KR100561317B1 - Clear soft capsule containing amino acid and athenol - Google Patents

Abstract

The present invention relates to a transparent soft capsule containing athenol, and more particularly, at least one hydrophilic solvent selected from polyethylene glycol or propylene glycol, an acidifying agent and polyvinylpyrrolidone as excipients to dissolve athenol. After filling into soft gelatin capsules or by dissolving amino acids and athenol in one or more hydrophilic solvents selected from polyethylene glycol or propylene glycol to prepare a water-soluble complex, and filling into soft gelatin capsules, filling into gelatin cells is easy, The present invention relates to a transparent soft capsule containing athenol having excellent stability due to no precipitation and fast dissolution and absorption after administration.

Athenol, Clear Soft Capsule, Stability

Description

Transparent soft capsule containing amino acid and Atenolol

The present invention relates to a transparent soft capsule containing athenol, and more particularly, at least one hydrophilic solvent selected from polyethylene glycol or propylene glycol, an acidifying agent and polyvinylpyrrolidone as excipients to dissolve athenol. After filling into soft gelatin capsules or by dissolving amino acids and athenol in one or more hydrophilic solvents selected from polyethylene glycol or propylene glycol to prepare a water-soluble complex, and filling into soft gelatin capsules, filling into gelatin cells is easy, The present invention relates to a transparent soft capsule containing athenol having excellent stability due to no precipitation and fast dissolution and absorption after administration.

Generally, the contents of the soft capsule are liquid or suspended and are filled in a capsule base containing gelatin as a main component. Soft capsules are convenient for the administration of Omi, malodor, or colored medicines, and have the characteristics of solidifying medicines that are difficult to take, such as oily and suspended phases, and making the dose constant. Due to the limited content excipients that can be used, soft capsules are difficult to solubilize the contents of the capsules and the problem of cell composition to ensure stability, it is common to manufacture the opaque soft capsules containing the drug in suspension. Transparent soft capsules are not many of them.

The transparent soft capsule is easy to fill into the gelatin cell because the contents of the soft capsule are dissolved compared to the opaque soft capsule containing the contents of the suspension, and it is excellent in stability because there is no precipitation phenomenon such as suspension, and the content of the manufactured capsules is uniform. Easy to maintain castle In addition, the liquid soft drug is filled into the transparent soft capsule, which is rapidly eluted and absorbed after administration, and thus exhibits high blood concentration. Therefore, the effect is expected to be faster than other preparations. You can also check the marketability.

When designing transparent soft capsules as soft capsules, materials that can be generally used as excipients include vegetable oils such as soybean oil and corn oil, polyethylene glycol 200-600, medium chain triglyceride, and polysorbate 20-80. Limited to. For this reason, it is difficult to select a content excipient that can dissolve all the main components and does not cause problems in physical stability such as phase separation or precipitate formation during the manufacturing process.

Athenol is the most widely used beta-blocker in Korea as well as in the world. Athenol selectively affects the beta 2 receptors involved in cardiac excitement without affecting the beta 2 receptors involved in smooth muscle relaxation, vascular relaxation, and the conversion of glycogen stored in liver and muscle among sympathetic receptors. Blocking kidney selectivity, it can be used safely in hypertensive patients with diabetes, asthma, etc., and also has a significant hypotensive effect in hypertensive patients with excessive smoking, which is not easy to lower blood pressure. In addition, water-soluble athenol does not easily cross the blood brain barrier, so there are few side effects to the central nervous system.

The half-life of athenol having the characteristics as described above is about 6-9 hours, and can be easily administered by a simple dose of 1 tablet per day, but has a problem in that absorption is only about 50% upon oral administration. Therefore, it was urgent to develop a formulation capable of increasing the dissolution and stability of atenool, encapsulating it in soft gelatin capsules and orally administering it, to increase absorption than general solid preparations.

The present invention is to solve the above problems, an object of the present invention is to soften after dissolving athenol using one or more hydrophilic solvents, acidifying agents and polyvinylpyrrolidone selected from polyethylene glycol or propylene glycol as excipients. Filling gelatin capsules, or dissolving amino acids and athenol in one or more hydrophilic solvents selected from polyethylene glycol or propylene glycol to prepare a water-soluble complex, and then filling into soft gelatin capsules, filling into gelatin cells is easy, precipitation phenomenon The present invention provides a transparent soft capsule containing athenol having excellent stability and fast dissolution and absorption after administration.

The transparent soft capsule containing the athenol of the present invention is prepared by dissolving athenol using at least one hydrophilic solvent selected from polyethylene glycol or propylene glycol, an acidifying agent, and polyvinylpyrrolidone as excipients, and then, in the soft gelatin capsule. It is characterized by being manufactured by filling.

Since soybean oil, corn oil, and the like, which are generally used as content excipients in the manufacture of soft capsules, are not mixed with water during oral administration, they cause layer separation and rather lower the dissolution of the drug. Therefore, in the present invention, a transparent soft capsule was prepared by dissolving athenol using polyethylene glycol and propylene glycol which are solvents compatible with water.

However, athenol is not dissolved in the presence of only polyethylene glycol and propylene glycol, but only dissolved in the presence of an acidifying agent. Therefore, after dissolving by adding an acidifying agent to a mixed solution of polyethylene glycol and propylene glycol, the polyvinylpyrrolidone is dissolved as a stabilizer and athenol is added to completely dissolve it, thereby preparing a transparent soft capsule contents, and filling it into a transparent gelatin cell. Prepare a clear soft capsule.

The transparent soft capsule containing the athenol of the present invention may be prepared by dissolving amino acids and athenol in one or more hydrophilic solvents selected from polyethylene glycol or propylene glycol to prepare a water-soluble complex, and then filling the soft gelatin capsule. .

In the case of preparing the amino acid complex as described above, the amino acid and athenol are added to the mixed solution of polyethylene glycol and propylene glycol, followed by stirring to dissolve the transparent soft capsule contents, and the transparent gelatine cells are filled to prepare the transparent soft capsule. do.

Referring to the method of manufacturing a transparent soft capsule containing atenolol of the present invention in detail.

Polyethylene glycol and propylene glycol, which are hydrophilic solvents, are heated to about 60 DEG C and dissolved with acidic hydrochloric acid, citric acid and ascorbic acid. When the acidifying agent is completely dissolved, it is cooled to room temperature, and then, polyvinylpyrrolidone is dissolved, athenol is added, and the mixture is stirred for a predetermined time.

Athenol as a pharmaceutical active ingredient in the present invention is preferably contained 10 to 40% by weight based on the total weight of the capsule contents. If athenol is less than 10% by weight relative to the total weight of the capsule content, it is not suitable for effective pharmaceutical concentrations, and if it is more than 40% by weight there is a lack of solvents and excipients to dissolve the athenol, resulting in suspension or recrystallization or precipitation. It is not desirable because it may cause problems.

When only polyethylene glycol is present in the hydrophilic solvent, athenol is not completely dispersed, and when used with propylene glycol, dispersion is well performed. The mixed solution of polyethylene glycol and propylene glycol is preferably contained 60 to 90% by weight based on the total weight of the capsule contents. If the mixed solution of polyethylene glycol and propylene glycol is less than 60% by weight based on the total weight of the capsule content, athenol is not completely dissolved. If the mixture is more than 90% by weight, the volume of the soft capsule increases, making it difficult to take orally. . As for the average molecular weight of polyethyleneglycol, 200-600 are preferable.

In the present invention, an acidifying agent is added to assist the dissolution of athenol in a hydrophilic solvent, which is preferably hydrochloric acid, citric acid or ascorbic acid. The acidifying agent is preferably added in an amount of 2 to 10% by weight based on the total weight of the capsule contents. If the acidifying agent is contained in less than 2% by weight relative to the total weight of the capsule content, it is not possible to completely dissolve the athenol. If it contains more than 10% by weight, the hydrogen ion concentration of the content is so low that after the soft capsule production, the film is hydrolyzed. This is undesirable because the contents may leak.

If the content of athenol exceeds 20% by weight, polyvinylpyrrolidone is added as a stabilizer in order to suppress this phenomenon, because recrystallization or precipitation may occur when the storage temperature drops or insoluble particles are present. The polyvinylpyrrolidone preferably has an average molecular weight of 2,500 to 400,000, and preferably 0.5 to 10% by weight based on the total weight of the capsule contents. If the polyvinylpyrrolidone is contained in less than 0.5% by weight relative to the total weight of the capsule content, it may not function satisfactorily as a stabilizer, and when contained in excess of 10% by weight, the viscosity of the content is too high, filling is not preferable. .

In addition, the amino acid complex is prepared by adding a water-soluble amino acid and athenol to polyethylene glycol and propylene glycol, stirring the solution for a predetermined time to dissolve it to obtain a transparent liquid. The amino acid complex has excellent characteristics in terms of stability since the complex is formed even when no acidifying agent or stabilizer is added separately.

Athenol, a pharmaceutically effective ingredient in the preparation of the amino acid complex, is preferably included in an amount of 10 to 40% by weight based on the total weight of the capsule contents. If athenol is less than 10% by weight relative to the total weight of the capsule content, it is not suitable for effective pharmaceutical concentrations, and if it is more than 40% by weight there is a lack of solvents and excipients to dissolve the athenol, resulting in suspension or recrystallization or It is not preferable because problems of precipitation may occur.

As amino acids that can be used for the preparation of the amino acid complex, most amino acids can be used because they are water-soluble, but glycine, valine, aspartic acid or proline, which are relatively soluble in water, are preferable.

It is preferable that water-soluble amino acid is contained in 1-2 mol concentration with respect to main medicine. If the amino acid is contained in less than 1 mole concentration relative to the main drug, it is difficult to form a satisfactory amino acid complex, and when contained in excess of 2 mole concentration, it becomes difficult to dissolve the amino acid itself. Since the molecular weight of the amino acid varies greatly from glycine (Mw: 75.07) to tryptophan (Mw: 204.23), the amino acid is preferably included in an amount of 3 to 20% by weight based on the total weight of the capsule contents.

After dissolving athenol as described above to obtain a transparent solution, a transparent soft capsule is prepared using a normal soft capsule film.

Hereinafter, the present invention will be described in more detail with reference to the following examples and comparative examples. However, the scope of the present invention is not limited by the following examples.

Comparative Example 1

  Ingredient Name weight %   Athenol 27.03   Polyethylene Glycol 400 54.05   Propylene glycol 13.51   Hydrochloric acid 5.41

Hydrochloric acid was added to the mixed liquid of polyethylene glycol and propylene glycol, and then athenol was added and stirred for a predetermined time to completely dissolve to obtain a transparent liquid.

Comparative Example 2

  Ingredient Name  weight%   Athenol  27.03   Polyethylene Glycol 400  54.05   Propylene glycol  13.51   Citric acid  5.41

The mixed solution of polyethylene glycol and propylene glycol was heated to about 60 DEG C, dissolved with citric acid and completely dissolved. Then, athenol was added and stirred for a while to completely dissolve to obtain a transparent solution.

Comparative Example 3

  Ingredient Name  weight%   Athenol  27.78   Polyethylene Glycol 400  55.56   Propylene glycol  13.89   Ascorbic acid  2.77

The mixed solution of polyethylene glycol and propylene glycol was heated to about 60 ° C., and ascorbic acid was added to dissolve completely. Then, athenol was added and stirred for a while to completely dissolve to obtain a transparent solution.

Example 1

  Ingredient Name  weight%   Athenol  26.88   Polyethylene Glycol 400  53.76   Propylene glycol  13.44   Citric acid  5.38   Polyvinylpyrrolidone K-12  0.54

The mixed solution of polyethylene glycol and propylene glycol was heated to about 60 ° C. and dissolved completely by adding citric acid. After dissolving with polyvinylpyrrolidone K-12, athenol was added and stirred for a while to completely dissolve. .

Example 2

  Ingredient Name  weight%   Athenol  13.09   Polyethylene Glycol 400  48.95   Propylene glycol  31.41   Citric acid  2.62   Polyvinylpyrrolidone K-12  3.93

The mixed solution of polyethylene glycol and propylene glycol was heated to about 60 ° C. and dissolved completely by adding citric acid. After dissolving with polyvinylpyrrolidone K-12, athenol was added and stirred for a while to completely dissolve. .

Example 3

  Ingredient Name  weight %   Athenol  15.04   Polyethylene Glycol 400  60.16   Propylene glycol  15.04   Proline  9.76

Proline and athenol were added to the mixed solution of polyethylene glycol and propylene glycol, and the mixture was stirred for a certain time to completely dissolve to obtain a transparent solution.

Comparative Examples 1 to 3 and Examples 1 to 3 were prepared, filtered with a 0.1 μm filter, and filled into a gelatin cell to prepare an athenol soft capsule.

On the other hand, the coating formulation of the soft capsule was used the most commonly used prescription, the contents of the prescription is as follows.

  Ingredient Name  weight%   gelatin  58.2   Concentrated glycerin  28.0   D-sorbitol  12.5   Preservative  0.4   Flavor  0.9

The transparent athenol soft capsule production of the present invention was molded into an Oval 6 type by a conventional charging method using a rotary automatic charger, which is generally used, and then made into a prototype through drying and sorting processes.

[Comparative Example 4]

Athenol, lactose, microcrystalline cellulose, corn starch, crospovidone and silicon dioxide were mixed in a speed mixer, and magnesium stearate was added and mixed for 5 minutes. After tableting using a Lorati tablet press, the film was coated using a Hi-coater.

  Ingredient Name   weight%   Athenol   24.27   Lactose   37.38   Microcrystalline cellulose   16.02   Corn starch   16.50   Crospovidone    1.46   Magnesium stearate    0.97   Silicon dioxide    0.49   Coating base    2.91

[Test Example 1]

In order to evaluate the safety of the preparation, the sample was stored under accelerated conditions (40 ° C, 75% RH) and visually checked for changes in properties and formation of precipitates. The content of athenol was measured.

Comparative Example 1 Comparative Example 2 Comparative Example 3 Example 1 Example 2 Example 3 Properties just after manufacturing transparent transparent transparent transparent transparent Brown and transparent Change of color - - Browning - - - Precipitation - Sedimentation Sedimentation - - - content(%) 55.62 96.26 94.42 98.80 99.12 97.12

As in Example 3, when a water-soluble complex was prepared using the amino acid proline, the proline was colored brown and a colorless liquid could not be prepared. As in Comparative Example 3, when ascorbic acid was used as the acidifying agent and no stabilizer was added, the solution was colorless and transparent immediately after preparation, but gradually changed to blackish brown after passing through light yellow color. As in Comparative Example 2 or 3, when citric acid and ascorbic acid were used as the acidifying agent and no stabilizer was added, athenol precipitation was formed over time, but as in Example 1 or 2, When citric acid was used and polyvinylpyrrolidone was used as a stabilizer, this precipitation phenomenon could be suppressed.

As a result of measuring the content of athenol after 6 months after preparation, when using hydrochloric acid as an acidifying agent and adding no stabilizer as in Comparative Example 1, the content was reduced to about 50%. As citric acid 2 or 3, when citric acid and ascorbic acid were used as the acidifying agent, and no stabilizer was added, precipitation was generated to cause a decrease in content.

However, when citric acid was used as an acidifying agent and polyvinylpyrrolidone was used as a stabilizing agent, as in Example 1 or 2, it was found that no precipitation was generated and there was almost no content decrease. In addition, when using the amino acid proline as in Example 3, no precipitation was generated and the content was not large.

[Test Example 2]

In order to evaluate the dissolution characteristics of the athenol soft capsules, the test solution was purified water, and the test method was the method of dissolution test method No. 8 of the Korean Pharmacopoeia, and the temperature of the test solution was 37 ± 0.5 ° C. and the stirring speed was 50 rpm. It was. The content of athenol was determined using HPLC, which is a quantification method of the athenol tablet term of USP.

Example 1 Comparative Example 4 5 minutes 85.7 18.4 10 minutes 99.3 27.1 15 minutes 99.8 37.6 30 minutes 100.1 95.9

Athenol soft capsules were affected by the disintegration time of the soft capsule coating, but most of the main drug was eluted as the coating disintegrated. However, tablet disintegration time was fast but drug dissolution rate was relatively low.

The transparent soft capsule containing the athenol of the present invention is easy to fill in the gelatin cell because the contents of the soft capsule are in a liquid state, and there is no precipitation phenomenon that may occur when preparing the suspension, and the stability is excellent, and the content of the manufactured capsules It is easy to maintain uniformity. In addition, the liquid soft drug is filled into the transparent soft capsule, which is rapidly eluted and absorbed after administration, and thus shows a high blood concentration. Therefore, the effect is expected to be faster than other solid preparations. You can also check the marketability.

Claims (4)

A transparent soft capsule containing athenol, wherein the amino acid and athenol are dissolved in at least one hydrophilic solvent selected from polyethylene glycol or propylene glycol to prepare a water-soluble complex, followed by filling into a soft gelatin capsule. The method of claim 1, wherein the athenol is a transparent soft capsule, characterized in that 10 to 40% by weight based on the total weight of the capsule contents. 2. The transparent soft capsule containing athenol according to claim 1, wherein the amino acid is at least one selected from glycine, valine, aspartic acid or proline. The transparent soft capsule containing athenol according to claim 1, wherein the amino acid is contained in an amount of 3 to 20% by weight based on the total weight of the capsule contents.