KR20040023503A - Compression molded hypnotic preparation - Google Patents

Abstract

PURPOSE: A compression molded hypnotic preparation is provided, which preparation has hypnotic/sedative actions, does not discolor, is stable, masks its bitter taste, and quickly and surely produces its effects. To provide a preparation which, while containing diphenhydramine or its acid salt as a medicinal component having hypnotic/sedative actions, does not discolor, is stable, masks its bitter taste, and quickly and surely produces its effects. CONSTITUTION: The compression molded hypnotic preparation contains the diphenhydramine or its acid salt as the medicinal component having hypnotic/sedative actions, a lowly swellable polymer, and a highly swellable polymer, wherein the lowly swellable polymer is selected from crystalline cellulose, ethylcellulose and aminoalkyl methacrylate copolymer RS.

Description

Hypnotic compression molding agent {COMPRESSION MOLDED HYPNOTIC PREPARATION}

The present invention relates to a hypnotic compression molding agent, and more specifically, it contains diphenhydramine or its acid addition salt as a medicinal ingredient of hypnotic and soothing action, is free from discoloration, is stable, conceals bitterness at the time of taking, and expresses the effect. This rapid and reliable hypnotic compression molding agent.

Diphenhydramine or its acid addition salts have antihistamine action and central action. Conventionally, diphenhydramine and acid addition salts have been used as active ingredients of rhinitis, skin diseases, cold medicines and antitussives.

For example, it is known that diphenhydramine hydrochloride and diphenhydramine citrate have hypnotic action that is almost equivalent to a mild hypnotic agent. In addition, since the loss from the blood is relatively quick and there is no habit, it is used in a dose of 50 mg per adult as a hypnotic drug which does not require a prescription corresponding to a general medicine in Japan.

However, due to the sedative action of diphenhydramine hydrochloride, the plasma concentration at which drowsiness occurs is 50 ng / ml or more, which is higher than the plasma concentration at which antihistamine action occurs. In addition, the average value of the time course of plasma concentration when oral administration of 50 mg of diphenhydramine hydrochloride slightly exceeds 50 ng / ml over 2 to 4 hours after administration (Carruthers et al .: Clin. Pharmacol. Ther .; 23 (4); 375-382, 1978). For this reason, when used as a hypnotic agent for oral administration, when the disintegration or elution of the formulation is delayed depending on the dosage conditions, the effect as a hypnotic agent cannot be sufficiently obtained.

On the other hand, the taste of diphenhydramine or acid addition salts thereof has a strong irritating bitter taste, and has a property of imparting discomfort when taken. However, the conventional method of concealing the taste of slowing the elution by a fat or oil-containing film or matrix containing an insoluble polymer does not impede the effectiveness of the antihistamine drug, but the expression of the effect as a hypnotic drug becomes uncertain or insufficient. There was concern. In addition, in the method of concealing a taste such as blending a sweetening agent or a mating agent, masking is incomplete and a bitter taste remains on the tongue.

In addition, a preparation containing diphenhydramine or an acid addition salt thereof may be discolored depending on preparation additives such as excipients to be blended, or wet or preparations may adhere to each other under humid conditions. In addition, since diphenhydramine or its acid addition salt itself is discolored by light, even if there is no decrease in content, these cases have a drawback that the product value becomes lost.

Therefore, it has been required to provide a preparation which contains diphenhydramine or its acid addition salt as a medicinal active ingredient for sleep and soothing action, is free from discoloration, is stable, conceals bitterness at the time of taking, and has rapid and reliable expression of effects. .

MEANS TO SOLVE THE PROBLEM As a result of earnestly examining in order to solve the said subject, the present inventors compression-molded diphenhydramine or its acid addition salt with the some polymer which differs in swellability, and does not affect solubility, but changes the discoloration and bitter taste of diphenhydramine. It was found that it was possible to suppress and to obtain a hypnotic compression molding agent excellent in the certainty of expression of effects such as hypnosis.

That is, the present invention provides a hypnotic compression molding agent comprising diphenhydramine or an acid addition salt thereof, a low swellable polymer and a high swellable polymer as a medicinal active ingredient having sleep and soothing action.

The present invention also provides the use of diphenhydramine or acid addition salts thereof for the preparation of hypnotic compression molding formulations to improve the limit.

[Embodiment of the Invention]

Hypnotic compression molding agent of the present invention (hereinafter referred to as "the formulation of the present invention") is a combination of diphenhydramine or acid addition salts thereof, low-swellable polymer and high swellable polymer to prepare a granule for compression molding, and It is prepared via.

In the formulation of the present invention, the diphenhydramine used as the active ingredient having sleep and soothing action may be in the form of a base or an acid addition salt. However, since it is liquid in a base state, for example, it is necessary to hold | maintain a base in powder, such as hard silicic acid anhydride, and to use it, it is preferable to use acid addition salt in the manufacture of this invention preparation actually. Examples of such acid addition salts of diphenhydramine include diphenhydramine hydrochloride, salicylic acid diphenhydramine, citric acid diphenhydramine, tannin acid diphenhydramine, lauryl sulfate diphenhydramine, and diphenhydramine sulfate. Preferred acid addition salts include diphenhydramine hydrochloride and diphenhydramine citrate, and particularly preferred acid addition salts include diphenhydramine hydrochloride.

The average particle diameter of the bulk component of these diphenhydramines or acid addition salts thereof can be used without any limitation, but is preferably 30 µm or more and 500 µm or less, particularly preferably 50 to 300 µm. Adjustment of an average particle diameter can be performed by a conventional method, such as grind | pulverizing or crushing a bulk component as needed, The method is not specifically limited. For example, grinding may be performed using a mill such as a hammer mill, speed mill, roller mill, pin mill, ball mill, vibrating ball mill, vibrating mill, jet mill, and the like. It can be carried out using an air flow type breaker.

Although the content rate of diphenhydramine or its acid addition salt (hereinafter referred to as "diphenhydramine", etc.) in the formulation of the present invention varies depending on the dosage form, the dosage, and the like, it is generally not limited, but is usually in the range of about 5 to 30% by mass. It is preferable to set it as. In addition, although the compounding quantity of diphenhydramine etc. contained in one formulation of this invention is not restrict | limited, Since single dose of diphenhydramine etc. is 50 mg, it is an integer fraction of 50 mg in the range of 12.5-50 mg per one Do it.

On the other hand, the low swellable polymer used in the formulation of the present invention is insoluble in water and has a low swelling property, and needs to be low in reactivity such as blending with diphenhydramine or the like and not discoloring after compression molding. Specific examples of such low-swellable polymers include crystalline cellulose, ethyl cellulose, aminoalkyl methacrylate copolymer RS, and the like, and these may be used alone or in combination of two or more thereof. Among these, the most preferred specific example is crystalline cellulose. It is preferable to use 1 mass part or more of these low-swelling polymers with respect to 1 mass part, such as diphenhydramine, and it is more preferable to use 2 mass parts or more with respect to 1 mass part, such as diphenhydramine. Although the addition amount with respect to the gross mass of the formulation of this invention of this low swelling polymer differs with content of diphenhydramine etc. and the gross mass of a formulation, it is about 3-90 mass%, Preferably it is the range of 5-80 mass%.

The high swellable polymer used in the formulation of the present invention is insoluble in water and has a high swelling property, and further needs low reactivity that does not change color after blending with diphenhydramine or the like and compression molding. Specific examples of such high swellable polymers include croscarmellose sodium, low-substituted hydroxypropyl cellulose, crospopidone, and the like, and these may be used alone or in combination of two or more thereof. Most preferred specific examples include sodium croscarmellose sodium. The amount of the highly swellable polymer added to the total mass of the preparation of the present invention varies depending on the content of diphenhydramine or the like and the total mass of the preparation, but is approximately 0.1 to 5 mass%, preferably 0.5 to 3 mass%.

In the present invention, it is necessary to use a combination of these low swellable polymers and high swellable polymers, but the mixing ratio in this case is 0.01 mass times or more, preferably 0.2 mass times or more, of the high swellable polymers relative to the low swellable polymers. .

The formulations of the present invention are known as necessary for the low swellable polymer and the high swellable polymer, such as diphenhydramine, as described above, for example, excipients, binders, disintegrants, lubricants, stabilizers, surfactants, dissolution aids, For compression molding by adding a reducing agent, a buffer, an adsorbent, a fluidizing agent, an antistatic agent, a coating agent, a plasticizer, an anti-sticking agent, a light shielding agent, a brightening agent, an antioxidant, a sweetening agent, a copulating agent, a cooling agent, a colorant, a flavoring agent, a flavoring agent, a fragrance agent, etc. Powder is prepared by compression molding according to a conventional method.

The pharmaceutical additive for use in the formulation of the present invention is one or two or more selected from water-soluble polymers, hard silicic anhydrides, sugars, sugar alcohols, starches, talc, magnesium stearate, blended with diphenhydramine and the like, which are not discolored after compression molding. It is preferable to mix | blend.

Among these, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyethylene glycol, etc. are mentioned as water-soluble polymer which does not cause discoloration after compounding with diphenhydramine or the like. Examples of the starch include alpha starch, corn starch, potato starch, wheat starch, rice starch, and the like, and sugars and sugar alcohols include lactose, mannitol, xylitol, dextrin, sorbitol and the like. Since the amounts of these water-soluble polymers, starches, sugars and sugar alcohols vary depending on the size of the compression molding agent and the method of producing the powder for compression molding, the amount thereof cannot be specified. Mass%.

In addition, among the above-mentioned pharmaceutical additives, hard silicic anhydride increases the fluidity of the granules for compression molding, and has a function of preventing wetting and sticking of the compression molding agent. This hard silicic anhydride is so preferable that the average particle diameter is small, and it is preferable to use hard silicic anhydride with an average particle diameter of 4-5 nm. It is preferable to use 1-10 mass% of addition amounts with respect to the gross mass of a compression molding agent.

Moreover, it is preferable to add both talc and magnesium stearate, or both to 0.1-5 mass% with respect to the gross mass of a compression molding agent.

The granulated material for compression molding may be used as a granulated powder while the powder or the above components are mixed. When the granular powder is used as a granulated powder, wet granulation methods generally used, for example, spray granulation method using a solution or dispersion containing water or an organic solvent, agitation granulation method, flow granulation method, electric granulation method, and electric granulation method are used. And dry granulation methods such as consolidation granulation method using a granular binder can be used.

Said mixed powder or granulated powder becomes the formulation of this invention via a compression molding process. Specific compression molding processes include a method of using a tableting machine such as a rotary tableting machine, a single tableting machine, or a method of using a hydraulic press. The method of using a tableting machine is preferable, and in particular, when a rotary tableting machine is used, the production efficiency is good. Do. In addition, although the compression molding pressure varies depending on the size and shape of the compression molding agent and the type and amount of the pharmaceutical additive, for example, 300 kg / cm 2 or more is preferable for a compression molding agent having a diameter of 9 mm, and 500 to 1500 kg. / Cm 2 is more preferred.

The formulation of the formulation of the present invention thus obtained is a tablet, and its shape is not particularly limited, such as circular tablets, release tablets, and the like. In addition, a split line may be added to this tablet.

In addition, the formulation of the present invention can be made into a fast-soluble coating formulation or dragee formulation by a plate coating method, a fluidized bed coating method, a rolling coating method, a dry coating method, or a combination of these methods. In this case, the water-soluble or gas-soluble coating agent may be dissolved or dispersed in water or an organic solvent to spray coating, or the coating agent may be directly sprayed, followed by dry coating by applying heat or pressure. Furthermore, as a coating agent, you may add a plasticizer, an adhesion inhibitor, a light-shielding agent, an extender, etc.

The best embodiment of the formulation of the present invention described above contains 12.5-50 mg of diphenhydramine hydrochloride in one formulation, and at least 2 parts of crystalline cellulose as one part of diphenhydramine hydrochloride as a low-swelling polymer and a high swellable polymer Sodium croscarmellose sodium is 0.1 to 5% by mass relative to the total mass of the formulation of the present invention, light silicic anhydride is 1 to 10% by mass relative to the total mass of the formulation of the present invention, hydroxypropyl cellulose as a water-soluble polymer Compression molding powder obtained by mixing 1 to 5% by mass relative to the total mass, lactose to 20 to 80% by mass relative to the total mass of the formulation of the invention, and 0.1 to 5% by mass of talc and magnesium stearate relative to the total mass of the formulation of the invention. It is a formulation which was compression-molded at a pressure of 500-1500 kg / cm <2> with a tableting machine so that the mass per formulation may be 100-750 mg using the following.

The formulation of the present invention thus obtained contains low swellable polymers and high swellable polymers, such as diphenhydramine, so that they are free from discoloration, are stable, conceal bitter taste at the time of taking, and provide rapid and reliable expression of effects such as hypnosis. . This preparation can be used for insomnia, sedation such as tension, excitement and nervousness, head pain accompanying these symptoms, alleviation of fatigue boredom, and relief of anxiety.

EXAMPLE

Hereinafter, although an Example is given and this invention is demonstrated further more concretely, this invention is not restrict | limited at all by these Examples.

Example 1

Compression Molding Agent (1):

100 g of diphenhydramine hydrochloride (average particle size 220 µm), 100 g of crystalline cellulose, 728 g of lactose, 20 g of sodium croscarmellose, 48 g of hard silicic anhydride were mixed, and 240 g of an ethanol solution of 10% hydroxypropyl cellulose was added thereto. After kneading, granulation, and drying, the sieve was cut into 20 mesh sieves. 1009.8 g of the granules were mixed with 9.8 g of magnesium stearate and 9.8 g of talc, and the resulting compression molding granules were compression-molded with a rotary tablet press at a pressure of about 900 kg / cm 2, each having a diameter of 9 mm, a thickness of 4.2 mm, and a mass of 260 mg. Compression molding agents were obtained.

Example 2

Compression Molding Agents (2):

A compression molding agent having a diameter of 9 mm, a thickness of 4.2 mm, and a mass of 260 mg per tablet was obtained in the same manner except for changing the crystal cellulose of Example 1 to 200 g and the lactose to 628 g.

Example 3

Compression Molding Agents (3):

A compression molding agent having a diameter of 9 mm, a thickness of 4.2 mm, and a mass of 260 mg per tablet was obtained in the same manner except changing 400 g of the crystalline cellulose of Example 1 and 428 g of lactose.

Example 4

Compression Molding Agents (4):

A compression molding agent having a diameter of 9 mm, a thickness of 4.2 mm, and a mass of 260 mg per tablet was obtained in the same manner except for changing the crystal cellulose of Example 1 to 600 g and the lactose to 228 g.

Example 5

Compression Molding Agents (5):

A compression molding agent having a diameter of 9 mm, a thickness of 4.2 mm, and a mass of 260 mg per tablet was obtained in the same manner except for changing the crystal cellulose of Example 1 to 800 g and lactose to 28 g.

Example 6

Compression Molding Agents (6):

125 g of diphenhydramine hydrochloride (average particle diameter: 220 µm), crystalline cellulose (380 g), lactose (385 g), 20 g of croscarmellose sodium, and 50 g of hard silicic anhydride were mixed, and 200 g of an ethanol solution of 10% hydroxypropyl cellulose was added. After addition, kneading, granulation and drying, 20 mesh sieve was passed. The granules for compression molding obtained by mixing 960.4 g of the granules with 9.8 g of magnesium stearate and 9.8 g of talc were compression-molded with a rotary tablet press at a pressure of about 900 kg / cm 2, each having a diameter of 5.5 mm, a thickness of 4.2 mm, and a mass of 1 000 mg. Compression molding agents were obtained.

Example 7

Compression Molding Agents (7):

37.5 g of diphenhydramine hydrochloride (average particle size: 220 µm), 375 g of crystalline cellulose, 652.5 g of lactose, 24 g of sodium croscarmellose, 60 g of hard silicic anhydride, and 270 g of an ethanol solution of 10% hydroxypropyl cellulose Was added, kneaded, assembled and dried before passing through 20 mesh sieves. The compression molding granules obtained by mixing 11.8 g of magnesium stearate and 11.8 g of talc with 1152.5 g of the granules were compression-molded with a rotary tablet press at a pressure of about 900 kg / cm 2, each having a diameter of 10 mm, a thickness of 4.3 mm, and a mass of 400 mg. A molding agent was obtained.

Example 8

Compression Molding Agents (8):

500 g of diphenhydramine hydrochloride (average particle size 220 μm), 500 g of crystalline cellulose, 77 g of lactose, 20 g of sodium croscarmellose, 55 g of hard silicic anhydride were mixed, and 240 g of an ethanol solution of 10% hydroxypropyl cellulose was added thereto. After kneading, assembling and drying, 20 mesh sieves were passed. 1152.5 g of this granule was mixed with 11.8 g of magnesium stearate and 11.8 g of talc, and the resultant compression molding granules were compression-molded at a pressure of about 900 kg / cm 2 with a rotary tablet press to compress and mold 6 mm in diameter, 4 mm thick, and 120 mg in mass per tablet. The formulation was obtained.

Example 9

Compression Molding Agents (9):

150 g of diphenhydramine hydrochloride (average particle size: 220 µm), crystalline cellulose (465 g), lactose (450 g), croscarmellose sodium (24 g), and 60 g of hard silicic anhydride were mixed, and 270 g of an ethanol solution of 10% hydroxypropyl cellulose was added thereto. After kneading, assembling and drying, 20 mesh sieves were passed. 1152.5 g of this granule was mixed with 11.8 g of magnesium stearate and 11.8 g of talc, and the resulting compression molding granules were compression molded using a rotary tablet press at a pressure of about 900 kg / cm 2 to compress a diameter of 10 mm, a thickness of 4.3 mm, and a mass of 400 mg per tablet. A molding agent was obtained.

Comparative Example 1

Comparative Compression Molding Agent (1):

A compression molding agent having a diameter of 9 mm, a thickness of 4.2 mm, and a mass of 260 mg per tablet was obtained in the same manner except that the crystalline cellulose of Example 1 was removed and the lactose was changed to 828 g.

Comparative Example 2

Comparative Compression Molding Agent (2):

A compression molding agent having a diameter of 9 mm, a thickness of 4.2 mm, and a mass of 260 mg per tablet was obtained in the same manner except changing the crystal cellulose of Example 1 to 40 g and lactose to 788 g.

Comparative Example 3

Comparative Compression Molding Agent (3):

A compression molding agent having a diameter of 9 mm, a thickness of 4.2 mm, and a mass of 260 mg per tablet was obtained in the same manner except for changing the crystal cellulose of Example 1 to 60 g and lactose to 768 g.

Comparative Example 4

Compression Molding Agents (4):

Sodium croscarmellose sodium of Example 1 was removed, and the compression molding agent having a diameter of 9 mm, a thickness of 4.2 mm, and a mass of 260 mg per tablet was obtained in the same manner except that the crystal cellulose was changed to 200 g and lactose to 648 g.

Example 10

Compression Molding Agents (10):

100 g of diphenhydramine hydrochloride (average particle diameter: 220 µm), 440 g of crystalline cellulose, 4109 lactose, and 10 g of sodium croscarmellose were mixed and passed through a 20 mesh sieve. 940.8 g of this granule was mixed with 19.6 g of hard silicic anhydride, 9.8 g of magnesium stearate, and 9.8 g of talc, and the resulting mixture was compression-molded with a rotary tablet press at a pressure of about 900 kg / cm 2, with a diameter of 9 mm, thickness of 4.1 mm, and mass per tablet. 250 mg of compression molding agent were obtained.

Example 11

Compression Molding Agents (11):

200 g of diphenhydramine hydrochloride (average particle size 220 µm), 400 g of crystalline cellulose, 200 g of lactose, and 192 g of corn starch were mixed, and 160 g of an ethanol solution of 5% hydroxypropyl cellulose was added, kneaded, granulated and dried, 20 mesh sieve was passed. 980 g of this granule was mixed with 882 g of crystalline cellulose, 19.6 g of croscarmellose sodium, 39.2 g of hard silicic anhydride, 19.6 g of magnesium stearate, and 19.6 g of talc, and the resulting compression molding granules were approximately 900 kg / cm 2. Compression molding was carried out under pressure to obtain a compression molding agent having a diameter of 9 mm, a thickness of 4.0 mm, and a mass of 250 mg.

Example 12

Compression Molding Agents (12):

200 g of diphenhydramine hydrochloride (average particle diameter: 220 µm), 640 g of crystalline cellulose, 1016 g of lactose, 40 g of sodium croscarmellose, and 96 g of hard silicic anhydride were added, and 480 g of an ethanol solution of 10% hydroxypropyl cellulose was added thereto. After kneading, assembling and drying, 20 mesh sieves were passed. Compression molding granules obtained by mixing 19.6 g of magnesium stearate and 19.6 g of talc with 1999.2 g of the granules were compression-molded at a pressure of about 900 kg / cm 2 with a rotary tablet press to form a compression of 9 mm in diameter, 4.2 mm in thickness, and 260 mg in mass. The formulation was obtained.

Example 13

Compression Molding Agent (13):

To 6000 tablets of the compression molding agent obtained in Example 12, a 10% aqueous coating solution containing 150 g of hydroxypropylmethylcellulose, 10 g of polyethylene glycol, 22 g of titanium oxide and 18 g of talc was dried at 5 mg / tablet for tablets. Spray coating.

Comparative Example 5

Comparative Compression Molding Agent (5):

A compression molding agent having a diameter of 9 mm, a thickness of 4.2 mm, and a mass of 260 mg per tablet was obtained in the same manner except that the lactose of Example 1 was changed to refined white sugar.

Comparative Example 6

Comparative Compression Molding Agent (6):

A compression molding agent having a diameter of 9 mm, a thickness of 4.2 mm, and a mass of 260 mg per tablet was obtained in the same manner except that the lactose of Example 1 was changed to glucose.

Comparative Example 7

Comparative Compression Molding Agent (7):

Except having changed the hydroxypropyl cellulose of Example 1 into polyvinylpyrrolidone, it carried out similarly and obtained the compression molding agent of diameter 9mm, thickness 4.2mm, and mass 260 mg per tablet.

Comparative Example 8

Comparative Compression Molding Agent (8):

A compression molding agent having a diameter of 9 mm, a thickness of 4.2 mm, and a mass of 260 mg per tablet was obtained in the same manner except that the croscarmellose sodium of Example 1 was changed to carboxymethyl cellulose calcium.

Test Example 1

Taste Test:

Each of the compression molding agents obtained in the above Examples and Comparative Examples was put in the oral cavity, chewed for 10 seconds, kept unbroken and then turned over. About the taste at this time, bitter taste was evaluated by ten healthy adults according to the following evaluation criteria. Table 1 shows the results of the average of 10 people. It was found that the compression molding agent which blended 1 mass part or more of low-swelling polymers with respect to diphenhydramine hydrochloride does not feel a bitter taste at the time of taking.

<Taste evaluation criteria> <score>

Does not feel bitter: 0 points

Slightly bitter: 1 point

Bitter: 2 points

Taste (average) Taste (average) Taste (average) Example 1 0.6 Example 8 0.5 Comparative Example 2 1.6 Example 2 0.3 Example 9 0.3 Comparative Example 3 1.3 Example 3 0.3 Example 10 0.2 Comparative Example 4 0.2 Example 4 0.1 Example 11 0.1 Comparative Example 5 0.5 Example 5 0.1 Example 12 0.2 Comparative Example 6 0.6 Example 6 0.4 Example 13 0.1 Comparative Example 7 0.5 Example 7 0.1 Comparative Example 1 1.8 Comparative Example 8 0.7

Test Example 2

Decay test:

The compression molding agent obtained in the above Examples and Comparative Examples was subjected to 37 ° C pure water on a diskless condition using the NT-2HS Type Disintegration Tester (manufactured by Toyama Industries, Ltd.) in accordance with the Disintegration Test Method of the 14th Amendment of Pharmacy. It measured using. Table 1 shows the ranges of the collapse times of the six compression molding agents. Compression molding agents containing high swellable polymers immediately collapsed.

Disintegration time (minutes) Disintegration time (minutes) Disintegration time (minutes) Example 1 2.9 to 4.6 Example 8 3.6 to 4.8 Comparative Example 2 3.2 to 4.8 Example 2 3.2 to 4.7 Example 9 3.8 to 5.8 Comparative Example 3 3.3 to 4.8 Example 3 3.1 to 5.2 Example 10 2.3-4.2 Comparative Example 4 9.2 to 15.3 Example 4 3.4 to 5.4 Example 11 3.2 to 4.2 Comparative Example 5 3.4 to 4.6 Example 5 3.5 to 5.9 Example 12 3.4 to 4.9 Comparative Example 6 3.5 to 4.8 Example 6 2.7 to 4.2 Example 13 3.8 to 5.3 Comparative Example 7 3.3 to 4.4 Example 7 3.8 to 5.8 Comparative Example 1 2.8 to 4.5 Comparative Example 8 3.5 to 5.2

Test Example 2

Preservation Stability Test:

The compression molding agents obtained in the above examples and comparative examples were stored for 6 months (40 ° C., 75% relative humidity) and 1 year (25 ° C.), observed changes over time in appearance, and evaluated based on the following evaluation criteria. The results are shown in Table 3. The formulation of the present invention was excellent in storage stability.

<Preservation stability evaluation criteria> <Evaluation>

No change: ○

A little yellowish discoloration: △

Discoloration to yellow: ×

6 months ^* 1 year ^** 6 months ^* 1 year ^** 6 months ^* 1 year ^** Example 1 ○ ○ Example 8 ○ ○ Comparative Example 2 ○ ○ Example 2 ○ ○ Example 9 ○ ○ Comparative Example 3 ○ ○ Example 3 ○ ○ Example 10 ○ ○ Comparative Example 4 ○ ○ Example 4 ○ ○ Example 11 ○ ○ Comparative Example 5 △ △ Example 5 ○ ○ Example 12 ○ ○ Comparative Example 6 × × Example 6 ○ ○ Example 13 ○ ○ Comparative Example 7 × × Example 7 ○ ○ Comparative Example 1 ○ ○ Comparative Example 8 △ △

* 40 ℃ CRH 75%

** 25 ℃

Example 14

Compression Molding Agents (14):

200 g of diphenhydramine hydrochloride (average particle size 220 µm), 640 g of crystalline cellulose, 1016 g of lactose, 40 g of sodium croscarmellose, 96 g of hard silicic anhydride, 48 g of hydroxypropyl cellulose, 20 g of magnesium stearate and 20 g of talc According to a conventional method, tableting granules were prepared, and compressed to a pressure of about 900 kg / cm 2 to obtain a compression molding agent having a diameter of 9 mm, a thickness of 4.2 mm, and a weight of 260 mg per tablet.

Example 15

Compression Molding Agents (15):

200 g of diphenhydramine hydrochloride (average particle diameter: 403 μm) instead of 200 g of diphenhydramine hydrochloride (average particle size 220 μm) of Example 14 was used in the same manner as in Example 15 to obtain a diameter of 9 mm, a thickness of 4.2 mm, and a weight of 260 mg per tablet. Compression molding agents were obtained.

Comparative Example 9

Comparative Compression Molding Agent (9):

A tableting granule was prepared according to a conventional method using 640 g of crystal cellulose, 1216 g of lactose, 40 g of sodium croscarmellose, 96 g of hard silicic anhydride, 48 g of hydroxypropyl cellulose, 20 g of magnesium stearate, and 20 g of talc, The tablet was compressed at a pressure of about 900 kg / cm 2 to obtain a compression molding agent having a diameter of 9 mm, a thickness of 4.2 mm, and a weight of 260 mg per tablet.

Test Example 3

Hypnosis Test:

Compression molding agents obtained in Examples 14 and 15 and Comparative Example 9 were administered to two adults with weak insomnia tendency to take two tablets for about 30 minutes before bed for 7 days, and fell asleep, The effect was tested. Table 4 shows the results of the sleep test. Table 5 shows the results of the sleep test. Compression molding agents of the present invention were superior to sleep and sleep compared to comparative compression molding agents.

Fall asleep Good Slightly good No change Slightly bad Bad Example 14 3 3 One One 0 Example 15 2 4 One One 0 Comparative Example 9 0 0 7 One 0

Sleep Good Slightly good No change Slightly bad Bad Example 14 2 4 2 0 0 Example 15 One 5 2 0 0 Comparative Example 9 0 0 6 One 0

Example 16

Compression Molding Agents (16):

In the same manner as in Example 14, except that 200 g of diphenhydramine hydrochloride (average particle diameter: 220 μm) was used in place of Example 14, 200 g of diphenhydramine hydrochloride (average particle size: 54.3 μm) was used in a tablet of 9 mm in diameter, 4.2 mm in thickness, and 260 mg in weight. The compression molding agent of was obtained.

Test Example 4

Taste Test:

Each of the compression molding agents obtained in Examples 14 to 16 was placed in the oral cavity, chewed for 10 seconds, held without breaking, and swallowed. About the taste at this time, the bitter taste was evaluated by 10 healthy adults according to the evaluation criteria similar to the test example 1. Table 6 shows the results of the average of 10 people. The compression molding agent of the present invention was excellent in not feeling bitter.

Taste (average) Example 14 0.3 Example 15 0.2 Example 16 0.6

Hypnotic compression molding agent of the present invention containing diphenhydramine and the like as an active ingredient for sleep and soothing action is free from discoloration by concealing a low swellable polymer and a high swellable polymer, and hides the bitter taste when taken and is easy to take. Hypnotic compression molding agent. In addition, the formulation itself obtained by the combination compression molding of these low-swelling polymers and high-swelling polymers is easy to disintegrate, and a sufficient amount of diphenhydramine or the like can appear in the blood as an active ingredient for sleep and soothing action.

Therefore, it is possible to effectively use the sleep and soothing action of diphenhydramine as a medicine, soothing insomnia, tension, excitement, nervousness, head pain accompanying these symptoms, relief of fatigue boredom, anxiety The hypnotic compression molding agent can be provided quickly and surely.

Claims (7)

A hypnotic compressive molding agent comprising diphenhydramine or an acid addition salt thereof, a low-swelling polymer and a high-swelling polymer as a medicinal active ingredient having a sleep and soothing action. The compressive molding agent for hypnotic molding of Claim 1 whose compounding quantity of a high swellable polymer is 0.01 mass times or more of the compounding quantity of a low swellable polymer. The hypnotic compression molding agent according to claim 1 or 2, wherein the low swellable polymer is one or two or more selected from crystalline cellulose, ethyl cellulose and aminoalkyl methacrylate copolymer RS. The hypnotic compression molding agent according to claim 1 or 2, wherein the high swellable polymer is one or two or more selected from croscarmellose sodium, low-substituted hydroxypropyl cellulose and crospopidon. The hypnotic compression molding agent according to claim 1, which further contains one or two or more selected from water-soluble polymers, hard silicic anhydrides, sugars, sugar alcohols, starches, talc, and magnesium stearate. The hypnotic compression molding according to any one of claims 1 to 5, wherein the single dose of diphenhydramine or acid addition salt thereof is 50 mg. Use of diphenhydramine or acid addition salts thereof for preparing hypnotic compression molding agents to improve sleep.