KR101728799B1 - Injections and its preparation method for producing a homogeneous solution was formed by solubilizing poorly soluble active pharmaceutical ingredient - Google Patents

Abstract

The present invention relates to an injection formulation and eye drop formulation formed into a homogeneous solution by solubilizing sparingly soluble pharmacologically active ingredients, and a method for preparing the same. Particularly, the injection formulation and eye drop formulation are formed into a homogeneous solution by mixing and dissolving a sparingly soluble material which has a pharmacologically active ingredient and is slightly soluble in an alcohol but insoluble in water with a detergent, ethanol and a solubilizer so that the sparingly soluble pharmacologically active ingredient may be solubilized. Preferably, the sparingly soluble material is rebamipide or curcumin, and the solubilizer is any one of alkaline amino acids including histidine, lysine and arginine or a combination thereof. Therefore, it is possible to obtain a homogeneous solution containing a sparingly soluble drug and to provide an injection formulation and eye drop formulation causing no precipitation and deposition of a drug and having no side effect.

Description

[0001] The present invention relates to a method for producing a homogeneous solution, which comprises solubilizing an insoluble active pharmaceutical ingredient using ethanol and an alkaline amino acid,

The present invention relates to solubilization of an insoluble active pharmacological ingredient, and more particularly, to solubilization of an insoluble active ingredient having an effective pharmacological ingredient by using a detergent, an alkaline amino acid and a small amount of ethanol as a solubilizing agent to form a homogeneous solution Solubilization of an insoluble active pharmacological component using ethanol and an alkaline amino acid.

Due to the development of medicine, the efficacy of currently available pharmacological ingredients has been revealed, and these pharmacological ingredients have been used for various purposes.

While developing the pharmaceutical technology, the inventors of the present invention have been able to find a drug that is insoluble with conventional techniques. The present inventors have studied and found that a poorly soluble substance can be solubilized using an alkaline amino acid and a detergent according to Korean Patent Application No. 10-2015-0171734. It can be applied to cyclosporin, dexamethasone, fluorometholone, diclofenac, tacrolimus, and Compound K, which is an active ginseng saponin component.

For reference, the effective pharmacological components differ depending on the solvent. Solubility in alcohol or water is different, and the expression of degree of melting is used as soluble, insoluble or insoluble. On the other hand, some expressions such as good melting, hardly melting or difficult to melt are also used. In order to understand the meanings of these expressions, we shall use the following in accordance with the provisions of the Korean Pharmacopoeia.

According to the Korean Pharmacopoeial Specification, it is said that the amount of solvent required to dissolve 1 g of solute is well soluble in 1 ml or less, and when 1 ml or more is less than 10 ml, it is well dissolved. If more than 10 ml is less than 30 ml It is defined as melting when 30 ml to less than 100 ml is needed. It is defined that if it is less than 100 ml and less than 1,000 ml, it is difficult to dissolve. It is defined as difficult to melt. In particular, it is defined that almost 10,000 ml or more of the solvent is not dissolved and this case is insoluble.

In the case of components that are hardly soluble in ethanol and are hardly soluble in water according to the above rules, another formulation technique will be required. In the case of curcumin, which is the main component of ganghwang or gilt, 10 mg / ml is slightly soluble in ethanol. Rebamipide used for protection of gastrointestinal tract and dry eye syndrome is less than 1 mg / ml, which is very difficult to dissolve in ethanol. It is said that it is very difficult to scientifically dissolve in 100 ml of solution with a solubility of 0.1 g or less, and rebamipide is said to dissolve only trace amounts in ethanol. These drugs do not dissolve more in water, they are insoluble enough to exhibit sufficient drug efficacy, and there is a problem of loss when they are manufactured. It seems to be possible to solve various problems by producing uniform and effective drugs by solving the problems.

Therefore, there is an urgent need for a preparation method of a homogeneous solution having a low side effect on the human body and being safe and excellent in the stability of the preparation.

Korean Patent Application No. 1020150171734: Injectable and ointment formulations which are formed into a homogeneous solution by solubilization of an insoluble active pharmacological ingredient and a preparation method thereof. Korean Patent Publication No. 1020150000405: A water-in-oil type emulsion composition of a poorly soluble drug and a method for producing the same.

DISCLOSURE Technical Problem Accordingly, the present invention has been made to solve the above-mentioned problems and it is an object of the present invention to solve the above problems, and to provide a method of solubilizing effective pharmacological components which are low in solubility in water and insoluble in ethanol, The present invention also provides a method for manufacturing a pharmaceutical preparation which prevents the re-precipitation by temperature.

It is another object of the present invention to provide an injectable or eyedropper which is free from side effects and easy to use by solubilizing effective pharmacological components which are hardly dissolved in water and hardly dissolved in ethanol.

In order to accomplish the above object, the present invention provides a method for producing a water-soluble polymer, which comprises uniformly mixing a substance having an effective pharmacological component and slightly soluble in alcohol and hardly soluble in water and a detergent; Dissolving an insoluble matter mixed with the detergent in an alcohol; Adding the alcoholic solution prepared in the above step to an aqueous solution containing the solubilizing agent; Sterilization by filtration or high temperature steam sterilization; And a step of performing a sealing treatment by aseptic operation,

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Uniformly mixing a weakly soluble substance having an effective pharmacological component, which is hardly soluble in ethanol and hardly soluble in water, and a detergent; Mixing an insoluble matter mixed with the starter into a small amount of alcohol; Adding the alcoholic solution prepared in the above step to an aqueous solution containing the solubilizing agent; Sterilizing the solution prepared in the above step by filtration or high temperature steam sterilization; Adding alcohol to the solution prepared in the above step by aseptic operation; Treating the solution to which ethanol is added in the above step by ultrasonication to prepare a fine suspension solution; Separating the solution prepared in the above step by aseptic operation and performing a sealing treatment, and a method for preparing a solubilized homogeneous solution preparation of an insoluble active pharmacological component using ethanol and an alkaline amino acid.

By preparing a homogeneous solution containing a poorly soluble drug, there is an effect of providing injections and eyedrops which do not cause sedimentation and precipitation of drugs and have no side effects.

In addition, there are other effects that can be provided by a simple method, thereby providing a more economical advantage through reduction in manufacturing cost.

Another effect is that the poorly soluble drug can be extended to various uses by forming a homogeneous solution.

FIG. 1 is a graph showing the results obtained by adding 1.0% of tween 80 to 1% rebamipide, 0.5% of propylene glycol as a solubilizer, 0.5% of lysine, adjusting pH to 8.6 and adding 1.0% of tween 80 to 1% rebamipide (B) adding 1% of rebamipide to 1.0% of tween 80, adding 1.0% of lysine as a solubilizing agent and adjusting the pH to 8.0, (c) adjusting the acidity to 7.0 by adding 1.0% 1% rebamipide was prepared by adding 0.9% Lysine as a solubilizer and 0.1% sodium alginate to adjust the pH to 8.6 (d).
FIG. 2 is a photograph showing the addition of 1.0% of tween 80 to 1% rebamipide and the addition of 1.0% of lysine as a solubilizer to adjust the pH to 8.0.
FIG. 3 is a photograph showing a fine suspension prepared by adding 1.0% of tween 80 to 1% rebamipide and adding 1.0% of lysine as a solubilizer to adjust the acidity to 9.0.
FIG. 4 is a photograph showing a state where 1.0% of tween 80 was added to 1% rebamipide, 1.0% of lysine was added as a solubilizer, and the acidity was adjusted to 10.0.
FIG. 5 is a photograph showing a clear view of adding 1.0% of tween 80 to 1% rebamipide and adding 1.0% of lysine as a solubilizer to adjust the pH to 12.0
FIG. 6 shows the results of a slight blurry solubilization (a) with 1% rebamipide, 0.9% Lysine as a solubilizing agent and 0.1% sodium alginate to adjust the acidity to 8.6, 0.5% Lysine as a solubilizing agent in 1% rebamipide (B), 1% rebamipide was added with 0.5% Lysine as a solubilizing agent, and 1% tween 80 was added to the solution. (C) in a cloudy state with the pH adjusted to 8.57.
FIG. 7 is a photograph showing a 1.0% reconstitution of lysine as a solubilizer in 1% rebamipide and a clear appearance by adjusting the pH to 8.5 by adding 1% of tween 80% and 1% of ethanol.
FIG. 8 is a photograph showing the addition of 1.0% of lysine as a solubilizer to 1% rebamipide, and adjusting the acidity to 8.6 by adding 1% of tween 80% and 3% of ethanol.
FIG. 9 is a photograph showing the results of photographs (a) and (b) of 100 ml of curcumin prepared by adding 1 g of lysine as a solubilizer to curcumin, adding 1 g of tween 80, adding 1 g of ethanol and adjusting the acidity to 8.6, To 1 g of lysine as a solubilizing agent in 75 mg of curcumin, 1 g of tween 80 was added thereto, 3.0 g of ethanol was added thereto, and the pH was adjusted to 8.6 to adjust the acidity to 8.6 to prepare a 100-milliliter b).
Fig. 10 is a photograph of the ultrasonic treatment after the high-temperature steam sterilization treatment of Fig. 9 (b).
FIG. 11 is a photograph of (b) of FIG. 9 showing addition of 0.1% citric acid as an antioxidant and ultrasonic treatment after high temperature steam sterilization.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will now be described in detail with reference to the drawings. The present invention mainly relates to a process for producing a homogeneous solution (5) by adding raw materials (1), a mixture using a detergent (2), an alcohol mixture (3), a solubilizer mixture (4) And sterilization (6). Hereinafter, each step will be described in detail.

(1) Preparation of raw materials

The raw materials used in the present invention are those having effective pharmacological components which can be used as injections or eyedrops in the human body. These pharmacological ingredients are insoluble in water and therefore have a very low solubility in water, and the solubility in hot water However, since the crystals precipitate at various sizes of amorphous form when left at room temperature, they can hardly be used as injections or eye drops. In addition, ethanol is a substance having a small melting property.

There are many such substances, but representatively, rebamipide and curcumin will be exemplified in the present invention. Revamipid is a gastric and gastric ulcer treatment drug developed in Japan and manufactured and sold by Mitsukoshi Pharmaceutical Co., Ltd. in Korea. The molecular formula is C ₁₉ H ₁₅ CIN ₂ N ₄ and the molecular weight is 370.8. White crystalline powder has no odor I have a taste. Methanol and ethanol are difficult to dissolve, and water and ether are said to be almost insoluble. Curcumin, which is known as the main component of turmeric and turmeric, is C ₂₁ H ₂₀ O ₆ and its molecular weight is 368.38. It is extracted from the roots of Curcuma longa Linn (Zingiberaceae), a plant belonging to the ginger family of Dong-in Province, It is known to be an anti-tumor, antioxidant, anti-amyloid and anti-inflammatory effect as turmeric curcuminoid, which is a yellow polyphenol yellow spice. It is also difficult to dissolve in methanol and ethanol. It is said to be almost insoluble.

Therefore, the above-mentioned rebamipide and / or curcumin should be in the form of a homogeneous solution in order to form a clear solution form for use as injections and eyedrops. Also, the dissolved pharmacological components should not be precipitated in various sizes of amorphous form even at room temperature or refrigerated storage for a long time. Of course, there should be no side effects on the human body.

At the end of many trial and error of the present inventors, we have found a detergent and a solubilizing agent which are required to satisfy solubility of such poorly soluble pharmacological ingredients and precipitation problems during storage for a long time and to be acceptable for injections and eye drops, Processing.

(2) Dispersing using the detergent

The available detergents were Sodium dodecyl sulfate, Polyoxyethylene sorbitan monooleate (Tween 80), Polyoxyethylene sorbitan monostearate (Tween 60), Polyoxyethylene sorbitan monopalmitate (Tween 40), Polyoxyethylene sorbitan monolaurate (Tween 20), Triton x-100, Np-40 nonionic polyoxyethylene surfactant (Brii).

Such a detergent serves as a dispersant that prevents effective pharmacological components from aggregating in an aqueous solution, and the concentration thereof is usually 0.01% to 1% (w / v) or less based on the amount of pharmacological components And more preferably not less than 0.5% and not more than 1.0%. When the amount of the detergent of less than 0.01 was used, it was found that the pharmacological components gradually changed from a clear homogeneous solution to a suspension over time. When the detergent of 1% or more was used, for example, May cause eye damage. Such a starter is added to the pharmacological components to be mixed evenly.

(3) dissolved in ethanol

The pharmacological components in which the detergent is uniformly mixed are soluble in alcohol, and therefore are dissolved in a small amount of alcohol. This is to make the subsequent work easier. That is, mixing of the liquid phase with the liquid phase is easier to control than mixing the solid phase with the liquid phase, so it is dissolved in alcohol. In the present invention, since these pharmacological ingredients are used for injection formulations or eye drops, methanol is not used because it has serious side effects such as blindness even if it is the same alcohol, and ethanol should be used within the allowable range. 3% or less should be used.

(4) Preparation of solution by adding solubilizing agent

Histidine, lysine and arginine amino acids showing basicity are suitable as the solubilizing agents that can be used. The amount of such a solubilizing agent is increased as the amount thereof is increased, but the amount of such solubilizing agent is limited. That is, basically, in order to be used as injections and eyedrops, it is necessary to maintain the salt concentration of 0.6 to 2% of the physiological saline concentration and maintain the acidity of 4.5 to 8.6 (preferably 7.4 to 8.6), so that the effective pharmacological components, Mixing ranges of solubilizers and other additives should be within this range. That is, since the solubilizing agent itself is an amino acid, it is useless to the human body. Therefore, the amount of the solubilizing agent to be used is not limited within a range in which the amount of the detergent and the amount of the solubilizing agent make the total physiological saline concentration.

These solubilizing agents can be used alone or in combination, and it is found that there is no problem.

(5) Preparation of homogeneous solution

As described above, effective pharmacological ingredients are not soluble in water since they are insoluble in water. They are dissolved in a small amount of ethanol, then added with a solubilizing agent, mixed with an aqueous solution, and adjusted to an acidity of 8.6 to increase solubility. Rebamipide has a carboxyl group, which is precipitated in the acid and has a property of melting in the alkali. However, it can not be used as eye drops when the acidity is higher than 8.6, and when the drug concentration is about 1%, it has a property of precipitating even at an acidity of about 8.

Although it is not classified as a separate step, the physiological saline concentration must be maintained for injections and eyelashes to have no foreign body sensation. Therefore, it is desirable to maintain the range of the physiological saline concentration and maintain the concentration at least at the salt concentration of 0.6% or more and at the concentration of 2% or less. In the case of a poorly soluble preparation, it is more preferable to have an alkaline range and an acidity of from 7.0 to 8.5 which is harmless to the human body. Acid with an acidity of 8.6 or higher causes pain at the site of administration and cell destruction may occur.

After the above-mentioned state is over, the solution is filtered with a bacterial filter to obtain an aseptic clean solution in which the poorly soluble pharmacological components are solubilized, and an aliquot is sealed. In the case of using a high-pressure steam sterilizer used in place of a bacterial filter, a specific example is omitted by a conventional method. It is enough to carry out the aseptic treatment naturally in this sealing process as well, It will be omitted.

(6) Ultrasonic processing

Although not classified as a step process, ultrasonic treatment may sometimes be performed to form a homogeneous solution. In other words, ultrasonic treatment was performed for homogeneity as a clear solution or a suspension solution in the form of injection solution, and it was found that the precipitation phenomenon does not occur during the formation and preservation of homogeneous solution during long-term storage.

After preparing a homogeneous solution in the form of a clear solution by the above method, it is necessary to store the solution at room temperature or refrigerate until it is actually used. In this case, crystal precipitation may occur although the amount is small when stored for a long period of time, which may cause side effects when used as an injection, and thus it is necessary to prevent this.

Therefore, according to various experiments of the present inventors, it has been found that by ultrasonic treatment, there is no crystal precipitation even when stored at room temperature or refrigeration for a long time, and in this case, it can be used as an injection.

According to the results of experiments conducted by the inventors of the present invention, it has been found that ultrasonic processing can be performed for about 10 minutes under 40 kHz, and about 15 minutes for processing under 20 kHz. That is, the higher the intensity of the ultrasonic waves to be processed, the shorter the processing time.

Hereinafter, an embodiment of a clear solution for injecting main use of the above-described rebamipide of the present invention as an active ingredient will be described.

Hereinafter, embodiments will be described.

The detailed description of known technology, which is considered to be unnecessarily obscured by the gist of the present invention, will be omitted and given as a concrete example.

 First, an example in which rebamipide is used will be described.

Levamipide is a drug for oral administration and is an amino acid derivative of 2- (1H) -quinolinone with a molecular weight of 370.786 g. This drug is a therapeutic agent for gastroduodenal ulcers and gastritis. It has the ability to remove free radicals and promote mucous membrane protection and is used in Korea, Japan, China and India. There are studies showing effects on dry eye syndrome, and some studies have shown that they also work on senile hearing loss.

100 mg of rebamipide was weighed and 100 mg of tween 80 was added. To this solution, 50 mg of propylene glycol was added as a dissolution aid. In addition, 50 mg of lysine was added, and purified water was added to fill the flask to about 8 milliliters. The acidity was adjusted to 8.6 using hydrochloric acid, and the flask was filled with purified water and filled with 10 milliliters. As shown in Fig. 1 (a).

In a further experiment, 100 mg of rebamipide was weighed and 100 mg of tween 80 was added. 100 mg of lysine was added thereto, purified water was added thereto, and the mixture was filled to about 8 milliliters. The acidity was adjusted to 7.0 using hydrochloric acid, and the mixture was filled with purified water and filled with 10 milliliters. As shown in Fig. 1 (b).

 In a further experiment, 100 mg of rebamipide was weighed and 100 mg of tween 80 was added. 100 mg of lysine was added thereto, purified water was added thereto, and the mixture was filled to about 8 milliliters. The acidity was adjusted to 7.0 using hydrochloric acid, and the mixture was filled with purified water and filled with 10 milliliters. As shown in Fig. 1 (c). When this solution was adjusted to an acidity of 8.0, it was not solubilized.

In another experiment, 100 mg of rebamipide was weighed, 90 mg of lysine was added as a solubilizing aid, 10 mg of sodium alginate was added to adjust the acidity to 8.6, and purified water was filled to prepare 10 milliliters of solubilized (Fig. 1 (d)) .

 This solution was steam sterilized at 121 ° C for 15 minutes and then observed again after treatment to reveal fine particles. This is because sodium alginate was partially decomposed at high temperature or the acidity of the solution was changed. The acidity of the solution was not changed. It was therefore found that the high temperature treatment was not appropriate in this process.

 100 mg of rebamipide was weighed, and 100 mg of tween 80 was added. 100 mg of lysine was added thereto, purified water was added thereto, and the mixture was filled with about 8 milliliters. The acidity was adjusted to 8.0 using hydrochloric acid, and the mixture was filled with purified water and filled with 10 milliliters. As shown in Fig. In a further experiment, 100 mg of rebamipide was weighed and 100 mg of tween 80 was added. 100 mg of lysine was added thereto, purified water was added thereto, and the mixture was filled to about 8 milliliters. The acidity was adjusted to 9.0 using hydrochloric acid, and the mixture was filled with purified water and filled with 10 milliliters. And dissolved as shown in FIG. Further experiments were conducted to see that the solution was adjusted to an acidity of 10.0 (FIG. 4) and a clear appearance and a pH of 12 (FIG. 5).

It was found that the solubility can be determined between 8 and 9, and that the acidity of 8.6 or less, which can be used as an eye drop, is very important.

100 mg of rebamipide was weighed and added with 90 mg of lysine. To this, 10 mg of sodium alginate was added, and purified water was added thereto. The resulting solution was filled with about 8 milliliters, adjusted to 8.6 with hydrochloric acid, and then filled with purified water to make up to 10 milliliters. A slight faded solubilized state (see Fig. 6 (a)).

100 mg of rebamipide was added, and 50 mg of lysine was added as a solubilizing agent. 100 mg of tween 80 was added, and ethanol was added at a concentration of 100 mg. The pH of the mixture was adjusted to 8.54 to prepare 10 ml of purified water. . (Fig. 6 (b) can be seen.

Separately, 50 mg of Lysine was added to 100 milligrams of rebamipide, and 100 mg of tween 80 was added to adjust the acidity to 8.57 to prepare 10 milliliters of purified water. In the absence of ethanol, a cloudy state (Fig. 6 (c)) could be observed.

This result implies that ethanol acts on the solubilization of poorly soluble substances and it is necessary to elucidate that it is better to apply less than 3% concentration which can be administered as eye drops to human body.

 Separately, 100 mg of rebamipide was weighed, 100 mg of lysine was added as a solubilizer, 100 mg of tween 80 was added, ethanol was added at a concentration of 100 mg, and the pH was adjusted to 8.5 to prepare 10 ml of purified water. As shown in Fig. 7, the solubilized state can be seen. The solution was refrigerated and observed after 16 hours. The gel was gelled and was present in a semi-solid form rather than a solution state. This was re-dissolved when left at room temperature, but it took a considerable amount of time. This means that it may not be stored in the refrigerator or in winter, and therefore, it needs to be improved.

 100 mg of rebamipide was added, and 100 mg of lysine was added as a solubilizing agent. 100 mg of tween 80 was added thereto, and ethanol was added to the solution at a concentration of 300 mg. The acidity was adjusted to 8.5 to prepare 10 ml of purified water. As a result, as shown in FIG. 8, 2% ethanol was further added to make a 1% solution of rebamipide containing ethanol with a final concentration of 3%, resulting in a clear liquid formulation. In addition, a clear solution was maintained in the refrigerated state.

This means that the ethanol concentration is important, and it is necessary to sterilize the ethanol separately in the future and add the correct amount. Therefore, it is considered that ethanol should be sterilized by high-temperature steam sterilization or sterilized by filtration.

The following is an example of curcumin.

An experiment on Curcumim was performed. Curcumin is a component of turmeric or ugly, containing about 0.3% in roots and up to 1% absorbed by oral administration. The results of the UCLA study of the University of the United States showed that beta-amyloid was specifically inhibited and was shown to be excellent for the treatment and prevention of dementia. In addition, it is effective for anti-inflammatory, memory, cancer prevention, immunity enhancement, obesity prevention, . Therefore, the development of an oral administration agent with absorption promotion is required, and development of a formulation through uniform solubilization and microsuspension will contribute to the development of pharmaceuticals or foods of Curcumin.

To 100 mg of curcumin, 1 g of lysine was added as a solubilizing agent, 1 g of tween 80 was added thereto, 1 g of ethanol was added, and the pH was adjusted to 8.6 to prepare 100 ml of purified water. As shown in Fig. 9 (a), a slightly cloudy Curcumin solution was observed. It was not completely solubilized and the uniformity was maintained to some extent. To prepare 75 g of curcumin, 1 g of lysine was added to 75 mg of curcumin, 1 g of tween 80 was added thereto, and 3.0 g of ethanol was further added thereto The acidity was adjusted to 8.6 and purified water was filled to make 100 milliliters.

In this case, as shown in FIG. 9 (b), the transparency was very high, and it showed a clear appearance, and a slight cloud-like shape was seen in the light. The solution of the formulation retained significant homogeneity and some precipitate was observed after treatment with high temperature steam sterilization (121 캜, 1.1 kg / cm ² , 15 min).

To 75 mg of Curcumin, 0.5 ml of ethanol and 1.925 g of lysine were added as a dissolving aid, 1 g of tween 80 was added, and the pH was adjusted to 8.6 to prepare 100 ml of purified water. After the preparation, the mixture was sterilized by high-temperature steam, and then taken out of the sterilizer, 2.5 ml of ethanol was aseptically added thereto, and mixed well. The ultrasonic treatment was performed again and the treatment was carried out at a frequency of 10 kHz to 100 kHz within 5 to 20 minutes. This is because ethanol is volatilized at high temperature steam sterilization, so it is added aseptically after sterilization to treat a more accurate amount of ethanol. Ultrasonic processing is a process that is processed to produce a finer and more transparent solution.

As shown in Fig. 10, in this case, the transparency was further enhanced, the solution was clear, and a slight cloudy appearance was observed in the light, but the solution remained substantially uniform. This can be aliquoted into small doses by aseptic manipulation to prepare injectable or ointment preparations.

To 75 mg of Curcumin, 0.5 ml of ethanol, 1.825 g of lysine and 0.1% of citric acid were added as a dissolving aid 1 g of tween 80 was added thereto, and the pH was adjusted to 8.6 to prepare purified water to make 100 milliliters. After the preparation, the mixture was sterilized by high-temperature steam, and then taken out of the sterilizer, 2.5 ml of ethanol was aseptically added thereto, and mixed well. The ultrasonic treatment was performed again and the treatment was carried out at a frequency of 10 kHz to 100 kHz within 5 to 20 minutes. As shown in FIG. 11, in this case, the transparency was further increased, the red color was pale yellow, and the light was seen to have a fine cloud-like shape, but the solution remained substantially uniform . This can be aliquoted into small doses by aseptic manipulation to prepare injectable or ointment preparations.

As can be seen from the above examples, rebamipide and curcumin can be basically prepared as a clear solution using a small amount of alcohol, a detergent with a detergent and an alkaline amino acid, It can be seen that various applications of existing pharmacological components are possible.

In the above description, it is shown that curcumin is divided into two portions of ethanol. It is possible to use once alcohol as in rebamipide. However, in order to obtain more effective results, this example shows two cases of use, in which the content of ethanol is very important for the solubilization of curcumin and the concentration is at least 2% It can be solved. Therefore, 0.5% ethanol was first used to dissolve and some of it volatilized during sterilization, so 2.5% was added to meet the maximum available capacity of 3% or less. This is because when the product is produced in a large amount, the alcohol will volatilize a lot due to a long heating time, and if the amount is small, the volatilization amount of the alcohol will be small. Therefore, the final concentration should be at least 2% and not exceed 3% at maximum. Therefore, the drug-containing solution was formulated using 0.5% of the solution and added with 2.5% ethanol after sterilization at high temperature.

Claims (15)

delete delete delete delete delete delete delete Rebamipide or curcumin, which has an effective pharmacological component and is hardly soluble in alcohol and hardly soluble in water, is uniformly mixed with a detergent, and the added detergent is added in an amount of 0.01% or more relative to unflavored rebamipide or communicin 1% (w / v);
Adding rebamipide or curycylamine mixed with the starter to ethanol and adding ethanol to the total weight of not less than 0.5% and not more than 3%;
The ethanol solution prepared in the above step is added to an aqueous solution containing a solubilizing agent composed of any one or more of histidine, lysine and arginine, which are alkaline amino acids, and the solubilizing agent is added so that the total solution has a physiological saline concentration of 0.6 to 2 % (w / v);
Sterilization by filtration or high temperature steam sterilization; And a step of performing a sealing treatment by aseptic operation. The method for producing a homogeneous solution preparation of a solubilized insoluble active pharmacological ingredient using ethanol and an alkaline amino acid. delete 9. The method of claim 8,
The detergent may be selected from the group consisting of Sodim dodecyl sulfate, Polyoxyethylene sorbitan monooleate (Tween 80), Polyoxyethylene sorbitan monostearate (Tween 60), Polyoxyethylene sorbitan monopalmitate (Tween 40), Polyoxyethylene sorbitan monolaurate (Tween 20), Triton x-100, polyoxyethylene surfactant (Brij), or a combination of two or more thereof. The method for producing a homogeneous solution preparation according to claim 1, wherein the solubilization effective pharmaceutical ingredient is ethanol or an alkaline amino acid. Uniformly mixing curcumin, which has an effective pharmacological component and is hardly soluble in ethanol and is hardly soluble in water, with a starch having an amount of not less than 0.01% and not more than 1% (w / v) relative to the comminum;
Mixing a curcumin mixed with the starch into a small amount of ethanol;
The ethanol solution prepared in the above step is added to an aqueous solution containing a solubilizing agent consisting of any one of histidine, lysine or arginine, which is an alkaline amino acid, or a mixture thereof, and the amount of the solubilizing agent used is such that the total solution has a physiological saline concentration of 0.6 - 2% (w / v);
Sterilizing the solution prepared in the above step by filtration or high temperature steam sterilization;
Adding ethanol to the solution prepared in the above step by aseptic operation;
Treating the solution to which ethanol is added in the above step by ultrasonication to prepare a fine suspension solution;
Separating the solution prepared in the above step by an aseptic operation and performing a sealing treatment,
Wherein the ethanol added in the first and second stages is added in an amount of not less than 0.5% and not more than 3% based on the total weight of the solution. delete 12. The method of claim 11,
The detergent may be selected from the group consisting of Sodim dodecyl sulfate, Polyoxyethylene sorbitan monooleate (Tween 80), Polyoxyethylene sorbitan monostearate (Tween 60), Polyoxyethylene sorbitan monopalmitate (Tween 40), Polyoxyethylene sorbitan monolaurate (Tween 20), Triton x-100, polyoxyethylene surfactant (Brij), or a combination of two or more thereof. The method for producing a homogeneous solution preparation according to claim 1, wherein the solubilization effective pharmaceutical ingredient is ethanol or an alkaline amino acid. 12. The method of claim 11,
Wherein the ultrasonic treatment is performed using an ultrasonic wave at an intensity of 10 KHz to 100 KHz within 5 minutes to 20 minutes. The method for preparing a solubilized homogeneous solution of an insoluble active pharmaceutical ingredient using ethanol and an alkaline amino acid. 12. The method of claim 11,
Wherein the citric acid is added in an amount of 0.01% to 1% (w / v) relative to the insoluble substance.

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