JP2705787B2 - Easy to take bitterness improving H 改善 2Ｈ blocker solid preparation - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION The present invention relates to a method for producing a material having a heat of dissolution of -60 KJ /
The present invention relates to an easy-to-take bitterness-improving solid dosage form of H ₂ blocker, which is obtained by adding a sugar alcohol of not more than kg, preferably not more than -100 KJ / kg, and a method for producing the same.

[0002]

2. Description of the Related Art Conventionally, in the treatment using pharmaceuticals,
A method was used that emphasized its effects. At present, the economy is highly developed, various substances are overflowing, and we can live a rich life. As the elderly population increases and stress becomes a problem, comfort and suitability are required. Improvement of the quality of life has been advocated. If the same drug is administered in the treatment, there is a demand for the development of a formulation that is more favorable for patients, does not involve bitterness, pain, etc., and does not require a large amount of water when taken, and is easy to use. Precise medication is a prerequisite for drug therapy, and unless the patient adheres to the medication, the drug therapy cannot be effective. However, the rate at which patients do not take medication accurately is surprisingly high,
In some cases, patients have responded that they are taking medication, but have determined that they have not taken medication by measuring drug blood levels.

[0003] Therefore, it is important to determine the patient's compliance, that is, how seriously the patient is taking it as instructed after the medication. Unpalatable preparations can also cause patients to fail to take them, and their improvement leads to increased compliance. Famotidine, cimetidine, ranitidine hydrochloride, nizatidine, H ₂ blockers such as hydrochloric acid roxatidine acetate are capsules are formulated as tablets and powders. Although it is extremely insoluble in water, it has a large surface area, such as powders, granules, and chewable tablets, and in dosage forms that stay in the oral cavity for a while, bitterness causes a feeling of resistance when taken.

[0004] Conventionally, additives for powders and granules include
From the viewpoints of granulation workability, stability and economy, lactose,
Starch and a small amount of sweetening agent is used, it can not be erased of H ₂ blockers bitter. In addition, lactose, starch, etc. become sticky with a small amount of saliva in the oral cavity,
The feeling of taking is by no means good. Usually, enteric polymers such as cellulosic and polyacrylic acids, water-insoluble polymers, and gastric-soluble polymers AEA are used to improve the taste of bitter substances.
In addition to these methods, a method is used in which a bitter substance or a core substance comprising a bitter substance and lactose is coated with a fatty acid and its derivatives, oils and fats to mask bitterness. JP 6
In JP-A-219939, as a method of masking the bitterness of famotidine, masking is performed by coating a particle composed of famotidine, lactose, and PVP with a coating material composed of cellulose acetate and / or cellulose acetate butyrate and PVP. However, the production process is complicated and complicated, and the use of an organic solvent such as acetone, methanol or methylene chloride is expected to deteriorate the working environment.

[0005]

SUMMARY OF THE INVENTION It is an object of the present invention, without using the process a large number of complicated manufacturing process, also without the use of organic solvents, easy taking of solid having improved of H ₂ blockers bitter An object of the present invention is to provide a preparation and a method for producing the same.

[0006]

Means for Solving the Problems As a result of intensive studies on the solid preparation of H ₂ blocker, the present inventors did not improve the bitterness by adding various sugars such as sugar and glucose. by combining a specific sugar alcohol surprisingly does not require a complicated production process with many number of steps, such that the pre-coated masking in H ₂ blockers, bitterness is improved, and is easily taken of the solid preparation The inventors have found that the present invention can be obtained, and have completed the present invention. The specific sugar alcohols referred to in the present invention are those having a heat of dissolution of -60 kJ / kg or less, preferably -100 kJ / kg or less, which are the same as or less than sugar or glucose whose bitterness has not been improved. despite only has sweetness shows the bitterness-improving effect of the H ₂ blocker.

[0007] The heat of dissolution is the amount of heat absorbed or generated when a solute is dissolved in a solvent (water), and is represented by-when absorbed and + when generated. The heat of dissolution of -60 kJ / kg or less means that the heat of absorption is greater than 60 kJ / kg. The sugar alcohol used in the present invention is not particularly limited as long as the heat of dissolution is −60 KJ / kg or less.
It is more preferable that the concentration is −100 KJ / kg or less. Examples thereof include xylitol, sorbitol, mannitol, erythritol and the like. When heat of dissolution of the sugar alcohol is not less -60KJ / kg, rather than cooling sensation is felt sweetness of sugar alcohols heavy, it is coupled with complicated flavor with H ₂ blockers bitterness, it is impossible to obtain good ingestion feeling . For example, maltitol, lactitol and the like having a heat of dissolution of not more than -60 kJ / kg could not obtain a bitter taste improving effect. However, the heat of dissolution is -60 KJ / kg
By using a sugar alcohol of preferably -100 KJ / kg or less, the bitterness is improved, and there is a refreshing feeling.
Rapidly dissolved in the mouth, easy taking of H ₂ blockers solid preparation which can disintegrate is obtained provided. These sugar alcohols are very easy to dissolve in water and have a sweet taste, but they are taken up into cells without the need for insulin action, so they do not raise blood sugar levels. The “H ₂ blocker” in the present invention includes, for example, famotidine, cimetidine, ranitidine hydrochloride, nizatidine, roxatidine hydrochloride acetate and the like. Among them, famotidine is particularly preferred.

[0008] The "solid preparation" in the present invention includes powders, granules, chewable tablets and the like. Preferred are powders and granules, and most preferred are powders. The powder according to the present invention also includes fine granules. "Easy-to-take" as used in the present invention means that it has a refreshing sensation, dissolves and disintegrates quickly in the mouth, does not have a feeling of roughness when taken, and can provide a palatable, easy-to-take form. Things.

In the present invention, the heat of solution is -60 KJ / k.
g or less preferably the following sugar alcohol -100KJ / kg whereas H ₂ blockers 1 part, 25 parts or more, preferably not less than 40 parts, and, relative to total weight of the preparation, 50%
９９99.9%, preferably 80-99.9%. If it is removed, the refreshing sensation will be weakened, it will not dissolve or disintegrate quickly in the mouth, and a good feeling of taking it will not be obtained.
These sugar alcohols used in the present invention can be used alone or in combination of two or more. In particular, it is desirable to add sorbitol having a good formability to a dosage form requiring an appropriate formability such as a chewable tablet.

Further, in the present invention, by adding 1-menthol, H ₂ by sugar alcohol having a heat of dissolution of -60 KJ / kg or less, preferably -100 KJ / kg or less is added.
The effect of improving the bitterness of the blocker can be further improved. The amount of 1-menthol added is usually 1% or less, preferably 0.1% or less. H ₂ blockers and dissolution heat of manufacturing in the present invention is -60KJ / kg or less, preferably -10
0 KJ / kg or less of sugar alcohol or H ₂ blocker and heat of dissolution is −60 KJ / kg or less, preferably −100
Compositions consisting of sugar alcohols of up to KJ / kg and 1-menthol can be used as excipients normally used in formulation,
Stabilizers, binders, lubricants, fluidizers, flavors, sweeteners,
By adding a pigment or the like, powders, granules or tablets, preferably chewable tablets, can be prepared by a conventional method. H ₂ blockers solid preparation of the present invention, without requiring more complex manufacturing process of the number of steps, moreover without using harmful organic solvents, usually conducted are using the production method, can be produced in fewer steps .

(Production method) As the granulation method, fluidized bed granulation method, stirring granulation method, high-speed stirring granulation method, which is a usual production method,
It can be manufactured using a tumbling fluidized-granulation method or the like. The fluidized bed granulation method and the tumbling fluidized granulation method are preferred, and the fluidized bed granulation method is most suitable. The heat of dissolution used in the present invention is -60 KJ / kg or less, preferably -100 KJ / kg.
Since sugar alcohols of less than kg are extremely soluble in water, undesired coarse particles and agglomerates due to excessive moisture are likely to be formed during granulation. The fluidized-bed granulation method is easy to control the particle size of the granulated material because the moisture control is simple, and is most suitable for the production of the present invention. Production methods using fluidized bed granulation will be described in detail, but these do not limit the present invention.

One or more heats of dissolution are -60K
J / kg or less, preferably -100 KJ / kg or less, and crushed H ₂ blocker were mixed with HP
After granulating with a fluidized bed granulator using an aqueous solution of a binder such as C or PVP and adjusting the particle size to a desired value, pulverized 1-menthol and a fluidizing agent such as light anhydrous silicic acid are blended with a mixer. And
Powders or granules may be used. Add the necessary amount of lubricant such as magnesium stearate, talc, etc. to the obtained granules, mix with a mixer, and tablet with a tableting machine by a conventional method to make chewable tablets. Can also. On this occasion,
Heat of dissolution is -60 KJ / kg or less, preferably -100 KJ
When the sugar alcohol of less than / kg is a crystal having a large particle size, it is desirable to carry out a pulverizing treatment with a small amount of a fluidizing agent before granulation. Spray Also, if H ₂ blockers low content, in order to obtain a uniform content in the formulation, was dispersed in a binder solution, heat of dissolution is less preferred -60KJ / kg on the following sugar alcohol -100KJ / kg It is desirable to granulate while performing.

[0013]

According to the present invention, a solid preparation in which the bitterness of an H ₂ blocker is improved by a sugar alcohol having a sweetness similar to or less than that of sugar, ie, -60 KJ / kg, preferably -100 KJ / kg, is provided. can get. These preparations dissolve and disintegrate promptly in the mouth, and are easy to take with a pleasant refreshing sensation without a feeling of roughness when taken. Further, the present invention can provide a better dosage form without requiring a large amount of water to be taken.
In addition, since it does not require a complicated manufacturing method having many steps, does not deteriorate the environment due to an organic solvent, and is manufactured in a general manufacturing process, it is economical and has high industrial productivity.

[0014]

EXAMPLES Hereinafter, described in more detail by of H ₂ blockers containing solid preparation and a production method of the present invention in the Examples,
The present invention is not limited to these examples.

Example 1 667.8 parts of xylitol powder and light anhydrous silicic acid
After roughly mixing 5 parts, the mixture is taken into a fluidized bed granulator FLO-1.
A liquid in which 14 parts of famotidine pulverized with a 1.0-mm screen pulverizer was dispersed and sprayed into 140 parts of a 7.5% HPC aqueous solution was granulated. The obtained granules were sieved with a No. 30 sieve, and mixed with 3.5 parts of light anhydrous silicic acid in a V-type mixer.
After mixing for 0 minutes, a 2% famotidine powder was obtained.

Example 2 Instead of xylitol powder, sorbitol powder 667.8
A 2% famotidine powder was obtained in the same manner as in Example 1 except that the parts were used.

Example 3 299.7 parts of the powder obtained in Example 1 was ground with a mortar.
-0.3 part of menthol was added and mixed with a V-type mixer for 10 minutes to obtain a 2% famotidine powder.

Example 4 457.3 parts of sorbitol powder, erythritol powder 2
After roughly mixing 00 parts and 3.5 parts of light anhydrous silicic acid, the mixture was placed in a fluidized bed granulator FLO-1, and a 10% HPC aqueous solution 21 was added.
A liquid in which 14 parts of famotidine pulverized by a pulverizer with a 1.0 mm screen was dispersed in 0 part was sprayed and granulated. The obtained granules were sieved with a No. 12 sieve to give 1-menthol 0.1.
7 parts, 3.5 parts of light anhydrous silicic acid with V-type mixer 1
Mixing was performed for 0 minutes to obtain 2% famotidine granules.

Example 5 Mannitol powder 667.8 was used instead of xylitol powder.
A 2% famotidine powder was obtained in the same manner as in Example 1 except that the parts were used.

Example 6 299.7 parts of the powder obtained in Example 5 was crushed with a mortar.
-0.3 part of menthol was added and mixed with a V-type mixer for 10 minutes to obtain a 2% famotidine powder.

Example 7 Erythritol powder was used instead of xylitol powder.
A 2% famotidine powder was obtained in the same manner as in Example 1 except that 8 parts were used.

Example 8 299.7 parts of the powder obtained in Example 7 was crushed with a mortar.
-0.3 part of menthol was added and mixed with a V-type mixer for 10 minutes to obtain a 2% famotidine powder.

Example 9 0.5 part of lemon flavor was added to 1.0 part of light anhydrous silicic acid, mixed well in a mortar, and mixed with 499.5 parts of the powder obtained in Example 2 in a V-type mixer. After mixing for 10 minutes, 10 parts of magnesium stearate was further added and mixed for 10 minutes.
Tablets having a thickness of 5.0 mm and a thickness of 5.5 mm were tabletted to obtain chewable tablets containing 20 mg of famotidine in each tablet.

Test Example 1 The oral preparation of famotidine-containing solid preparation obtained in Examples 1 to 4 and the following Comparative Example was placed in the mouth of 10 panelists.
The sensory test was performed by allowing the sample to be included for 0 second. Tables 1 and 2 show the bitterness, the refreshing sensation, and the feeling of taking such as mouthfeel. (Comparative Example) 20 parts of famotidine, 845 parts of lactose and 100 parts of corn starch pulverized by a pulverizer with a 1.0 mm screen were placed in a fluidized bed granulator FLO-1 and 10% H was added.
After granulating 300 parts of an aqueous PC solution as a binder, the mixture was sieved with a No. 30 sieve and mixed with 5 parts of light anhydrous silicic acid for 10 minutes in a V-type mixer to obtain a 2% famotidine powder. <Bitterness> Bitterness is not felt: 0 Bitterness is hardly felt: 1 Bitterness is slightly felt: 2 Bitterness is felt: 3

[0025]

[Table 1] As is evident from the results in Table 1, all of the preparations of Examples 1 to 4 containing the same content of H ₂ blocker (famotidine) in the same content as those of the comparative examples using sugar (lactose) other than sugar alcohol were bitter. Was improved. <Taking feeling> Good taking feeling: 0 Neither: 1 Bad feeling of taking: 2

[0026]

[Table 2] As is clear from the results in Table 2, in Examples 1 to 4, there was a refreshing sensation, the dissolution was promptly in the mouth , the disintegration was not accompanied by a feeling of roughness when taken, and the result that the mouthfeel was good. I got On the other hand, in the comparative example using lactose, there was no refreshing sensation, rough and sticky feeling, and good feeling of taking was not obtained.

Test Example 2 2 parts of famotidine and 1-
A powdery product produced by adding 0.1 part of menthol and pulverizing was subjected to a sensory test by five panelists. Table 3 shows the results. Bitter taste is not felt: 0 Bitter taste is hardly felt: 1 Bitter taste is slightly felt: 2 Bitterness is felt: 3

[0028]

[Table 3] From these results, 50% or more of the sugar alcohol in the preparation was effective in improving the bitter taste of famotidine.

Test Example 3 A powdery product prepared by pulverizing 2 parts of famotidine or 2 parts of famotidine and 0.1 part of 1-menthol to 98 parts of each of the following compositions was subjected to a sensory test by five panelists. Table 4 shows the results. Bitter taste is not felt: 0 Bitter taste is hardly felt: 1 Bitter taste is slightly felt: 2 Bitterness is felt: 3

[0030]

[Table 4] As is clear from the results, the bitterness was improved when a sugar alcohol having a heat of solution of −60 kJ / kg or less was used.
On the other hand, with sugar alcohols or other saccharides having a heat of dissolution of -60 kJ / kg or less, no bitterness improving effect was observed. In addition, by using a sugar alcohol having a heat of dissolution of −60 kJ / kg or less and further adding 1-menthol, the effect of improving bitterness was improved.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification code Agency reference number FI Technical display location A61K 47/10 A61K 9/14 L (56) References JP-A-62-32855 (JP, A) Tokuhyo Hei 6-505498 (JP, A) Separate volume Food Chemical, published December 20, 1990, pp. 171-174 and 188-193

Claims (7)

(57) [Claims] A sugar alcohol having a heat of dissolution of -60 kJ / kg or less.
There with H ₂ blocker solid preparation obtained by adding a call
Te, sugar alcohols to _{H 2} blocker 1 part 25 parts or less
Above, wherein the amount of sugar alcohol in the formulation is 50-99.9
Bitterness improved easily taking ability H ₂ blocker solid preparation is%. 2. A sugar alcohol having a heat of dissolution of -60 kJ / kg or less.
There with H ₂ blocker solid preparation obtained by adding a call
Te, sugar alcohols to _{H 2} blocker 1 part 40 parts or less
Above, wherein the amount of sugar alcohol in the formulation is 80-99.9
Bitterness improved easily taking ability H ₂ blocker solid preparation is%. 3. A solid preparation powders, granules, solid preparation according to claim 1 or 2 wherein the chewable tablet. 4. The solid preparation according to claim 1, wherein a sugar alcohol having a heat of dissolution of -100 kJ / kg or less is added. 5. The method according to claim 1, wherein l-menthol is added.
The solid preparation according to any one of claims 4 to 4 . 6. A solid preparation according to claim 1-5, wherein the sugar alcohol is sorbitol. 7. A solid preparation according to claim 1 to 6, wherein H ₂ blocker is famotidine.