JPH1053538A - Easily administrable solid preparation of h2-blocker having reduced bitterness - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an easily administrable solid preparation of H2 -blocker having reduced bitterness without using both a complicated production method having many steps, and a solvent by adding a specific sugar alcohol. SOLUTION: This easily administrable solid preparation of H2 -blocker is obtained by adding >=25 pts.wt. sugar alcohol such as xylitol, sorbitol, mannitol and erythritol having <=-60kJ/kg, preferably <=-100kJ/kg heat of dissolution to 1 pt.wt. H2 -blocker so as to be 50-99.9% of the total amount of the medicine. The sugar alcohol regardless of which has about same or less sweetness as sugar or dextrose hardly improving the bitterness, shows effects improving the bitterness of the H2 -blocker. Moreover, the addition of 1-menthol can further improve the improving effect of the bitterness. This solid medicine is readily dissolved and collapsed in the mouth, hardly provides rough feeling and easily administered while providing refrigerant with smooth feeling. Further, the medicine can be formed into a better administration shape because hardly requiring the ingestion of large amount of water.

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 H ₂ blocker solid preparation comprising a sugar alcohol of not more than 100 kg / 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.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION The specific sugar alcohol referred to in the present invention has a heat of dissolution of -60 kJ / kg or less, preferably -10 kJ / kg or less.
And a 0kJ / kg the following, these sugar did not improve the bitterness, even though only have comparable or less sweet and glucose, shows the bitterness-improving effect of the H ₂ blocker. The heat of dissolution is the amount of heat absorbed or generated when a solute is dissolved in a solvent (water). Absorbing is represented by-and generating is represented by +. Heat of dissolution
60 kJ / kg or less means that the heat absorption is greater than 60 kJ / kg.

The sugar alcohol used in the present invention is not particularly limited as long as it has a heat of solution of -60 kJ / kg or less, and is more preferably -100 kJ / kg or less. Examples thereof include xylitol, sorbitol and mannitol. And erythritol. When the heat of dissolution of the sugar alcohol is not less than -60 kJ / kg, the sweetness of the sugar alcohol is heavier than the refreshing feeling, and H ₂
The taste becomes complicated in combination with the bitterness of the blocker, and a good feeling of taking cannot be obtained. For example, the heat of dissolution is -60 kJ
Maltitol, lactitol, etc., which were not less than / kg / kg, did not provide an effect of improving bitterness. However, the heat of solution is -60.
By kJ / kg or less, preferably using the following sugar alcohol -100kJ / kg, bitterness is improved, there is refreshing feel, rapidly dissolves in the mouth, provide easy dosing of the H ₂ blocker solid preparation which can disintegrate I got it. 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.

The "solid preparation" of 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
0kJ / kg or less of sugar alcohol or, H ₂ blockers and heat of dissolution preferably less -60kJ / kg -100
Compositions consisting of kJ / kg or less of sugar alcohols and 1-menthol are used as excipients ordinarily 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.

[0013] One or more heats of dissolution are -60k
J / kg or less, preferably -100 kJ / kg or less, and crushed H ₂ blocker are 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 / kg
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.

[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.

[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.

[0026]

[Table 2] As is evident from the results in Table 2, Examples 1-4 have a refreshing sensation, dissolve and disintegrate promptly in the mouth, and are not accompanied by a feeling of roughness when taken. The result was obtained. 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

[0029]

[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.

[0030]

According to the present invention, preferably -60kJ / kg with comparable or less sweetness and sugar by a sugar alcohol of -100kJ / kg, H ₂ blockers solid preparation bitterness is improved of 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.

Continuation of the front page (51) Int.Cl. ⁶ Identification number Agency reference number FI Technical display location A61K 45/00 AEM A61K 9/14 L

Claims (5)

[Claims] 1. A heat of dissolution become by adding the following sugar alcohol -60kJ / kg, bitter improved easily taking ability H ₂ blocker solid preparation. 2. The solid preparation according to claim 1, wherein the solid preparation is a powder, a granule or a chewable tablet. 3. The solid preparation according to claim 1, wherein a sugar alcohol having a heat of dissolution of -100 kJ / kg or less is added. Wherein a heat of dissolution bitterness improved easy taking agents H ₂ blocker solid preparation comprising the following sugar alcohol -60kJ / kg. 5. A method for improving the bitterness of a solid preparation of H ₂ blocker and making it easy to take by adding a sugar alcohol having a heat of dissolution of −60 kJ / kg or less.