifically, preferred examples include polyplastidone XL, polyplusdon. Examples include Don XL-10 and Polyplusdon INF-10.

  In the pharmaceutical composition of the present invention, the lower limit of the content ratio of naphthopidyl which is an active ingredient is not particularly limited, but is preferably 3% by weight or more, for example, 4% by weight or more with respect to the total weight of the pharmaceutical composition. More preferably, it is 5% by weight or more. The upper limit of the content is not particularly limited, but is preferably 60% by weight or less, more preferably 55% by weight or less, and particularly preferably 50% by weight or less based on the total weight of the pharmaceutical composition. The lower limit value of the content ratio of the excipient is, for example, preferably 45% by weight or more, more preferably 50% by weight or more, particularly preferably 55% by weight or more based on the total weight of the pharmaceutical composition. The upper limit of the content of the excipient is, for example, preferably 96% by weight or less, more preferably 94% by weight or less, particularly preferably 92% by weight, based on the total weight of the pharmaceutical composition.

  Although the content of naphthopidyl in the unit dosage form is not particularly limited, for example, it is preferably an amount reflecting the clinical dose. For example, the lower limit of the content in a tablet as a unit dosage form is preferably 20 mg or more, more preferably 22 mg or more, and particularly preferably 25 mg or more. The upper limit of the naphthopidyl content in one tablet is preferably 100 mg or less, more preferably 80 mg or less, and particularly preferably 75 mg or less.

  The shape of the tablet is not particularly limited as long as it is easy to take. Examples of the shape include a circle, an ellipse, a polygon, and a caplet (capsule type). Moreover, the size should just be easy to hold with a finger | toe and it is easy to include in a mouth, and the upper limit of a long diameter (in the case of circular) is preferable about 25 mm or less, about 22 mm or less is more preferable, About 20 mm or less is especially preferable. The lower limit is preferably about 5 mm or more, more preferably about 6 mm or more, and particularly preferably about 7 mm or more.

  The packaging form in the case of packaging the pharmaceutical composition is not particularly limited. For example, a light shielding treatment using a light shielding film or the like may be performed, and pillow packaging is applied to PTP (Press Through Package) packaging, strip packaging, or PTP packaging. Applied packaging can be employed. Examples of the packaging material include aluminum foil, polyvinyl chloride, cyclic polyolefin, polyvinylidene chloride, polychlorotrifluoroethylene, and polyethylene. Moreover, as a packaging container, the polyethylene bottle and glass bottle which performed the light-shielding process are illustrated.

The present invention will be described in more detail with reference to the following examples, but the scope of the present invention is not limited to these examples.
1) Hardness test It measured using the tablet hardness meter (TS-50N Okada Seiko make). The test was performed 6 times, and the average value was calculated. In the measurement, the hardness in each direction, such as length and width, was measured in advance for a subject such as a tablet, and measurement was performed from the direction giving the lowest numerical value of hardness.
2) Disintegration time by the Japanese Pharmacopoeia Disintegration Test Method The disintegration time was measured in accordance with the tablet section of the disintegration test method described in the Japanese Pharmacopoeia 14th revision. Water was used as a test solution, and measurement was performed under the condition that an auxiliary board was not used. The time required until the residue of the test sample was not observed in the glass tube was defined as the disintegration time. The value of disintegration time was shown as an average value of 6 test samples.

Example 1
750 g of naphthopidyl and 2160 g of erythritol (Nikken Chemical) were charged into a stirring granulator (Fukae Kogyo High Speed Mixer FS-10) and granulated by adding 425 g of 50% ethanol aqueous solution containing 60 g of hydroxypropyl cellulose (Nippon Soda), Furthermore, extrusion granulation was performed with a cylindrical granulator (Hata-Gure HU-G). Then, the granulated material was obtained through the sizing and drying processes. 30 g of magnesium stearate (Taihei Chemical Industry) was mixed with this mixture to obtain a tableting powder. This tableting powder was tableted with a tableting machine (Kikusui Seisakusho, CP-6 type) at a tableting pressure of 700 kg / kg to obtain a corner flat tablet with a diameter of 8.5 mm and a tablet weight of 200 mg. The tablet hardness was 7.6 kg and the disintegration time was 4.2 minutes.

Example 2
Using the tableting powder described in Example 1, using a tableting machine (Kikusui Seisakusho, CP-6 type), the tableting pressure was varied so that the tablets had a tablet hardness of about 1 kg, about 1.5 kg, and about 2 kg. I let you. The disintegration times of the obtained tablets were 12.3 seconds, 26.7 seconds, and 48.8 seconds, respectively. About these tablets, using a semi-automatic PTP packaging machine (manufactured by Daiwa Kasei), put each tablet on a PTP molded sheet (VSL4501-B, Sumitomo Bakelite), cover it with an aluminum sheet with a thickness of 26 μm, heat-seat the sheet, and PTP packaging did. When the tablets were taken out from the PTP package, 4 out of 10 tablets were damaged with a tablet having a tablet hardness of 1 kg. Two of the 10 tablets with a tablet hardness of 1.5 kg were damaged. All 10 tablets with a tablet hardness of 2 kg could be taken out without being damaged.

Example 3
750 g of naphthopidyl, 1860 g of white sugar (manufactured by Shimizu Minato), and 300 g of crystalline cellulose (Asahi Kasei Chemicals) were charged into a stirring granulator (Fukae Kogyo High Speed Mixer FS-10). A corner flat tablet having a diameter of 8.5 mm and a tablet weight of 200 mg was obtained. The tablet hardness was 7.3 kg and the disintegration time was 4.6 minutes.
Example 4
The sucrose used in Example 3 was changed to D-mannitol (Towa Kasei Kogyo Co., Ltd.), and thereafter the same operation as in Example 1 was performed to obtain a corner flat tablet having a diameter of 8.5 mm and a tablet weight of 200 mg. . The tablet hardness was 6.1 kg and the disintegration time was 3.4 minutes.
Example 5
750 g of naphthopidyl, 1935 g of erythritol (Nikken Chemical), and 225 g of precipitated calcium carbonate (Bikita powdering) were charged into a stirring granulator (Fukae Kogyo High Speed Mixer FS-10), and thereafter the same operation as in Example 1 was performed. A corner flat tablet having a diameter of 8.5 mm and a tablet weight of 200 mg was obtained. The tablet hardness was 4.8 kg and the disintegration time was 3.3 minutes.
Example 6
The precipitated calcium carbonate used in Example 5 was changed to magnesium oxide (Kyowa Chemical Industry), and thereafter the same operation as in Example 1 was performed to obtain a corner flat tablet having a diameter of 8.5 mm and a tablet weight of 200 mg. . The tablet hardness was 5.8 kg and the disintegration time was 2.8 minutes.

Example 7
7500 g of naphthopidyl and 4260 g of erythritol (Nikken Chemical) were charged into an agitation granulator (Powrec vertical granulator VG-50), and granulated by adding 1700 g of a 50% aqueous ethanol solution containing 240 g of hydroxypropylcellulose (Nippon Soda). Then, the granulated material A was obtained through the sizing and drying process. On the other hand, 17340 g of erythritol is charged into a stirring granulator, 2100 g of 95% ethanol aqueous solution containing 360 g of hydroxypropyl cellulose is added and granulated, and after extrusion granulation with a cylindrical granulator, the granulated product is subjected to granulation and drying processes. B was obtained. 12,000 g of the granulated product A, 17690 g of the granulated product B and 300 g of sodium stearyl fumarate (Wako Pure Chemical Industries, Ltd.) were mixed and tableted with a tableting pressure of 30 to 70 kg / kg. Thereafter, humidification was performed, followed by drying. The humidification conditions were a temperature of 50 ° C., a relative humidity of 85% or more, and a treatment time of 120 seconds. Drying conditions were a temperature of 60 ° C., a relative humidity of 15% or less, a treatment time of 10 minutes, and a circular tablet having a diameter of 9 mm and a weight of 200 mg was obtained. The tablet hardness was 4.8 kg and the disintegration time was 17 seconds.

Example 8
7500 g of naphthopidyl, 2000 g of D-mannitol, and 2260 g of erythritol (Niken Chemical) were charged into a stirring granulator (Paulec Vertical Granulator VG-50), and 1700 g of 50% ethanol aqueous solution containing 240 g of hydroxypropylcellulose (Nippon Soda) was added. And granulated. Thereafter, a granulated product C was obtained through a sizing and drying process. On the other hand, 10,000 g of D-mannitol and 7340 g of erythritol were charged into a stirring granulator, granulated by adding 2100 g of 95% ethanol aqueous solution containing 360 g of hydroxypropylcellulose, and further extruded and granulated with a cylindrical granulator. Granules D were obtained through the drying process. 12,000 g of granulated product C, 17690 g of granulated product D, and 300 g of sodium stearyl fumarate (Wako Pure Chemical Industries, Ltd.) were mixed and tableted with a tableting pressure of 30 to 70 kg / kg, and then humidified and dried. The humidification conditions were a temperature of 50 ° C., a relative humidity of 85% or more, and a treatment time of 120 seconds. Drying conditions were a temperature of 60 ° C., a relative humidity of 15% or less, a treatment time of 10 minutes, and a circular tablet having a diameter of 9 mm and a weight of 200 mg was obtained. The tablet hardness was 5.3 kg and the disintegration time was 24 seconds.

Example 9
7500 g of naphthopidyl, 1000 g of D-mannitol and 3260 g of erythritol (Nikken Chemical) were charged into a stirring granulator (Pauleck Vertical Granulator VG-50), and 1700 g of 50% ethanol aqueous solution containing 240 g of povidone (made by ISP) was added. Grained. Then, the granulated material E was obtained through the sizing and drying process. On the other hand, 5000 g of D-mannitol and 12340 g of erythritol were charged into a stirring granulator, granulated by adding 2100 g of 95% ethanol aqueous solution containing 360 g of hydroxypropylcellulose, and further extruded and granulated with a cylindrical granulator. Granules F were obtained through the drying process. Granules E12000 g, granule F17690 g, and sodium stearyl fumarate (Wako Pure Chemical Industries, Ltd.) 300 g were mixed, and tableted with a tableting pressure of 30 to 70 kg / kg, and then humidified and dried. The humidification conditions were a temperature of 50 ° C., a relative humidity of 85% or more, and a treatment time of 120 seconds. Drying conditions were a temperature of 60 ° C., a relative humidity of 15% or less, a treatment time of 10 minutes, and a circular tablet having a diameter of 9 mm and a weight of 200 mg was obtained. The tablet hardness of the tablet was 4.3 kg, and the disintegration time was 16 seconds.

Example 10
7500 g of naphthopidyl and 4260 g of erythritol (Nikken Chemical) were charged into a stirring granulator (Vertical Granulator VG-50, Pauleck Co., Ltd.), and 1700 g of a 50% ethanol aqueous solution containing 240 g of hydroxypropylcellulose (Nippon Soda) was added and granulated for 5 minutes. . Thereafter, 17340 g of erythritol was added, 2100 g of a 95% ethanol aqueous solution containing 360 g of hydroxypropyl cellulose was added, and granulated, and a granulated product was obtained through a sizing and drying process. 29690 g of the granulated product and 300 g of sodium stearyl fumarate (Wako Pure Chemical Industries, Ltd.) were mixed, compressed with a tableting pressure of 30 to 70 Kg / kg, and then humidified and dried. The humidification conditions were a temperature of 50 ° C., a relative humidity of 85% or more, and a treatment time of 120 seconds. Drying conditions were a temperature of 60 ° C., a relative humidity of 15% or less, a treatment time of 10 minutes, and a circular tablet having a diameter of 9 mm and a weight of 200 mg was obtained. The tablet hardness of the tablet was 4.8 kg, and the disintegration time was 20 seconds.

Example 11
7500 g of naphthopidyl, 1950 g of D-mannitol, and 810 g of crospovidone (ISP) were charged into a stirring granulator (Paulec Vertical Granulator VG-50), and 1700 g of 50% ethanol aqueous solution containing 240 g of hydroxypropylcellulose (Nippon Soda) was added. And then granulated through a sizing and drying process. 10500 g of a granulated product, 11850 g of granulated D-mannitol (Merck, Partec M200), 6000 g of crystalline cellulose (Asahi Kasei, Theolas KG802) and 1500 g of crospovidone are mixed, and then 150 g of magnesium stearate (Taihei Chemical Industry) Were mixed and tableted using a tableting machine (Kikusui Seisakusho, CP-6 type) to obtain a round tablet having a diameter of 9 mm and a weight of 200 mg. The tablet hardness of the tablet was 4.2 kg, and the disintegration time was 23 seconds.

Example 12
7500 g of naphthopidyl, 1950 g of D-mannitol and 810 g of crospovidone (ISP) were charged into a stirring granulator (Paulec Vertical Granulator VG-50), and 1700 g of 50% ethanol aqueous solution containing 240 g of hydroxypropyl cellulose (Nippon Soda) was added. In addition, it was granulated. Then, the granulated material was obtained through the sizing and drying processes. 10500 g of the granulated product, 11850 g of granulated D-mannitol (Merck, Partec M200), 6000 g of crystalline cellulose (Asahi Kasei, Theolas KG802) and 1500 g of crospovidone are mixed, and 150 g of magnesium stearate (Taihei Chemical Industry) is further mixed. After mixing, tableting was performed using a tableting machine (Kikusui Seisakusho, CP-6 type) to obtain a circular tablet having a diameter of 9 mm and a weight of 200 mg. The tablet hardness of the tablet was 4.8 kg, and the disintegration time was 20 seconds.

Example 13
D-mannitol of Example 12 was changed to erythritol, and thereafter, the same operation was performed to obtain a circular tablet having a diameter of 9 mm and a weight of 200 mg. The tablet hardness was 4.3 kg and the disintegration time was 28 seconds.
Example 14
D-mannitol of Example 12 was changed to trehalose, and thereafter, the same operation was performed to obtain a circular tablet having a diameter of 9 mm and a weight of 200 mg. The tablet hardness was 4.2 kg and the disintegration time was 18 seconds.
Comparative Example 1
The erythritol used in Example 1 was changed to lactose (DMV), and thereafter, the same operation as in Example 1 was performed to obtain a corner flat tablet having a diameter of 8.5 mm and a tablet weight of 200 mg. The tablet hardness of the tablet was 6.2 kg, and the disintegration time was 4.2 minutes.
Comparative Example 2
Naphtopidyl 750 g, lactose 300 g, and erythritol 1635 g were charged into an agitation granulator (Fukae Kogyo High Speed Mixer FS-10). Thereafter, the same operation as in Example 1 was performed, and a corner plane with a diameter of 8.5 mm and a tablet weight of 200 mg was used. I got a tablet. The tablet hardness of the tablet was 5.2 kg, and the disintegration time was 4.0 minutes.

Test Example In order to more specifically explain the effects of the present invention, the following optical tests were conducted on the preparations obtained in the examples.
Using an optical tester (manufactured by Nagano Scientific Co., Ltd., LT-120D3CJ), irradiation was performed for 200 hours using a D65 fluorescent lamp, and the appearance of the tablet after a total irradiation amount of 600,000 Lux · hr was inspected. The appearance inspection was carried out by visual observation. The results are shown in Table 1.

Claims (5)

Compressed orally disintegrating tablet form containing naphthopidyl or a physiologically acceptable salt thereof as an active ingredient and one or more additives for formulation, and causing no coloration due to coexistence of naphthopidyl and lactose A method for producing a pharmaceutical composition of sucrose, selected from the group consisting of sucrose, glucose, D-mannitol, erythritol, xylitol, maltitol, hydroxypropylcellulose, povidone, hydroxypropylmethylcellulose, magnesium stearate, and sodium stearyl fumarate is one or more Ri do and a pharmaceutical additives and naftopidil, after preparing granules containing no lactose, tablet hardness to produce more tablets 1Kg, followed by a humidification and drying of tableting material A method comprising the steps. The following steps:
(A) a step of granulating naphthopidyl or a physiologically acceptable salt thereof and the additive for formulation using a water-soluble polymer binder and drying to obtain a granulated product; and (b) the above The method according to claim 1 , further comprising a step of compressing and molding the granulated product obtained in step (a), followed by further drying. The method according to claim 2 , wherein a granulated product comprising naphthopidyl, erythritol, and hydroxypropylcellulose is obtained in step (a). The method according to claim 2 or 3 , further comprising the step of mixing a granulated product comprising erythritol and a water-soluble polymer binder with the granulated product obtained in step (a) in step (b). The method according to claim 4 , wherein the water-soluble polymer binder is hydroxypropylcellulose.