JPH0797325A - Stable solid pharmaceutical and its production - Google Patents

Abstract

PURPOSE:To prepare a stabilized pharmaceutical containing a dextromethorphan, a phenyl propanolamine and, if needed, ibuprofen. CONSTITUTION:A solid pharmaceutical containing a dextromethorphan and a phenyl propanolamine is formulated with a caffeine to stabilize the active ingredients of this solid pharmaceutical. The pharmaceutical may additionally contain ibuprofen. In addition to the caffeine formulation, if needed, each of the active ingredients or their appropriate combination is formulated separately, or a combination of the above formulations with a method in which the content of a reducing saccharide such as lactose is suppressed can further stabilize the active ingredients. As a result, change with time such as the degradation of the respective active ingredients can be suppressed significantly, thus the objective medicine as a solid pharmaceutical of high product value and stable over a long period of time can be obtained.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a stabilized solid preparation useful for treating and preventing cold symptom and its manufacturing method. More specifically, it contains dextromethorphan, an antitussive, expectorant, phenylpropanolamines and caffeine, which are decongestants effective for nasal discharge and nasal congestion, and is also used as an anti-inflammatory, analgesic and antipyretic agent. The present invention relates to a stabilized solid preparation which may contain ibuprofen and a method for producing the same. In particular, the present invention is a formulation containing dextromethorphans, ibuprofen and phenylpropanolamines, which is further mixed with caffeine to form a group, and even when granulated, decomposition of each active ingredient is suppressed, and stable. It is to provide a modified formulation.

[0002]

BACKGROUND OF THE INVENTION Ibuprofen was synthesized by Nicholson and Adamo in 1964 and was found in Boots Pure Drug in the United Kingdom.
Developed by the company, it has been applied exclusively as an anti-inflammatory, analgesic and antipyretic agent. On the other hand, phenylpropanolamines are
It is a sympathomimetic drug with a pharmacological action similar to that of ephedrine, and is used as a general drug for rhinitis because it has a therapeutic effect on runny nose and nasal congestion.

In Japanese Patent Publication No. 61-501913 corresponding to International Publication No. WO85 / 04589 and International Publication No. WO91 / 17746, nonsteroidal anti-inflammatory agents such as ibuprofen as an analgesic ingredient and a decongestant are described. , A cold medicine composition containing phenylpropanolamine hydrochloride, dextromethorphan hydrobromide as an antitussive, and chlorphenylamine maleate as an antihistamine. In all of these preparations, dextromethorphan, ibuprofen, and phenylpropanolamine hydrochloride are directly mixed with lactose and other bases to prepare preparations without special stabilization.

As a result of various investigations in order to find a more effective general cold remedies, the present inventors have found that a formulation containing the above-mentioned dextromethorphans, phenylpropanolamines (for example, phenylpropanolamine hydrochloride) and ibuprofen. It has been found to be particularly promising as a cold remedy.

However, in these preparations, not only the stability of the above-mentioned active ingredient is inferior, the content of the active ingredient decreases with time, but also the appearance changes.

More specifically, it has been confirmed that phenylpropanolamine hydrochloride reacts with certain sugars and decomposes depending on the pH of the liquid (RH Barry (BARR
Y.), J. Pharm. Sci. 71 , No. 1 Jan. 116-11
8, 1982). In addition, "Study on changes in pharmaceutical composition"
(Ueda, Toyama Pharmaceutical Research Institute, Vol. 1984/198
5, p127-234, 1987), lysozyme chloride, potassium guaiacolsulfonate, dextromethorphan hydrobromide and the like are contraindicated.

On the other hand, the melting point of ibuprofen is as low as 75 ° C., and the melting points of other components are often lowered. Also,
Formulations containing other active ingredients and ibuprofen have poor stability and tend to be accompanied by a decrease in the content of the active ingredient, a change in appearance and the like. For example, "Ibuprofen granule formulation change"
(Sato, Pharmacy, 27 , 12, 73-78, 1976) describes contraindications for compounding with methylephedrine and sodium hydrogen carbonate, and "Study on changes in drug combinations".
(Ueda, Toyama Pharmaceutical Research Institute, Vol. 1984/198
5, p127-234, 1987), contraindications for combination with dl-chlorpheniramine maleate, ascorbic acid and the like are described.

Particularly, in the preparation containing phenylpropanolamines, dextromethorphans and ibuprofen, the above-mentioned problems occur remarkably. For example, as shown in Experimental Example 1 below, in a preparation containing dextromethorphan hydrobromide, ibuprofen and phenylpropanolamine hydrochloride, each component tends to decompose over time at high temperature. In particular, the stability of phenylpropanolamine hydrochloride is poor, and appearance changes due to blending with ibuprofen and dextromethorphan hydrobromide are also exhibited. As described above, a stabilized preparation having sufficient practicability has not yet been found in the preparation containing dextromethorphan, ibuprofen and phenylpropanolamine hydrochloride.

[0009]

Therefore, the object of the present invention is to contain dextromethorphanes and phenylpropanols, which are compounding repellent, as active ingredients.
It is to provide a solid preparation in which the active ingredient is stabilized and a method for producing the same.

Another object of the present invention is, in addition to both components of dextromethorphans and phenylpropanols,
Further, it is to provide a solid preparation in which any of the above-mentioned active ingredients is stabilized despite containing ibuprofen and a method for producing the same.

Still another object of the present invention is to significantly suppress the daily degradation of dextromethorphans and phenylpropanolamines and further ibuprofen and the appearance change of the preparation, to prolong the quality assurance period of the product, It is to provide a solid preparation having a high value and a manufacturing method thereof.

[0012] Another object of the present invention is to provide a stabilizing method capable of efficiently stabilizing dextromethorphans and phenylpropanols, which are considered to be compounded, and also ibuprofen.

Still another object of the present invention is to provide a stabilizing method capable of maintaining the stability of the above-mentioned active ingredient, particularly phenylpropanols, at a high level for a long period of time.

Another object of the present invention is to provide a solid preparation useful as a cold medicine preparation such as a common cold preparation and a method for producing the same.

[0015]

Means for Solving the Problems The present inventors have conducted various studies on stabilization of a preparation containing dextromethorphans, ibuprofen and phenylpropanolamines, and found that dextromethorphans (if necessary, ibuprofen Surprisingly, when caffeine is added to phenylpropanolamines and phenylpropanolamines, all of the above components are surprisingly stabilized, and when the phenylpropanolamines are separated and added, the active ingredient becomes more stable. It was found that a stable formulation was obtained. The present invention has been completed after further studies based on the above findings.

That is, the present invention relates to (A) a stabilized solid preparation containing dextromethorphans, phenylpropanolamines and caffeine, (B)
Provided is a solid formulation further containing ibuprofen.
In this formulation, dextromethorphans and phenylpropanolamines (eg, phenylpropanolamine hydrochloride) may be combined in separate groups, and ibuprofen may be combined in the group of dextromethorphans. Good. Furthermore, it is desirable to limit the content of reducing sugars to the group of phenylpropanolamines to an amount that does not adversely affect stability.

In the method of the present invention, the active ingredient is stabilized by incorporating caffeine into a solid preparation containing dextromethorphans and phenylpropanolamines and, if necessary, ibuprofen as an active ingredient. Turn into. In this stabilization method, the existing form of caffeine is not particularly limited, and other active ingredients can be stabilized as long as caffeine coexists in the solid preparation.

Further, in the production method of the present invention, a stable solid preparation is produced by adding caffeine to a solid preparation containing dextromethorphans and phenylpropanolamines. In this method, a granulated powder containing dextromethorphans, phenylpropanolamines, caffeine, and optionally at least one active ingredient of ibuprofen, and other active ingredient which may be granulated, May be mixed. Each of the plurality of active ingredients may be individually granulated to form a number of granules corresponding to each active ingredient, and two or more active ingredients are contained in one granule. You may form 1 or 2 or more granulated powder.

In the present specification, the term "blended in another group" means
For example, it means that the dextromethorphan group and the phenylpropanolamine group are contained in a state where contact between the both is suppressed. The "mixing in different groups" may be hereinafter referred to as "grouping combination". In addition, the group of phenylpropanolamines may be simply referred to as "phenylpropanolamine group". Further, the "granulated powder" includes fine granules, granules and pills, in addition to the products in the usual process granulated by some method.

As the solid preparation of the present invention, specifically, granulated powder such as fine granules, granules and pills, orally administered solid preparation such as tablets and capsules are preferable. The formulations according to the invention are particularly suitable for colds formulations.

The dextromethorphans used in the present invention include dextromethorphan and its salts, such as dextromethorphan hydrobromide and dextromethorphan / phenolphthaline salt. The phenylpropanolamines contained as another medicinal component in the solid preparation of the present invention include pharmacologically acceptable salts and the like, for example, phenylpropanolamine hydrochloride and the like. Examples of caffeine include caffeine and its derivatives, such as anhydrous caffeine, caffeine (monohydrate), caffeine citrate, and sodium caffeine benzoate.

If desired, the preparation of the present invention may contain other medicinal components in addition to the aforementioned dextromethorphans, ibuprofen, phenylpropanolamines and caffeine. Such medicinal ingredients include, for example, acetaminophen, phenacetin, aspirin,
Aspirin Aluminum, Ethenzamide, Aminopyrine, Salicylamide, Lactylphenetidine, Isopropylantipyrine, Sazapyrine, Sodium salicylate, Phenylbutazone, Ketophenylbutazone, Indomethacin, Naproxen, Ibufenac, Seratiopeptidase, Lysozyme chloride, Mefenamic acid, Belladonna total alkaloids Antipyretic, analgesic and / or anti-inflammatory agents such as;
Cloperastine hydrochloride, codeines (for example, dihydrocodeine phosphate and codeine phosphate), oxymethebanol, epradinone hydrochloride, tipepidine, tipepidine citrate, ephedrine hydrochloride, aloclamide hydrochloride, carbetapentane phenate, sodium dibunato, tipepidine hibenzate. , Cloperastine fendizoate, trimethoquinol hydrochloride, methoxyphenamine hydrochloride, dl-methylephedrine hydrochloride, noscapine hydrochloride, noscapine hydrochloride, dimemorphan or a salt thereof (eg, phosphate, sulfate, etc.), antitussive and / or bromhexine hydrochloride, etc. Expectorant: Bronchodilator such as ephedrine, theophylline, diphenhydramine or a salt thereof (for example, hydrochloride), chlorpheniramine or a salt thereof (for example, D-maleate); licorice ( Nzou Glycyrrhizae Radix
), Senega, Saiko (Bupleuri Radix), cinnamon (Cinnamomi Cortex), Kuzukon (Pherariae Radix), Mao (Ephedrae Herba), Kaigai (Schizonepetae Herb)
a), Forsythia (Forsythiae Fructus), Kyounin (Armeniacae Semen), Half Summer (Hange Pinellae Tuber)
), Peony (Paeoniae Radix), spicy (Saishin)
AsiasriRadix), Ginger (Zingiberis Rhiz)
oma), Schisandrae Fructus (Gomishi), Soilla (Perillae Herba), Ginseng Radix, Aurantii Nobilis Pericarpium); Vitamin B ₁ , Fursultiamine, Vitamin B ₂ ,
Vitamin C and other vitamins; magnesium hydroxide, magnesium oxide, aluminum hydroxide, aluminum sulfate, magnesium aluminometasilicate [eg, Neusilin (trade name)], magnesium aluminosilicate,
Synthetic hydrotalcite [eg Alcamak (trade name)], coprecipitation product of aluminum hydroxide / sodium hydrogen carbonate [eg cumulite (trade name)], antacids such as sucralfate and mucosal protective agents; minerals; Examples include amino acids. In the case of a cold medicine formulation, these medicinal components are usually blended based on the cold medicine standard in the Pharmaceutical Manufacturing Guidelines (1991 edition, Yakuhin Jikhosha).

As described above, dextromethorphans are chemically repellent to phenylpropanolamines, and when both are used in combination, the stability of each active ingredient decreases. Furthermore, the combination of ibuprofen with the above ingredients also reduces the stability of each active ingredient. In particular,
The stability of phenylpropanolamines is impaired. In order to stabilize the active ingredient of such combination avoidance,
The use of the caffeines is effective.

In the present invention, caffeine is
Depending on the blending amount, it may exert a stabilizing effect on other active ingredients, and may exert a medicinal effect by itself.

(A) A formulation containing dextromethorphans and phenylpropanolamines as active ingredients, which does not contain ibuprofen, and caffeines are added to these ingredients in order to sufficiently stabilize the active ingredients. The amount of caffeine based on 100 parts by weight of the two active ingredients is 2 to 1000 parts by weight, preferably 4 to
750 parts by weight, more preferably about 7 to 500 parts by weight. A particularly preferred amount of caffeine used is 10 to 300 parts by weight based on 100 parts by weight of the total amount of the active ingredients,
Preferably 15 to 200 parts by weight, more preferably 25
It is about 100 parts by weight.

In the above-mentioned preparation (A), the content of each active ingredient can be appropriately selected. Generally, dextromethorphans are contained in an amount of 1 to 25% by weight, preferably 2 to 20% by weight, based on the total amount of the preparation. , Phenylpropanolamines are 2
It is economical and effective to incorporate ˜35% by weight, preferably 5 to 30% by weight, caffeines 1 to 60% by weight, preferably 2 to 55% by weight, more preferably 4 to 50% by weight. .

(B) In a preparation containing dextromethorphans, ibuprofen, phenylpropanolamines as an active ingredient and containing caffeine, in order to enhance the stabilization of the active ingredient, the total amount of the active ingredient is 100. 1 to 1000 parts by weight, preferably 3 to 750 parts by weight, and more preferably 5 parts by weight of caffeine relative to parts by weight.
It is preferable to use about 500 parts by weight. A particularly preferred amount of caffeine used is 5 to 200 parts by weight, preferably 10 to 100 parts by weight, and more preferably 12 to 50 parts by weight, based on 100 parts by weight of the total amount of the active ingredients.

Also in the above-mentioned preparation (B), the content of each active ingredient can be appropriately selected, and generally, dextromethorphans are contained in an amount of 1 to 15% by weight, preferably 2 to 10% by weight, based on the total amount of the preparation. Phenylpropanolamines are 1 to
20 wt%, preferably 2-15 wt%, ibuprofen 5-70 wt%, preferably 10-60 wt%, caffeine 1-80 wt%, preferably 2-55 wt%, more preferably 4 It is economical and effective to blend in an amount of up to 50% by weight.

In the above-mentioned preparations (A) and (B), the amount of caffeine used for each active ingredient can be selected according to the kind of the active ingredient, and for example, 0. 5 to 1000 parts by weight, preferably 5 to 5
00 parts by weight, more preferably about 10 to 300 parts by weight, and often about 25 to 200 parts by weight.

A feature of the present invention is that even if dextromethorphans and ibuprofen are mixed with phenylpropanolamines, the stability of the active ingredient can be improved by caffeine. Therefore, in the preparation of the present invention, the above components can be mixed in the same group, which is desirable from the viewpoint of productivity. That is, even if phenylpropanolamines and dextromethorphans and ibuprofen, which are chemically compounded with respect to phenylpropanolamines, are added to the same group, caffeine is added to the group, or By coexisting caffeine with the group, it is possible to significantly suppress the decrease in stability of each active ingredient.

Further, (1) a mixture of a group containing dextromethorphans and phenylpropanolamines and a group containing caffeine separated from this group, (2) dextromethorphans, ibuprofen and phenylpropanol By mixing the group containing amines and the group containing caffeines separated from this group, a preparation in which the active ingredient is stabilized can be obtained.

Further, it is preferable from the viewpoint of stability of the active ingredient that the group of dextromethorphans and the group of phenylpropanolamines are separated into separate groups. Ibuprofen is often added to the group of dextromethorphans. In this aspect, for example,
(3) A method of separating each component of the dextromethorphans, ibuprofen and phenylpropanolamines into separate groups, (4) a group of dextromethorphans or a group of dextromethorphans and ibuprofen, and phenylpropanolamine It is possible to adopt a method of separating into a group with a class. In these aspects,
Caffeine may be added to any group containing an active ingredient, for example, a group of phenylpropanolamines, or may form a group independent of the group containing an active ingredient.

The stabilizing effect of the present invention is achieved by incorporating caffeines into one preparation containing, if necessary, dextromethorphans and phenylpropanolamines together with ibuprofen.

Upon formulation, components having poor mixability may be blended in separate groups. Usually, it is convenient to use a carrier for suppressing contact between components having poor mixability.

As the carrier, there can be used conventional additives which do not impair the stability of the active ingredient and are used in the production of granulated powder. Examples of the carrier include lactose, sucrose, mannitol, corn starch, talc, crystalline cellulose [Avicel (trade name)], magnesium stearate, light anhydrous silicic acid, magnesium carbonate, calcium carbonate, L-cysteine and the like. Agents: starch, pregelatinized starch, gelatin, gum arabic powder, methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose,
Binders such as hydroxypropylmethylcellulose, polyvinylpyrrolidone, pullulan, and dextrin; carboxymethylcellulose calcium [carmellose calcium, for example, ECG505 (trade name)], low-substituted hydroxypropylcellulose, croscarmellose sodium [for example, Acdysol (trade name) )] And other disintegrants; anionic surfactants such as sodium alkylsulfate; nonionic surfactants such as polyoxyethylene sorbitan fatty acid esters, polyoxyethylene fatty acid esters and polyoxyethylene castor oil derivatives; Colorant; Flavoring agent; Adsorbent; Preservative; Wetting agent;
Antistatic agents; disintegration extenders and the like. Of these carriers, at least excipients and binders are commonly used,
Often used together with a disintegrant.

As described above, in the preparation of the present invention, each component of dextromethorphan, ibuprofen and phenylpropanolamine is stabilized by incorporating caffeine.

In a more preferable mode of stabilization, at least one of dextromethorphans (optionally with ibuprofen) and phenylpropanolamines is prepared by using a carrier in order to suppress contact with the active ingredient. It is contained in the granulated powder. In this case, the granulated powder of one group containing the active ingredient and the carrier may be mixed with the other group of the non-granulated active ingredient.

In a further preferred embodiment, dextromethorphans, ibuprofen and phenylpropanolamines may be contained in different granulated powders. Also, dextromethorphans and ibuprofen may be granulated in the same group and phenylpropanolamines may be granulated in another group to obtain a granulated powder. Caffeine may be added to each group, or may be added to any one group. Further, the caffeine may be an independent group of granulated powder separated from the granulated powder of the active ingredient as long as it coexists with the group of the active ingredient. In this case, for example, by mixing the granulated powder of the group of dextromethorphans, the granulated powder of the ibuprofen group, and the granulated powder obtained by grouping such as the granulated powder of the phenylpropanolamine group, Solid formulations can be prepared.

As a preferable mode of grouping, that is, a preferable method of blending into different groups, the above-mentioned (1) is used.
In addition to the method of separately granulating the active ingredients having poor compounding stability and reducing the contact area of each active ingredient to stabilize, (2) a mixture of the granulated powders grouped into capsules. Filling method, (3) tableting a mixture of grouped granulated powder, (4) using a layered tablet machine (for example, Kikusui Seisakusho) using each grouped granulated powder Method of forming tablet, (5) Method of forming sandwich type tablet by providing a buffer layer which may be thin between each layer in a tablet of multiple layers, (6) At least one group of active ingredients coated with polymer or micro It includes a method of encapsulating, separating and stabilizing both. More preferable and more specific methods of such grouping and compounding include, for example, the following methods.

That is, in the grouping formulation, the group containing dextromethorphans is prepared by mixing dextromethorphans with other drugs, if necessary, a carrier, preferably at least a binder and an excipient, It can be obtained by granulating by a conventional method. For example, when using the wet fluidized bed granulation method, the granulated powder of the dextromethorphan group contains dextromethorphans and, if necessary, other drugs, additives such as excipients and disintegrants, etc. It can be obtained by a method in which an appropriate amount is added and mixed, and a binder such as an aqueous solution of hydroxypropyl cellulose is sprayed with a fluidized bed granulator and dried. In addition, stirring granulation, extruding the kneaded product obtained by kneading, etc.,
After spheroidizing by spheronizing means such as Marumerizer,
A method such as drying is also possible.

On the other hand, the phenylpropanolamine group also
It can be obtained by using phenylpropanolamines instead of dextromethorphans and granulating in the same manner as in the above-mentioned dextromethorphan group.

When the group containing phenylpropanolamine contains a large amount of reducing sugars such as lactose and sucrose, both when the active ingredients are grouped and in the same group, phenylpropanolamine is contained. The stability of the class is impaired. Therefore, in the phenylpropanolamine group, the content of reducing sugars should be minimized within the range where the stability of the medicinal component can be maintained, that is, the same group contains an amount of reducing sugars that adversely affects the stability. Preferably not. More specifically, in the phenylpropanolamine group, (1) no reducing sugar is blended, or (2) when a reducing sugar is blended, 10% of the granulated powder containing phenylpropanolamines is added. Weight% or less, preferably 7% by weight
It is preferable to stop below. Further, (3) sugar alcohols having no reducing OH group in place of the reducing sugar,
For example, mannitol, maltitol, sorbitol and the like are preferably added.

In addition, phenylpropanolamines are
In some cases, coexisting caffeine can enhance the stability of the phenylpropanolamines even if the dextromethorphans and / or ibuprofen, which are compounding repellent, are compounded in combination with a reducing sugar.

In a formulation containing ibuprofen,
Ibuprofen may be added to the above-mentioned group of dextromethorphans, and as a different group, it can be granulated in the same manner as the group of dextromethorphans. In the case of grouping, caffeine may be blended with an active ingredient in each group and granulated, or may be blended in either group and granulated, or only caffeine. May be granulated in the same manner as above.

A preparation in which the active ingredient is mixed in the same group can also be granulated by a conventional granulation method using the active ingredient / carrier.

For the preparation of the granulated powder, generally used granulation methods, for example, spray granulation method using solution or dispersion containing water or organic solvent, stirring granulation method, fluidized granulation method, rolling Either a wet granulation method such as a granulation method or a tumbling flow granulation method, or a dry granulation method such as a consolidation granulation method using a powdery or granular binder can be used.

The solid preparation of the present invention is in the form of fine granules, granules, pills, tablets prepared by compressing the fine granules or granules, or capsules filled with the fine granules or granules in capsules. And so on. The average particle size of the fine granules is, for example, 10 to 5
It is about 100 μm, preferably about 100 to 500 μm.
The average particle size of the granules is, for example, about 500 to 1500 μm.

Solid formulations containing fine granules, granules and pills are
Granulated powder containing each active ingredient in the same group, or when the active ingredients are grouped and mixed, granulated powder containing one or more active ingredients (for example, dextromethorphans (including ibuprofen Granules of the group)
The granulated powder of the phenylpropanolamine group and, if necessary, the granulated powder of the ibuprofen group) may be mixed as they are, and the mixture may be divided into small parts and filled. In the case of a capsule, a granulated powder containing each of the active ingredients in the same group, or a granulated powder containing one or more active ingredients (for example, the dextromethorphans (including ibuprofen The granulated powder of the group), the granulated powder of the phenylpropanolamine group and, if necessary, the granulated powder of the ibuprofen group) may be mixed and directly filled into a capsule using a capsule filling machine. The granulated powder may be packed in two or more layers.

Further, the tablet may be a granulated powder containing each active ingredient in the same group, or a granulated powder containing one or more active ingredients (for example, the dextromethorphans (ibuprofen may be included). (Good) group, the phenylpropanolamine group, and optionally the ibuprofen group), and a carrier (for example, an excipient, a binder, a disintegrating agent, etc.), and the mixture is molded by compression. Can be prepared.

In the cold medicine preparation, the content of ibuprofen may be about 50 to 90% by weight, preferably about 60 to 80% by weight of the usual medical dose when the active ingredient is ibuprofen alone. Depending on the type of formulation, the dose of ibuprofen group depends on the dose of ibuprofen per adult,
1-1000 mg / day, preferably 1-600 mg / day
The amount is preferably 30 to 500 mg / day, more preferably about 30 to 500 mg / day.

The dose of dextromethorphans is 1 to 100 mg, preferably 3 to 7 per adult per day.
The dose of 5 mg of phenylpropanolamines is 0.5 to 200 mg, preferably 1 per adult per day.
~ 100 mg. The dose of caffeine is 3 to 500 mg, preferably 10 to 35, per adult per day.
It is 0 mg. The size of the preparation is appropriately determined depending on the amounts of the components to be mixed.

The formulations of the present invention may also be coated for various purposes of function. As the coating agent, a sugar coating composition containing a commonly used sugar as a main component and a film-forming composition containing a cellulosic base as a main component are used. As components of such a coating agent,
Generally, sugars (eg, granulated sugar, mannitol etc.), gum arabic, talc, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, ethyl cellulose, hydroxymethyl cellulose, cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, hydroxymethyl cellulose acetate succinate, acrylic acid. Copolymers, carboxymethylethyl cellulose, polyvinyl acetal diethylaminoacetate, shellac, waxes and the like can be mentioned, and two or more kinds of them may be used. As the coating agent, a commonly used coating aid may be used, and examples of such a coating aid include sugars (eg lactose, mannitol etc.), polyethylene glycol, polysorbates (eg Tween 80 etc.), oxidation Colorants such as titanium and red iron oxide are used.

The coating amount of the coating agent can be selected according to the type of solid preparation. The coating amount of the solid preparation is 0.1 to 30% by weight for tablets, preferably about 0.5 to 10% by weight, and 0.1 to 50% by weight for pills and granules, preferably 1 to 20% by weight. %, And for fine granules, it is 0.1 to 100% by weight, preferably 1 to 50% by weight.

The coating can be carried out in a conventional manner, for example by
A pan coating method, a fluidized coating method, a tumbling coating method, or a combination thereof can be adopted. When the coating agent is a solution or dispersion containing water or an organic solvent, a spray coating method can also be used. The use ratio of the water or the organic solvent is, for example, 25 to
It is about 99% by weight. The type of organic solvent is not particularly limited, and examples thereof include alcohols such as methanol, ethanol and isopropyl alcohol; ketones such as acetone; halogenated hydrocarbons such as chloroform, dichloromethane and trichloroethane. Preferred solvents include water and / or alcohols, especially water.

The solid pharmaceutical preparation of the present invention is stable because the decomposition of the active ingredient over time is suppressed. When the pharmaceutical composition of the present invention is used as a general cold remedies including general cold remedies for mammals such as humans for the treatment of colds, solid preparations such as tablets, granules and capsules are orally administered by a conventional method. be able to.

[0056]

INDUSTRIAL APPLICABILITY According to the present invention, each active ingredient can be stabilized by adding caffeine to a preparation containing dextromethorphan, phenylpropanolamine or a salt thereof together with ibuprofen, if necessary.
Degradation, deterioration and discoloration of each component are suppressed, and there is very little change in quality over time. Therefore, according to the present invention, a stable pharmaceutical solid preparation having a long quality guarantee period and a high product value can be obtained.

According to the method of the present invention, in addition to both dextromethorphans and phenylpropanols, which are active ingredients for avoiding compounding, and ibuprofen, the above active ingredients are stable. Can be converted. Therefore, the stability of the active ingredient, especially phenylpropanols, can be maintained at a high level for a long period of time.

[0058]

EXAMPLES The present invention will be described in more detail with reference to Examples, Comparative Examples and Experimental Examples, but these do not limit the present invention.

Example 1 Ibuprofen (hereinafter sometimes referred to as IBU)
1350 g, dextromethorphan hydrobromide (hereinafter sometimes referred to as DMP) 144 g, phenylpropanolamine hydrochloride (hereinafter sometimes referred to as PPA) 225 g, anhydrous caffeine (hereinafter referred to as CAF) 225 g, lactose 156 g, crystalline cellulose 600 g, hydroxypropyl cellulose (hereinafter sometimes referred to as HPC-L) 150 g, low-substituted hydroxypropyl cellulose (hereinafter L-HPC)
150 g of a high-speed agitation granulator (manufactured by Powrex: vertical granulator, FM-
While stirring in G25), 1200 g of distilled water was added all at once to granulate.

The granulated product was extruded into a thin column shape by an extrusion granulator (manufactured by Fuji Paudal: Dome Gran, DG-L1) equipped with a 0.35 mmφ punching screen, and then mulledizer (manufactured by Fuji Paudal). : QJ-23
In 0), it was made into spherical fine particles. Generate spherical fine particles at 40 ℃ 1
After vacuum drying for 0 hour, 2750 g of fine particles were obtained.

Example 2 1125 g of IBU, 120 g of DMP and 18 of PPA
8g, lactose 114g, crystalline cellulose 442g, HPC
While 111 g of -L and 110 g of L-HPC were stirred by a high-speed stirring type granulator, 884 g of distilled water was added all at once to granulate, followed by vacuum drying at 40 ° C for 14 hours to obtain a dried product of 1. Granulate with a crusher (Showa Kagaku Kikai: Power Mill, P-3S) with a 5mmφ punching screen set,
The sized powder (hereinafter also referred to as IDP) 201
0 g was obtained.

On the other hand, CAF 1500 g, lactose 124
g, crystalline cellulose 464 g, HPC-L 116 g,
After taking 116 g of L-HPC and stirring with a high-speed agitation granulator, the distilled water was added all at once to granulate, and the same procedure as for IDP sized powder was performed to obtain 2105 g of CAF sized powder.

IDP sized powder 884 g, CAF sized powder 11
6 g, crystalline cellulose 333 g, L-HPC 60 g,
Take 7 g of magnesium stearate and mix with a tumble type mixer (Showa Kagaku Kikai: tumbler mixer, TM-1
5) for 1 minute to obtain a mixed powder, and a rotary tableting machine (Kikusui Seisakusho, Collect 19) equipped with a 9.5 mmφ punch.
Using K), 280 mg per tablet and about 4300 lens-shaped tablets having a thickness of about 5 mm were obtained.

Example 3 1350 g of IBU, 144 g of DMP, 22 of PPA
5 g, CAF 225 g, corn starch 636 g, crystalline cellulose 300 g, HPC-L 30 g, ECG5
While taking 90 g of 05 and stirring with a high-speed stirring granulator,
Distilled water (600 g) was added all at once to granulate, and the mixture was extruded into a cylindrical shape with an extrusion granulator equipped with a 0.7 mmφ punching screen, and then made into spherical granules with a marumerizer.
The spherical granules were vacuum dried at 40 ° C. for 10 hours to obtain 2840 g of spherical granules. The spherical granules were made into a No. 1 capsule having a total amount of 340 mg by using a capsule filling machine (manufactured by IMA (IMA; Italy): Zanasi-6F). The major axis of the capsule was about 19 mm.

Comparative Example 1 The CAF sized powder was removed from the mixed powder of Example 2, and the same procedure was followed to obtain 4200 lens-shaped tablets having a thickness of about 5 mm and 275 mg per tablet.

Experimental Example 1 The tablets obtained in Example 2 and Comparative Example 1 were placed in a glass bottle, sealed and stored at 60 ° C. for 2 weeks, and the content of each component was quantified by high performance liquid chromatography. The residual ratio with respect to the content before storage was determined by the following formula, and the results are shown in Table 1. The appearance was visually observed for change.

Residual rate (%) = (content after storage at 60 ° C./content before storage) × 100

[0068]

[Table 1] From the results in Table 1, it can be seen that the CAF addition stabilizes the contents and appearance of IBU, DMP and PPA even if the preparation of the present invention is not grouped.

Experimental Example 2 The fine granules and capsules obtained in Examples 1 and 3 were placed in a glass bottle, sealed, and stored at 40 ° C. and 57% RH for 4 weeks. .

[0070]

[Table 2] From the results shown in Table 2, the preparation of the present invention contained in the same group IBU,
It can be seen that the content of the active ingredient is stable even when DMP, PPA and CAF are blended.

Example 4 1350 g of IBU, 144 g of DMP and 22 of PPA
5 g, CAF 250 g, belladonna total alkaloid 1.5 g, corn starch 241.5 g, crystalline cellulose 420 g, HPC-L 84 g, L-HP
While stirring 84 g of C with a high-speed stirring type granulator, 1000 g of distilled water was added all at once to perform granulation. Granulate the product with 0.
The mixture was extruded into a thin column shape by an extrusion granulator equipped with a 9 mmφ punching screen, and then formed into spherical granules by a Marumerizer. Vacuum-dry the spherical granules at 40 ° C for 16 hours, and
650 g of granules were obtained.

Comparative Example 2 1350 g of IBU, 144 g of DMP, 22 of PPA
5 g, crystalline cellulose 450 g, HPC-L 90
g, L-HPC 90 g, and lactose 651 g were stirred with a high-speed agitation granulator, and 1000 g of distilled water was added all at once to granulate. The granulated product was extruded into a thin column shape by an extrusion granulator equipped with a 0.7 mmφ punching screen, and then made into spherical granules by a Marumerizer. 40 spherical granules
It was vacuum dried at 16 ° C. for 16 hours to obtain 2860 g of granules.

Examples 5 to 9 In Comparative Example 2, part of lactose was replaced with CAF, and the CAF content in all the granules was 1% by weight (Example 5) and 2% by weight.
(Example 6) 3% by weight (Example 7), 4% by weight (Example 8) and 6% by weight (Example 9) were used to obtain granules in the same manner as in Comparative Example 2.

Experimental Example 3 The granules obtained in Comparative Example 2 and Examples 5 to 9 were placed in a glass bottle, sealed, and stored at 60 ° C. for 2 weeks, and the content of each component was quantified by high performance liquid chromatography. When the residual rate was calculated, the results shown in Table 3 were obtained.

[0075]

[Table 3]

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Internal reference number FI Technical display location A61K 31/485 ACG 9454-4C (72) Inventor Mitsutaka Isobe 2-8 Yamada Nishi, Suita City, Osaka Prefecture A8-812

Claims (34)

[Claims] 1. A stabilized solid preparation comprising dextromethorphans, phenylpropanolamines and caffeine. 2. The solid preparation according to claim 1, wherein dextromethorphans and phenylpropanolamines are mixed in separate groups. 3. The solid preparation according to claim 2, wherein an active ingredient of either dextromethorphan or phenylpropanolamine is contained in the granulated powder. 4. The solid preparation according to claim 2, wherein dextromethorphans and phenylpropanolamines are contained in different granulated powders. 5. The solid preparation according to claim 1, wherein dextromethorphans and phenylpropanolamines as active ingredients are stabilized with caffeine. 6. 2 per 100 parts by weight of the total amount of active ingredients
The solid preparation according to claim 5, wherein the active ingredient is stabilized by caffeine of about 1000 parts by weight. 7. A café containing 1 to 25% by weight of dextromethorphans and 2 to 35% by weight of phenylpropanolamines as an active ingredient based on the total amount of the preparation, and a cafe to 100 parts by weight of the total amount of the active ingredients. The solid preparation according to claim 5, which comprises 4-750 parts by weight of ins. 8. A dextromethorphan and phenylpropanolamines are contained as active ingredients, and 0.5 to 100 per 100 parts by weight of each active ingredient.
The solid preparation according to claim 1, wherein the active ingredient is stabilized by 0 part by weight of caffeine. 9. The solid preparation according to claim 1, which contains 2 to 20% by weight of dextromethorphan, 5 to 30% by weight of phenylpropanolamines, and 1 to 60% by weight of caffeine based on the total amount of the preparation. 10. A granulated powder in which caffeine is added to a group containing (1) dextromethorphans and phenylpropanolamines, or (2) a group containing dextromethorphans and phenylpropanolamines The solid preparation according to claim 1, comprising a granulated powder and a granulated powder containing caffeine. 11. A granulated powder containing dextromethorphans, and a granulated powder containing phenylpropanolamines,
Composed of caffeine that coexists with these granulated powders,
In the granulated powder containing the phenylpropanolamines,
The solid preparation according to claim 4, wherein the content of the reducing sugar is suppressed to a minimum within a range in which the stability of phenylpropanolamines can be maintained. 12. The solid preparation according to claim 1, which further contains ibuprofen. 13. The solid preparation according to claim 12, wherein ibuprofen is incorporated into the group of dextromethorphans. 14. The solid preparation according to claim 13, wherein ibuprofen, dextromethorphan, and phenylpropanolamine are contained in different granulated powders. 15. The active ingredient is stabilized with 1 to 1000 parts by weight of caffeine per 100 parts by weight of the total amount of the active ingredients, phenylpropanolamines, dextromethorphans and ibuprofen. 12. The solid preparation according to item 12. 16. Phenylpropanolamines, dextromethorphans and ibuprofen as active ingredients, and 100 parts by weight of each active ingredient,
The solid preparation according to claim 12, wherein the active ingredient is stabilized by 0.5 to 1000 parts by weight of caffeine. 17. A dextromethorphan compound in an amount of 1 to 15% by weight, a phenylpropanolamine compound in an amount of 1 to 20% by weight, an ibubrofen in an amount of 5 to 70% by weight, and a caffeine compound in an amount of 1 to 80% by weight based on the total amount of the preparation. 12. The solid preparation according to item 12. 18. Phenylpropanolamines, dextromethorphans and ibuprofen are contained as active ingredients in the same granulated powder, and the total amount of the active ingredients is 1
The solid preparation according to claim 12, wherein the active ingredient is stabilized by 5 to 500 parts by weight of caffeine relative to 00 parts by weight. 19. The solid preparation according to claim 1, which is a fine granule, a granule, a pill, a tablet, or a capsule. 20. The solid preparation according to claim 1, which is a cold medicine preparation. 21. A method for stabilizing caffeine by adding caffeine to a solid preparation containing dextromethorphans and phenylpropanolamines as active ingredients. 22. Caffeines are added to a solid preparation further containing ibuprofen as an active ingredient.
1. The stabilization method according to 1. 23. The stabilizing method according to claim 21, wherein 7 to 500 parts by weight of caffeine are allowed to coexist with 100 parts by weight of the total amount of the active ingredient. 24. A method for producing a stable solid preparation, which comprises adding caffeine to a solid preparation containing dextromethorphans and phenylpropanolamines. 25. The granulated powder containing at least one component selected from dextromethorphans, phenylpropanolamines and caffeine, and another optionally granulated component are mixed. A method for producing a stable solid preparation. 26. The method for producing a stable solid preparation according to claim 24, wherein dextromethorphans, phenylpropanolamines and caffeine are granulated using a carrier. 27. The stable solid preparation according to claim 24, wherein a granulated powder containing both components of dextromethorphans and phenylpropanolamines and a granulated powder containing caffeine are prepared and mixed. Manufacturing method. 28. The method for producing a stable solid preparation according to claim 24, wherein caffeines are further added to the solid preparation containing ibuprofen. 29. The method for producing a stable solid preparation according to claim 28, wherein phenylpropanolamines, dextromethorphans, ibuprofen and caffeine are granulated using a carrier. 30. A granulated powder containing dextromethorphans, ibuprofen and phenylpropanolamines and a granulated powder containing caffeine are mixed.
8. The method for producing a stable solid preparation according to 8. 31. The optionally granulated caffeine is allowed to coexist in a mixture of the granulated powder containing dextromethorphans and ibuprofen and the granulated powder containing phenylpropanolamines. A method for producing a stable solid preparation. 32. A method of using caffeine for stabilizing dextromethorphans and phenylpropanolamines. 33. The method for using caffeine according to claim 32, for stabilizing dextromethorphans and phenylpropanolamines contained in a solid preparation. 34. The method of using caffeine according to claim 32 for stabilizing phenylpropanolamines, dextromethorphans and ibuprofen contained in a solid preparation.