JPH107549A - Improvement in dissolution rate of substance - Google Patents

Abstract

PROBLEM TO BE SOLVED: To enable a remarkable increase in the dissolution rate of a substance having a low dissolution rate at low temperatures and further the dissolution thereof in cold water in an ultrashort time by adding a specific surfactant in a prescribed proportion to the substance. SOLUTION: (B) A sucrose ester of a fatty acid or a polyoxyethylene (20) sorbitan monooleate or both having 15-30 hydrophile-lipophile balance(HLB) in an amount of 0.1-10wt.% are added to (A) a substance having 0.001-20mg/sec dissolution rate in water at 15 deg.C. Furthermore, an aqueous solution of the ingredient B is preferably added or sprayed on the ingredient A and then dried. For example, L-ascorbic acid, potassium chloride or a black tea extract is preferably used as the ingredient A.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for improving the dissolution rate, and more particularly to a method for increasing the dissolution rate of a water-soluble substance.

[0002]

2. Description of the Related Art There have been many attempts to improve the solubility of hardly soluble substances (for example, see Japanese Unexamined Patent Publication No.
JP-A-7-189650, JP-A-57-189651, JP-A-63-230703, JP-A-3-3
2734, JP-A-6-345802).

[0003] However, these publications are mainly intended to improve the solubility of a substance which is originally hardly soluble in water, and in general, increasing the temperature increases the solubility. The temperature of the solvent is limited to 20 ° C. or higher. As described above, it is well known that the dissolution of a substance is affected not only by the temperature but also by the pH, the type of the solvent, the mechanical conditions at the time of stirring, the time, and the like.

[0004] On the other hand, when discussing the dissolution of a substance, together with the solubility in a certain system (final maximum solubility),
The time to reach this solubility is a very important factor, at least in practical terms. In other words, even for substances that have the same solubility, the time to reach equilibrium is actually significantly different due to various factors, and the difference in this part accounts for a large weight in determining the commercial value. But there are many in reality.

For example, in the field of pharmaceuticals, in the case of fast-dissolving tablets and granules, it is required to dissolve immediately within 30 seconds or 1 minute, rather than to require high solubility. Often. In addition, in the food field, even in the case of sweeteners used for iced coffee or iced tea, it is required to dissolve quickly within 1 to 2 minutes, and the same is true for powders of tea extracts such as black tea. It is also required for granules and granules. Furthermore, in the latter case, it is also necessary to consider the dissolution rate at around 5 ° C. for summer use.

[0006]

As described above, studies have been made mainly on increasing the solubility of poorly soluble substances, but the dissolution rate of substances including relatively water-soluble substances has been studied. At present, there has been little research or invention for increasing the amount of methane, especially at low temperatures.

In the food field, on the other hand, solid sweeteners are instantaneously dissolved in iced tea and iced coffee, and substances are dissolved at the lowest possible temperature in order to maintain flavor and flavor. The need to take measures such as dissolution at low temperatures to suppress degradation, and there are many needs in the pharmaceutical field such as increasing the bioavailability of drugs and providing immediate effects , On the other hand, exists.

[0008]

Means for Solving the Problems The present inventors have conducted intensive studies to meet these needs, and as a result, the substance having a dissolution rate at 15 ° C. of 0.001 to 20 mg / sec has a “dissolution rate curve”. '' Shows a very specific sigmoid curve, and furthermore, the shape of this curve was found to change dramatically when a certain surfactant was added at a certain ratio, and the present invention was completed. is there.

That is, according to the present invention, a sucrose fatty acid ester having an HLB of 15 to 30 and / or polyoxyethylene (20%) is used for a substance having a dissolution rate in water of 0.001 to 20 mg / sec at 15 ° C. ) A method for improving the dissolution rate of a substance to which sorbitan monooleate is added at 0.1 to 10% by weight is provided.

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION The term "dissolution rate in a substance having a dissolution rate in water at 15 ° C of 0.001 to 20 mg / sec" in the present invention means that 1 g of a solute is dissolved in 1000 cc of water at 15 ° C under stirring conditions (magnetic stirrer). At 100 rpm), and the time T until dissolution was measured.
(Mg / sec). Substances exhibiting a dissolution rate in the above range generally show a "dissolution rate curve with respect to temperature" that differs from a temperature of 20 to 30 [deg.] C. below and above as if as a separate system. Such a substance is not particularly limited as long as it has a dissolution rate in the range of 0.001 to 20 mg / sec.
It may be either an organic substance or an inorganic substance, or may be a natural product or an extract from a natural product.

For example, as organic substances, L-ascorbic acid, acetanilide, acetamide, citric acid, glycine, succinic acid, D-mannitol, L-phenylalanine, p-aminobenzoic acid, L-alanine, antipyrine, D-isoleucine And the like. Examples of the inorganic substance include potassium chloride, hydrogen phosphate, potassium permanganate, potassium hydroxide, magnesium chloride, magnesium sulfate, manganese chloride, sodium carbonate, sodium chloride, sodium sulfate, zinc chloride, and zinc sulfate. Natural products include black tea extract, rooibos extract, gymnema extract, green tea extract, oolong tea extract,
Caramel, licorice extract, red bean and the like.
These substances may contain a single substance or a mixture of two or more substances, or one or more of these substances and another substance.

[0012] In the present invention, the above-mentioned substance may contain sucrose fatty acid ester and / or polyoxyethylene (20).
Sorbitan monooleate is added. The sucrose fatty acid ester has an HLB of 15 to 30, preferably 15 to 2
0 or more carbon atoms, preferably 12 to 20 carbon atoms
Sucrose fatty acid esters. Preferred examples of the sucrose fatty acid ester include sucrose monostearate, sucrose monooleate, and sucrose monopalmitate, and these can be used alone or in combination. Examples of polyoxyethylene (20) sorbitan monooleate include Tween 80 and the like. These sucrose fatty acid esters and / or polyoxyethylene (20) sorbitan monooleate are each independently used in an amount of 0.1 to 10% by weight,
Preferably 0.3 to 5% by weight, or a total of 0.1 to 10% by weight, preferably 0.3 to 5% by weight in combination of sucrose fatty acid ester and polyoxyethylene (20) sorbitan monooleate Is done.

In the method for improving the dissolution rate of a substance according to the present invention, it is preferable that “the dissolution rate in water at 15 ° C. is 0.0
Examples of a method for adding a sucrose fatty acid ester and / or polyoxyethylene (20) sorbitan monooleate to the "01-20 mg / sec substance" include the following methods. That is, a sucrose fatty acid ester and / or polyoxyethylene (20) sorbitan monooleate are added to a solid substance of the present invention such as a powder or granules in a solid state such as a powder or granules, and optionally crushed and mixed. An aqueous solution of sucrose fatty acid ester and / or polyoxyethylene (20) sorbitan monooleate is added in advance to a part of the solid substance of the present invention such as powder or granules and infiltrated, A method of kneading with the rest of the substance, a method of adding an aqueous solution of sucrose fatty acid ester and / or polyoxyethylene (20) sorbitan monooleate to a solid substance of the present invention such as powder or granules, and kneading. An aqueous solution of sucrose fatty acid ester and / or polyoxyethylene (20) sorbitan monooleate according to the present invention in a solid form such as powder or granules A method of spraying an aqueous solution of sucrose fatty acid ester and / or polyoxyethylene (20) sorbitan monooleate with an aqueous solution or suspension of the substance of the present invention, or separately supplying And a method of spray-drying.

When sucrose fatty acid ester and / or polyoxyethylene (20) sorbitan monooleate is added to the "substance" in the present invention, any of the compounds may be added in any form and method other than the above. Addition and mixing are included in the present invention. When preparing an aqueous solution, a solvent such as ethanol may be used, or a substance obtained after mixing or the like may be appropriately subjected to a drying treatment. When preparing an aqueous solution, sucrose fatty acid ester and / or polyoxyethylene (2
0) Sorbitan monooleate is preferably contained at 0.1 to 80% by weight.

The substance obtained by the above method may be used as it is or in a form to which one or more various additives such as a suitable excipient, a binder, a foaming aid, a disintegrant, a coloring agent and the like are added. By doing so, the dissolution rate can be improved, or it can be processed into a desired solid preparation such as powder, granules, tablets, pills, buccal and used by a method known in the field of pharmaceuticals and the like. . Thus, when processing into a desired solid preparation, one or more various additives such as an excipient, a binder, a foaming aid, a disintegrant, and a colorant may be added. As the excipient, for example, sucrose, D-mannitol, maltose, glucose, fructose, glucose, powdered reduced maltose starch syrup, lactose, corn starch, wheat starch, potato starch, rice starch, inositol, ethyl cellulose,
Xylitol, crystalline cellulose, synthetic aluminum silicate, β-cyclodextrin, D-sorbitol, low-substituted hydroxypropylcellulose, dextrin, calcium lactate, hydroxypropyl starch, hydroxypropylcellulose, hydroxypropylmethylcellulose, pectin, methylcellulose and the like. .
As the binder, crystalline cellulose, methyl cellulose,
Low-substituted hydroxypropylcellulose, corn starch paste liquid, wheat starch paste liquid, potato starch paste liquid, rice starch paste liquid, starch syrup, sodium carboxymethylcellulose, gum arabic, corn starch, wheat starch,
Potato starch, rice starch, sodium alginate,
Xanthan gum, soft silicic anhydride, dextrin, tragacanth powder, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, macrogol, ethylcellulose, starch syrup and the like can be mentioned.
Examples of the foaming aid include potassium tartrate and sodium hydrogen carbonate. Disintegrants include carboxymethyl starch, pregelatinized starch, sodium carboxymethyl starch, hydrous silicon dioxide, guar gum, crystalline cellulose, corn starch, wheat starch,
Potato starch, rice starch, lactose, low-substituted hydroxypropylcellulose, hydroxymethylethylcellulose, hydroxypropylstarch, hydroxypropylcellulose, hydroxypropylmethylcellulose, macrogol, D-mannitol, methylcellulose and the like. Coloring agents include turmeric extract, yellow iron oxide, carbon black, caramel, β-carotene, carotene solution, licorice extract, food blue No. 1, food yellow 4
No., Food Yellow No. 5, Food Yellow No. 4, Aluminum Lake, Food Red No. 102, Food Red No. 2, Food Red No. 3,
Copper chlorophyll, red bean, riboflavin and the like can be mentioned.

For example, when L-ascorbic acid is used as a substance, sucrose monostearate and / or Tween 80, sucrose as an excipient, starch syrup as a binder, potassium tartrate as a foaming aid and hydrogen bicarbonate are used. It can be a granule preparation containing sodium. Generally, in the method for improving the dissolution rate of the substance of the present invention,
Although the target solvent is water, the amount of the solvent is a matter of course, not to mention “solubility”. In the Japanese Pharmacopoeia, Table 1
, The solubility is defined.

[0017]

[Table 1]

That is, the solubility of a substance depends on the amount of water as a solvent. In other words,
"Substances exhibiting 1% solubility" means that 1 g of solute is completely dissolved in 99 g of water, half the amount of water, 49.
Only 0.5 g of solute dissolves in 5 g of water. Also, 1
g of solute dissolves readily in 1000 g of water. When solubility is a problem, the amount of the solvent with respect to the solute plays a decisive role. On the other hand, in the case of the dissolution rate, the dependence on the amount of the solvent is small when the amount of the solvent is higher than the solubility. That is, the dissolution rate of the “substance showing 1% solubility” is 1000 even when the solvent is 200 g.
Even with g, the dissolution rate itself does not change as long as other conditions are the same.

However, in the present invention, “a substance having a dissolution rate in water at 15 ° C. of 0.001 to 20 mg / sec” includes a sucrose fatty acid ester having an HLB of 15 to 30 and / or polyoxyethylene (20). When sorbitan monooleate is added at 0.1 to 10% by weight, the dissolution rate at low temperatures is remarkably improved, whereas that at high temperatures is not much different, and as a result, the temperature dependence of the solubility curve is high. Was found to be significantly reduced. In other words, although it is not necessarily poorly soluble in water, the dissolution rate is actually low, and in practice, even for a problematic substance, the dissolution rate is significantly improved by the present invention.

[0020]

EXAMPLES The method for improving the dissolution rate of the present invention will be described below with reference to examples. In this example, in the field of processed foods, pharmaceuticals, and the like, usually, a system having an overwhelmingly large amount of a solvent with respect to the amount of a solute is targeted. The target was a system using water.

Example 1 Thomatin (natural sweetener) 1 mg Aspartame (artificial sweetener) 16 mg Erythritol 83 mg Total 100 mg When the powder of the above composition is kneaded with water to obtain granules, the dissolution rate of the obtained granules (1 g of granules is converted to 1000 g of water)
Is 0.5 mg at 5 ° C. as shown in Table 2.
/ Sec, 0.7 mg / sec at 15 ° C, 2 mg / sec at 30 ° C, 50
At 20 ° C. and the dissolution rate of granules of this composition is
It was found to be approximately equal to the dissolution rate of aspartame alone.

Then, the sucrose fatty acid ester was dissolved in water at various ratios, and the above composition was added to each aqueous solution and wetted, and then the mixture was kneaded to produce granules. The dissolution rates of the obtained granules at respective ratios of 5 to 50 ° C. are as shown in Table 2.

[0023]

[Table 2]

From Table 2, it was apparent that the dissolution rate of the granules of the above composition increased with an increase in the amount of sucrose fatty acid ester added. In addition, it was recognized that the dissolution rate increased remarkably in a temperature range of 30 ° C. or lower, and that the dissolution rate did not change at 50 ° C. depending on the amount of sucrose fatty acid ester added.

Example 2 Black tea extract 100 mg Erythritol 300 mg Total 400 mg When powder of the above composition is kneaded with water to form granules The dissolution rate of the obtained granules (1 g of granules is converted to 1000 g of water)
Dissolved in 0.4 mg at 5 ° C. as shown in Table 3.
/ S, 0.6 mg / s at 15 ° C, 4 mg / s at 30 ° C, 50
At 25 ° C. and the dissolution rate of granules of this composition is
It was found to be approximately equal to the dissolution rate of the black tea extract.

Then, polyoxyethylene (20) sorbitan monooleate was dissolved in water at various ratios, and the above composition was added to each aqueous solution and wetted, and then granulated as a kneading liquid. The dissolution rates of the obtained granules at respective ratios of 5 to 50 ° C. are as shown in Table 3.

[0027]

[Table 3]

From Table 3, it was apparent that the dissolution rate of the granules of the above composition increased with an increase in the amount of polyoxyethylene (20) sorbitan monooleate added. In addition, it is recognized that the dissolution rate increases particularly from 0.1% of the amount of polyoxyethylene (20) sorbitan monooleate added, and that when the amount exceeds 10%, almost equilibrium is reached. At 50 ° C., it was confirmed that the dissolution rate did not change depending on the amount of polyoxyethylene (20) sorbitan monooleate added.

(Example 3) Substance A having a small dissolution rate (aspirin: dissolution rate of 0.0006 mg / sec at 15 ° C.) and large substance B (powdered sugar (ground granulated sugar): dissolution rate at 25 ° C. at 25 ° C.) ), The sucrose fatty acid ester was dissolved in water at various ratios, and the above composition was added to each aqueous solution and wetted, and then the mixture was kneaded to produce granules. Table 4 shows the dissolution rate when the obtained granules were dissolved in water at 15 ° C.

[0030]

[Table 4]

As shown in Table 4, the dissolution rate at 15 ° C. was 0.1%.
In the case of substance A, which is extremely small at 0006 mg / sec, the dissolution rate increases with an increase in the amount of sucrose fatty acid ester added, but only up to 0.001 mg / sec at the maximum.
It can be said that this increase is a practically meaningless improvement. In the case of the substance B having a dissolution rate as high as 25 mg / sec, it was recognized that the dissolution rate hardly changed due to an increase in the amount of sucrose fatty acid ester added.

[0032]

According to the method for improving the dissolution rate of the present invention,
HLB is 15 ~
By adding 0.1 to 10% by weight of 30 sucrose fatty acid esters and / or 0.1 to 10% by weight of polyoxyethylene (20) sorbitan monooleate, the dissolution rate of such substances is significantly increased. be able to. Thus, many processed foods and pharmaceuticals can be dissolved in cold water in a very short time.

As a result, it is possible to improve the various processes and the productivity, and to increase the commercial value and the bioavailability of pharmaceuticals by rapidly and completely dissolving the composition. And the like.

Claims (3)

[Claims] 1. A substance having a dissolution rate in water of 0.001 to 20 mg / sec at 15 ° C. has an HLB of 15
0.1 to 10 of sucrose fatty acid ester and / or polyoxyethylene (20) sorbitan monooleate.
A method for improving the dissolution rate of a substance, characterized in that the substance is added in a percentage by weight. 2. The method according to claim 1, wherein the aqueous solution of sucrose fatty acid ester and / or polyoxyethylene (20) sorbitan monooleate is added to the substance, followed by drying. 3. The method according to claim 1, wherein the substance is sprayed with an aqueous solution of sucrose fatty acid ester and / or polyoxyethylene (20) sorbitan monooleate, and then dried.