JP6431576B2 - Solid formulation containing loxoprofen sodium and clemastine fumarate - Google Patents

Description

  The present invention relates to a solid preparation containing loxoprofen sodium having excellent stability.

  Currently, in general cold medicines and antipyretic analgesics, pharmaceutical preparations containing a plurality of medicinal ingredients are widely used. For example, in general cold medicines, over-the-counter drugs containing many medicinal ingredients such as antipyretic analgesics, antitussive expectorants, rhinitis drugs, etc. are widely sold. In a preparation in which many medicinal ingredients are blended, securing the stability of the preparation is an important issue from the viewpoint of safety that prevents unexpected side effects such as the generation of decomposition products due to the interaction of the blended ingredients.

  Loxoprofen sodium or its hydrate is widely used clinically as a non-steroidal antipyretic analgesic. Moreover, clemastine or its salt is known as an antihistamine, and is blended as an active ingredient of a general cold medicine.

  There has already been a report on a combination of loxoprofen sodium or a hydrate thereof and clemastine or a salt thereof, or a pharmaceutical composition containing the same (for example, see Patent Document 1).

  In addition, there is a problem in that when klemastine or a salt thereof is mixed with loxoprofen or a salt thereof, there is a problem that a color tone or a property is changed. It was necessary to devise a formulation that does not contact each other (for example, see Patent Document 2). In general, in order to avoid these changes, loxoprofen sodium or a hydrate thereof and clemastine or a salt thereof are not brought into contact (mixed), for example, loxoprofen sodium or a hydrate thereof and clemastine or a salt thereof are It is necessary to devise not to bring both components into contact with each other, such as blending into separate granules or making a multilayer tablet, and there are problems in manufacturing time, manufacturing operation complexity, and manufacturing cost.

JP 2009-185058 A JP 2012-031147 A

The present inventors prepared a physical mixture containing loxoprofen sodium or a hydrate thereof and clemastine or a salt thereof in a composition containing loxoprofen sodium or a hydrate thereof and clemastine or a salt thereof at the same time, and stored it. It has been found that there is a problem that the content of clemastine or a salt thereof decreases with the change in color tone and properties with time.
Accordingly, an object of the present invention is a solid preparation in which loxoprofen sodium or a hydrate thereof and clemastine or a salt thereof are homogeneously mixed, and the color and property change of the preparation and the content of clemastine or a salt thereof without granulation. An object of the present invention is to provide a stable solid preparation having no reduction.

  As a result of repeated studies of the preparations to solve the above-mentioned problems, the present inventors have added basic pharmaceutical additives and / or hydrous silicon dioxide, so that loxoprofen sodium or its hydrate, and clemastine or its Even in the case of a composition in which a salt is homogeneously mixed, the present inventors have found that there is no change in the color tone and properties of the composition, the decrease in the content of clemastine or a salt thereof is suppressed, and the productivity is improved. The invention has been completed.

That is, the present invention provides the following (1) to (15).
(1) A solid pharmaceutical preparation characterized by adding a basic pharmaceutical additive and / or hydrous silicon dioxide, and containing loxoprofen sodium or a hydrate thereof and clemastine or a salt thereof.
(2) A basic pharmaceutical additive and / or hydrated silicon dioxide is added, which contains loxoprofen sodium or a hydrate thereof, and clemastine or a salt thereof, and is wet-granulated after homogeneous mixing. Formulation.
(3) It is characterized by the addition of basic pharmaceutical additives and / or hydrous silicon dioxide, containing loxoprofen sodium or its hydrate, and clemastine or its salt, mixed homogeneously, wet granulated, and then compression molded Solid formulation.
(4) The basic pharmaceutical additive is at least one selected from the group consisting of magnesium metasilicate aluminate, synthetic hydrotalcite, magnesium oxide, light anhydrous silicic acid, heavy anhydrous silicic acid, and calcium silicate. The solid preparation according to any one of (1) to (3).
(5) The solid preparation according to any one of (1) to (3), wherein the basic pharmaceutical additive is one or more selected from the group consisting of light anhydrous silicic acid and heavy anhydrous silicic acid.
(6) The solid preparation according to any one of (1) to (5), wherein loxoprofen sodium or a hydrate thereof is loxoprofen sodium dihydrate.
(7) The solid preparation according to any one of (1) to (6), wherein clemastine or a salt thereof is clemastine fumarate.
(8) The solid preparation according to any one of (3) to (7), wherein the dosage form is a tablet.
(9) A method for producing a solid preparation containing loxoprofen sodium or a hydrate thereof, clemastine or a salt thereof, and a basic pharmaceutical additive and / or hydrous silicon dioxide,
A method for producing a solid preparation, comprising a step of homogeneously mixing and a step of wet granulation.
(10) A method for producing a solid preparation containing loxoprofen sodium or a hydrate thereof, clemastine or a salt thereof, and a basic pharmaceutical additive and / or hydrous silicon dioxide,
A method for producing a solid preparation, comprising a step of homogeneously mixing, a step of wet granulation, and a step of compression molding.
(11) The basic pharmaceutical additive is at least one selected from the group consisting of magnesium aluminate metasilicate, synthetic hydrotalcite, magnesium oxide, light anhydrous silicic acid, heavy anhydrous silicic acid, and calcium silicate. The method according to claim 9 or 10.
(12) The method according to (9) or (10), wherein the basic pharmaceutical additive is at least one selected from the group consisting of light anhydrous silicic acid and heavy anhydrous silicic acid.
(13) The production method according to any one of (9) to (12), wherein the loxoprofen sodium or a hydrate thereof is loxoprofen sodium dihydrate.
(14) In a composition containing loxoprofen sodium or a hydrate thereof, and clemastine or a salt thereof,
A method for suppressing change in composition by mixing loxoprofen sodium or a hydrate thereof with clemastine or a salt thereof, comprising adding a basic pharmaceutical additive and / or hydrous silicon dioxide.
(15) In a composition containing loxoprofen sodium or a hydrate thereof, and clemastine or a salt thereof,
A method for suppressing a decrease in the content of clemastine or a salt thereof by mixing loxoprofen sodium or a hydrate thereof with clemastine or a salt thereof, comprising adding a basic pharmaceutical additive and / or hydrous silicon dioxide.

  By adding a basic pharmaceutical additive and / or hydrous silicon dioxide to a composition containing loxoprofen sodium or a hydrate thereof, and clemastine or a salt thereof, the solid preparation of the present invention can be obtained by adding loxoprofen sodium or a water thereof. It is characterized in that it can provide a stable solid preparation that avoids compounding changes such as discoloration due to coexistence of a Japanese product with clemastine or a salt thereof.

  The “solid preparation” of the present invention is a granule, powder, capsule, tablet, pill or the like described in the 15th revised Japanese Pharmacopoeia, preferably a granule, powder, capsule or tablet. is there.

  Further, as the granule or tablet of the present invention, those in which the preparation is coated with a water-soluble polymer and those in which the tablet is coated with sugar are also suitable. That is, a film-coated granule, a film-coated tablet, a sugar-coated tablet, etc. can be mentioned as a suitable thing.

  Furthermore, when the solid preparation of the present invention is a tablet, a multilayer tablet obtained by compressing and molding powders or granules having different compositions in two layers or three or more layers can also be mentioned as a preferred embodiment.

  Examples of the “loxoprofen sodium or hydrate thereof” used in the present invention include loxoprofen sodium, loxoprofen sodium monohydrate, and loxoprofen sodium dihydrate, and loxoprofen sodium dihydrate is preferable. Loxoprofen sodium dihydrate is listed in the 15th revision Japanese Pharmacopoeia.

  “Clemastine or a salt thereof” used in the present invention is listed in the 15th revision Japanese Pharmacopoeia. As clemastine or a salt thereof, clemastine fumarate is preferable.

The “basic pharmaceutical additive” used in the present invention is an additive having a pH of 7% or higher in a 5% suspension, or an antacid power test method described in the 15th revised Japanese Pharmacopoeia. Means an additive. Specific examples of basic pharmaceutical additives include dry aluminum hydroxide gel, magnesium aluminate silicate, magnesium silicate, synthetic aluminum silicate, synthetic hydrotalcite, magnesium oxide, magnesium alumina hydroxide, aluminum hydroxide gel, Aluminum hydroxide / sodium bicarbonate coprecipitation product, aluminum hydroxide / magnesium carbonate mixed dry gel, aluminum hydroxide / magnesium carbonate / calcium carbonate coprecipitation product, magnesium hydroxide, magnesium carbonate, precipitated calcium carbonate, metasilicate aluminum Examples include magnesium phosphate, anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate, bandit bone, stone decision, volley, light anhydrous silicic acid, heavy anhydrous silicic acid, and calcium silicate. Over-the-counter manufacturing ( ON) approval criteria (2000), has been listed 2007 pharmaceutical additives encyclopedia, and in 2007 the pharmaceutical additives handbook.
The basic pharmaceutical additive in the present invention is preferably at least one selected from the group consisting of magnesium aluminometasilicate, synthetic hydrotalcite, magnesium oxide, light anhydrous silicic acid, and calcium silicate.

  As the “hydrous silicon dioxide” in the present invention, those listed in the 2007 Pharmaceutical Additives Encyclopedia may be used, but those having a grade characterized by being particularly porous and excellent in oil supply capability. Desirably, for example, Adsolider 102 (Freund Sangyo), Carplex # 67 (DSL. Japan), Carplex # 80 (DSL. Japan), hydrous silicon dioxide (Tosoh Silica) and the like can be mentioned.

  In the present invention, loxoprofen sodium or a hydrate thereof, and clemastine or a salt thereof, components include magnesium aluminate metasilicate, synthetic hydrotalcite, magnesium oxide, light anhydrous silicic acid, calcium silicate, and hydrous dioxide It is preferably at least one selected from the group consisting of silicon.

  The solid preparation of the present invention may further contain a “desiccant” as necessary. Examples of the “desiccant” in the present invention include those described in JP 2010-215611 A, and examples thereof include silica gel, silica alumina gel (allophane), natural zeolite, synthetic zeolite (molecular sieve), One type or two or more types selected from calcium chloride, quicklime (calcium oxide), bentonite clay (montmorillonite), magnesium chloride and magnesium oxide can be mentioned, and a mixture of these and activated carbon may be used. One or more selected from the group consisting of silica gel, silica alumina gel (allophane), synthetic zeolite (molecular sieve) and calcium chloride are more preferred, and synthetic zeolite is more preferred.

  In the solid preparation of the present invention, the content ratio of loxoprofen sodium or a hydrate thereof, clemastine or a salt thereof, and a basic pharmaceutical additive is 0.001 to 1 part by weight of loxoprofen sodium or a hydrate thereof, respectively. 0.5 parts by weight and 0.01 to 30 parts by weight; preferably 0.001 to 0.3 parts by weight and 0.01 to 15 parts by weight, respectively.

The method for producing the solid preparation of the present invention includes a step of uniformly mixing loxoprofen sodium or a hydrate thereof, clemastine or a salt thereof, and a basic pharmaceutical additive and / or hydrous silicon dioxide. There is no limit.
Here, “homogeneously mixed” means loxoprofen sodium or a hydrate thereof, clemastine or a salt thereof, a basic pharmaceutical additive and / or hydrous silicon dioxide, and a commonly used mixer such as a stirring type mixer. What is necessary is just to mix and mix by a machine etc.

  In addition, “mixing” and “mixing” used in the present invention means “mixing” is a “mixing” of two or more components using, for example, a mixer that is usually used for pharmaceutical use, such as a stirring type mixer. "Mixing" means a state in which two or more kinds of components are homogeneously mixed and the original component cannot be identified.

  Furthermore, as a manufacturing method of the solid formulation of this invention, it is preferable to granulate the composition containing loxoprofen sodium or its hydrate, clemastine or its salt, a basic pharmaceutical additive, and / or a hydrous silicon dioxide. Examples of such granulation include dry granulation and wet granulation. In the present invention, wet granulation is preferable. As wet granulation in producing the solid preparation of the present invention, it is usually used in the fields of pharmaceuticals such as stirring granulation, spray granulation, tumbling granulation, fluidized bed granulation, extrusion granulation and the like. If it is a wet granulation method, it will not specifically limit.

  Furthermore, in the present invention, the granulated product obtained by the granulation is preferably compression-molded to form a tablet.

  When preparing the solid preparation of the present invention, other medicinal ingredients are blended if necessary, and if necessary, preparation additives other than the basic pharmaceutical additives and / or hydrous silicon dioxide listed above are added. It may be added. The formulation additive used for the formulation of the solid formulation of the present invention includes a pharmaceutically acceptable carrier such as an excipient, a binder, a disintegrant, a disintegration aid, a lubricant, a fluidizing agent, a gloss. Agent, foaming agent, moisture-proofing agent, surfactant, stabilizer, emulsifier, antioxidant, filler, preservative, preservative, sweetener, flavoring agent, cooling agent, fragrance, fragrance, colorant, Bases, coating agents, dragees, plasticizers, dispersants, antifoaming agents and the like can be mentioned, and conventionally known formulation additives that can be used for solid formulations can be used for the above purpose.

  In order to describe the present invention in more detail, examples and comparative examples are described below, but the present invention is not limited thereto. The following medicinal ingredients used in the present invention are loxoprofen sodium dihydrate (Daiichi Sankyo Propharma Co., Ltd.), bromhexine hydrochloride (Daiichi Fine Chemical Co., Ltd.), clemastine fumarate (Sekisui Medical Corporation) and dl-methylephedrine hydrochloride (Daiichi Fine Chemical Co., Ltd.).

Test example: Storage stability test Production of physical blends and solid preparations (Comparative Example 1)
After mixing 19.87 g of loxoprofen sodium dihydrate and 0.13 g of clemastine fumarate in a plastic bag, the mixed powder was sieved with a sieve (No. 42) to obtain a physical mixture.

(Comparative Example 2)
Loxoprofen sodium dihydrate 45.9g, bromhexine hydrochloride 2.7g, clemastine fumarate 0.3g, dl-methylephedrine hydrochloride 13.5g, D-mannitol 337.0g, and appropriate amount of crystalline cellulose are added and mixed Mixing and spraying hydroxypropylcellulose aqueous solution as a binder to prepare 529.2 g of granulated granules. After mixing and blending 480.0 g of the granulated granule with croscarmellose sodium (14.4 g) and magnesium stearate (7.2 g), the mixture was tableted to produce a plain tablet.

(Example 1)
Loxoprofen sodium dihydrate (12.55 g), clemastine fumarate (0.08 g) and light anhydrous silicic acid (7.37 g) were mixed in a plastic bag. An admixture was obtained.

(Example 2)
Loxoprofen sodium dihydrate (12.55 g), clemastine fumarate (0.08 g) and hydrous silicon dioxide (7.37 g) were mixed in a plastic bag, and the mixed powder was sieved with a sieve (No. 42) to physically mix. I got a thing.

Example 3
Loxoprofen sodium dihydrate (12.55 g), clemastine fumarate (0.08 g) and synthetic hydrotalcite (7.37 g) were mixed in a plastic bag, and the mixed powder was passed through a sieve (No. 42) to physically An admixture was obtained.

(Example 4)
Loxoprofen sodium dihydrate (12.55 g), clemastine fumarate (0.08 g) and calcium silicate (7.37 g) were mixed in a plastic bag, and the mixed powder was sieved with a sieve (No. 42) and physically mixed. I got a thing.

(Example 5)
After mixing loxoprofen sodium dihydrate 12.55g, clemastine fumarate 0.08g and magnesium metasilicate aluminate 7.37g in a plastic bag, the mixed powder is sieved with a sieve (No. 42). A physical blend was obtained.

(Example 6)
Loxoprofen sodium dihydrate 10.0 g, clemastine fumarate 1.0 g, light anhydrous silicic acid 10.0 g, and appropriate amounts of crystalline cellulose are added, mixed, and mixed, and sprayed with a hydroxypropylcellulose aqueous solution as a binder. Granules were prepared. A granulated granule (49.5 g) was mixed and mixed with 0.5 g of magnesium stearate, and then tableted to produce a bare tablet.

(Example 7)
Loxoprofen sodium dihydrate 45.9 g, bromohexine hydrochloride 2.7 g, clemastine fumarate 0.3 g, dl-methylephedrine hydrochloride 13.5 g, D-mannitol 337.0 g, hydrous silicon dioxide 27.0 g, and An appropriate amount of crystalline cellulose was added, mixed and mixed, and an aqueous hydroxypropylcellulose solution was sprayed as a binder to prepare 529.2 g of granulated granules. After mixing and blending 480.0 g of the granulated granule with croscarmellose sodium (14.4 g) and magnesium stearate (7.2 g), the mixture was tableted to produce a plain tablet.

(Example 8)
Loxoprofen sodium dihydrate 10.0 g, clemastine fumarate 1.0 g, synthetic hydrotalcite 10.0 g, and appropriate amounts of crystalline cellulose are added, mixed and mixed, and sprayed with a hydroxypropylcellulose aqueous solution as a binder. Granules were prepared. A granulated granule (49.5 g) was mixed and mixed with 0.5 g of magnesium stearate, and then tableted to produce a bare tablet.

Example 9
Loxoprofen sodium dihydrate 10.0 g, clemastine fumarate 1.0 g, calcium silicate 10.0 g, and appropriate amounts of crystalline cellulose are added, mixed, and mixed, and granulated by spraying hydroxypropylcellulose aqueous solution as a binder. Granules were prepared. A granulated granule (49.5 g) was mixed and mixed with 0.5 g of magnesium stearate, and then tableted to produce a bare tablet.

(Example 10)
Loxoprofen sodium dihydrate 45.9 g, bromohexine hydrochloride 2.7 g, clemastine fumarate 0.3 g, dl-methylephedrine hydrochloride 13.5 g, D-mannitol 337.0 g, magnesium metasilicate aluminate 27.0 g Then, an appropriate amount of crystalline cellulose was charged, mixed and mixed, and an aqueous hydroxypropylcellulose solution was sprayed as a binder to prepare 529.2 g of granulated granules. After mixing and blending 480.0 g of the granulated granule with croscarmellose sodium (14.4 g) and magnesium stearate (7.2 g), the mixture was tableted to produce a plain tablet.

2. Test Method The physical admixture of Comparative Example 1 and the physical mixing powder of Example 1-5 were filled in a glass bottle and left for 1 week (60 ° C., sealed plug 1 W) under the conditions of 60 ° C. sealed. After storage, the color change and property change were confirmed using the refrigerator stored product as a control.

  In addition, the tablets of Comparative Example 2 and Example 6-10 were filled into glass bottles (4k standard bottles), and left for 4 weeks (60 ° C. sealed plug 4W) under 60 ° C. sealed conditions. After storage, the color change and property change were confirmed using the refrigerator stored product as a control. Moreover, the residual rate of loxoprofen sodium dihydrate and clemastine fumarate was measured.

  The change in color tone was evaluated in four stages: A: no discoloration, B: slight discoloration, C: discoloration, D: significant discoloration.

  The change in properties was evaluated in four stages: A: no change, B: slight change, C: change, D: significant change.

  The color difference is measured using a spectroscopic color difference meter (SE2000: Nippon Denshoku Industries Co., Ltd.). The difference between L * (brightness), a *, b * (hue saturation) of a product stored at 60 ° C. for 4 weeks using the initial product as a comparison. Thus, the color difference (ΔE) was obtained by the following formula 1. The measurement was performed three times, and the average value of the color difference was adopted.

3. Test results As shown in Tables 1 to 4, when a basic pharmaceutical additive is added to a composition in which loxoprofen sodium dihydrate and clemastine fumarate are uniformly present, granulation is performed. It is not necessary to add a special process such as, and can be produced without any trouble such as adhesion of a can during granulation. Furthermore, since the appearance change (color tone, property and color difference) and the decrease in the content of clemastine fumarate can be suppressed, it is advantageous compared to the conventional production method.

  According to the present invention, a solid preparation containing loxoprofen sodium or a hydrate thereof and clemastine or a salt thereof can be produced simply and at low cost. Such a solid preparation is useful because it can be used for the treatment of colds and the like.

Claims (10)

A solid preparation containing light anhydrous silicic acid and / or heavy anhydrous silicic acid, and containing loxoprofen sodium or a hydrate thereof, and clemastine or a salt thereof. (However, tranexamic acid, loxoprofen sodium hydrate, clemastine fumarate, bromhexine hydrochloride, dl-methylephedrine hydrochloride, dihydrocodeine phosphate , thiamine nitrate (vitamin B1 nitrate), riboflavin (vitamin B2), trehalose, (Excluding tablets containing crystalline cellulose, macrogol 6000, croscarmellose sodium, polyvinyl alcohol, light anhydrous silicic acid, hydrogenated oil, and magnesium stearate.) The solid formulation of Claim 1 whose loxoprofen sodium or its hydrate is loxoprofen sodium dihydrate.   The solid preparation according to claim 1 or 2, wherein clemastine or a salt thereof is clemastine fumarate.   The solid preparation according to any one of claims 1 to 3, wherein the dosage form is a tablet. A method for producing a solid preparation containing loxoprofen sodium or a hydrate thereof, clemastine or a salt thereof, and light anhydrous silicic acid and / or heavy anhydrous silicic acid,
A method for producing a solid preparation, comprising a step of homogeneously mixing and a step of wet granulation. (However, tranexamic acid, loxoprofen sodium hydrate, clemastine fumarate, bromhexine hydrochloride, dl-methylephedrine hydrochloride, dihydrocodeine phosphate , thiamine nitrate (vitamin B1 nitrate), riboflavin (vitamin B2), trehalose, (Excluding the manufacturing method of the tablet containing crystalline cellulose, macrogol 6000, croscarmellose sodium, polyvinyl alcohol, light anhydrous silicic acid, hydrogenated oil, and magnesium stearate.) A method for producing a solid preparation containing loxoprofen sodium or a hydrate thereof, clemastine or a salt thereof, and light anhydrous silicic acid and / or heavy anhydrous silicic acid,
A method for producing a solid preparation, comprising a step of homogeneously mixing, a step of wet granulation, and a step of compression molding. (However, tranexamic acid, loxoprofen sodium hydrate, clemastine fumarate, bromhexine hydrochloride, dl-methylephedrine hydrochloride, dihydrocodeine phosphate , thiamine nitrate (vitamin B1 nitrate), riboflavin (vitamin B2), trehalose, (Excluding the manufacturing method of the tablet containing crystalline cellulose, macrogol 6000, croscarmellose sodium, polyvinyl alcohol, light anhydrous silicic acid, hydrogenated oil, and magnesium stearate.)   The manufacturing method of the solid formulation of Claim 5 or Claim 6 whose loxoprofen sodium or its hydrate is loxoprofen sodium dihydrate.   The method for producing a solid preparation according to any one of claims 5 to 7, wherein clemastine or a salt thereof is clemastine fumarate. Loxoprofen sodium or a hydrate thereof, and a composition containing clemastine or a salt thereof (however, tranexamic acid, loxoprofen sodium hydrate, clemastine fumarate, bromhexine hydrochloride, dl-methylephedrine hydrochloride, dihydrocodeine phosphate A tablet containing thiamine nitrate (vitamin B1 nitrate), riboflavin (vitamin B2), trehalose, crystalline cellulose, macrogol 6000, croscarmellose sodium, polyvinyl alcohol, light anhydrous silicic acid, hydrogenated oil, and magnesium stearate Except)
Addition of light anhydrous silicic acid and / or heavy anhydrous silicic acid, a method for suppressing change in formulation by mixing loxoprofen sodium or a hydrate thereof with clemastine or a salt thereof. Loxoprofen sodium or a hydrate thereof, and a composition containing clemastine or a salt thereof (however, tranexamic acid, loxoprofen sodium hydrate, clemastine fumarate, bromhexine hydrochloride, dl-methylephedrine hydrochloride, dihydrocodeine phosphate A tablet containing thiamine nitrate (vitamin B1 nitrate), riboflavin (vitamin B2), trehalose, crystalline cellulose, macrogol 6000, croscarmellose sodium, polyvinyl alcohol, light anhydrous silicic acid, hydrogenated oil, and magnesium stearate Except)
A method for suppressing a decrease in the content of clemastine or a salt thereof by mixing loxoprofen sodium or a hydrate thereof with clemastine or a salt thereof, comprising adding light anhydrous silicic acid and / or heavy anhydrous silicic acid.