JP6106359B2 - Solid formulation containing loxoprofen sodium and vitamin B1 - Google Patents

Description

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

  Currently, for general cold medicines and antipyretic analgesics, preparations containing a plurality of medicinal ingredients are widely used. For example, it is known that many components such as antipyretic analgesics, antitussive expectorants, rhinitis drugs are blended in the common cold medicine. These drugs are widely sold as over-the-counter drugs, and from the viewpoint of safety, they need to have excellent stability as a preparation.

  Loxoprofen sodium or its hydrate is widely used clinically as a non-steroidal antipyretic analgesic.

  Vitamin B1 or a derivative thereof is blended as an active ingredient of a general cold medicine as a nourishing tonic at the time of physical exhaustion.

  A pharmaceutical composition in which loxoprofen sodium or a hydrate thereof and vitamin B1 are combined is already known (see, for example, Patent Documents 1 and 2). These documents include loxoprofen sodium or a hydrate thereof. In addition, since there is no description regarding the blending change of vitamin B1 and the like, it is not known about the stability of a preparation in which loxoprofen sodium or a hydrate thereof and vitamin B1 are blended.

JP 2001-172175 A JP 2001-199882 A

  The present inventors prepared a preparation containing the same granule containing loxoprofen sodium or a hydrate thereof and vitamin B1 or a derivative thereof, and when this was stored, the content of vitamin B1 or a derivative thereof was reduced by storage over time. Found a problem. Accordingly, an object of the present invention is to provide a solid preparation excellent in stability without discoloration or a decrease in content in a solid preparation containing loxoprofen sodium or a hydrate thereof and vitamin B1 or a derivative thereof.

  As a result of intensive studies to solve the above-mentioned problems, the present inventors formulated loxoprofen sodium or a hydrate thereof and vitamin B1 or a derivative thereof so as to exist without substantially contacting each other in the preparation. As a result, it was found that a stable preparation can be obtained, and the present invention has been completed.

That is, the present invention provides the following (1) to (8).
(1): In a solid preparation containing loxoprofen sodium or a hydrate thereof, and vitamin B1 or a derivative thereof,
A solid preparation characterized in that loxoprofen sodium or a hydrate thereof and vitamin B1 or a derivative thereof are present in the preparation without substantial contact.
(2): Loxoprofen sodium or a hydrate thereof and vitamin B1 or a derivative thereof are contained in the preparation by containing a granule a containing loxoprofen sodium or a hydrate thereof and a granule b containing vitamin B1 or a derivative thereof. The solid preparation according to (1), which exists substantially without contact.
(3): The solid preparation according to (2), wherein the granule a and the granule b contain a cellulose derivative.
(4): The solid preparation according to any one of (1) to (4), wherein loxoprofen sodium or a hydrate thereof is loxoprofen sodium dihydrate.
(5): The solid preparation according to any one of (1) to (4), wherein the solid preparation is a granule, powder, capsule, pill, or tablet.
(6): The solid preparation according to any one of (1) to (4), wherein the solid preparation is a tablet.
(7): a multi-layered tablet comprising at least two layers of a layer a containing loxoprofen sodium or a hydrate thereof and a layer b containing vitamin B1 or a derivative thereof, loxoprofen sodium or a hydrate thereof, and vitamin B1 Alternatively, the solid preparation according to (6), wherein the derivative is present in the preparation without substantial contact.
(8): In a method for producing a solid preparation containing loxoprofen sodium or a hydrate thereof and vitamin B1 or a derivative thereof;
A method for producing a solid preparation, characterized in that loxoprofen sodium or a hydrate thereof and vitamin B1 or a derivative thereof are present in the preparation without substantial contact.

  According to the present invention, a solid preparation containing loxoprofen sodium or a hydrate thereof and vitamin B1 or a derivative thereof and having excellent storage stability can be provided.

  “Loxoprofen sodium or a hydrate thereof” in the present invention includes loxoprofen sodium, loxoprofen sodium monohydrate, and loxoprofen sodium dihydrate. Loxoprofen sodium dihydrate is listed in the 15th revision Japanese Pharmacopoeia as loxoprofen sodium hydrate and is readily available.

  Examples of vitamin B1 or a derivative thereof in the present invention include thiamine nitrite, thiamine chloride hydrochloride, benfotiamine, and fursultiamine. Thiamine nitrate and thiamine chloride hydrochloride are listed in the 15th revised Japanese pharmacopoeia, and benfotiamine and fursultiamine are listed in the Japanese Pharmacopoeia Standards for Pharmaceuticals 2002, both of which are publicly known These compounds are readily available.

  As vitamin B1 or a derivative thereof in the present invention, thiamine nitrate or benfotiamine is preferable; benfotiamine is more preferable.

  The solid preparation of the present invention contains loxoprofen sodium or a hydrate thereof, and vitamin B1 or a derivative thereof, and the content ratio is not particularly limited as long as the effect of the present invention is not affected, but loxoprofen sodium 2 water The content ratio of vitamin B1 or its derivative per 1 part by weight of the Japanese product is preferably in the range of 0.05 to 1.0 part by weight; more preferably in the range of 0.05 to 0.5 part by weight.

  Specific examples of the “solid preparation” of the present invention include granules, powders, capsules, tablets, or pills described in the 15th revised Japanese Pharmacopoeia. The “solid preparation” of the present invention is preferably a granule, powder, capsule or tablet, and more preferably a tablet.

  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, film-coated granules, film-coated tablets, sugar-coated tablets and the like can be mentioned as preferred granule and tablet embodiments.

  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.

  In the present invention, “exist substantially without contact in the preparation” means that when a plurality of drugs are present in the solid preparation, there is no presence of uniformly mixed drugs that are not preferred to coexist. That is, it refers to a state where the drugs are present in the same solid preparation without direct contact and interaction. For example, an inert additive substance that does not react with a drug such as a binder or excipient exists between the drugs, the drug exists as a plurality of granules existing in different granules, or the drugs are different. A solid preparation having the form of a multilayer tablet existing in the layer can be mentioned. As specific embodiments, a granule in which loxoprofen sodium or a hydrate thereof and vitamin B1 or a derivative thereof are blended and mixed in separate granules, or a tablet obtained by compression-molding the granules may be used. In the case where the solid preparation is a multi-layer tablet or a dry-coated tablet, it is a tablet that is divided into a layer a containing loxoprofen sodium or a hydrate thereof and a layer b containing vitamin B1 or a derivative thereof. Also good.

  As described above, since the drug “exists substantially without contact in the preparation”, even if a plurality of drugs exist in the same solid preparation, discoloration of the solid preparation or A decrease in the content of the active ingredient can be suppressed.

  In addition, when caffeine is contained in the solid preparation of the present invention, the combination of such caffeine is substantially composed of a mixture of loxoprofen sodium or a hydrate thereof and caffeine, vitamin B1 or a derivative thereof. It is preferably present without contact.

  The caffeine in the present invention is preferably caffeine or anhydrous caffeine.

  The method for preparing the solid preparation of the present invention is not particularly limited. When the granule a containing loxoprofen sodium or a hydrate thereof and the granule b containing vitamin B1 or a derivative thereof are separated and blended, if necessary, In this granule, other medicinal ingredients may be blended within a range that does not affect the present invention, and a formulation additive may be added if necessary, and the granules may be produced according to a conventional method.

  For example, as a method for preparing a film-coated tablet in which a granule a containing loxoprofen sodium or a hydrate thereof and a granule b containing vitamin B1 or a derivative thereof are mixed, loxoprofen sodium or a hydrate thereof and a preparation additive are used. And a granule b containing vitamin B1 or a derivative thereof and a preparation additive, and after mixing each granule and lubricant, tablets are prepared by tableting. After preparation of the tablet, it may be put into a film coating machine and sprayed with a film coating solution to prepare a film coated tablet.

  Here, preparation additives used for the preparation of solid preparations include pharmaceutically acceptable carriers such as excipients, binders, disintegrants, disintegration aids, lubricants, fluidizing agents, glossy agents. Agent, foaming agent, moisture-proofing agent, surfactant, stabilizer, emulsifier, antioxidant, filler, preservative, preservative, sweetener, flavoring agent, refreshing agent, fragrance, fragrance, colorant, A coating agent, a dispersing agent, an antifoaming agent, etc. are mentioned, The formulation additive which can be used for a conventionally well-known solid formulation can be used for said objective.

  In particular, in the present invention, the formulation additive used for the granule a containing loxoprofen sodium or a hydrate thereof and the granule b containing vitamin B1 or a derivative thereof preferably contains an excipient. As, it is preferable to contain the 1 type (s) or 2 or more types chosen from a cellulose derivative. Here, as the cellulose derivative, for example, carboxymethyl ethyl cellulose, carmellose, carmellose calcium, carmellose sodium, croscarmellose sodium, crystalline cellulose, microcrystalline cellulose, crystalline cellulose (fine particles), crystalline cellulose (particles), powdered cellulose , Low substituted hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose 2208, hydroxypropylmethylcellulose 2906, hydroxypropylmethylcellulose 2910, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, methylcellulose, ethylcellulose, etc. 1 or 2 Carmellose calcium, carmellose sodium, croscarmellose sodium, crystalline cellulose, microcrystalline cellulose, crystalline cellulose (fine particles), crystalline cellulose (grains), low-substituted hydroxypropyl cellulose, and hydroxypropyl cellulose 1 type or 2 types or more chosen from are preferable.

  In the present invention, it is preferable to prepare a solid preparation containing granule a containing loxoprofen sodium or a hydrate thereof and a cellulose derivative, and granule b containing vitamin B1 or a derivative thereof and a cellulose derivative; loxoprofen sodium or water thereof It is more preferable to prepare a solid preparation containing granules a containing Japanese and crystalline cellulose, and granules b containing vitamin B1 or a derivative thereof and crystalline cellulose; loxoprofen sodium or a hydrate thereof, caffeine and crystalline cellulose It is particularly preferable to prepare a solid preparation containing granule a containing, and granule b containing vitamin B1 or a derivative thereof and crystalline cellulose.

  The blending amount of the formulation additive blended in the present invention is not particularly limited as long as loxoprofen sodium or a hydrate thereof and vitamin B1 or a derivative thereof can be present without substantially contacting in the formulation. When the formulation additive is a cellulose derivative, 0.05 to 100 parts by weight of the cellulose derivative is preferably added to 1 part by weight of loxoprofen sodium or a hydrate thereof; 0.1 to 50 parts by weight is added. More preferably; 0.1 to 10 parts by weight is even more preferable.

  Examples of medicinal ingredients other than loxoprofen sodium or a hydrate thereof and vitamin B1 or a derivative thereof that can be blended in the solid preparation of the present invention include antihistamines such as chlorpheniramine maleate, mequitazine, and clemastine fumarate, ambroxol hydrochloride Expectorants such as salt, bromhexine hydrochloride, belladonna total alkaloids, belladonna extract, parasympathetic nerve inhibitors such as scopolamine hydrobromide, dextromethorphan hydrobromide, dihydrocodeine phosphate, dl-methylephedrine hydrochloride And antitussives such as noscapine, and vitamins such as riboflavin, ascorbic acid and calcium ascorbate.

  In order to describe the present invention in more detail, test examples, comparative examples, and examples are described below, but the present invention is not limited thereto.

Test example: Comparative test with tablets Preparation method of tablet The tablet of the comparative example was manufactured by the process of an Example and (A ')-(C') by the process of following (A)-(C).

(Manufacture of the tablet of an Example)
(A) Manufacture of granule a: Loxoprofen sodium dihydrate (Daiichi Sankyo Propharma Co., Ltd.) 102.9 g, anhydrous caffeine 37.5 (Shiratori Pharmaceutical Co., Ltd.), fluidized bed granulator The appropriate amount of crystalline cellulose (manufactured by Asahi Kasei Chemicals Co., Ltd.) and the appropriate amount of D-mannitol (manufactured by Mitsubishi Shoji Foodtech Co., Ltd.) described in the examples of the above are added and mixed, and hydroxypropylcellulose is added. An aqueous solution of Nippon Soda Co., Ltd. was sprayed to obtain granules a.
(B) Production of granules b: In a fluidized bed granulator, 12.5 g of benfotiamine (manufactured by Yonezawa Hamari Co., Ltd.), (medicinal component B) described in the following examples, and as a formulation additive An appropriate amount of crystalline cellulose was added and mixed, and an aqueous hydroxypropylcellulose solution was sprayed to obtain granules b.
(C) Manufacture of tablets: The granules a and b, croscarmellose sodium (manufactured by Asahi Kasei Chemicals Corporation), and magnesium stearate (manufactured by Merck Japan Co., Ltd.) were mixed and then tableted to obtain tablets.

  The tablets of Examples 1 to 10 below were produced by the above-described tablet preparation method.

Example 1
(Medicinal component A): No addition.
(Medicinal component B): 12.5 g of thiamine nitrate instead of 12.5 g of benfotiamine in step (B) above.

(Example 2)
(Medicinal component A): No addition.
(Medicinal component B): 375.0 g of tranexamic acid, 0.67 g of clemastine fumarate, and 6.0 g of riboflavin.

(Example 3)
(Medicinal component A): 6.0 g of dihydrocodeine phosphate, 0.15 g of belladonna total alkaloid, and 3.0 g of riboflavin.
(Medicinal component B): 10.0 g of ambroxol hydrochloride, 7.5 g of chlorpheniramine maleate, 24.0 g of noscapine, and 3.0 g of riboflavin.

Example 4
(Medicinal component A): Noscapine 24.0 g.
(Medicinal component B): Thiamine nitrification instead of 6.0 g of bromhexine hydrochloride, 0.67 g of clemastine fumarate, 30.0 g of dl-methylephedrine hydrochloride, and 12.5 g of benfotiamine in the above step (B) 12.5 g of product.

(Example 5)
(Medicinal component A): 6.0 g of dihydrocodeine phosphate and 3.0 g of riboflavin.
(Medicinal component B): Clemastine fumarate 0.67 g, dihydrocodeine phosphate 6.0 g, dl-methylephedrine hydrochloride 30.0 g, and riboflavin 3.0 g.

(Example 6)
(Medicinal component A): 6.0 g of dihydrocodeine phosphate, 0.15 g of belladonna total alkaloid, and 3.0 g of riboflavin.
(Medicinal component B): clemastine fumarate 0.67 g, noscapine 24.0 g, and riboflavin 3.0 g.

(Example 7)
(Medicinal component A): No addition.
(Medicinal component B): Bromohexine hydrochloride 6.0 g, clemastine fumarate 0.67 g, dihydrocodeine phosphate 12.0 g, dl-methylephedrine hydrochloride 30.0 g, and riboflavin 6.0 g.

(Example 8)
(Medicinal component A): In step (A), 37.5 g of anhydrous caffeine was not added, and other additional components were 6.0 g of dihydrocodeine phosphate, 0.15 g of belladonna total alkaloids, and 3.0 g of riboflavin. .
(Medicinal component B): 10.0 g of ambroxol hydrochloride, 7.5 g of chlorpheniramine maleate, 24.0 g of noscapine, 37.5 g of anhydrous caffeine, and 3.0 g of riboflavin.

Example 9
(Medicinal component A): In the above step (A), 37.5 g of anhydrous caffeine was not added, and other additional components were 6.0 g of dihydrocodeine phosphate and 3.0 g of riboflavin.
(Medicinal component B): 10.0 g of ambroxol hydrochloride, 6.0 g of dihydrocodeine phosphate, 30.0 g of dl-methylephedrine hydrochloride, 37.5 g of anhydrous caffeine, and 3.0 g of riboflavin.

(Example 10)
(Medicinal component A): In step (A), 37.5 g of anhydrous caffeine was not added, and other additional components were 6.0 g of dihydrocodeine phosphate, 0.15 g of belladonna total alkaloids, and 3.0 g of riboflavin. .
(Pharmaceutical component B): 10.0 g of ambroxol hydrochloride, 6.0 g of dihydrocodeine phosphate, 24.0 g of noscapine, 30.0 g of dl-methylephedrine hydrochloride, 37.5 g of anhydrous caffeine, and 3.0 g of riboflavin .

(Manufacture of tablet of comparative example)
(A ') Manufacture of granule a: Loxoprofen sodium dihydrate 102.9g, benfotiamine 12.5g, anhydrous caffeine 37.5 (manufactured by Shiratori Pharmaceutical Co., Ltd.), formulation additive in fluid bed granulator An appropriate amount of crystalline cellulose and an appropriate amount of D-mannitol were added and mixed, and an aqueous hydroxypropylcellulose solution was sprayed to obtain granules a.
(B ′) Manufacture of granules b: Into a fluidized bed granulator, (medicinal component B ′) described in the following examples and an appropriate amount of crystalline cellulose as a preparation additive are charged and mixed, and an aqueous hydroxypropyl cellulose solution Were sprayed to obtain granules b.
(C ′) Manufacture of tablets: The granules a and b, croscarmellose sodium (manufactured by Asahi Kasei Chemicals Corporation), and magnesium stearate (manufactured by Merck Japan Co., Ltd.) were mixed and then tableted to obtain tablets.

  Tablets of the following Comparative Examples 1 to 11 were produced by the steps (A ′) to (C ′) described in the above (Manufacture of Tablets of Comparative Examples).

(Comparative Example 1)
(Medicinal component B ′): No addition.

(Comparative Example 2)
(Medicinal component B ′): 12.5 g of thiamine nitrate instead of 12.5 g of benfotiamine in the above step (B ′).

(Comparative Example 3)
(Medicinal component B ′): tranexamic acid 375.0 g, clemastine fumarate 0.67 g, and riboflavin 6.0 g.

(Comparative Example 4)
(Medicinal component B ′): 10.0 g of ambroxol hydrochloride, 7.5 g of chlorpheniramine maleate, 24.0 g of noscapine, and 3.0 g of riboflavin.

(Comparative Example 5)
(Medicinal component B '): Instead of 6.0 g of bromhexine hydrochloride, 0.67 g of clemastine fumarate, 30.0 g of dl-methylephedrine hydrochloride, and 12.5 g of benfotiamine in the above (B') step Thiamine nitrate 12.5g.

(Comparative Example 6)
(Medicinal component B ′): Clemastine fumarate 0.67 g, dihydrocodeine phosphate 6.0 g, dl-methylephedrine hydrochloride 30.0 g, and riboflavin 3.0 g.

(Comparative Example 7)
(Medicinal component B ′): Clemastine fumarate 0.67 g, noscapine 24.0 g, and riboflavin 3.0 g.

(Comparative Example 8)
(Medicine component B ′): Bromohexine hydrochloride 6.0 g, clemastine fumarate 0.67 g, dihydrocodeine phosphate 12.0 g, dl-methylephedrine hydrochloride 30.0 g, and riboflavin 6.0 g.

(Comparative Example 9)
In the step (A ′), 37.5 g of anhydrous caffeine was not added, and 6.0 g of dihydrocodeine phosphate, 0.15 g of belladonna total alkaloids, and 3.0 g of riboflavin were added as other additional components.
(Medicinal component B ′): 10.0 g of ambroxol hydrochloride, 7.5 g of chlorpheniramine maleate, 24.0 g of noscapine, 37.5 g of anhydrous caffeine, and 3.0 g of riboflavin.

(Comparative Example 10)
In the step (A ′), 37.5 g of anhydrous caffeine was not added, and 6.0 g of dihydrocodeine phosphate and 3.0 g of riboflavin were added as other additional components.
(Medicinal component B ′): 10.0 g of ambroxol hydrochloride, 6.0 g of dihydrocodeine phosphate, 30.0 g of dl-methylephedrine hydrochloride, 37.5 g of anhydrous caffeine, and 3.0 g of riboflavin were added.

(Comparative Example 11)
In the step (A ′), 37.5 g of anhydrous caffeine was not added, and 6.0 g of dihydrocodeine phosphate, 0.15 g of belladonna total alkaloids, and 3.0 g of riboflavin were added as other additional components.
(Medicinal component B '): Ambroxol hydrochloride 10.0 g, dihydrocodeine phosphate 6.0 g, noscapine 24.0 g, dl-methylephedrine hydrochloride 30.0 g, anhydrous caffeine 37.5 g, and riboflavin 3. 0 g was added.

2. Test Method Each of the tablets of Examples and Comparative Examples was filled in glass bottles (6k standard bottles) and left for 2 weeks under the conditions of 60 ° C. sealed cap and 50 ° C. sealed cap. After storage, the contents of loxoprofen sodium dihydrate and benfotiamine, the color change of the appearance of the tablet, and the change of properties were confirmed using the refrigerator stored product as a control.

  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: changed, B: slight change, C: changed, and D: significant change.

3. Test Results The tablets of the Examples showed almost no change in color tone or properties even when stored for 2 weeks under severe conditions of 50 ° C. and 60 ° C. In addition, no decrease in the contents of loxoprofen sodium dihydrate and benfotiamine was observed. On the other hand, the tablet of Comparative Example 1 in which loxoprofen sodium dihydrate and benfotiamine were blended into the same granule showed a decrease in the content of benfotiamine under both the 50 ° C and 60 ° C sealed conditions. It was. From this result, it was found that a tablet produced by dividing loxoprofen sodium dihydrate and benfotiamine into separate granules was excellent in storage stability.

According to the present invention, a solid preparation containing loxoprofen sodium dihydrate and vitamin B1 or a derivative thereof and having excellent storage stability can be provided. The solid preparation of the present invention is useful as a general cold medicine, cold medicine or antipyretic analgesic.

Claims (6)

In a solid preparation containing loxoprofen sodium or a hydrate thereof, and vitamin B1 or a derivative thereof,
By containing granule a containing loxoprofen sodium or a hydrate thereof and granule b containing vitamin B1 or a derivative thereof , loxoprofen sodium or a hydrate thereof and vitamin B1 or a derivative thereof are substantially A solid preparation characterized in that it exists without contact. The solid preparation according to claim 1, wherein the granule a and the granule b contain a cellulose derivative. The solid preparation according to any one of claims 1 to 2, wherein loxoprofen sodium or a hydrate thereof is loxoprofen sodium dihydrate . The solid preparation according to any one of claims 1 to 3, wherein the solid preparation is a granule, a powder, a capsule, a pill, or a tablet. The solid preparation according to any one of claims 1 to 3, wherein the solid preparation is a tablet. In a method for producing a solid preparation containing loxoprofen sodium or a hydrate thereof, and vitamin B1 or a derivative thereof,
By containing granule a containing loxoprofen sodium or a hydrate thereof and granule b containing vitamin B1 or a derivative thereof, loxoprofen sodium or a hydrate thereof and vitamin B1 or a derivative thereof are substantially The manufacturing method of the solid formulation characterized by existing without contacting.