WO2006001344A1 - Isosorbide-containing jelly preparation - Google Patents

Abstract

An isosorbide preparation as a therapeutic agent for Meniere’s disease that is improved with respect to administrability properties, such as bitterness, without detriment to the requisite performance of rapid efficacy exertion. There is provided an isosorbide-containing jelly preparation characterized by containing not only isosorbide but also agar. Preferably, cacao powder is further contained. The amount of agar added is preferably in the range of 0.3 to 2 w/w% based on the whole of jelly preparation. Further, there is provided a process for producing an isosorbide-containing jelly preparation, characterized by comprising mixing together at least agar, isosorbide and water, heating for dissolution and cooling to room temperature or below.

Description

 Specification

 Isosorbide-containing jelly preparation

 Technical field

 [0001] The present invention is an invention in the field of pharmaceuticals, and relates to a device for isosorbide preparation that is hard to take and difficult to take.

 Background art

 [0002] Isosorbide is a therapeutic drug for Meniere, which is rapidly absorbed by the gastrointestinal tract, but is not metabolized in the body, thus increasing serum osmotic pressure. As a result, this drug exhibits diuretic action, brain pressure lowering action, intraocular pressure lowering action and endolymphatic pressure lowering action. Isosorbide also has seizures such as dizziness, which is a symptom of Meyerre's disease, and is often taken as a forceful dose, so its medicinal effect needs to appear immediately after taking it. In general, drugs are effective when dissolved and absorbed in the gastrointestinal tract after taking the drug. Therefore, in order for isosorbide to express its effect quickly, it must be dissolved quickly in the gastrointestinal tract. Internal medicines are commercialized as pharmaceuticals based on isosorbide. The reason why the liquid agent is selected as a dosage form is that the liquid agent is already in a dissolved state, so that it can be expected to quickly exhibit a medicinal effect.

[0003] On the other hand, this drug is characterized by being very bitter. For this reason, even in the above liquid preparations, bitterness reduction by adding sweeteners and the like is being promoted, but the effect is not sufficient. This is because it is necessary to take 21g to 28g of isosorbide having a bitter taste at a time, so that the concentration of isosorbide in the liquid is reduced to 70w / w with the aim of minimizing the amount of liquid taken by the patient at a time. This is because it needs to be as high as v%. For this reason, it is very difficult to reduce the bitterness of isosorbide. In addition, in the case of potatoes, sales liquids show strong bitterness after the sourness of the flavoring agent added to prevent bitterness and often makes it difficult for patients to take isosorbide. Therefore, reducing the bitter taste of isosorbide and improving the taking ability is highly desired in the medical field.

[0004] Many drugs that exhibit an unpleasant taste such as bitterness such as isosorbide are important issues in the development of pharmaceuticals, and various studies have been made to improve the unpleasant taste. For example, for tablets containing bitter ingredients, bitterness is reduced by applying sugar coating or film coating. In addition, various powders, fine granules, and granules containing bitter ingredients are reduced in bitterness by applying film coating in the same manner as tablets or by adding sweeteners such as sucrose. Further, a method of containing a bitter component in an insoluble base to suppress dissolution in the oral cavity (JP 54-95719, JP 63-303928, JP 2-288821, JP 4-187629, JP 4 -327528, JP-A-6-501027, etc.), a method of adding a protein-lipid complex as an additive to reduce bitterness (JP-A-6-316 537), a method of blending essential oil or an essential oil component (JP-A-5-255126) In addition, a method of adding acidic phospholipid or its lyso form (JP-A-7-67552), a method of adding cacao powder (JP-A 2000-95710) and the like are disclosed. These all relate to solid preparations, and the bitterness reduction of solid preparations containing a small amount of bitterness components of lg or less can be carried out comparatively easily by these methods.

 [0005] On the other hand, no effective method has been found in examples of improving the ingestibility of liquids, except for general methods such as adding sweeteners. Although a method using jelly (JP-A-2001-226293) is also disclosed, it is estimated that bioavailability will be reduced and the onset of drug efficacy will be delayed in this method in order to suppress the dissolution of active ingredients that show bitterness. Is done.

 [0006] Patent Document 1: Japanese Patent Laid-Open No. 54-95719

 Patent Document 2: JP-A 63-303928

 Patent Document 3: JP-A-2-88821

 Patent Document 4: JP-A-4-187629

 Patent Document 5: JP-A-4-327528

 Patent Document 6: JP-A-6-501027

 Patent Document 7: JP-A-6-316537

 Patent Document 8: JP-A-5-255126

 Patent Document 9: JP-A-7-67552

 Patent Document 10: JP 2000-95710 A

 Patent Document 11: JP 2001-226293 A

Disclosure of the invention Problems to be solved by the invention

 [0007] As described above, isosorbide liquid, which is a therapeutic agent for Meniere's disease, has a strong bitter taste and is strongly desired to improve its ingestibility. However, an isosorbide preparation with good ingestibility has not been achieved yet. Accordingly, it is an object to provide an isosorbide preparation with improved dosing ability without impairing the characteristics of rapid and powerful drug efficacy required for an isosorbide preparation.

 Means for solving the problem

[0008] The present inventors diligently studied for the purpose of improving the dosage of an isosorbide solution that is bitter and difficult to drink. First, we tried to prepare a jelly preparation containing isosorbide using various gelling agents. As a result, it was found that the elution of isosorbide with this jelly formulation was significantly slower than that of the liquid, as was feared that the effect of improving the dosage of isosorbide by jelly formation was observed. This was thought to be due to the suppression of elution of isosorbide, which is a bitter component, by gelling. Therefore, the present inventors conducted further diligent investigations, and surprisingly, by using agar as a gelling agent, isosorbide can be quickly dissolved in the jelly formulation as well as the liquid, and the ingestion can be improved. I found it. Furthermore, as a result of adding cacao powder to improve the bitterness, it was found that the bitterness is reduced synergistically and it is easy to take large changes. Based on this knowledge, the inventors have completed the present invention.

 [0009] That is, the present invention is an isosorbide-containing jelly preparation characterized by containing isosorbide and agar. The preparation of the present invention preferably further contains cacao powder. The amount of agar added is preferably 0.3-2 w / w% of the total jelly preparation.

 [0010] The present invention also provides a method for producing an isosorbide-containing jelly preparation. That is, the method of the present invention is a method for producing an isosorbide-containing jelly preparation characterized in that at least agar, isosorbide and water are mixed, dissolved by heating and then cooled to room temperature or lower. Here, it is preferable to add and mix cacao powder together with agar, isosorbide and water. The invention's effect

[0011] By using the isosorbide-containing jelly preparation of the present invention, the patient can take it without worrying about the strong bitter taste of isosorbide, and it can be expected to improve the compliance. In addition, the preparation of the present invention is rapidly isolated in the gastrointestinal tract in the same manner as an internal solution. Since the drug is eluted, the medicinal effects are rapidly developed in the same manner as the internal solution.

 BEST MODE FOR CARRYING OUT THE INVENTION

 Hereinafter, the jelly preparation of the present invention will be described in more detail.

 The concentration of isosorbide contained in the preparation of the present invention is not particularly limited, but is preferably 50 to 80 w / w%. This is because it is natural that the bitterness is alleviated if the content of isosorbide in a certain amount of jelly preparation is reduced. Since the single dose of isosorbide is very high, 21g to 28g, When the content of isosorbide is low, it is necessary to take a large amount of jelly at a time, which makes it difficult to take isosorbide.

 [0013] From the jelly preparation of the present invention, isosorbide shows rapid elution as in the case of liquids, so that it can be expected that the drug will be rapidly taken or a powerful drug effect will be exhibited. Here, rapid and powerful dissolution means that, in the Japanese Pharmacopoeia dissolution test method, the dissolution of isosorbide from the jelly preparation after 15 minutes is 85% or more. Isosorbide elutes quickly even in the digestive tract, and immediately develops a medicinal effect in the same way as a solution.

[0014] The agar used in the present invention is a polysaccharide having galactose as a basic skeleton, and has different molecular weights and functional groups depending on the origin and production method of seaweed as a raw material, so that its characteristics are also different. Accordingly, the amount of addition cannot be generally defined, but is preferably 0.3 to 2 w / w%, more preferably 0.5 to 1.5 w / w% with respect to the total weight of the jelly preparation. When the amount of agar used is less than the above range, the elution of isosorbide from the jelly preparation is not affected, but the strength of the jelly is reduced and the bitterness reduction effect is reduced. Also, it may not gel. Conversely, when the amount used is increased, poor agar dissolution may occur, or the viscosity of the liquid before gelation may be very high, making it difficult to fill the container. Furthermore, the jelly becomes too hard and the feeling of administration becomes worse, and the elution of isosorbide, which is a jelly preparation, is delayed. Therefore, the amount of agar is preferably within the above range in order to improve the feeling of taking by reducing the bitter taste of isosorbide and to ensure rapid dissolution of isosorbide from the jelly preparation. As the gelling agent, it is desirable to use agar alone, but other gelling agents can be added. Examples of the gelling agent to be added to agar include carrageenan, xanthan gum, low-strength bean gum, and alginate. However, a lot of these Doing so should impair the properties of the agar, so the added amount should be small.

 [0015] The effect of improving the dosage by reducing the bitter taste of isosorbide of the present invention is enhanced by adding cacao powder. The optimal amount is 0.1 to 5 w / w% based on the total weight of the jelly preparation. In addition, glucose, fructose, maltose, xylose, honey, sucrose (sucrose), starch syrup, sorbitol, mannitol, xylitol, maltitol, powdered reduced maltose starch syrup, stevia extract, aspartame, chocolate flavor, saccharin sodium If you have a sweetener such as coffee, you can add coffee or other luxury products or flavorings. Of these, the combination of chocolate flavor and saccharin sodium is most preferable for the bitterness of isosorbide.

 [0016] The method for producing the preparation of the present invention, that is, jelly formation, is carried out by adding water to agar, isosorbide, cocoa powder, flavor, sweetener as necessary, stirring and dissolving at 90-100 ° C for several minutes, Cool down to the following. Here, the order of addition of the additives is not particularly defined. In some cases, it may further contain additives such as a pH adjusting agent, a coloring agent, and a preservative. The prepared isosorbide-containing jelly preparation can be stored and packaged in a cup, bag, tube, or the like.

 Hereinafter, the present invention will be described in more detail with reference to examples and comparative examples.

 Example

 [0018] Example 1 (isosorbide + agar + additive)

 1.2 g of agar, 0.24 g of citrate, 0.48 g of anhydrous sodium hydrogenphosphate and 0.6 g of saccharin sodium were added to about 60 mL of water, and the mixture was stirred and dissolved at 90-100 ° C for several minutes. Next, 140 g of isosorbide was added and dissolved little by little, and 0.4 g of cacao powder and 0.2 g of chocolate flavor were added and mixed uniformly, filled into a cup and cooled to room temperature.

[0019] Example 2 (isosorbide + agar)

 1.2 g of agar was added to about 60 mL of water, and dissolved under heating and stirring at 90 to 100 ° C. for several minutes. Next, 140 g of isosorbide was added little by little, and the mixture was melted and mixed uniformly. Then, the cup was filled and cooled to room temperature.

 [0020] Example 3 "isosorbide + (agar + carrageenan) + additive"

Approximately 60mL of water, 1.2g of agar, 0.6g of carrageenan, 0.6g of dipotassium hydrogen phosphate, dihydrogen phosphate Potassium (0.1 g), potassium chloride (0.03 g) and sodium saccharin (0.6 g) were added and dissolved by stirring at 90-100 ° C for several minutes. Next, 140 g of isosorbide was added and dissolved little by little, and 0.4 g of power and 0.2 g of chocolate flavor were added and mixed uniformly, filled into a cup, and cooled to room temperature.

 [0021] Example 4 "isosorbide + (agar + xanthan gum) + additive"

 About 60 mL of water, add 1.2 g of agar, 0.3 g of xanthan gum, 0.6 g of dipotassium hydrogen phosphate, 0.1 g of potassium dihydrogen phosphate, 0.03 g of potassium chloride, and 0.6 g of sodium saccharin, and heat at 90-100 ° C for several minutes. Dissolve with heating and stirring. Next, 140 g of isosorbide was added and dissolved little by little. Further, 0.4 g of strength powder and 0.2 g of chocolate flavor were added and mixed uniformly, filled into a cup, and cooled to room temperature.

 [0022] Example 5 "isosorbide + (agar + sodium alginate) + additive"

 About 60 mL of water, add 1.2 g of agar, 0.3 g of sodium alginate, 0.6 g of dipotassium hydrogen phosphate, 0.1 g of potassium dihydrogen phosphate, 0.03 g of potassium chloride and 0.6 g of sodium saccharin and count at 90 to 100 ° C. Dissolve with heating and stirring for minutes. Next, 140 g of isosorbide was added little by little, and 0.4 g of cacao powder and 0.2 g of chocolate flavor were added and mixed uniformly, filled into a cup and cooled to room temperature.

 [0023] Example 6 (Increase / decrease in the amount of agar)

 0.6 g of agar, 0.24 g of citrate, 0.48 g of anhydrous sodium hydrogen phosphate and 0.6 g of saccharin sodium were added to about 60 mL of water, and the mixture was heated and dissolved at 90-100 ° C for several minutes with stirring. Next, 140 g of isosorbide was added and dissolved little by little, and 0.4 g of cacao powder and 0.2 g of chocolate flavor were added and mixed uniformly, filled into a cup and cooled to room temperature.

 [0024] Nao (Increase / decrease in agar amount)

 Approximately 60 mL of water was charged with 3 g of agar, 0.24 g of citrate, 0.48 g of anhydrous sodium hydrogenphosphate and 0.6 g of sodium saccharin, and dissolved by stirring at 90-100 ° C for several minutes. Next, 40 g of isosorbide 140 was added and dissolved little by little, and 0.4 g of cacao powder and 0.2 g of chocolate flavor were added and mixed uniformly, filled into a cup, and cooled to room temperature.

 [0025] Emperor (change in agar)

About 60 mL of water, 7 g of agar, 0.24 g of citrate, 0.48 g of anhydrous sodium hydrogen phosphate and saccharide 0.6 g of sodium carbonate was added and dissolved by stirring at 90-100 ° C for several minutes. Next, 40 g of isosorbide 140 was added and dissolved little by little, and 0.4 g of cacao powder and 0.2 g of chocolate flavor were added and mixed uniformly, filled into a cup, and cooled to room temperature.

[0026] Control 1 (Liquid)

 30 mL of water was dissolved in 70 g of isosorbide and dissolved.

[0027] Control Example 2 (isosorbide + pectin + additive)

 In about 55 mL of water, pectin lg, 4.8 g of citrate and 0.6 g of saccharin sodium were added and dissolved by stirring at 90 to 100 ° C. for several minutes. Next, 140 g of isosorbide was added little by little, and 0.4 g of cacao powder and 0.2 g of chocolate flavor were added and mixed uniformly, filled into a cup and cooled to room temperature.

[0028] Needle illumination example 3 (Isosonolevid + locust bean gum + xanthan gum)

 In about 60 mL of water, 0.56 g of locust bean gum, 0.56 g of xanthan gum, 0.3 g of bibasic hydrogen phosphate and 0.6 g of sodium saccharin were added and dissolved by stirring at 90-100 ° C. for several minutes. Next, 140 g of isosorbide was added and dissolved little by little, and 0.4 g of cacao powder and 0.2 g of chocolate flavor were added and mixed uniformly, filled into a cup and cooled to room temperature.

[0029] Needle illumination example 4 (Isosonolevid + Darcomannan + Xanthan gum)

 To about 60 mL of water, 0.5 g of dalcomannan, 0.5 g of xanthan gum and 0.6 g of saccharin sodium were added, and dissolved by stirring with heating at 90 to 100 ° C. for several minutes. Next, 140 g of isosorbide was added little by little to dissolve, and 0.4 g of cacao powder and 0.2 g of chocolate flavor were mixed and mixed uniformly, filled into a cup and cooled to room temperature.

[0030] Control Example 5 (Isosonolevid + locust bean gum + xanthan gum)

 Locust bean gum (1.4 g), xanthan gum (1.4 g), citrate (0.24 g), anhydrous sodium hydrogenphosphate (0.48 g) and saccharin sodium (0.6 g) were added to about 55 mL of water, and dissolved by stirring at 90-100 ° C for several minutes. . Next, 140 g of isosorbide was added little by little to dissolve, and 0.4 g of cacao powder and 0.2 g of chocolate flavor were added and mixed uniformly, filled into a cup and cooled to room temperature.

[0031] Control Example 6 (Isosonolevid + dielan gum)

About 60 mL of water, 0.9 g of dielan gum, 0.6 g of dipotassium hydrogen phosphate, sodium citrate lg and 0.6 g of saccharin sodium was added and dissolved by stirring at 90-100 ° C for several minutes. Next, 140 g of isosorbide was added and dissolved little by little. Further, 0.4 g of cacao powder and 0.2 g of chocolate flavor were mixed and mixed uniformly, filled into a cup, and cooled to room temperature.

[0032] [Test Example 1] (Sensory test)

 The feeling of administration of Example Example 2 and Control Example 1 was evaluated by five subjects. Here, the subject put about 5 g of jelly preparation in his mouth and chewed several times for evaluation. In addition, about 5g of the liquid was put in the mouth and evaluated. The evaluation was based on a five-step evaluation, with 1 being no bitterness and 5 being very bitter and difficult to take. The test results are shown in Table 1.

 [0033] [Table 1]

【table 1】

[0034] The jelly preparation that also has isosorbide and agar power improved the feeling of taking isosorbide solution.

 Normally, cacao powder will not be effective unless several tens of percent or even hundreds of percent of the bitter substance is added, but in Example 1, isosorbide, a bitter substance, is contained at a high concentration of 70%. In spite of this, it was confirmed that a small amount of cacao powder showed an excellent bitterness reduction effect due to the synergistic effect of agar and cacao powder.

 [Test Example 2] (Sensory test and gel hardness; influence of agar amount)

Six subjects compared the feeling of administration of the jelly preparations of Example 6, Example 7, and Example 8, and examined the effect of the amount of agar added. The subjects put about 5 g of jelly preparation into their mouth and chewed several times for evaluation. Regarding the evaluation of bitterness, since the bitterness of the miscellaneous jelly preparations has also been reduced, it was difficult to set an evaluation standard. Ranking in ascending order of bitterness. In addition, the overall ease of taking was evaluated based on a five-step evaluation, with 1 being very easy to take and 5 being difficult to take. The hardness of the jelly was measured by compressing the jelly at a rate of 60 mm / min using a rheometer with a fixed area plunger and measuring the strength when the jelly breaks. The test results are shown in Table 2, Table 3, and Figure 1.

 [Table 2]

[Table 2]

 Relative evaluation

 [0037] [Table 3]

[Table 3]

 Total ease of taking

[0038] Example 6 was relatively less effective in reducing bitterness. The reason for this was thought to be that the gel collapsed in the mouth and the synergistic effect between the agar and cacao powder was weak. Conversely, the gel of Example 8 with a large amount of agar added is very hard as shown in FIG. From the questionnaire results, although the bitterness reduction effect was sufficiently confirmed, the feeling of taking was very bad. In addition, it was considered impossible to mass-produce with very high viscosity during production. Therefore, it is considered that 0.3-2 w / w% is preferred as the amount of the agar supplement, and more preferably 0.5-1.5 w / w%.

 [0039] [Test Example 3] (Dissolution test; comparison with other gelling agents)

 The elution properties of isosorbide having the jelly preparation strength obtained from Example 1 and Control Example 2 to Control Example 6 were tested by the Japanese Pharmacopoeia dissolution test method paddle method. However, water, 900 mL of the Japanese Pharmacopoeia Disintegration Test Method 1 and 2 were used as the test solution, and the paddle rotation speed was 50 rpm. The jelly preparation was pulverized into a size of about 2 mm in consideration of mastication. The quantification was performed by the HPLC method. A comparison of the dissolution properties of isosorbide with jelly preparations prepared using a jelly preparation using agar and other gelling agents is shown in Figs. 2 to 4, and Fig. 5 shows the results of Example 1 and each control example. The elution rate after minutes was shown together.

 [0040] Only in Example 1, which is a jelly preparation using agar as a gelling agent, even if the test solution of water, the first solution, and the second solution is misaligned, isosorbide is rapidly dissolved, It was remarkable that it showed rapid elution independent of the environment. The amount of each gelling agent used in each control example is a commonly used amount, and the hardness of the jelly preparation obtained in the control example is the same as or softer than that in Example 1. The test is not a comparison under conditions unfavorable to the control.

 [0041] [Test Example 4] (Elution test; influence of cacao powder, etc.)

 The dissolution test of isosorbide from the jelly preparations of Example 1 and Example 2 was performed in the same manner as in Test Example 3. Figure 6 shows a typical example of the test results. The cacao powder and other additives did not affect the elution of isosorbide with jelly preparation ability using agar, and in both Examples 1 and 2, isosorbide quickly eluted with jelly preparation ability. Regarding jelly preparations prepared using other gelling agents, cocoa powder and other additives did not affect the elution of isosorbide.

 [0042] [Test Example 5] (Dissolution test; influence of agar amount)

The dissolution test of isosorbide from the jelly preparations of Example 1 and Examples 6 to 8 was performed in the same manner as in Test Example 3. The test results are shown in Figs. From jelly preparations The elution of isosorbide was not greatly affected by the amount of agar added, but the amount added was very large, indicating a slight delay in elution.

 [0043] [Test Example 6] (Dissolution test; mixed gelation system)

 Examples The dissolution test of isosorbide from the jelly preparations of Examples 3 to 5 was performed in the same manner as in Test Example 5. The test results are shown in Figs. In the case of an isosorbide-containing jelly preparation using agar as the gelling agent, the rapid dissolution characteristics of isosorbide were maintained even when other gelling agents were added.

 Brief Description of Drawings

 FIG. 1 is a graph showing the relationship between the hardness of an isosorbide-containing jelly preparation and the amount of agar added.

 FIG. 2 is a graph showing the results of an elution test of an isosorbide-containing jelly preparation into the “JP” disintegration test method solution 1 (pH 1).

 FIG. 3 is a graph showing the results of a dissolution test for isosorbide-containing jelly preparations in water.

 FIG. 4 is a graph showing the results of an elution test of an isosorbide-containing jelly preparation into the second solution (pH 6.8) of “JP” disintegration test method.

 FIG. 5 is a graph showing the dissolution rate of an isosorbide-containing jelly preparation after 15 minutes in each dissolution test solution.

 FIG. 6 is a graph showing the effect of adding cacao powder on the dissolution properties of isosorbide-containing jelly preparations.

 FIG. 7 is a graph showing the effect of the amount of agar added on the dissolution properties of an isosorbide-containing jelly preparation into the “JP” disintegration test method solution 1 (pH 1).

 FIG. 8 is a graph showing the effect of the amount of agar added on the dissolution property of isosorbide-containing jelly preparations in water.

 FIG. 9 is a graph showing the effect of the amount of agar added on the dissolution properties of isosorbide-containing jelly preparations into the “JP” disintegration test method solution 2 (pH 6.8).

 FIG. 10 is a graph showing the effect of addition of other gelling agents on the dissolution properties of isosorbide-containing jelly preparations into the “JPA” disintegration test method solution 1 (pH 1).

FIG. 11 is a graph showing the influence of other gelling agent-added calories on the solubility of isosorbide-containing jelly preparations in water. [12] This is a graph showing the effect of addition of other gelling agents on the dissolution properties of jelly preparations containing isosorbide into the “JPA” disintegration test method solution 2 ( _PH 6.8).

Claims

The scope of the claims  [1] An isosorbide-containing jelly preparation comprising isosorbide and agar.  [2] The sorbate containing isosorbide according to claim 1, further comprising cacao powder.  [3] The isosorbide-containing jelly preparation according to claim 1 or 2, wherein the amount of the agar added is 0.3 to 2 w / w% of the whole jelly preparation. [4] A method for producing an isosorbide-containing jelly preparation, comprising mixing at least agar, isosorbide and water, dissolving by heating and then cooling to room temperature or lower. [5] The method for producing an isosorbide-containing jelly preparation according to [4], wherein cocoa powder is further added and mixed together with agar, isosorbide and water.