JP2003300874A - Solid preparation containing pseudoephedrine hydrochloride - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a solid preparation containing pseudoephedrine hydrochloride having stability with time, excellent efficacy of the drug and a high commercial value. <P>SOLUTION: This solid preparation containing pseudoephedrine hydrochloride is produced (i), by separately formulating pseudoephedrine hydrochloride with one or more drugs selected from the group consisting of acetaminophen, mequitazine, dihydrocodeine phosphate and guaifenesin, is (ii) not mixed with lactose and is (iii) stabilized by reduction in water content of the preparation. <P>COPYRIGHT: (C)2004,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a solid preparation containing pseudoephedrine hydrochloride.

[0002]

BACKGROUND ART Pseudoephedrine hydrochloride (pseudoephedr)
is a known compound having an action of suppressing rhinitis (snot, nose, sneezing, etc.), like phenylpropanolamine hydrochloride. However, it has been revealed that there is a problem with stability over time in the solid preparation of a comprehensive cold medicine containing pseudoephedrine hydrochloride. That is, together with antipyretic analgesics, antitussives, rhinitis suppressors, central stimulants and vitamins commonly used for cold medicines, pseudoephedrine hydrochloride is blended as a component for suppressing rhinitis, and further used as excipients in tablets and bound. When tablets were manufactured according to a conventional method by adding a disintegrating agent and a disintegrant, a change in appearance of the tablets and a decrease in the content of pseudoephedrine hydrochloride were observed in the stability test with time. Therefore, it has been demanded to develop a solid preparation having good stability.

[0003]

Accordingly, it is an object of the present invention to provide a solid preparation containing pseudoephedrine hydrochloride, which is highly stable over time.

[0004]

[Means for Solving the Problems] In the course of research for achieving the above-mentioned object, the present inventors separately prepared pseudoephedrine hydrochloride and a specific active ingredient, and stabilized when a specific carrier was not added. It has been found that a highly stable preparation can be obtained, and the preparation can be stabilized by lowering the water content of the preparation to obtain a highly stable preparation. The present invention has been completed after further studies based on the above findings.

That is, the present invention provides (1) a stabilized solid preparation containing pseudoephedrine hydrochloride, (2)
1 or more selected from the group consisting of acetaminophen, mequitazine, dihydrocodeine phosphate, and guaifenesin, and pseudoephedrine hydrochloride, and 1 selected from the group consisting of acetaminophen, mequitazine, dihydrocodeine phosphate, and guaifenesin. The solid preparation according to (1) above, which is stabilized by separately mixing and manufacturing the above-mentioned drugs, (3) The solid preparation according to (1), which is stabilized by not adding lactose, (4) ) The solid preparation described in (1) above, which is stabilized by reducing the water content of the preparation, and (5) the solid preparation described in (4), which is stabilized by setting the equilibrium relative humidity of the preparation to 50% or less. , (6) Further acetaminophen, mequitazine, dihydrocodeine phosphate and guaifenesi It contains one or more agents selected from the group consisting of is selected from the group consisting of (i) and pseudoephedrine hydrochloride, acetaminophen, mequitazine, phosphate dihydrocodeine and guaifenesin 1
A solid preparation according to the above (1), which is stabilized by separating and mixing the above-mentioned agents with each other, (ii) not adding lactose, and (iii) reducing the water content of the preparation. To do.

[0006]

The dosage form of the solid preparation of the present invention is not particularly limited and includes dosage forms such as fine granules, granules, pills, tablets (including film-coated tablets), capsules and the like. . The solid preparation of the present invention comprises an effective amount of pseudoephedrine hydrochloride and an active ingredient optionally added, and an excipient, a binder, a disintegrating agent, a film coating agent, a lubricant, which are optionally added respectively. It contains conventional formulation additives such as antioxidants, fragrances, and colorants in appropriate amounts.

The active ingredient which the solid preparation of the present invention may contain in addition to pseudoephedrine hydrochloride is not particularly limited and is selected according to the use of the solid preparation of the present invention. For example, when the solid preparation of the present invention is a cold medicine preparation, acetaminophen, mequitazine, dihydrocodeine phosphate, guaifenesin, anhydrous caffeine, hesperidin and the like can be mentioned. However, in this regard, the present inventors have reported that pseudoephedrine hydrochloride,
It has been found that the stability of the solid formulation decreases when it is combined with one or more drugs selected from the group consisting of acetaminophen, mequitazine, dihydrocodeine phosphate and guaifenesin. Furthermore, the present inventors have selected from the group consisting of pseudoephedrine hydrochloride, acetaminophen, mequitazine, dihydrocodeine phosphate, and guaifenesin 1 based on these findings.
It was found that the pseudoephedrine hydrochloride-containing preparation can be stabilized by separately compounding the above-mentioned agents.
That is, one embodiment of the present invention is a solid preparation containing pseudoephedrine hydrochloride and one or more drugs selected from the group consisting of acetaminophen, mequitazine, dihydrocodeine phosphate and guaifenesin, wherein pseudoephedrine hydrochloride and acetoacetate are used. It is a solid preparation containing pseudoephedrine hydrochloride stabilized by separately compounding one or more drugs selected from the group consisting of aminophen, mequitazine, dihydrocodeine phosphate and guaifenesin. As a method of separation and blending, a conventional method suitable for the dosage form of the solid preparation described above may be adopted. For example, in the case of granules, it is divided into a group containing pseudoephedrine hydrochloride and a group containing one or more drugs selected from acetaminophen, mequitazine, dihydrocodeine phosphate, and guaifenesin, and then granulated. The granulated powder thus obtained may be mixed. Alternatively, the active ingredients of at least one group of the granulated powder thus obtained may be coated with a polymer and then mixed. In the case of tablets, as in the case of the above-mentioned granules, the mixture of granulated powder obtained by grouping and granulating may be tabletted. Alternatively, a granulated powder obtained by grouping and granulating may be used to form a tablet having two layers by a commercially available laminated tablet machine.

[0008] Usually, in the production of solid preparations, excipients are used for various purposes such as dilution of the active ingredient and increase of the preparation. As the excipient, lactose, which has many advantages such as low hygroscopicity and low reactivity with various main drugs, is most often used. However, the present inventors have unexpectedly found that, in a solid preparation containing pseudoephedrine hydrochloride, this lactose affects stability, and that the pseudoephedrine hydrochloride-containing solid preparation can be stabilized by not adding lactose. Found. That is, one aspect of the present invention is a pseudoephedrine hydrochloride-containing solid preparation stabilized by not adding lactose. As the excipient used in the solid preparation of the present invention, it is necessary to use something other than lactose. Further, it is preferable to use a substance other than the disaccharide. Examples of suitable excipients used in the solid preparation of the present invention include sugar alcohols such as D-mannitol; starches such as starch, α-starch, dextrin and carboxymethyl starch or derivatives thereof; crystalline cellulose, low-substituted hydroxypropyl. Cellulose and cellulose or cellulose derivatives such as internally cross-linked sodium carboxymethyl cellulose; arabila gum; dextran; pullulan; light silicic anhydride,
Examples thereof include silicic acid such as synthetic aluminum silicate and magnesium aluminometasilicate or a salt thereof; inorganic salts such as calcium phosphate, calcium carbonate and calcium sulfate. Among them, D-mannitol is particularly preferable. These excipients may be used in the amounts usually used for producing solid preparations. The binder, disintegrant, film coating agent, lubricant, antioxidant, fragrance, and colorant used in the solid preparation of the present invention are not particularly limited,
Pharmaceutical additives commonly used in solid preparations can be used in the amounts usually used. For example, crystalline cellulose, hydroxypropyl cellulose or the like can be used as the binder, and croscarmellose sodium or the like can be used as the disintegrant. As the film coating agent, hydroxypropylmethyl cellulose or the like can be used.

The present inventors have also found that the water content in the air affects the stability of the pseudoephedrine hydrochloride-containing solid component, and by reducing the water content of the formulation, the pseudoephedrine hydrochloride-containing solid component can be stabilized. I found that. That is, one aspect of the present invention is a pseudoephedrine hydrochloride-containing solid preparation stabilized by reducing the water content of the preparation. To reduce the water content of the preparation, specifically, it is preferable to prepare the preparation so that the final equilibrium relative humidity (ERH) of the preparation is 75% or less. More preferably, it is 50% or less. What is equilibrium relative humidity?
When about 1 g of the solid preparation of the present invention is placed in an airtight container at 25 ° C., it means the equilibrium relative humidity indicated by the space in the airtight container, the following formula: Equilibrium relative humidity = P / PS × 100 P indicates the water vapor pressure on the surface of the substance, and PS indicates the water vapor pressure on pure water at the same temperature as the substance. ] Can be obtained by the calculation formula. The equilibrium relative humidity can be easily measured by a commercially available apparatus for measuring water activity such as Hygroscope DT type (trade name, manufactured by Rotronic (Switzerland)). Equilibrium relative humidity (E.
R. The H) can be adjusted to a certain value or less by a known method such as measuring the equilibrium relative humidity of the preparation and adjusting the amount of water used in the preparation. After the formulation, the equilibrium relative humidity (E.
R. It is preferable to maintain H).

By any of the above, the solid preparation containing pseudoephedrine hydrochloride can be stabilized.
By combining two or three of these, it is possible to further stabilize the solid formulation containing pseudoephedrine hydrochloride.

The blending amount of pseudoephedrine hydrochloride in the solid preparation of the present invention is not particularly limited as long as it exhibits its medicinal effect, but is usually 1 to 50% by weight, preferably 2 to 20% by weight, more preferably Is 3 to 8% by weight
Is. Other active ingredients may be added in an effective amount usually used for solid preparations.

The solid preparation of the present invention can be produced by any conventional method (eg, agitation granulation method, fluidized bed granulation method, dry method, etc.) depending on the dosage form, except for the above-mentioned limitation for stabilization. Granulation method,
Etc.) can be adopted.

The solid preparation of the present invention, depending on its dosage form,
It can be administered in the same manner as a usual solid preparation. The dose varies depending on the use of the preparation, but for example, in the case of a cold medicine preparation, administration is usually carried out three times a day, and generally in adults (60k
In (g), the dose of pseudoephedrine hydrochloride is about 50 mg to 200 mg, preferably about 100 to 150 mg per day.

[0014]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited thereto.

Example 1 According to the formulation shown in Table 1, acetaminophen, mequitazine, dihydrocodeine phosphate, pseudoephedrine hydrochloride, guaifenesin, anhydrous caffeine, hesperidin, corn starch, crystalline cellulose and croscarmellose sodium were added to form a fluidized bed. Granulator (FD-5S
Type fluidized granulator, made by Paulec), supply air temperature 70 ℃
Then, a 6% aqueous solution of hydroxypropyl cellulose was sprayed as a binder to granulate, and then dried to produce a granulated powder. Power mill (Showa Kagaku Kikai, screen size 2 mm
φ) to obtain a sized powder, crystalline cellulose, croscarmellose sodium, and magnesium stearate are added and roughly mixed, and then placed in a tumbler mixer (TM-60S type manufactured by Showa Kagaku Kikai) at 10 rpm. And mixed for 3 minutes. Then, an uncoated tablet was obtained using a collect 12HUK tableting machine (Kikusui Seisakusho, 30 pm) with an 8.5 mmφR plain plain punch at a weight of 270 mg per tablet and a compression pressure of 1200 kg / per punch. The obtained plain tablets are coated with a film coating device (Dower Coater DRC manufactured by Paulec Co., Ltd.).
-500 type), the film coating liquid prepared according to the formulation of Table 2 was rotated at 8 rpm, air supply temperature was 70 ° C., air supply amount was 4 m ³ / min, liquid supply rate was 12 g / min, and spray air amount was 4000 Nl / hr. The film-coated tablet was obtained by operating under the conditions of.

[0016]

[Table 1]

[0017]

[Table 2]

Example 2 Acetaminophen, mequitazine, dihydrocodeine phosphate, pseudoephedrine hydrochloride, guaifenesin, anhydrous caffeine, hesperidin, corn starch, crystalline cellulose, croscarmellose sodium and D-mannitol were added according to the formulation shown in Table 3. After granulating in the same manner as in Example 1, uncoated tablets were produced and film-coated to obtain film-coated tablets.

[0019]

[Table 3]

Example 3 As shown in Table 4, the M group was acetaminophen, mequitazine, dihydrocodeine phosphate, guaifenesin, corn starch, crystalline cellulose and croscarmellose sodium in a fluid bed granulator (FD-5S type fluid). A layered granulator (manufactured by Powrex) was charged, and a 6% aqueous solution of hydroxypropyl cellulose as a binder was sprayed at an air supply temperature of 70 ° C. to granulate and then dried to produce a granulated powder. On the other hand, P group is pseudoephedrine hydrochloride, anhydrous caffeine, hesperidin, corn starch, crystalline cellulose, croscarmellose sodium, and fluid bed granulator (FD-5S).
Type fluidized bed granulator, made by Paulec), and supply air temperature 70
6% hydroxypropyl cellulose as binder at ℃
After the aqueous solution was sprayed and granulated, it was dried to produce a granulated powder.
Both granulated powders were pulverized by the same method as in Example 1 to produce sized powders, and plain tablets were obtained. Then, film coating was performed under the same conditions to obtain film-coated tablets.

[0021]

[Table 4]

Control Example 1 As shown in Table 5, acetaminophen, mequitazine, dihydrocodeine phosphate, pseudoephedrine hydrochloride, guaifenesin, anhydrous caffeine, hesperidin, lactose, corn starch, crystalline cellulose, and croscarmellose sodium were added to the fluidized bed. Granulator (FD-5
The mixture was placed in an S-type fluidized bed granulator, manufactured by Paulex), and a 6% aqueous solution of hydroxypropyl cellulose as a binder was sprayed at an air supply temperature of 70 ° C. to granulate, followed by drying to manufacture a granulated powder. Then, an uncoated tablet was produced by the same method as in Example 1, and then film-coated under the same conditions to obtain a film-coated tablet.

[0023]

[Table 5]

Test Example 1 Stability Test 80 plain tablets and film-coated tablets produced in each of Examples 1 to 3 and the control example were placed in a bottle and tightly stoppered at 40 ° C.
Store at 50 ° C, 60 ° C, 40 ° C 11% R.C.
H. , 53% R.S. H. , 40 ° C. 75% R.I. H. The bottle was stored by opening the bottle and taken out with time, and the appearance change of the tablet was observed with the naked eye, and evaluated by 5 grades as follows. The results are shown in Table 6 (plain tablets) and Table 7 (film-coated tablets).
The change with time of the pseudoephedrine hydrochloride content of the film-coated tablets obtained in Example 1 and the control example was measured by the following high performance liquid chromatography. The results are shown in Table 8.

[Evaluation] (+++): Partial deliquescent of surface, large change (++): Large browning change (+): There is a change (±): slightly changed (-): No change

[High-performance liquid chromatography measurement conditions] Column: octadecylsilylated silica gel column (YMC-
Pack AM302, YMC, Inner Diameter 4.6 mm, Length 1
5 cm, average particle size 5 μm) Eluent: 0.02 mol / L phosphoric acid aqueous solution containing sodium lauryl sulfate (5 → 10000) / acetonitrile mixture (66:34) Flow rate: 1.0 mL / min Column temperature: around 40 ° C. Constant temperature detection: UV absorptiometer (measurement wavelength: 210 nm)

As is clear from Tables 6 and 7, the plain tablets and the film-coated tablets obtained in Examples 1, 2 and 3 were compared with those obtained in the control under any storage condition. The change in appearance was also small. On the other hand, as shown in Table 8, the content of pseudoephedrine hydrochloride was stable in the film-coated tablet of Example 1, but tended to decrease in the film-coated tablet of the control example.

[0028]

[Table 6]

[0029]

[Table 7]

[0030]

[Table 8]

Example 4 As shown in Table 9, chlorpheniramine maleate d,
Pseudoephedrine hydrochloride, belladonna total alkaloids, dipotassium glycyrrhizinate, crystalline caffeine, corn starch, and low-substituted hydroxypropylcellulose were added to anhydrous caffeine and mixed (25 L vertical granulator, manufactured by Paulec), and then an aqueous hydroxypropylcellulose solution was added. In addition, it granulated. After vacuum drying (40 ℃), pulverize and tumbler mixer with magnesium stearate (Showa Kagaku Kikai, TM-60S)
Type) and mixed for 3 minutes to obtain granules for tableting. And
Collect 12HUK tablet press (Kikusui Seisakusho, 20pm)
To produce a caplet (tableting pressure 10 KN / per punch).

[0032]

[Table 9]

Example 5 As shown in Table 10, d-chlorpheniramine maleate, pseudoephedrine hydrochloride, belladonna total alkaloids, dipotassium glycyrrhizinate were mixed with white sugar, aspartame, stevia extract and yellow ferric sesquioxide (25 L vertical granules). (Made by Paulec, Inc.) and then kneaded with purified water. After that, extrusion granulation (Dome Gran, made by Fuji Paudal) was performed and 4
It was vacuum dried at 0 ° C. and passed through a standard sieve to obtain fine particles.

[0034]

[Table 10]

Control Example 2 As shown in Table 11, d-chlorpheniramine maleate, pseudoephedrine hydrochloride, total belladonna alkaloids, dipotassium glycyrrhizinate, anhydrous caffeine, lactose, crystalline cellulose, corn starch, low-substituted hydroxypropyl cellulose. Add and mix (25 L
(Vertical granulator, manufactured by Paulec), and then an aqueous solution of hydroxypropyl cellulose was added for granulation.
Then, the same operation as in Example 3 was performed to produce a caplet.

[0036]

[Table 11]

Control Example 3 As shown in Table 12, d-chlorpheniramine maleate, pseudoephedrine hydrochloride, belladonna total alkaloid, dipotassium glycyrrhizinate, lactose, sucrose, aspartame, stevia extract and yellow ferric sesquioxide were mixed and mixed (25 L). Vertical granulator, manufactured by Paulec), and then kneaded with purified water. Then, it manufactured similarly to Example 5 and obtained the fine grain.

[0038]

[Table 12]

Stability test 80 caplets each, or about 1 g of fine granules were placed in a bottle and tightly closed, and stored at 40 ° C., 50 ° C. and 60 ° C., and further 40 ° C.
11% RH, 40 ° C 53% RH, 40 ° C 75% R.
The container was opened and stored in H., taken out with time, and the appearance change was visually observed. (+++): Partial deliquescent surface, large change (++): Large browning change (+): Change (±): Slight change (-): No change

Results of stability test As a result, as shown in Table 13, in Examples 4 and 5, no significant change in appearance was observed under each temperature storage condition as compared with Comparative Examples 2 and 3. Moreover, a difference was observed even under humidity conditions and it was stable.

[0041]

[Table 13]

[0042]

INDUSTRIAL APPLICABILITY According to the present invention, a solid preparation containing pseudoephedrine hydrochloride, which is stable over time, has excellent medicinal effects, and has a high commercial value, can be obtained.

Front page continuation (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61K 9/48 A61K 9/48 31/09 31/09 31/167 31/167 31/485 31/485 31/5415 31 / 5415 F term (reference) 4C076 AA31 AA36 AA44 AA53 BB01 CC01 CC04 CC10 CC50 DD29 DD38 DD41 DD67 EE31 EE32 EE38 FF63 FF70 4C086 AA01 AA10 BC89 CB23 MA03 MA08 MA14 MA14 MA34 A14 A34 A14 A34 A34 A14 A34 A34 A34 A34 A34 A34 A34 A34 A34 A34 A34 A54 A34 A34 A34 A34 A34 A34 A34 A34 A14 A34 A34 A34 A54 A34 A34 A54 A34 A34 A14 A34 A54 A34 A34 A34 A34 A34 A34 A54 A10 A34 A53 GA31 MA04 MA54 MA55 MA57 MA61 MA72 NA03 ZA07 ZA08 ZA34 ZC54

Claims (6)

[Claims] 1. A stabilized solid preparation containing pseudoephedrine hydrochloride. 2. A group comprising pseudoephedrine hydrochloride and acetaminophen, mequitazine, dihydrocodeine phosphate and guaifenesin, which further comprises one or more agents selected from the group consisting of acetaminophen, mequitazine, dihydrocodeine phosphate and guaifenesin. The solid preparation according to claim 1, which is stabilized by separately blending with one or more drugs selected from the above, and producing it. 3. The solid preparation according to claim 1, which is stabilized by not adding lactose. 4. The solid preparation according to claim 1, which is stabilized by reducing the water content of the preparation. 5. The solid preparation according to claim 4, which is stabilized by adjusting the equilibrium relative humidity of the preparation to 50% or less. 6. Further comprising at least one drug selected from the group consisting of acetaminophen, mequitazine, dihydrocodeine phosphate and guaifenesin, and (i)
Pseudoephedrine hydrochloride and acetaminophen, mequitazine, one or more agents selected from the group consisting of dihydrocodeine phosphate and guaifenesin are separately compounded and produced, (ii) Lactose is not compounded,
And (iii) The solid preparation according to claim 1, which is stabilized by reducing the water content of the preparation.