TW200404004A - Molded medicament for promotion of sleeping - Google Patents

Abstract

An ideal medicament contains diphenhydramine or an acid adduct thereof as a medicinal ingredient for assisting sleeping or sedation, and has properties including color steadiness, stability, bitterness masking while taking the medicine, and rapid display of medicinal effects, etc.; said medicament is a compression formulation characterized in comprising diphenhydramine or an acid adduct thereof having sleep promotion and sedation effects, polymers with low swelling properties, and with high swelling properties.

Description

200404004 (1) Description of the invention [Technical field to which the invention belongs] The present invention relates to a compression-molded preparation for hypnosis, and more specifically to a drug containing diphenhydramine or an acid salt thereof as a hypnotic and tranquilizing drug It is a compression molded preparation for hypnosis which is effective, has no discoloration, is stable, masks the bitter taste when taken, and can quickly and reliably show its efficacy.

[Previous technology] Diphenhydramine or its acid-added salt has antihistamine and central effects. The prior technology is used as the active ingredient of rhinitis, dermatology, cold medicine, and cough sputum medicine. However, Easy to cause side effects of drowsiness and disadvantages.

For example, diphenhydramine hydrochloride and diphenhydramine citrate are known to have a hypnotic effect almost simultaneously with the soothing hypnotic agent. Moreover, it disappears quickly from blood and fluids, and it is also not habitual. Therefore, in Europe and the United States, hypnotics, which are generally used in Japan without a prescription, are used at a dosage of 50 mg per adult. However, after the sedative effect of diphenhydramine hydrochloride, the drowsiness-producing plasma concentration is 50 ng / ml or more, which is higher than the plasma concentration of antihistamine effect. In addition, the time-lapse of plasma concentration of diphenhydramine hydrochloride when taken orally at 50 mg was less than 50 ng / m 1 at 2 to 4 hours after taking it (Carruthers et al: Clin, Pharmacol. Ther .; 23 (4); 3 7 5 to 3 8 2. 1 97 8). Therefore, when used as an oral hypnotic, depending on the taking conditions, the preparation disintegrates and the dissolution is delayed, and the hypnotic effect cannot be fully obtained. -5- (2) 200404004 In addition, the taste of diphenhydramine or its acid-added salt strongly stimulates bitterness, and it has an unpleasant nature when taken. However, in the method of delaying the dissolution to cover the taste by using a film and a matrix containing oil and insoluble polymers to mask the taste, it does not cause an obstacle when it is used as an antihistamine, but it may not be sufficient as a hypnotic. Share effect. In addition, in the method of blending sweeteners and flavoring agents to mask the taste, there is a disadvantage that bitterness is left on the tongue without being fully masked.

In addition, diphenhydramine or a preparation containing an acid-addition salt thereof is a mutual preparation that is moistened or fixed under the condition that discoloration occurs after the addition of an excipient such as an excipient, and discoloration occurs. In addition, discoloration occurs due to the light of diphenhydramine or its acid-added salt, so even if the content is not reduced, there is a disadvantage that the commodity price is lost in this case. [Summary of the Invention]

Therefore, it is expected to provide a preparation containing diphenhydramine or an acid addition salt thereof as a medicinal ingredient for sleep and calming effect, and without discoloration and stability, it can cover the bitter taste when taken, and clearly and quickly appear the effect. In order to solve this problem, the present inventors conducted detailed investigations and found that after diphenhydramine or an acid-added salt thereof was combined with a plurality of polymers having different swelling properties, the solubility was suppressed by compression molding, and benzene was suppressed. Hyramin's discoloration is 'bitter, a compression molding agent for hypnosis that clearly shows good hypnotic effects, etc.' and completed the present invention. That is, the present invention provides a low-swelling polymer and a high-swelling polymer containing diphenhydramine or an acid addition salt thereof as a medicinal ingredient having sleep and tranquility-6- (3) 200404004 It is characterized by compression molding for hypnosis. The present invention also provides a compression molded preparation for hypnosis using diphenhydramine or an acid addition salt thereof for improving sleep. [Embodiment] [Embodiment of Invention] The compression molding preparation for hypnosis of the present invention (hereinafter referred to as "the preparation of the present invention")

) Is a combination of diphenhydramine or its acid-addition salt, and low-swelling polymer and high-swelling polymer, and then it is made into powder and granules for compression molding, which are prepared through compression molding steps.

In the preparation of the present invention, diphenhydramine, which is used as a medicinal ingredient having sleep and calming effects, can be directly in the form of a salt, or it can be an acid-added salt. However, if the form of the salt base is liquid, for example, it must be used after keeping the salt base in a powder such as light anhydrous silicic acid to make a powder and granule. Therefore, when the preparation of the present invention is actually manufactured, the use of an acid-added salt is used as should. Examples of additional salts of diphenhydramine acid are: diphenhydramine hydrochloride, diphenhydramine salicylate, diphenhydramine citrate, diphenhydramine tannin, diphenhydramine lauryl sulfate , Diphenhydramine sulfate cases. In addition, examples of the ideal acid additional salt include diphenhydramine hydrochloride and the example of diphenhydramine citrate, and particularly preferable examples of the additional acid salt are diphenhydramine hydrochloride. The average particle size of the original powder of diphenhydramine or its acid-added salt is not particularly limited. Generally, it is preferably 30 μm or more and 500 μm or less, and particularly preferably 50 to 300 μm. The adjustment of the average particle diameter may be performed by a conventional method such as pulverization or sieving when necessary, and the method is not limited. Such as

(4) 200404004: Crushing can be carried out using hammer mills, rapid honing machines, roller honing machines, pin mills, ball mills, oscillating ball mills, oscillating honing machines, injection honing machines, etc. This is done by using a screen-type continuous vibrating screen machine and an airflow screen machine.

The proportion of diphenhydramine or an acid addition salt thereof (hereinafter referred to as "diphenhydramine and the like" in the present invention) varies depending on the dosage form, the dosage, etc., and is usually about 5 to 30% by mass. In addition, the compounding amount of diphenhydramine and the like contained in one preparation of the present invention is not limited. Generally, the dosage of diphenhydramine and the like is 50 mg at a time. Therefore, one is in the range of 12.5 to 5011 ^. An integer of 5011 ^ may be set to 1.

In addition, the low-swelling polymer used in the preparation of the present invention is one which is insoluble in water and has a low swelling property. After blending with diphenhydramine and the like, it must be a low-reactivity low-color after compression molding. Specific examples of the low-swelling polymer include crystalline cellulose, ethyl cellulose, and amine-based methyl propionate copolymer RS. These may be used alone or in combination. Used above. The most preferable specific example is a crystalline cellulose. These low-swelling polymers are preferably used by users of 1 part by mass or more of diphenhydramine and the like, and more preferably 2 parts by mass or more. This low-swelling polymer is based on the total mass of the preparation of the present invention, and its added amount depends on the amount of diphenhydramine and the like, and the total mass of the preparation varies, generally about 3 to 90% by mass, and the more preferred is 5 to 80% by mass. The highly swellable polymer used in the preparation of the present invention is one which is insoluble in water and has a large swellability, and with the combination of diphenhydramine and the like, it must show low color reactivity after compression molding. Specific examples of this highly swellable polymer include: cross-carboxymethylcellulose sodium, low-substituted hydroxypropyl cellulose, -8-(5) 200404004 crosspovidone (ne) These can be used singly or in combination. The most preferable specific example is: the example of sodium carboxymethyl cellulose. The amount of this highly swellable polymer added to the total mass of the preparation of the present invention depends on its content such as diphenhydramine and the total mass of the preparation. It is generally about 0.1 to 5% by mass, and more preferably 0.5 to 3% by mass. %.

In the present invention, it is necessary to use a combination of these low-swellable polymers and high-swellable polymers. At this time, the mixing ratio is preferably such that the high-swellable polymers are 0.01 mass times or more of the low-swellable polymers. Preferably, it is 0.2 mass times or more.

When necessary, the formulation of the present invention can add well-known pharmaceutical additives such as excipients, binders, disintegrating agents, lubricants, and stabilizers to the diphenhydramine, the low-swelling polymer and the high-swelling polymer. Agents, surfactants, dissolution aids, reducing agents, buffering agents, adsorbents, fluidizers, antistatic agents, coating agents, plasticizers, adhesion preventive agents, sunscreen agents, gloss agents, antioxidants, sweeteners , Flavoring agent, depressant, coloring agent, flavoring agent, perfume, fragrance, etc. are added, and then the powder and granules for compression molding are prepared and manufactured by compression molding according to the usual method. As a medicinal additive used in the present invention, at least one or two or more kinds of water-soluble polymers, light anhydrous silicic acid, sugars, sugars that are not discolored after compression molding with diphenhydramine and the like are blended. Alcohol, starch, talc, magnesium stearate are preferred. Among them, those that are water-soluble polymers that have not changed color after compression molding such as diphenhydramine, such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, and polyethylene glycol, are examples. In addition, as examples of starch, such as: alpha starch, corn starch, Ma-9-. • 乂 WA r · (6) 200404004 potato starch, wheat starch, rice starch, etc., and as sugars, sugar alcohols such as : Examples of lactose, mannitol, xylitol, dextrin, sorbitol. The amount of these water-soluble polymers, starches, sugars, and sugar alcohols varies depending on the size of the compression molding preparation and the method for manufacturing the powder for compression molding, and the amount is not particularly limited, and is generally about the total mass. 0 to 80% by mass.

In addition, the light anhydrous silicic acid in the medicinal additive can increase the fluidity of the powder and granules for compression molding, and also has the function of preventing the wetting and binding of the compression molding preparation. The smaller the average particle size of the light anhydrous silicic acid, the better. It is preferable to use a light anhydrous silicic acid having an average particle diameter of 4 to 5 nm. The addition amount is preferably 1 to 10% by mass of the total mass of the compression molding preparation. It is more desirable to add 0.1 to 5% by mass of talc or magnesium stearate to the total mass of the compression-molded preparation. The powder and granules for compression molding can be directly mixed with the component powder or use it

Part or all used as granulated powder. When granulating powder from this powder, you can use the granulation method generally used, such as: aqueous, organic solvent solution, or spray granulation method using dispersion liquid, stirring granulation method, flow granulation method Dry granulation methods such as wet granulation methods such as rotary granulation method and rotary flow granulation method, and compacted granulation method using powder-granular binder. The mixed powder or granulated powder is made into a formulation of the invention through a compression molding step. As a specific compression molding step, for example, a method of using a rotary ingot press, a single-shot ingot press, or a method of using a hydraulic press, and the use of an ingot press It is suitable, especially the production efficiency of using a rotary spindle beater is better. In addition, the pressure of compression molding varies according to the size and shape of the compression molding preparation and the type and amount of medical additives -10- -n Γ (7) 200404004. For example, when the compression molding preparation is 9mm in diameter, It is preferably 300 kg / cm2 or more, and more preferably 5,000 to 1,500 kg / cm2. The dosage form for obtaining the preparation of the present invention is a lozenge, the shape of which is a round lozenge, a special-shaped lozenge, and the like, which are not particularly limited. In addition, this lozenge can also be given a tangent.

In addition, the preparations of the present invention can also be made into coating preparations and sugar-coated preparations with more rapid solubility by the flat coating method, the fluid layer coating method, the spin coating method, the dry coating method, a combination of these methods, and the like. . In this case, a water-soluble or gastric-soluble coating agent is dissolved or dispersed in water or an organic solvent and spray-coated, or a dry coating method in which the coating agent is directly dispersed and then heated and pressed. Plasticizers, anti-adhesive agents, sunscreen agents, extenders, etc. can be added to the coating agent.

The best embodiment of the formulation of the present invention described above is that one formulation contains 12.5-5 mg of diphenhydramine hydrochloride, and the crystalline cellulose as a low-swelling polymer is 1 part of diphenhydramine hydrochloride 2 As a high-swelling polymer, sodium carboxymethylcellulose sodium is 0.1 to 5% by mass of the total mass of the preparation of the present invention, and light anhydrous silicic acid is 1 to 1 mass of the total mass of the formulation of the present invention. %, Hydroxypropyl cellulose as the water-soluble polymer is 1 to 5 mass% of the total mass of the preparation of the present invention, and lactose is 20 to 80 mass% of the total mass of the preparation of the present invention. Talc and magnesium stearate The powder for compression molding obtained after the formulation is 0.1 to 5% by mass of the total mass of the preparation of the present invention is used. The mass of one preparation is 100 to 7500 mg with a tableting machine, 5 00 to 1 500 kg / cm2 Those who are compression molded under pressure. [Effect] -11-(8) (8) 200404004 The person who obtained the preparation of the present invention has diphenhydramine and other low-swelling polymers and high-swelling polymers. Therefore, it is not discolored, stable, and when taken A preparation that masks bitterness and does quickly cause hypnosis. This preparation can be used for insomnia, tension, excitement, anxiety, etc., quietness, heavy head accompanied by these symptoms, relief of fatigue and fatigue, etc. [Examples] Examples are given below to describe the present invention more specifically, but the present invention is not limited to these examples. [Example 1] Compression molding preparation (1): 100 g of diphenhydramine hydrochloride (average particle size 220 μm), 100 g of crystalline cellulose, 72 8 g of lactose, and 20 g of sodium carboxymethylcellulose After 4 8 g of light anhydrous silicic acid, 240 g of 10% hydroxypropyl cellulose in ethanol solution was added for mixing, granulation and drying, and then sieved with a 20 mesh screen. After mixing 9.8g of magnesium stearate and 9.8g of talc into 1009.4g of the granules, the pellets for compression molding were obtained by compression molding using a rotary tableting machine at a pressure of about 900 kg / cm2 to obtain 1 ingot. A compression molded preparation having a diameter of 9 mm, a thickness of 4.2 mm, and a mass of 260 mg. [Example 2] Compression molding preparation (2): Change the crystalline cellulose of Example 1 to 20 g and lactose to 62 8 g (9) 200404004. Obtain 1 ingot with a diameter of 9111111 and a thickness of 4.2111111. A compression molded preparation with a mass of 26〇11 ^. [Example 3] Compression molding preparation (3):

The compressive molding preparation of Example 1 was changed to 400 g of crystalline cellulose and 42 8 g of lactose, and 1 tablet having a diameter of 9 mm, a thickness of 4.2 mm, and a mass of 260 mg was obtained. [Example 4] Compression molding preparation (4): Change the crystalline cellulose of Example 1 to 600 g and lactose to 2 2 8 g, and simultaneously obtain 1 ingot with a diameter of 9 mm, a thickness of 4.2 mm, and a mass It is a 260mg compression molding preparation.

[Example 5] Compression molding preparation (5): Change the crystalline cellulose of Example 1 to 800 g and lactose to 28 g, except for the simultaneous acquisition of 1 ingot with a diameter of 9 mm, a thickness of 4.2 mm, and a mass of 260 mg Compression molding preparation. [Example 6] Compression molding preparation (6): 1 2 5 g of diphenhydramine hydrochloride (average particle size 2 2 μm), 3 8 0 g -13- (10) 200404004 crystalline cellulose, 3 8 5 g of lactose, 20 g of sodium carboxymethylcellulose, 50 g of light anhydrous silicic acid, 200 g of 10% hydroxypropyl cellulose in ethanol solution was added for kneading, granulating, and drying. Screen 20 mesh screen. After mixing 9 · 8 g of magnesium stearate and 9.8 g of talc into 9 6 0.4 g of the granules, compression molding using a rotary tabletting machine at a pressure of about 900 kg / cm2 was performed. A compression molded preparation having a diameter of 5.5 mm, a thickness of 4.2 mm, and a mass of 100 mg was obtained.

[Example 7] Compression molding preparation (7):

Mix 37.5 diphenhydramine hydrochloride (average particle size 220 μιη), 3 75 g of crystalline cellulose, 652.5 g of lactose, 24 g of sodium carboxymethylcellulose, 60 g of light anhydrous silicic acid, and add 270 g of 10 After mixing, granulating and drying the ethanol solution of% hydroxypropyl cellulose, it is sieved with a 20 mesh screen. After mixing 11.8 g of magnesium stearate and 1 1.8 g of talc in 11 52.5 g of the granules, compression molding of the obtained granules for compression molding was carried out using a rotary tabletting machine at a pressure of about 900 kg / cm2. After molding, one ingot was obtained as a compression-molded preparation having a diameter of 10 mm, a thickness of 4.3 mm, and a mass of 400 mg. [Example 8] Compression molding preparation (8): 500 g of diphenhydramine hydrochloride (average particle size 220 μm), 500 g of crystalline cellulose '77 g of lactose, 20 g of cross-carboxymethyl cellulose sodium, 5 After 5g of light anhydrous silicic acid, 240g of 10% hydroxypropyl cellulose ethyl 14- (11) 200404004 alcohol solution was added for kneading, granulating and drying, and then sieving through a 20 mesh screen. Mix 1 1 · 8 g of magnesium stearate and 1 1.8 g of talc in 1 1 2 5 · 5 g of granules, and obtain it with a rotary tableting machine at a pressure of about 900 kg / c m2. After compression molding of the particles for compression molding, a compression molding preparation having a diameter of 6 mm, a thickness of 4 mm, and a mass of 120 mg was obtained. [Example 9]

Compression molding preparation (9): Mix 150g of diphenhydramine hydrochloride (average particle size 220 μm), 465g of crystalline cellulose, 450g of lactose, 24g of sodium carboxymethylcellulose, 60g of light anhydrous silicon After the acid, 270 g of a 10% hydroxypropyl cellulose in ethanol solution was added for kneading, granulating and drying, and sieving through a No. 20 mesh sieve. 11.8 g of magnesium stearate and 11.8 g of talc were mixed with 1152.5 g of the granules, and then a compression molding process was performed using a rotary tableting machine at a pressure of about 900 kg / cm2 to obtain pellets for compression molding. A compression molded preparation having a diameter of 4.3 mm and a mass of 400 mg. [Comparative Example 1] Comparative compression molding preparation (1): Except that the crystalline cellulose of Example 1 was removed, and lactose was changed to 82, except that one ingot having a diameter of 9 mm, a thickness of 4.2 mm, and a mass of 260 mg was obtained. Plastic molding preparation. [Comparative Example 2] -15- (12) (12) 200404004 Comparative compression molding preparation (2): The crystalline cellulose of Example 1 was changed to 40 g and the lactose was 788 g. Other than that, the diameter of one ingot obtained by the same method was A compression molded preparation with a thickness of 9 mm, a thickness of 4.2 mm and a mass of 260 mg. [Comparative Example 3] Comparative compression molding preparation (3): The crystalline cellulose of Example 1 was changed to 60 g, and the lactose was 7 6 g. Other than that, a sharp diameter of 9 mm and a thickness of 4.2 were obtained in the same manner. A compression molded preparation having a mm 'mass of 260 mg. [Comparative Example 4] Compression molding preparation (4): Remove the sodium carboxymethylcellulose of Example 1 'and change the crystalline cellulose to 200 g and lactose to 648 g. Except that, the diameter of 1 sharp was 9 mm. Made of compression molding with a thickness of 4.2 mm and a mass of 260 mg ^ ° [Example 10] Compression molding preparation (100): 100 g of diphenhydramine hydrochloride (average particle size 220 μm), 440 g of crystalline cellulose 40.0 g of lactose and 10 g of sodium carboxymethylcellulose were sieved through a 20 mesh screen. 19.6g of light anhydrous silicic acid, 9.8g of magnesium stearate, and talc of 9.8§ were mixed with the granules of 940.8§, and then performed by a rotary tableting machine at a pressure of about 900 kg / cm2. Obtain the compression molding of the mixture into -16-(13) (13) 200404004 type, and obtain a compression molded preparation with a diameter of 9 mm, a thickness of 4.1 mm, and a mass of 250 mg. [Example 11] Compression molding preparation (1 1): 200 g of diphenhydramine hydrochloride (average particle size 220 μηι), 400 g of crystalline cellulose, 200 g of lactose, 192 g of corn starch, and 160 g of 5% hydroxypropyl After the ethanol solution of cellulose-based cellulose is kneaded, granulated and dried, it is sieved through a 20 mesh screen. 8.82 g of crystalline cellulose, 1 9.6 sodium carboxymethylcellulose, 3 9 · 2 light anhydrous silicic acid, 19.6 g of magnesium stearate, and 19.6 g of talc were mixed in 98 0 g of the granules, and the tablets were rotated and tableted. The machine performs compression molding to obtain particles for compression molding under a pressure of about 900 kg / cm2, and obtains a compression molding preparation having a diameter of 9 mm, a thickness of 4.0 mm, and a mass of 250 mg. [Example 12] Compression molding preparation (1 2): 200 g of diphenhydramine hydrochloride (average particle size 220 μηι), 640 g of crystalline cellulose, 10 16 g of lactose, 40 g of sodium carboxymethylcellulose, After 96 g of light anhydrous silicic acid, 480 g of 10% hydroxypropyl cellulose in ethanol solution was added for kneading, granulating, and drying, and then sieving through a 20 mesh screen. 1 9.9 g of magnesium stearate and 1 9.6 g of talc were mixed in 1 9 9 · 2 g of the granules, and the pellets for compression molding were obtained by using a rotary tabletting machine at a pressure of about 900 kg / cm2. After compression molding, one ingot having a diameter of 9 mm -17- (14) 200404004, a thickness of 4.2 mm, and a mass of 260 mg was obtained as a compression-molded preparation [Example I3] A compression-molded preparation (1 3): Obtained in Example 12 Of the 6000 ingots of the compression molding formulation, 'the bare ingot was sprayed in a dry state, containing 150 g of hydroxypropyl cellulose', 10 g of polyethylene glycol, 22 g of titanium oxide, and 18 g of 10% aqueous coating solution of talc. Make it 5mg / per spinner. [Comparative Example 5] Comparative compression molding preparation (5): The lactose of Example 1 was changed to refined white sugar, and a compression molding preparation having a diameter of 9 mm and a thickness of 4.2 mm and a mass of 260 mg was obtained by the same method.

[Comparative Example 6] Comparative compression-molded preparation (6): The lactose of Example 1 was changed to glucosamine '. Further, a compression-molded preparation having a diameter of 9 mm, a thickness of 4.2 mm, and a mass of 260 mg was obtained in the same manner. [Comparative Example 7] Comparative compression molding preparation (7): except that the hydroxypropyl cellulose of Example 1 was changed to polyvinylpyrrolidone ', 1 ingot having a diameter of 9 mm, a thickness of 4.2 mm, and a mass of 260 mg -18 was obtained. -(15) (15) 200404004 compression molding preparation. [Comparative Example 8] Comparative compression molding preparation (8): In addition to changing the sodium carboxymethylcellulose sodium of Example 1 to a continuous methylcellulose calcium, a diameter of 9 mm and a thickness of 4.2 mm were obtained by the same method. 'Compression molded preparation with a mass of 260 mg ° [TEST EXAMPLE 1] Taste test: Take one each of the compression molded preparations obtained in this example and the comparative example, and swallow them without chewing in the mouth for 10 seconds. The bitterness was evaluated according to the following evaluation criteria for the healthy taste at this time based on 10 healthy adults. The average results of 10 people are shown in Table 1. Compression molding formulations containing diphenhydramine hydrochloride in combination with 1 part by mass or more of a low-swelling polymer have proven that no strong bitterness occurs during administration. < Taste evaluation criteria > < Points > 1 No bitterness: 〇 Slight bitterness: 1 point Bitterness: 2 points -19- (16) (16) 200404004 [Table i] Taste taste taste (average) (Average) (Average) Example 10 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. 1 Comparative Example 7 0.5 ΐ1 Example 7 0. .1 Comparative Example 1 1 .8 Comparative Example 8 0., 7 [Test Example 2] Disintegration test: The compression-molded preparations obtained in this example and the comparative example are in accordance with No. 1 4 The revised version of the Japanese Pharmacopoeia's disintegration test method is based on the NT-2HS type disintegration tester (manufactured by Toyama Sangyo Co., Ltd.), and it is measured with 37 t of pure water without a disc. Table 1 shows the disintegration time ranges of the six compression-molded preparations. Compression molding formulations with high swelling polymers are immediately disintegrated. -20- (17) 200404004 [Table 2] Disintegration time Disintegration time Disintegration time (minutes) (minutes) (minutes) Sample Example 1 2.9 ^ -4.6. Example 8 3.6 ~ 4.8 Comparative Example 2 3.2 ^ -4.8 Example 2 3.2 ^ -4 .7 Example 9 3.8 ~ 5.8 Comparative Example 3 3.3 ^ ^ 4.8 Example 3 3. Bu-5, .2 Example 1 〇2.3 ~ 4. .2 Comparative Example 4 9.2 ~ 15.3 Example 4 3. Heart, 4 Example 1 1 3.2 ~ 4., 2 Comparative Example 5 3 Heart-4.6 Example 5 3.5. -5, .9 Example 1 2 3.4 ~ 4 · 9 Comparative Example 6 3.5 ^ -4.8 Example 6 2.7 ^ -4 .2 Example 1 3 3.8 ~ 5.3 Comparative Example 7 3.3 ^ -4.4 Example 7 3.8 ^- 5, .8 Comparative Example 1 2.8 to 4.5 Comparative Example 8 3.5 ^ -5.2 [Test Example 2] Storage stability test: The compression-molded preparations obtained in this example and the comparative example were stored for 6 months (40 ° C, After the relative humidity was 75%) and one year (25 ° C), the appearance changes over time were observed and evaluated according to the following evaluation criteria. The results are shown in Table 3. The preparation of the present invention is one with good storage stability. < Storage stability evaluation criteria > < Evaluation > No change: 〇 Slightly yellow: △

X

Yellow (18) 200404004 [Table 3] 6 months * 1 year 氺 氺 6 months * 1 ^ * 6 months * 1 year * * Example 1 〇〇fen Example 8 〇 Comparative Example 2 〇〇 Example 2 Example 100 Example Comparative Example 3 Example Example 3 Example Example 1 Comparison Example 4 Example Example 4 Example Example 1 Example Comparative Example 5 Δ Δ Example 5000 Example 12 2000 Comparative Example 6 XX Example 6 2000 Example 13 1 Comparative Example 7 XX Example 7 Comparative Example 1 Comparative Example 8 Δ Δ

[Example M] Compression-molded preparation (1 4): 200 g of diphenhydramine hydrochloride (average particle size 220 Km) '64 0 g of crystalline cellulose, 101 6 g of lactose' 40 g of cross-carboxymethyl cellulose sodium '9 6 g of light anhydrous oxalic acid, 4 8 § via propyl cellulose' 20 g of magnesium stearate 'and 20 g of talc, producing granules for ingoting by conventional methods' at about 900 kg / c An ingot was made under a pressure of m2 to obtain a compression-molded preparation having a diameter of 9 mm, a thickness of 4.2 mm, and a weight of 260 mg. [Example 15] A compression-molded preparation (1 5): 200 g of diphenhydramine hydrochloride ( (Average particle size 403 Km) instead of 200 g of diphenhydramine hydrochloride (average particle size 220 Km) used in Example 14 except (-22) (2004) 200404004, the same method as in Example 14 was used to obtain 1 ingot with a diameter of 9 mm and a thickness of A compression molded preparation of 4.2 mm and a weight of 260 mg. [Comparative Example 9] Comparative compression molding preparation (9): 640 g of crystalline cellulose, 1216 g of lactose '40 g of sodium carboxymethylcellulose, 9 6 g of light anhydrous silicic acid, 4 8 g of hydroxypropyl cellulose, 20 g of magnesium stearate and 20 g of talc were used to make granules for ingot making according to the usual method. The ingot was made at a pressure of about 900 kg / cm2 to obtain 1 ingot having a diameter of 9 mm, a thickness of 4.2 mm, and a weight of 260 mg. Compression molding preparation. [Experimental Example 3] Hypnosis test: For 8 adults who have a slight tendency to sleeplessness, take 2 tablets of the compression-molded preparations obtained in Examples 14 and 15 and Comparative Example 9 30 minutes before bedtime every day for 7 days, The effect of the drug on falling asleep and sleeping state was tested. The results of the sleep test are shown in Table 4, and the test results of the sleep state are not shown in Table 5. The cast-molded preparation of the present invention is superior to comparing the sleep-on and sleep states of compression-molded preparations. [Table 4] Sleep well, but may not be slightly worse. Example 1 4 3 3 1 1 〇 Example 1 5 2 4 1 1 〇 Comparative Example 9 0 0 7 1 〇-23- (20) 200404004 [Table 5] Sleep state is good, but may not change slightly _ bad Example 1 4 2 4 2 0 〇 Example 1 5 1 5 2 0 〇 Comparative Example 9 0 1 6 1 〇 ---------- [Example 16] pressure Molded preparation (16): 200 g of diphenhydramine hydrochloride (average particle size 54.3 Pm) was used in place of 200 g of diphenhydramine hydrochloride (average particle size 220 μm) of Example 14, except that the same method was used as in Example 14 A compression-molded preparation having a diameter of 9 mm, a thickness of 4.2 mm, and a weight of 260 mg was obtained. [Test Example 4] Taste test:

Each of the compression-molded preparations obtained in Examples 4 to 16 of Example 1 was held in the mouth for 10 seconds without being chewed, and then pressed. With regard to the taste at this time, the bitterness was evaluated on the basis of 10 healthy adults according to the same criteria as in Test Example 1. The average result of 10 people is shown in Table 6. The bitter taste of the compression-molded preparation of the present invention is desirable. -24- (21) 200404004 [Table 6] Taste (average) Example 1 4 · 0.3 Example 1 5 0.2 Example 1 6 0.6 [Inventive effect] Diphenhydramine and the like are used for hypnotic and calming effects The hypnotic compression-molded preparation of the present invention is composed of a low-swelling polymer and a high-swelling polymer, which are medicinal ingredients, and have no discoloration, cover bitterness when taken, and are easy to take. In addition, the compression-molded preparations combining these low-swelling polymers and high-swelling polymers are easy to disintegrate, and can appear in the blood as a satisfactory amount of diphenhydramine as a hypnotic and calming effect. 〇Therefore, diphenhydramine and other drugs with sleep and tranquillity can be effectively used as pharmaceuticals. For insomnia, tension, excitement, restlessness, etc., it is accompanied by the symptoms of these symptoms, the relief of fatigue and fatigue, The release of anxiety can provide a compression molding agent for hypnosis with a clear and rapid effect.

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Claims (1)

200404004 (υ, application patent scope 1) A compression molding preparation for hypnosis, which is characterized by containing diphenhydramine or its acid additional salt, a low-swelling polymer and Highly swellable polymers 2. If the compression molding agent for hypnosis of item 1 of the patent application range, wherein the blending amount of the swelling polymer is more than 0.01 mass times the blending amount of the low-swelling polymer. 3. If the compression molding agent for hypnosis according to item 1 or item 2 of the scope of the patent application, wherein the low-swelling polymer is one or more kinds selected from crystalline cellulose, ethyl cellulose, and amino alkyl group Methacrylate copolymer RS 04. For the hypnotic compression-molded preparation of item 1 or item 2 of the patent application range, wherein the high-swelling polymer is one or two or more selected from crosslinked carboxymethyl Croscarmellose sodium, low-substitution via propyl cellulose, cross-povidone. 5. For example, the compression molding preparation for hypnosis according to item 1 of the patent application scope, wherein the preparation is more Contains 1 or 2 species The above are selected from water-soluble polymers, light anhydrous silicic acid, sugars, sugar alcohols, starches, talc, and magnesium stearate. 6 · As for the hypnotic pressure of any one of the first to the fifth of the scope of patent application Plastic forming preparation, wherein one dose of the diphenhydramine or its acid additional salt is 5 Omg. 7. A use of diphenhydramine or its acid additional salt, characterized in that the preparation can improve sleep hypnosis Those who use compression molding preparations. -26- 200404004 柒, (1), the representative representative of this case is: None (二), the component representative symbols of this representative illustration are simply explained: Μ 捌, if there is a chemical formula in this case, please disclose the most Chemical formula capable of showing the characteristics of the invention: te · -4-