JP5999892B2 - Solid formulation containing loxoprofen sodium and bromhexine - 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 medicine, it is widely sold as an over-the-counter drug containing many ingredients such as antipyretic analgesics, antitussive expectorants, and rhinitis drugs, and it is formulated from the viewpoint of safety to prevent unexpected side effects. It must be excellent in stability.

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

  There has already been a report on the combined use of loxoprofen sodium or its hydrate and bromhexine hydrochloride and a pharmaceutical composition combining them (for example, see Patent Document 1).

  In addition, blending of loxoprofen or its salt with bromhexine hydrochloride or ambroxol, which is also an expectorant, causes changes in color and properties. It was necessary to devise a formulation such as adding xol and a desiccant into the container (for example, see Patent Document 2).

JP 2008-13542 A JP 2010-215611 A

  The present inventors have a problem that after preparation of a physical mixture containing loxoprofen sodium or a hydrate thereof and bromohexine hydrochloride, the content of bromhexine hydrochloride decreases with the change in color and properties over time during storage. I found out. In general, in order to avoid these changes, do not contact (mix) loxoprofen sodium or its hydrate with bromhexine hydrochloride, for example, separate loxoprofen sodium or its hydrate and bromhexine hydrochloride from each other. It is necessary to blend in the granule or insert a desiccant, and there are problems of manufacturing time, manufacturing operation complexity, and manufacturing cost. Accordingly, an object of the present invention is to provide a solid preparation in which loxoprofen sodium or a hydrate thereof and bromohexine hydrochloride are homogeneously mixed, and change the color and properties of the preparation and the content of bromohexine hydrochloride without inserting a desiccant. An object of the present invention is to provide a stable solid preparation having no reduction.

  As a result of repeated researches on preparations to solve the above problems, the present inventors have added basic pharmaceutical additives and / or hydrous silicon dioxide, so that loxoprofen sodium or a hydrate thereof, and bromhexine hydrochloride Even when the composition is uniformly mixed, the inventors have found the surprising result that there is no change in the color tone and properties of the composition and that the decrease in the content of bromohexine hydrochloride is suppressed, and the present invention has been completed. It was.

That is, the present invention provides the following (1) to (12).
(1): A homogeneously mixed solid preparation characterized by adding a basic pharmaceutical additive and / or hydrous silicon dioxide and containing loxoprofen sodium or a hydrate thereof and bromhexine hydrochloride.
(2): characterized by adding basic pharmaceutical additives and / or hydrous silicon dioxide, containing loxoprofen sodium or its hydrate, and bromhexine hydrochloride, mixed homogeneously and then wet granulated Formulation.
(3): characterized by the addition of basic pharmaceutical additives and / or hydrous silicon dioxide, containing loxoprofen sodium or its hydrate, and bromohexine hydrochloride, mixed homogeneously, wet granulation, compression molding Solid formulation.
(4): The basic pharmaceutical additive is at least one selected from magnesium aluminometasilicate, synthetic hydrotalcite, magnesium oxide, light anhydrous silicic acid, and calcium silicate, (1) to (3) The solid preparation according to any one of the above.
(5): The solid preparation according to any one of (1) to (3), wherein loxoprofen sodium or a hydrate thereof is loxoprofen sodium dihydrate.
(6): The solid preparation according to any one of (3) to (5), wherein the dosage form is a tablet.
(7): The solid preparation according to any one of (1) to (6), which does not contain a desiccant.
(8): Loxoprofen sodium or a hydrate thereof, bromhexine hydrochloride, and a basic pharmaceutical additive and / or hydrated silicon dioxide, including a step of wet granulation after homogeneous mixing, A method for producing a solid preparation.
(9): Contains loxoprofen sodium or its hydrate, bromhexine hydrochloride, basic pharmaceutical additive and / or hydrous silicon dioxide, and after mixing homogeneously, wet granulation, and further compression molding A method for producing a solid preparation, characterized in that
(10) The method according to (8) or (9), wherein the basic pharmaceutical additive is at least one selected from magnesium metasilicate aluminate, synthetic hydrotalcite, magnesium oxide, and calcium silicate.
(11) The production method according to any one of (8) to (10), wherein the loxoprofen sodium or a hydrate thereof is loxoprofen sodium dihydrate.
(12): In a composition containing loxoprofen sodium or a hydrate thereof and bromohexine hydrochloride,
A method for suppressing a change in formulation by mixing loxoprofen sodium or a hydrate thereof with bromhexine hydrochloride, which comprises adding a basic pharmaceutical additive and / or hydrous silicon dioxide.

  The solid preparation of the present invention can be obtained by adding a basic pharmaceutical additive that functions as a stabilizer and / or hydrous silicon dioxide to a composition containing loxoprofen sodium or a hydrate thereof and bromhexine hydrochloride, It is characterized in that it can provide a stable solid preparation that avoids compounding changes such as discoloration due to coexistence of the hydrate and bromhexine hydrochloride.

  The “solid preparation” of the present invention is a granule, powder, capsule, tablet, pill or the like described in the 15th revision 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 coating granule, a film coating tablet, a sugar-coated tablet, etc. are mentioned.

  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 “loxoprofen sodium or a hydrate thereof” used in the present invention include loxoprofen sodium, loxoprofen sodium monohydrate, and loxoprofen sodium dihydrate. In the present invention, loxoprofen sodium 2 Hydrates are preferred. Loxoprofen sodium dihydrate is listed in the 15th revision Japanese Pharmacopoeia.

  “Bromhexine hydrochloride” used in the present invention is listed in the 15th revision Japanese Pharmacopoeia.

  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. Hydrous silicon dioxide is listed in the 2007 Pharmaceutical Additives Encyclopedia.

  The basic pharmaceutical additive in the present invention is preferably at least one selected from magnesium aluminometasilicate, synthetic hydrotalcite, magnesium oxide, light anhydrous silicic acid, and calcium silicate.

  In the present invention, loxoprofen sodium or a hydrate thereof, and bromhexine hydrochloride, components include magnesium aluminate metasilicate, synthetic hydrotalcite, magnesium oxide, light anhydrous silicic acid, calcium silicate, and hydrous silicon dioxide It is preferable that it is 1 or more types chosen from.

  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 silica gel, silica alumina gel (allophane), synthetic zeolite (molecular sieve) and calcium chloride are more preferred; synthetic zeolite is more preferred.

  The content ratio of loxoprofen sodium or a hydrate thereof, bromhexine hydrochloride and a basic pharmaceutical additive in the solid preparation of the present invention is 0.01 to 1 with respect to 1 part by weight of loxoprofen sodium or a hydrate thereof, respectively. 0.0 parts by weight and 0.01 to 30 parts by weight; preferably 0.01 to 0.5 parts by weight and 0.01 to 15 parts by weight, respectively.

  The method for producing the solid preparation of the present invention is not particularly limited as long as it includes a step of mixing homogeneously loxoprofen sodium or its hydrate, bromhexine hydrochloride, basic pharmaceutical additive and / or hydrous silicon dioxide. There is no.

  Here, “homogeneously mixed” means loxoprofen sodium or a hydrate thereof, bromhexine hydrochloride, and basic pharmaceutical additives and / or hydrous silicon dioxide, which are usually used in a mixer such as a stirring mixer. What is necessary is just to mix and mix by etc.

  In addition, “mixing” and “mixing” used in the present invention means that “mixing” means “mixing” two or more components using, for example, a mixer usually used for pharmaceutical use, for example, a stirring mixer. "Mixing" means a state in which two or more components are homogeneously mixed and the original components cannot be distinguished from each other by appearance.

  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, bromhexine hydrochloride, a basic pharmaceutical additive, and / or 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, if necessary, other medicinal ingredients are blended, and if necessary, preparation additives other than the basic pharmaceutical additives and / or hydrous silicon dioxide mentioned 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.

Test example: Comparative test of stabilizers Production of physical blends and solid preparations (Comparative Example 1)
After mixing 10.0 g of loxoprofen sodium dihydrate and 1.0 g of bromohexine hydrochloride in a plastic bag, the mixed powder was passed through a sieve (No. 20) to obtain a physical mixture.

(Comparative Example 2)
After mixing 10.0 g of loxoprofen sodium dihydrate, 1.0 g of bromhexine hydrochloride and 10.0 g of citric acid in a plastic bag, the mixed powder is sieved with a sieve (No. 20) to obtain a physical mixture. Obtained.

(Comparative Example 3)
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 10.0 g, bromohexine hydrochloride 1.0 g, magnesium metasilicate aluminate 10.0 g, and crystalline cellulose in appropriate amounts were added, mixed and mixed, and a hydroxypropylcellulose aqueous solution was sprayed 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 2)
Loxoprofen sodium dihydrate 10.0 g, bromhexine hydrochloride 1.0 g, magnesium oxide 10.0 g, and appropriate amounts of crystalline cellulose are added, mixed and mixed, and a hydroxypropyl cellulose aqueous solution is sprayed as a binder to form granulated granules. 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 3)
Loxoprofen sodium dihydrate 10.0 g, bromhexine hydrochloride 1.0 g, synthetic hydrotalcite 10.0 g, and appropriate amount 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 4
Loxoprofen sodium dihydrate 10.0 g, bromhexine hydrochloride 1.0 g, calcium silicate 10.0 g, and appropriate amounts of crystalline cellulose are added, mixed and mixed, and granulated granules are sprayed with hydroxypropylcellulose aqueous solution as a binder. Was 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 5)
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. A granulated granule (480.0 g) was mixed and mixed with croscarmellose sodium (14.4 g), magnesium metasilicate aluminate (14.4 g) and magnesium stearate (7.2 g), and then tableted to produce a plain tablet.

(Example 6)
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. A granulated granule (480.0 g) was mixed and mixed with croscarmellose sodium (14.4 g), synthetic hydrotalcite (14.4 g), and magnesium stearate (7.2 g), and then tableted to produce a plain tablet.

(Example 7)
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. The granulated granules (480.0 g) were mixed and mixed with croscarmellose sodium (14.4 g), calcium silicate (14.4 g), and magnesium stearate (7.2 g), and then tableted to produce a plain tablet.

(Example 8)
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・ Mixed and sprayed with hydroxypropylcellulose aqueous solution as a binder to prepare 529.2 g of granulated granules. A granulated granule (480.0 g) was mixed and mixed with croscarmellose sodium (14.4 g), hydrous silicon dioxide (14.4 g), and magnesium stearate (7.2 g), and then tableted to produce a plain tablet.

Example 9
Loxoprofen sodium dihydrate 45.9 g, bromohexine hydrochloride 2.7 g, clemastine fumarate 0.3 g, dl-methylephedrine hydrochloride 13.5 g, synthetic hydrotalcite 27.0 g, D-mannitol 310.2 g, Then, an appropriate amount of crystalline cellulose was added, mixed and mixed, and an aqueous hydroxypropylcellulose solution was sprayed as a binder to prepare 529.3 g of granulated granules. The granulated granules (480.0 g) were mixed and mixed with croscarmellose sodium (14.4 g) and magnesium stearate (4.8 g), and then tableted to produce a plain tablet.

2. Test Method The physical blends of Comparative Examples 1 and 2 and the tablets of Example 1-4 were filled in glass bottles (4k standard bottles) and allowed to stand for 2 months under conditions of 50 ° C. release (50 ° C. open 2M). 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 bromhexine hydrochloride was measured.

  In addition, the tablets of Comparative Example 3 and Example 5-9 were filled in glass bottles (8k standard bottles), and left for 2 weeks (60 ° C. sealed plug 2W) under the conditions of 60 ° C. sealed caps. 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 bromhexine hydrochloride 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.

3. Test results As shown in Tables 1 to 4, when loxoprofen sodium dihydrate and bromohexine hydrochloride are uniformly present, a basic pharmaceutical additive or hydrous silicon dioxide is added. Was able to produce a pharmaceutical solid preparation capable of significantly suppressing color change, property change, and bromohexine hydrochloride content decrease.

*: ○ means containing.

  According to the present invention, a solid preparation containing loxoprofen sodium or a hydrate thereof and bromhexine hydrochloride 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 (8)

The synthetic hydrotalcite and / or hydrated silicon dioxide that is characterized to be added, Loxoprofensodium or solid form preparations you containing hydrate thereof, and bromhexine hydrochloride. The solid formulation of Claim 1 whose loxoprofen sodium or its hydrate is loxoprofen sodium dihydrate. The solid formulation of any one of Claims 1-2 whose dosage form is a tablet. The solid preparation according to any one of claims 1 to 3, which does not contain a desiccant. A method for producing a solid preparation, comprising loxoprofen sodium or a hydrate thereof, bromhexine hydrochloride, and synthetic hydrotalcite and / or hydrous silicon dioxide, and including a step of wet granulation after homogeneous mixing. . It contains loxoprofen sodium or its hydrate, bromhexine hydrochloride, synthetic hydrotalcite and / or hydrous silicon dioxide, and includes a step of wet granulation after homogeneous mixing, and a step of compression molding The manufacturing method of a solid formulation. The manufacturing method of any one of Claims 5-6 whose loxoprofen sodium or its hydrate is loxoprofen sodium dihydrate. In a composition comprising loxoprofen sodium or a hydrate thereof and bromhexine hydrochloride,
A method for suppressing change in formulation by mixing loxoprofen sodium or a hydrate thereof and bromhexine hydrochloride, which comprises adding synthetic hydrotalcite and / or hydrous silicon dioxide.