JPH06157312A - Bitterness-improved dry syrup granule of terfenadine - Google Patents

Abstract

PURPOSE:To produce a bitterness-improved dry syrup granule of terfenadine improved in bitter taste and exhibiting an antihistaminic effect by adding xylitol exhibiting a sweetness almost equal to white sugar to terfenadine. CONSTITUTION:The dry syrup granule of terfenadine improved in bitter taste can be produced by adding xylitol to a medicine composed mainly of terfenadine exhibiting an antihistaminic effect. Xylitol is a sugar alcohol corresponding to D-xylose, remarkably soluble in water, slightly soluble in methanol and almost insoluble in ethanol. This substance exhibits a sweetness almost equal to that of white sugar and a cool feeling. Xylitol can be taken into the cell without requiring insulin and metabolism of xylitol, therefore, is not disturbed even in the case of insulinopenic disorder of sugar utilization. Accordingly, there is no problem about rise of blood-sugar level. In addition, the pharmaceutical permissibility of xylitol is very high since xylitol is a physiological metabolite. The amount of added xylitol is 0.1 to 0.5wt.%, especially preferably 0.2 to 0.3wt.% based on the weight of the whole preparation.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to dry syrup granules containing terfenadine containing xylitol as a main component and having an improved bitterness.

[0002]

2. Description of the Related Art Terfenadine is a drug having an antihistamine effect and is almost insoluble in water, so that it is formulated as a powder, tablet or granule. Dry syrup is a syrup used by dissolving or suspending powder, fine granules or granules in water before use. By the way, even a small amount of terfenadine is dissolved in water,
Or, when it is suspended, it has a bitter taste, and a resistance occurs when it is taken. Especially for infants, it may be difficult to administer even if prepared as a syrup. BACKGROUND ART Sucrose has heretofore been widely used as a fine-grain sweetener for syrup, and the amount thereof is usually about 70% or more based on the total weight of the preparation. When the bitterness of the drug is strong and the taste is not sufficiently improved, methods such as increasing the amount of sucrose added and coating the drug with a polymer substance have been adopted. However, there is a limit to the use of sucrose, and excessive use thereof causes juvenile diabetes, which is not preferable. In addition, the latter has the drawback that the formulation operation becomes complicated. The inventors of the present invention prepared fine granules for syrup using sucrose in terfenadine and found that the bitterness of terfenadine was not improved even if the amount of sucrose used was increased. It was discovered that the addition of xylit having the same degree of sweetness shows a bitterness-improving effect despite the fact that the above is not improved, and the present invention has been completed.

[0003]

The present invention provides a bitterness-improving terfenadine dry syrup granule characterized by containing xylit.

The term "xylit" as used in the present invention usually means
It is a sugar alcohol corresponding to D-xylose and is also called xylitol. There are various production methods, for example, sulfuric acid is added to xylan, heated to hydrolyze, and then pH 4 to
Adjust to 5 and concentrate under reduced pressure to obtain a concentrated solution of D-xylose. It is obtained by reducing this concentrated solution with pressurized hydrogen using sodium amalgam or nickel as a catalyst. Those obtained by other methods can also be used in the present invention. “Xylit” as a compound has a molecular formula of C ₅ H ₁₂
Mp61 of orthorhombic crystals having O ₅ by recrystallization from THF and columnar crystals by recrystallization from ethanol.
Stable crystals with a temperature of -94.5 ° C and d1.52 are obtained. Further, hygroscopic metastable crystals with a mp of 61 to 61.5 ° C., which are colorless and single crystal thin plate crystals, are obtained from anhydrous methanol.
Very soluble in water, slightly soluble in methanol, almost insoluble in ethanol. Its sweetness is similar to that of white sugar, but it has a cool sensation. Xylit is taken up into cells without the action of insulin. Therefore, the metabolism of xylit is not hindered and the blood glucose level is not increased even when the glucose utilization is impaired by insulin deficiency. In addition, xylit is a physiological metabolite and is therefore well tolerated.

In the present invention, xylite is preferably used in an amount of about 40% or more, more preferably about 50% or more, most preferably about 70% or more, based on the total weight of the preparation. Xylit may be used alone or may be mixed with a sweetener such as lactose or sucrose, and the total weight of xylit and the sweetener is about 85% to about 98% based on the total weight of the preparation, More preferably, it is used in an amount of about 94% to about 96%.

The "dry syrup" is defined as a syrup, and is prepared by adding a sweetener such as sucrose, an emulsifier, a suspending agent, etc. to a drug to prepare a solution or suspension before use. A granular preparation. Examples of emulsifiers or suspending agents (thickeners) include gum arabic, methyl cellulose (MC), carboxymethyl cellulose (C
MC) -Na, hydroxypropyl cellulose, sodium alginate, polysorbate 80, sodium lauryl sulfate, tragacanth and the like can be used. If necessary, an antifoaming agent such as a silicone resin may be added to make a solution or suspension before use. "Granule"
Include ordinary granules in which 80% or more of the particle diameter (μm) is 355 to 1400 and fine granules in which 85% or more is 75 to 500.

To improve the bitterness, it is more preferable to add a certain antacid. Examples of the antacid that can be used include magnesium aluminometasilicate, hydrotalcite, magnesium alumina hydroxide, sodium hydrogen carbonate and the like. These are 0.02 to 2% by weight, preferably 0.1 to 0.5% by weight, based on the total weight of the preparation.
It is more preferable to add 0.2 to 0.3% by weight. Terfenadine contained in the dry syrup granules of the present invention is usually 1 to 5% by weight, preferably 1 to 3% by weight, based on the total weight of the preparation. In addition, it may contain additives contained in ordinary granules and, if necessary, other pharmaceutically active ingredients, and the total preparation weight is 100% by weight.

The dry syrup granules of the present invention are conventional granule production methods, for example, extrusion granulation method, tumbling granulation method, crushing granulation method, fluidized bed granulation method, spray granulation method, It can be produced using a crushing granulation method or the like. Therefore, additives such as commonly used excipients, binders, preservatives and the like as granules can also be included. As an excipient,
Examples include sugars such as lactose, sucrose, glucose, and mannitol. As the binder, gum arabic, gelatin, MC, hydroxypropyl cellulose (HPC),
Examples thereof include polyvinyl alcohol. Examples of the preservative include benzoic acid, sodium benzoate, paraoxybenzoic acid esters, propylene glycol and the like.

The constitution and effects of the present invention will be specifically described below with reference to examples and test examples, but the present invention is not limited to these. Example 1 Terfenadine 30 g (1.5% by weight) Sucrose 545 (27.3)
〃) Xylit 1400 (70
〃) HPC-SL * 20 (1
〃) Hydrotalcite ** 4 (0.2
〃) Fragrance Trace amount Total amount about 2000 g * HPC-SL (trade name) is hydroxypropyl cellulose manufactured by Nippon Soda Co., Ltd. ** Alkamak (trade name: Kyowa Chemical Industry Co., Ltd.) was used as hydrotalcite. After mixing the above 4 components with a twin-screw kneader for 10 minutes,
% Alcohol and knead for 15 minutes. This kneaded product was granulated with a cylindrical granulator (diameter 0.45 mm), dried, and then sized,
Sieve to obtain 1900 g of 30-100 mesh granules. To this granule, 4 g of hydrotalcite and a trace amount of an aromatic agent are added and mixed with a mixer for 5 minutes to obtain a terfenadine dry syrup fine granule.

Examples 2 to 6 The dry syrup fine granules of the present invention are prepared in the same manner as in Example 1 using the following formulation (unit is mg). Example number 2 3 4 5 6 Terfenadine 30 15 15 15 15 30 Sucrose 257 272 272 72 257 Lactose --- 300 Xylit 700 500 700 900 900 400 Mannitol -200 --- HPC-SL 10 10 10 10 10 10 Hydrotalcite. 22-2-Antacid A *-2-2 Fragrance A trace amount A trace amount A trace amount A total amount (about) 1000 1000 1000 1000 1000 1000 * The antacid A is magnesium aluminometasilicate.

Test Example 1 (Preliminary Bitter Sensory Test) A formulation having the following formulation (unit: mg) was prepared in advance, and a bitter sensory test was conducted. The sensory test was carried out by two panelists, 10 ml of each 20% suspension was contained in the mouth for 10 seconds, and the bitterness was judged according to the following evaluation criteria.
The results are shown in Table 1. ◎ No bitterness is felt ○ Little bitterness is felt △ Little bitterness is felt × Bitterness is felt

[Table 1] Prescription examples 1 2 3 4 5 6 7 8 9 10 Terfenagene 30 30 30 30 30 30 30 30 30 30 Lactose − − − − 260 260 260 260 460 560 White sugar 960 − − − 700 − − − − − Amalu Tee * − 960 − − − 700 − − − − Xylit − − 960 − − − 700 − 500 400 Mannit − − − 960 − − − 700 − − HPC-SL 10 10 10 10 10 10 10 10 10 10 Total 1000 1000 1000 1000 1000 1000 1000 1000 1000 1000 Bitterness × × ◎ × × × ◎ × ○ △ * Amalty is powdered maltose starch syrup (commonly known as maltitol) manufactured by Towa Kasei Co., Ltd. Results With respect to the four sweeteners, in the prescription examples in which only the sweeteners were changed in the prescription examples 1 to 4 and 5 to 8, the sweetness was 0.65 to 1.0 when sucrose was 1.0. And
Amalti 0.75 to 0.95, Mannit 0.5
The bitterness-improving effect was clearly seen only in xylit. In particular, sucrose and amalty did not show a bitterness-improving effect, although they had sweetness comparable to that of xylit. It was found that xylit has a bitterness improving action different from that of sweetness.

Test Example 2 As a control example, a formulation having the following formulation (unit: mg) was prepared and subjected to a bitter sensory test. Control Example 1 Control Example 2 Terfenadine 30 30 Sucrose 959 259 Mannitol-700 HPC-SL 10 10 Fragrance Trace amount Trace amount Total amount (about) 1000 1000 20 for each formulation of Examples 1, 4, 6 and Control Examples 1 and 2. % Suspension was prepared. 10 ml for each panel (1
(0 person) was put in the mouth for 10 seconds, a sensory test was performed, and the evaluation was made according to the following evaluation criteria. The results are shown in Table 2. 0: No bitterness 1: Little bitterness 2: Little bitterness 3: Bitterness

[Table 2] Panelists 1 2 3 4 5 6 7 8 9 10 Formulation of the present invention Example 1 0 0 0 0 1 1 0 0 0 1 1 0 Example 4 0 1 0 0 0 0 0 1 1 0 1 1 Example 6 1 1 1 1 2 2 1 1 2 1 1 1 Control formulation Control example 1 3 3 2 3 3 3 3 3 3 2 2 Control example 2 2 3 2 3 3 2 2 3 3 3 3 Results Significantly improved bitterness compared to the control formulation I understand.

Claims (1)

[Claims] 1. A terfenadine dry syrup granule for improving bitterness, which is obtained by adding xylit.