WO2021080184A1 - Small-sized, sustained release pharmaceutical composition comprising choline alfoscerate - Google Patents

Abstract

The present invention pertains to a small-sized, sustained release pharmaceutical composition including choline alfoscerate as an effective component, and preparations of various dosage forms using same. A small-sized, sustained release choline alfoscerate preparation, for oral administration, prepared according to the present invention, uses a pharmaceutically acceptable sustained release substrate, and thus the elution of a drug is continuously maintained over a long period, reducing the number of times the drug is administered in a day. Also, in addition to reducing the number of times a drug is administered compared to conventional preparations, convenience of administration is improved by reducing the size of the individual preparations, and an improvement in treatment effect can be expected for patients taking a drug over a long period, compared to conventional preparations.

Description

Small form sustained-release pharmaceutical composition containing choline alfoscerate

The present invention relates to a sustained-release pharmaceutical composition containing choline alfoscerate as an active ingredient, and to a pharmaceutical composition prepared in a small dosage form while having sustained-release properties.

This application claims the benefit of priority based on Korean Patent Application No. 10-2019-0131784 filed on October 22, 2019, and all contents disclosed in the documents of the Korean patent application are included as part of this specification.

Life span extension and aging are taking place around the world, and this phenomenon is occurring more remarkably especially in advanced countries. The number of dementia patients is gradually increasing compared to the past with the global aging, and interest in the development of dementia treatments is also rising.

Alzheimer's disease is the most common cause of dementia, which accounts for about 60-70% of all dementia. When Alzheimer's disease occurs, a decrease in the activity of acetylcholine is a major phenomenon, which leads to a decrease in cholinergic neurons and a decrease in cholinergic function of the brain, leading to a decrease in cognitive function. In addition, when Alzheimer's dementia occurs, abnormal proteins such as amyloid plaque and neurofibrillary tangle accumulate in the brain, destroying brain cells and reducing brain tissue, resulting in loss of brain function. There are also reports that decreased activity is associated with the formation of amyloid plates.

Choline alfoscerate is a cholinergic precursor and has a high bioavailability of 88%, and in particular, it passes through the blood brain barrier by 45% and has a significant amount of its medicinal effect in the brain. In the body, choline and glycerophosphate are separated and acted. Choline is used as a precursor for synthesizing acetylcholine, which normalizes the neurotransmitter function reduced by brain nerve damage. It is metabolized to normalize the function of damaged nerve cells. In addition, 85% of it is excreted as carbon dioxide due to its characteristic of being a precursor of a biological material, and it is reported that there are few serious adverse reactions even when administered for a long period, and it is currently attracting great attention as a powerful alternative to dementia treatment.

Choline alfoscerate, an active ingredient in the present invention, is a compound also called L-α-glyceryl phosphoryl choline (L-GPC), and has the following chemical structure.

Currently commercially available choline alfoscerate formulations are commercially available in soft capsules and tablets with a dose of 3 times a day, but the amount of active ingredient administered is choline alfoscerate once, which is 400 mg, which is a large size (large Treaty standard long axis: 16.1mm, short axis: 8.5mm, thickness: 8.5mm, reference drug: Chong Kun Dang gliatyrin soft capsule) The number of doses is often 3 times, so there is insufficient part to satisfy patients' adherence.

In addition, in the case of soft capsules containing choline alfoscerate, due to the extremely water-soluble properties of the active ingredient, quality problems such as crushing may occur due to the transition to the same water-soluble soft gelatin film. Due to hygroscopicity, quality problems such as content may occur when exposed to the outside for a long period of time.

The stability problem of the soft capsule formulation can be improved when it is manufactured in a tablet formulation. Prior Art Document 1 (Korean Patent Laid-Open Patent No. 10-2013-0010044) uses choline alfoscerate as an active ingredient, and uses insoluble bases such as hypromellose and ethyl cellulose as a coating solution and a fluidized bed coater on choline alfoscerate powder. A sustained-release tablet was developed in a form in which particles coated with a sustained-release coating were prepared by spraying with and then the particles were tableted together with an additional excipient. However, because the tablet size is too large, it is very weak in dosage convenience, and the production yield is low because the productivity problem that occurs in the sustained-release coating process cannot be solved. Therefore, there are still problems in terms of economy and convenience in taking patients.

In this regard, Prior Art Document 2 (Korean Patent Laid-Open Patent No. 10-2015-0066937) uses calcium silicate as an adsorbent to reduce the weight of the excipient of the conventional formulation, which was caused by an excessive amount of the excipient, thereby reducing the weight of the formulation. When the weight of the formulation is reduced, the difficulty of the manufacturing process is lowered, and the process steps can also be simplified. In addition, since the total weight of the tablet is lowered, the size of the formulation is reduced, so that the convenience of taking medicine can be increased. However, in the case of Prior Document 2, triple coating is performed as a method to block the inflow of moisture in the air after uncoated production. The difficulty of the process is very high to maintain the stability of each layer while coating the uncoated tablet three times, and the calcium silicate used as an adsorbent is also an excipient that often causes tableting disorders due to its very low tabletting properties, so this is also an efficient method for mass production. I can't.

Prior Art Document 3 (Korea Patent Registration No. 10-1796628) is a film-coated tablet coated with hydroxypropylmethylcellulose and polyvinyl alcohol by adsorbing choline alfoscerate on magnesium metasilicate and tableting uncoated tablets. Are presented. However, since the amount of magnesium metasilicate aluminate used is 62.5% compared to the active ingredient, the total weight is large, and the size of the tablet increases, so there is still a weak side in terms of ease of administration.

That is, in the case of a conventional soft capsule formulation, due to the nature of the formulation, the size is large and it is necessary to take it three times a day, so there is a problem in that it is not suitable for long-term storage because it is not suitable for long-term storage because it is not convenient to take. On the other hand, tablet formulations have advantages in that sustained release is easy and stability is easy to secure compared to soft capsules, but when sustained-release and stability are secured together, there is a problem in that the formulation size is very large or the manufacturing yield is low, so economical efficiency is poor.

Therefore, in the oral administration formulation containing choline alfoscerate, there is still a need for a formulation having excellent stability while securing sustained release to reduce the number of doses while reducing the number of doses, while the size of the formulation is small, so that there is no discomfort when taking medication.

It is an object of the present invention to provide a pharmaceutical composition containing choline alfoscerate sustained release so that sufficient pharmacological effects can be achieved by administering only once a day with respect to the conventional choline alfoscerate formulation administered three times a day. It is done. In addition, it is intended to enhance the convenience of taking medicine by taking a plurality of smaller preparations per dosage unit.

One formulation of the pharmaceutical composition according to the present invention is a pharmaceutical composition containing choline alfoscerate or a pharmaceutically acceptable salt thereof as an active ingredient, and comprising a sustained-release agent and an adsorbent, based on the total weight of the pharmaceutical composition. The active ingredient is characterized in that it comprises 30 to 40% by weight, the sustained-release base agent is 30 to 50% by weight, and the adsorbent comprises 2 to 4% by weight.

If the content of the active ingredient is out of the range, sufficient pharmacological activity may not appear, or the blood concentration may increase excessively, causing side effects. In addition, the sustained-release agent is intended to exhibit a sustained-release effect for a long time and serves to maintain a constant dissolution rate, and if it is out of the above range, it may dissolve too quickly and the lasting effect may be short, or sufficient dissolution may not occur while remaining in the body. .

The adsorbent is intended to reduce tabletting disorders during tablet manufacturing, and if it is included in less than 2% by weight, obstacles may frequently appear during the tableting process such as low flowability and sticking during tableting, and when included in excess of 4% by weight, capping, It is not preferable because it may cause obstacles in the tableting process of uncoated tablets such as laminating.

At this time, the sustained-release base is one or two selected from the group consisting of hydroxypropylmethylcellulose, sodium alginate, polyethylene oxide, polyvinyl alcohol, ethyl methacrylate and chlorotrimethylammonium ethyl acrylate copolymer, and hydroxypropylcellulose A mixture of the above can be used, and the most desirable effect is obtained when using polyethylene oxide.

Meanwhile, the adsorbent may be one or a mixture of two or more selected from the group consisting of calcium silicate, meglumine, and colloidal silicon dioxide.

The pharmaceutical composition is a tablet having a total weight of 30 to 40 mg, has excellent stability, and has a very small tablet size, so even if a plurality of unit formulations are included in one package per oral dosage unit, the medication convenience is excellent.

On the other hand, in another formulation of the present invention, as a pharmaceutical composition containing choline alfoscerate or a pharmaceutically acceptable salt thereof as an active ingredient, a tablet layer comprising an active ingredient, an excipient, an adsorbent, and a sustained-release base agent And it may be to include a sustained-release coating layer containing a sustained-release base.

At this time, the content of the sustained-release agent in the tablet layer is preferably 10 to 20% by weight based on the total weight of the pharmaceutical composition, and more preferably 13 to 17% by weight.

In addition, since the formulation further includes a sustained-release base agent in the sustained-release coating layer, a more excellent sustained-release effect may be exhibited even in a small size. At this time, the content of the sustained-release agent in the sustained-release coating layer may be 5 to 15% by weight, more preferably 7 to 10% by weight, based on the total weight of the pharmaceutical composition.

In addition, the sustained-release base of the tablet layer may be a generally used sustained-release base, but in the present invention, hydroxypropylmethylcellulose was used. At this time, among the sustained-release bases that may be included in the sustained-release coating layer, excellent effects are exhibited in combination with the sustained-release bases included in the purification layer: ethyl methacrylate/ethacrylic acid chlorotrimethylammonium ethyl copolymer, ethyl cellulose, and polyvinyl acetic acid. It may be one or a mixture of two or more selected from the group consisting of.

The active ingredient is characterized in that it contains 35 to 45% by weight based on the total weight of the pharmaceutical composition, and the total weight is 55 to 65mg, and exhibits excellent sustained-release effect even though it is prepared as a very small sized tablet.

The present invention is a pharmaceutical composition containing choline alfoscerate or a pharmaceutically acceptable salt thereof as an active ingredient, the active ingredient is filled inside the soft capsule film, and the soft capsule includes a capsule base, a plasticizer, and a sustained-release base. Another type of pharmaceutical composition is provided.

In this case, the sustained-release base agent may preferably be included in 10 to 30% by weight, more preferably 15 to 25% by weight based on the total weight of the pharmaceutical composition. At this time, the sustained-release base is one or two selected from the group consisting of hydroxypropylmethylcellulose, sodium alginate, polyethylene oxide, polyvinyl alcohol, ethyl methacrylate and chlorotrimethylammonium ethyl acrylate copolymer, and hydroxypropylcellulose. The above mixture can be used.

On the other hand, the plasticizer may be included in 7 to 20% by weight based on the total weight of the capsule base, more preferably 8 to 15% by weight.

The plasticizer is characterized in that it is one or a mixture of two or more selected from the group consisting of concentrated glycerin, propylene glycol, sorbitol, and polyethylene glycol.

In addition, the present invention provides a pharmaceutical composition in a single-layer dosage form prepared in a seamless form as another pharmaceutical composition containing choline alfoscerate or a pharmaceutically acceptable salt thereof as an active ingredient.

The pharmaceutical composition may further include a gelling agent, a curing agent, and a sustained-release agent in addition to the active ingredient as needed, and as a seamless formulation, it is characterized in that it is formed in a single layer while having characteristics similar to that of a soft capsule, so that it is simple to manufacture and has excellent stability. It is done.

At this time, the gelling agent may be used by mixing one or two or more selected from the group consisting of carbomer, gelatin, agar, pectin, poloxamer, xanthan gum, carrageenan, and starch.

In addition, the curing agent may use one or two or more silicon-based compounds or cellulose derivatives containing silicon having excellent physical properties in terms of adsorption properties.

As non-limiting examples of the silicon-based compound or cellulose derivative of the curing agent, magnesium aluminate, calcium silicate, microcrystalline cellulose, colloidal silicon dioxide, and light anhydrous silicic acid may be used.

On the other hand, the sustained-release base is one or two selected from the group consisting of hydroxypropylmethylcellulose, sodium alginate, polyethylene oxide, polyvinyl alcohol, ethyl methacrylate and chlorotrimethylammonium ethyl acrylate copolymer, and hydroxypropylcellulose The above can be mixed and used.

On the other hand, with respect to the total weight of the gelling agent, the curing agent is preferably contained in an amount of 30 to 80% by weight, more specifically 40 to 60% by weight, 50 to 70% by weight may be included, and most preferably 50 to 60% by weight Can be included. The curing agent is necessary to maintain the moldability and stability of a seamless single-layer soft capsule formulation formed by mixing choline alfoscerate and a gelling agent.If the content is too low compared to the gelling agent, the capsule is not sufficiently cured to maintain its shape. It becomes difficult, and if it is too high, the capsule may not be smoothly molded in the manufacturing process.

In addition, the sustained-release base agent may preferably be included in 30 to 60% by weight based on the total weight of the pharmaceutical composition, more specifically, 30 to 50% by weight, may be included in 40 to 60% by weight, most preferably 40 To 45% by weight may be included.

On the other hand, the present invention is a pharmaceutical composition containing choline alfoscerate or a pharmaceutically acceptable salt thereof as an active ingredient, the active ingredient is filled inside the soft capsule film, and the sustained release including a sustained-release base on the surface of the soft capsule film It provides a pharmaceutical composition, characterized in that the chemical coating layer is formed. This formulation is a sustained-release coating layer formed with a coating solution containing a sustained-release agent on the surface of a conventional soft capsule film, and is a sustained-release pharmaceutical composition with low adhesion, and exhibits excellent stability that does not cause denaturation even during long-term storage.

At this time, the soft capsule may be used by selecting one or two or more selected from the group consisting of carbomer, gelatin, agar, pectin, poloxamer, xanthan gum, carrageenan, and starch. In addition, the sustained-release base may be used by selecting one or two or more selected from the group consisting of ethyl methacrylate·chlorotrimethylammonium ethyl acrylate copolymer, ethyl cellulose, and polyvinyl acetic acid.

On the other hand, between the soft capsule film and the sustained-release coating layer, a separation coating layer including a separator obtained by mixing one or two or more selected from the group consisting of hydroxypropylmethylcellulose, povidone, and polyvinyl alcohol is formed. The weight ratio of the separator and the sustained-release agent may be preferably 1:5 to 1:10, more preferably 1:6 to 1:8. The separation coating layer serves to protect the soft capsules vulnerable to moisture from being dissolved in the solvent of the sustained-release agent to prevent adhesion, and the separation agent and the sustained-release agent preferably maintain the weight ratio. If the separator is too small, the capsule film may melt and stick, and if it is too high, the uniformity of the sustained-release coating may decrease.

In addition, the sustained-release base may be included in 10 to 30% by weight, more preferably 15 to 25% by weight, based on the total weight of the pharmaceutical composition in order to exhibit a desirable sustained-release effect.

The choline alfoscerate sustained-release small formulation for oral administration prepared according to the present invention is to simultaneously orally administer a plurality of formulations in a single dosage unit, and the conventional oral administration formulation is taken once a day. It is characterized by being able to achieve a sufficient effect just by itself. The size of individual formulations has been minimized so that dozens of formulations are administered at the same time, so that discomfort is not felt. It is possible to contain all of the formulations. In addition, each formulation is designed to maintain a certain dissolution pattern despite its very small size, so it is possible to achieve a quick pharmacological effect even with fewer side effects. You can expect improvement.

In addition, it has excellent moisture stability compared to conventional formulations, and since the manufacturing process is simple and the yield is high, it is economical and suitable for mass production.

FIG. 1 shows the results of a dissolution test in water performed with 100 tablets (1200 mg as choline alfoscerate) as one unit for the small tablets prepared in Examples 1 to 6 and Comparative Example 1. FIG.

FIG. 2 shows the results of a dissolution test in water performed with 50 tablets (1200 mg as choline alfoscerate) as one unit for the small tablets prepared in Examples 7 to 9 and Comparative Example 2. FIG.

FIG. 3 shows the results of a dissolution test in water performed with each 40 capsules (1200 mg as choline alfoscerate) as one unit for the sustained-release small soft capsules prepared in Examples 10 to 15 and Comparative Example 3.

FIG. 4 shows the results of a dissolution test in water performed with each 100 capsules (1200 mg as choline alfoscerate) as one unit for the sustained-release small soft capsules prepared in Examples 16 to 21 and Comparative Example 4. FIG.

FIG. 5 shows the results of a dissolution test in water performed with each 50 capsules (1200 mg as choline alfoscerate) as one unit for the sustained-release small soft capsules prepared in Examples 22 to 24 and Comparative Example 5. FIG.

Hereinafter, the present invention will be described in more detail through comparative examples and examples. The following examples are for explaining the present invention in more detail, and the scope of the present invention is not limited by these examples.

<Examples 1 to 6 and Comparative Example 1: Choline alfoscerate sustained-release small tablet containing a sustained-release base agent inside the tablet>

After mixing the components according to the components and contents described in Table 1 below, choline alfoscerate sustained-release small tablets according to Examples 1 to 6 and Comparative Example 1 were prepared through tableting. The preparations prepared for each group may contain 1200 mg of choline alfoscerate per unit (100 tablets).

Classification Ingredient (unit: mg) Comparative Example 1 Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Remark chief ingredient Choline alfoscerate 12.0 12.0 12.0 12.0 12.0 12.0 12.0 absorbent Calcium silicate 1.2 1.2 1.2 1.2 1.2 1.2 1.2 Excipient Microcrystalline cellulose 12.7 4.7 4.7 4.7 4.7 4.7 4.7 Excipient Lactose hydrate 1.5 1.5 1.5 1.5 1.5 1.5 1.5 Slow release agent Hypromellose 2208 - 15.0 - - - - - Viscosity: 100,000mpa Sodium alginate - - 15.0 - - - - Polyethylene oxide - - - 15.0 - - - Polyvinyl alcohol - - - - 15.0 - - Eudragit® RS PO Ethyl Methacrylate·Chlorotrimethylammonium Ethacrylate Copolymer - - - - - 15.0 - Hydroxypropyl cellulose - - - - - - 15.0 Grade: H Lubricant Magnesium stearate 0.6 0.6 0.6 0.6 0.6 0.6 0.6 Total (mg/tablet) 28.0 35.0 35.0 35.0 35.0 35.0 35.0 1 unit (positive) 100.0 100.0 100.0 100.0 100.0 100.0 100.0

<Test Example 1>

For the choline alfoscerate formulations prepared in Examples 1 to 6 and Comparative Example 1, a comparative dissolution test was conducted to confirm the effect of sustained-release drugs according to the type of sustained-release agent added in the tablet. The dissolution test was conducted on 1 unit of preparation prepared by group (1200 mg as choline alfoscerate), and as test conditions, 900 mL of water eluate, paddle method of 50 rotations per minute (10 revisions of the Korean Pharmacopoeia, method 2 of dissolution test) was applied. I did. The test results are shown in FIG. 1.

The formulations of Examples 1 to 6 are tablet formulations, and in order to solve the problem of tableting disorders due to the hygroscopicity of choline alfoscerate, 2 to 4% by weight of an adsorbent is used based on the total weight of the tablet. In this case, as the adsorbent, calcium silicate or a material having similar physical properties, for example, meglumine, colloidal silicon dioxide, etc. may be used, but the present invention is not limited thereto. The adsorbent is to reduce tableting difficulties and stability problems of tablets that may occur due to the strong hygroscopicity of the main component during tableting.If the adsorbent is contained in less than 2% by weight, tableting problems such as sticking during the manufacture of uncoated tablets, tableting It is not suitable because quality problems including properties due to the absorption of moisture in the air of the post tablet may frequently occur. On the other hand, if the adsorbent exceeds 4% by weight and contains too much, obstacles may occur during the process of processing uncoated tablets such as capping and laminating, and since the total dosage of the pharmaceutical composition per oral dosage unit increases, it is inconvenient to pass the neck. And the administration time is prolonged, so the patient's convenience in medication may be degraded.

As a result of the test, Examples 1 to 3 exhibited a sustained-release effect for a long time and the dissolution rate was constantly increased, resulting in the most desirable results. Accordingly, when the total weight of the tablet contains 30 to 40% by weight of the active ingredient choline alfoscerate, and 30 to 50% by weight of the sustained-release base agent, based on the total weight of the pharmaceutical composition, the sustained-release effect is I could see that it appeared. At this time, when using hydroxypropylmethylcellulose (hypromellose 2208) or polyethylene oxide as a sustained-release base, the most desirable effect was exhibited. It was confirmed that most of the formulations prepared in Examples 1 to 6 were eluted after a maximum of about 6 hours.

<Examples 7 to 9 and Comparative Example 2: Choline alfoscerate sustained-release small tablet containing a sustained-release base in the inner and outer coating layers of the tablet>

According to the components and contents shown in Table 2 below, the main component, adsorbent, excipient, sustained-release agent, and lubricant were mixed and tableted, and then the coating base was mixed with water to prepare a coating solution having a concentration of 10%. Thereafter, the coating solution was sprayed onto tablets tableted in a conventional manner using a pan coater to prepare choline alfoscerate sustained-release small film-coated tablets according to Examples 7 to 9 and Comparative Example 2. The preparations prepared for each group were made to contain 1200 mg of choline alfoscerate per unit (50 tablets).

Classification Ingredient (unit: mg) Comparative Example 2 Example 7 Example 8 Example 9 Remark chief ingredient Choline alfoscerate 24.0 24.0 24.0 24.0 absorbent Calcium silicate 2.4 2.4 2.4 2.4 Excipient Microcrystalline cellulose 10.0 10.0 10.0 10.0 Slow release agent Hypromellose 2208 9.0 9.0 9.0 9.0 Viscosity: 100,000 mpa Lubricant Magnesium stearate 1.2 1.2 1.2 1.2 1st coating base Hypromellose 2910 6.0 1.4 1.4 1.4 Pharmacoat ® 606 subcoating 2nd coating base Eudragit ® RS 30D Ethyl Methacrylate·Chlorotrimethylammonium Ethacrylate Ethyl Copolymer Dispersion - 4.6 - - Dry weight for 30% solution Surelease ® ethylcellulose dispersion - - 4.6 - Dry weight for 25% solution Kollicoat ® SR 30D polyvinylacetic acid dispersion - - - 4.6 Dry weight for 30% solution Plasticizer Triethyl citrate 0.6 0.6 0.6 0.6 Anti-adhesion agent Talc 4.8 4.8 4.8 4.8 Total (mg/tablet) 58.0 58.0 58.0 58.0 1 unit (positive) 50.0 50.0 50.0 50.0

<Test Example 2>

For the choline alfoscerate formulations prepared in Examples 7 to 9 and Comparative Example 2, a comparative dissolution test was conducted to confirm the drug sustained-release effect according to the type of sustained-release coating base coated on the tablet surface. The dissolution test was conducted on 50 tablets (1200 mg as choline alfoscerate) for 1 unit of preparation prepared by group, and as test conditions, 900 mL of water eluate, paddle method with 50 rotations per minute (Revised Korean Pharmacopoeia 11, method 2 ) Was applied. The test results are shown in FIG. 2.

The formulations of Examples 7 to 9 are coated tablet formulations coated with a sustained-release base agent on the surface of a tablet containing choline alfoscerate as an active ingredient, and the total weight is 55 to 65 mg, based on the total weight of the pharmaceutical composition including the coating layer, It contains 35 to 45% by weight of an active ingredient.

The sustained-release agent may be included in both the tablet and the coating layer. It is preferable to use hydroxypropylmethylcellulose or polyethylene oxide as the sustained-release agent included in the tablet, but when the sustained-release agent in the tablet is used alone, the sustained-release effect was found to be insufficient to sustain the drug release time for a long time. . It is believed that because of the strong hydrophilicity of choline alfoscerate, even if a sustained-release agent is included, the drug is rapidly released into the eluate due to strong affinity with water. As the content of the active ingredient is contained twice as compared to Examples 1 to 6, the reason is that sufficient dissolution control is not performed for the entire amount of the increased active ingredient just by including a sustained-release agent in the tablet. Is judged. Accordingly, as a result of repeated research by the present applicant, a formulation form was devised that additionally includes a sustained-release agent in the coating layer outside the tablet surrounding the tablet. At this time, the coating layer including the sustained-release agent is included in the second coating layer after first sub-coating the uncoated tablet so that the sustained-release agent does not interact with the active ingredient in the tablet. At this time, the sustained-release base included in the secondary coating layer may be selected from the group consisting of ethyl methacrylate and chlorotrimethylammonium ethyl acrylate copolymer, ethyl cellulose, and polyvinyl acetic acid, and such a sustained-release coating base may be additionally used. By inclusion, results in the desired sustained elution form have been shown.

Meanwhile, the sustained-release base included in the tablet is preferably included in 10 to 20% by weight based on the total weight of the pharmaceutical composition including the coating layer, and the sustained-release base included in the coating layer is preferably included in 5 to 15% by weight.

When the total weight of the sustained-release agent and the content composition ratio of each component are exceeded, the sustained-release characteristics of the pharmaceutical composition may be deteriorated or excessive.

<Examples 10 to 15 and Comparative Example 3: Preparation of choline alfoscerate sustained-release small soft capsules in which a sustained-release base agent is mixed with a capsule base>

Choline alfoscerate sustained-release according to Examples 10 to 15 and Comparative Example 3 including a capsule base, a plasticizer, and a sustained-release agent as a soft capsule film, including the main component and excipient in the content solution according to the ingredients and contents shown in Table 3 below. Castle small soft capsules were prepared. The soft capsule formulation according to the present embodiment is characterized in that the tablet size is minimized, unlike the conventional soft capsule, so that it has excellent medication convenience and high moisture stability. The preparations prepared for each group were made to contain 1200 mg of choline alfoscerate per unit (40 capsules).

Classification Ingredient (unit: mg) Comparative Example 3 Example 10 Example 11 Example 12 Example 13 Example 14 Example 15 Remark chief ingredient Choline alfoscerate 30.0 30.0 30.0 30.0 30.0 30.0 30.0 Excipient Concentrated glycerin 6.0 6.0 6.0 6.0 6.0 6.0 6.0 Excipient Purified water 4.5 4.5 4.5 4.5 4.5 4.5 4.5 Capsule base gelatin 15.0 8.8 8.8 8.8 8.8 8.8 8.8 Plasticizer Concentrated glycerin 0.8 0.8 0.8 0.8 0.8 0.8 0.8 Slow release agent Hypromellose 2208 - 12.5 - - - - - Viscosity: 100,000mpa Sodium alginate - - 12.5 - - - - Polyethylene oxide - - - 12.5 - - - Polyvinyl alcohol - - - - 12.5 - - Eudragit® Ethyl Methacrylate·Chlorotrimethylammonium Ethacrylate Ethyl Copolymer - - - - - 12.5 - Hydroxypropyl cellulose - - - - - - 12.5 Grade: H Total (mg/capsule) 56.3 62.6 62.6 62.6 62.6 62.6 62.6 1 unit (capsule) 40.0 40.0 40.0 40.0 40.0 40.0 40.0

<Test Example 3>

For the choline alfoscerate formulations prepared in Examples 10 to 15 and Comparative Example 3, a comparative dissolution test was conducted to confirm the effect of sustained-release drugs according to the type of sustained-release agent added in the soft capsule film. The dissolution test was conducted on 1 unit of preparation prepared by group (1200 mg as choline alfoscerate), and as test conditions, 900 mL of water eluate, paddle method of 50 rotations per minute (10 revisions of the Korean Pharmacopoeia, method 2 of dissolution test) was applied. I did. The test results are shown in FIG. 3.

Examples 10 to 15 are characterized in that the choline alfoscerate formulation is filled inside the soft capsule film, and the soft capsule includes a plasticizer and a sustained-release base in addition to the capsule base.

At this time, the capsule base may be one or a mixture of two or more selected from the group consisting of carbomer, gelatin, agar, pectin, poloxamer, xanthan gum, carrageenan, and starch. Gelatin was used.

Meanwhile, the sustained-release base included in the soft capsule is 1 selected from the group consisting of hydroxypropylmethylcellulose, sodium alginate, polyethylene oxide, polyvinyl alcohol, ethyl methacrylate/ethacrylic acid chlorotrimethylammonium ethyl copolymer, and hydroxypropylcellulose. It may be a species or a mixture of two or more. At this time, the content of the sustained-release agent is preferably 10 to 30% by weight based on the total weight of the pharmaceutical composition including the soft capsule film. When the content of the sustained-release base is less than 10% by weight or does not contain a sustained-release base as in Comparative Example 3, the sustained-release effect cannot be achieved, and when it exceeds 30% by weight, the viscosity of the capsule base solution becomes too high. It can cause disturbances during the molding process.

Meanwhile, the plasticizer may be one or a mixture of two or more selected from the group consisting of concentrated glycerin, propylene glycol, sorbitol, and polyethylene glycol, and is preferably contained in 7 to 20% by weight of the total weight of the capsule base. If the plasticizer is less than the above range, the capsule is liable to break due to insufficient flexibility, and if the plasticizer exceeds the above range, the size increases as the weight of the formulation increases, which is not preferable in terms of ease of medication.

<Examples 16 to 21 and Comparative Example 4: Preparation of small sustained-release soft capsules containing choline alfoscerate comprising a sustained-release base and consisting of a single layer>

Examples 10 to 15 are formulations containing an active ingredient in a film made of a capsule base and a sustained-release base. The soft capsule formulation containing a film, like the corresponding formulation, must have a hydrophilic property on the surface of the film in order to smoothly disintegrate in the body to achieve dissolution of the contents. However, since choline alfoscerate contained in the film as an inner solution is also a drug having high hydrophilicity, in the case of a general soft capsule form as in Examples 10 to 15, the solution may affect the stability of the film during long-term storage. . In order to prevent this problem, not only the type and content of the film, but also the composition of the content solution is limited.

In this regard, the applicant of the present invention has studied the choline alfoscerate soft capsule formulation in more depth, and unlike the conventional soft capsule consisting of an inner liquid and a film, there is no distinction between layers and does not contain liquid. It has developed a seamless soft capsule consisting of a single layer that does not change its properties.

When trying to manufacture a miniaturized soft capsule of less than about 100mg, the seamless type of soft capsule molding showed more excellent production stability and productivity than the generally used rotary type soft capsule molding, so the corresponding molding method was adopted. However, during the development of the choline alfoscerate soft capsule formulation molded in a seamless manner, a new problem that did not occur in the existing soft capsule formulation was discovered.

In the case of existing soft capsules, a semi-solid film base made of a low moisture content is used in the process of filling the contents with a film made of a capsule base such as gelatin, so even if the contents have strong hydrophilicity, the manufacturing process There was no problem of disintegration of the formulation due to the mixing of the film base and the inner solution.

When the manufacturing method is changed to a previously known seamless molding method, both the content liquid and the film base must have low viscosity due to the nature of the process so that the molding can occur smoothly. Due to the restrictions as described above, in the case of molding seamless soft capsules, the moisture content in the film base must be increased. However, when the solution of choline alfoscerate, which has strong hydrophilicity, comes into contact with the coating base, the coating is completely miscible with the solution due to the increased moisture content in the coating base, that is, it is not possible to form an appropriate form in which the solution and the coating are separated. I didn't.

Accordingly, the applicant of the present invention has repeatedly studied, screened the gelling agent and the curing agent, and combined them in a specific ratio to complete a sustained-release single-layer soft capsule capable of controlling the dissolution of active ingredients while having excellent moldability even when manufactured in a seamless method. Became. In addition, the single-layer soft capsule of the present invention has superior long-term storage compared to the conventional soft capsule, which is vulnerable to moisture, and has a smaller size compared to the conventional sustained-release tablet formulation, so that it has excellent medication convenience and a high manufacturing yield.

That is, the single-layer soft capsule of the present invention, which is prepared in a single layer by mixing all of choline alfoscerate, a gelling agent, a hardening agent, and a sustained-release agent, uses a gelling agent to prepare a capsule film and contains an active ingredient therein. Choline alfoscerate, a hydrophilic active ingredient that is difficult to manufacture in a conventional seamless method, differs from the conventional soft capsule formulation and is named as chewable formulation and gummy formulation. It is a novel single-layer soft capsule formulation of a seamless method that contains as an active ingredient and has excellent moldability and stability.

At this time, as the gelling agent, one or a mixture of two or more selected from the group consisting of carbomer, gelatin, agar, pectin, poloxamer, xanthan gum, carrageenan, and starch may be used. One or a mixture of two or more selected from the group consisting of calcium silicate, microcrystalline cellulose, colloidal silicon dioxide, and light anhydrous silicic acid may be used.

First, a suitable gelling agent and a curing agent were screened, and in order to find an optimal combination, the content of the curing agent was varied according to the content of the main component and gelatin, and it was confirmed whether or not the flexibility was reduced according to the content of the curing agent in order to form a seamless formulation. In this test, gelatin was used as a gelling agent, and colloidal silicon dioxide was used as a curing agent. The specific combination ratio of the composition used in the test is shown in Table 4 below.

Classification Ingredient (unit: mg) F1 F2 F3 F4 F5 F6 Remark Active ingredient Choline alfoscerate 1200.0 1200.0 1200.0 1200.0 1200.0 1200.0 Gelling agent gelatin 800.0 800.0 800.0 800.0 800.0 800.0 Hardener Colloidal silicon dioxide 100.0 200.0 300.0 400.0 500.0 600.0 Aeroperl ®300 Excipient Purified water 2000.0 2000.0 2000.0 2000.0 2000.0 2000.0 Dried in process

Flexibility reduction test according to hardener content

Based on the daily dose of 1200 mg of the active ingredient, a test to confirm the effect of reducing flexibility according to the change in the content of the curing agent was conducted for 800 mg of gelatin. First, it was confirmed that the mixture of the test formulations F1 to F6 according to Table 4 was sufficiently dried through a loss on drying test, and then the flexibility was measured, and the results are shown in Table 5 below.

Classification F1 F2 F3 F4 F5 F6 Loss on drying (%) 1.68 0.87 1.18 1.84 1.94 1.65 Flexibility (folding angle) 180° 180° 90° - - - Elongation (%) 3.22 3.07 1.44 0.71 0.68 0.60

When comparing the test results for the F1 to F6 formulations as shown in Table 5, it can be seen that the flexibility of the mixture of gelatin and choline alfoscerate decreases significantly as the content of colloidal silicon dioxide increases. That is, when the flexibility is excessively increased due to choline alfoscerate, it can be seen that the moldability problem can be solved by offsetting the flexibility of choline alfoscerate by using excipients with strong adsorption power such as colloidal silicon dioxide as a curing agent. .

Particularly, in the case of the F3 to F6 formulations, the elongation is low, and among them, the F4 to F6 is expected to have excellent molding stability since no folding phenomenon occurs.

Choline alfoscerate has properties similar to plasticizers that improve flexibility in terms of its physicochemical properties, so when mixed with gelatin and other gelatinizing agents and dried, it has the property of greatly increasing the flexibility of the dried product. In addition, the component has high moisture affinity, so even if it is mixed with a gelatinous agent such as gelatin and dried, it strongly absorbs moisture in the air, and the surface of the dried product has a viscous consistency. That is, when manufacturing a seamless single-layer soft capsule, a curing agent that reduces flexibility may be included in order to increase the quality stability of the prepared formulation. In addition, most of the hardeners have moisture-proof properties, and thus have the effect of blocking the moisture absorption of choline alfoscerate. Therefore, according to the above results, the curing agent is preferably 30 to 80% by weight based on the total weight of the gelling agent, more specifically 40 to 60% by weight, 50 to 70% by weight may be included, most preferably 50 It may contain to 60% by weight. When the curing agent is included in an amount of less than 30% by weight with respect to the total weight of the gelling agent, as shown in Table 5 above, the flexibility is too high and the elongation rate is high, so that even when dried, the curing is not sufficiently cured, and the soft capsules adhere to each other. May appear. That is, since the ratio of the curing agent is low, viscosity and flexibility due to the main component and the gelling agent remain, so that the capsules are not stable in quality, such as being attached to each other or deforming in shape. In addition, when it exceeds 80% by weight, the hardness of the soft capsules becomes too high, and the proportion of the gelling agent is relatively low, so the process in which the soft capsules must be rapidly hardened by the gelling agent in the molding machine is not smoothly performed, resulting in a spherical shape. It cannot be maintained, and the viscosity of the solution itself to be molded is also strong, and the capsule is molded in a non-uniform size.

Based on the above test results, the composition of the sustained-release single-layer soft capsule of the seamless method according to the present invention was derived, and specifically shown in Table 6 below.

Prepared a choline alfoscerate sustained-release small soft capsule composed of a single layer according to Examples 16 to 21 and Comparative Example 4 containing a main component, a gelling agent, a hardening agent, and a sustained-release agent in the contents according to the ingredients and contents shown in Table 6 below. I did. The preparations prepared for each group were made to contain 1200 mg of choline alfoscerate per unit (100 capsules).

Classification Ingredient (unit: mg) Comparative Example 4 Example 16 Example 17 Example 18 Example 19 Example 20 Example 21 Remark chief ingredient Choline alfoscerate 12.0 12.0 12.0 12.0 12.0 12.0 12.0 Gelling agent gelatin 31.5 10.5 10.5 10.5 10.5 10.5 10.5 Hardener Colloidal silicon dioxide 5.5 5.5 5.5 5.5 5.5 5.5 5.5 Aeroperl®300 Slow release agent Hypromellose 2208 - 21.0 - - - - - Viscosity: 100,000mpa Sodium alginate - - 21.0 - - - - Polyethylene oxide - - - 21.0 - - - POLYOX ^TM coagulantLEO Polyvinyl alcohol - - - - 21.0 - - Eudragit® Ethyl Methacrylate·Chlorotrimethylammonium Ethacrylate Ethyl Copolymer - - - - - 21.0 - Hydroxypropyl cellulose - - - - - - 21.0 Grade: H Total (mg/tablet) 49.0 49.0 49.0 49.0 49.0 49.0 49.0 1 unit (capsule) 100.0 100.0 100.0 100.0 100.0 100.0 100.0

<Test Example 4>

For the choline alfoscerate formulations prepared in Examples 16 to 21 and Comparative Example 4, a comparative dissolution test was conducted to confirm the effect of sustained-release drugs according to the type of sustained-release agent added in the single-layer soft capsule. The dissolution test was conducted on 1 unit of preparation prepared by group (1200 mg as choline alfoscerate), and as test conditions, 900 mL of water eluate, paddle method of 50 rotations per minute (10 revisions of the Korean Pharmacopoeia, method 2 of dissolution test) was applied. I did. The test results are shown in FIG. 4.

On the other hand, as the sustained-release base, one or two or more types selected from the group consisting of hydroxypropylmethylcellulose, sodium alginate, polyethylene oxide, polyvinyl alcohol, ethyl methacrylate and chlorotrimethylammonium ethacrylate copolymer, and hydroxypropylcellulose Mixtures can be used.

At this time, the sustained-release base agent may be included in 30 to 60% by weight based on the total weight of the pharmaceutical composition, and more specifically, 30 to 50% by weight, 40 to 60% by weight may be included, most preferably 40 to 45% by weight Can be included. If the sustained-release agent is out of the above range, the sustained-release effect or pharmacological effect may be reduced.

In addition, in order to further increase the sustained-release effect, a sustained-release coating layer including a sustained-release agent may be added to the surface of the pharmaceutical composition prepared seamlessly. In addition, since the seamless formulation is a formulation in which gelatin and an active ingredient are mixed and is vulnerable to moisture, when a coating layer is formed by using an insoluble substance as a sustained-release base, an additional effect of further excellent formulation stability can be obtained in addition to the sustained-release effect.

As the sustained-release base agent, water-insoluble cellulose and derivatives thereof may be selectively used. Ethyl cellulose, cellulose acetate, cellulose acetate phthalate, hydroxypropylene methyl cellulose phthalate, etc. can be selectively used by mixing one or two or more.

<Examples 22 to 24 and Comparative Example 5: Preparation of choline alfoscerate sustained-release soft capsules coated with a film-coated sustained-release coating base>

According to the ingredients and contents shown in Table 7 below, a soft capsule composed of a main component and an excipient as an inner solution, a capsule base and a plasticizer as a soft capsule film was prepared. Thereafter, the coating base was mixed with water to prepare a coating solution of 10% concentration, and the choline alfoscerate sustained-release soft capsule according to Examples 22 to 24 and Comparative Example 5 was sprayed onto the soft capsule in a conventional manner using a pan coater. Was prepared. The preparations prepared for each group are capable of containing 1200 mg of choline alfoscerate per unit (50 capsules).

Classification Ingredient (unit: mg) Comparative Example 5 Example 22 Example 23 Example 24 Remark chief ingredient Choline alfoscerate 24.0 24.0 24.0 24.0 Excipient Concentrated glycerin 4.8 4.8 4.8 4.8 Excipient Purified water 3.6 3.6 3.6 3.6 Capsule base gelatin 7.0 7.0 7.0 7.0 Plasticizer Concentrated glycerin 0.6 0.6 0.6 0.6 1st coating base Hypromellose 2910 7.0 2.4 2.4 2.4 Pharmacoat ®606 subcoating 2nd coating base Eudragit ® RS 30D Ethyl Methacrylate·Chlorotrimethylammonium Ethacrylate Ethyl Copolymer Dispersion - 4.6 - - Dry weight for 30% solution Surelease ® ethylcellulose dispersion - - 4.6 - Dry weight for 25% solution Kollicoat ® SR30D polyvinyl acetic acid dispersion - - - 4.6 Dry weight for 30% solution Plasticizer Triethyl citrate 0.6 0.6 0.6 0.6 Anti-adhesion agent Talc 7.4 7.4 7.4 7.4 Total (mg/capsule) 55.0 55.0 55.0 55.0

<Test Example 5>

For the choline alfoscerate formulations prepared in Examples 22 to 24 and Comparative Example 5, a comparative dissolution test was conducted to confirm the drug sustained-release effect according to the type of sustained-release coating base coated on the surface of the soft capsule. The dissolution test was conducted on 1 unit of preparation prepared by group (1200 mg as choline alfoscerate), and as test conditions, 900 mL of water eluate, paddle method of 50 rotations per minute (10 revisions of the Korean Pharmacopoeia, method 2 of dissolution test) was applied. I did. The test results are shown in FIG. 5.

Examples 22 to 24 are pharmaceutical compositions in which an active ingredient, choline alfoscerate, is filled into a soft capsule film, and a coating liquid containing a sustained-release agent is coated on the surface of the soft capsule film.

The pharmaceutical composition is prepared by preparing a capsule film using a capsule base and a plasticizer, filling the inner liquid with an active ingredient and an excipient, and then coating the capsule film with a coating solution containing a sustained-release base.

For the capsule coating, one or a mixture of two or more selected from the group consisting of carbomer, gelatin, agar, pectin, poloxamer, xanthan gum, carrageenan, and starch may be used.

Meanwhile, as the sustained-release base, one selected from the group consisting of ethyl methacrylate-chlorotrimethylammonium ethyl acrylate copolymer, ethyl cellulose, and polyvinyl acetic acid may be used.

The sustained-release base may contain 5 to 15% by weight based on the total weight of the pharmaceutical composition, and if it is out of the above range, the sustained-release may be lowered or the pharmacological effect may not be sufficiently exhibited.

At this time, between the sustained-release coating layer containing the sustained-release agent and the soft capsule film, the active ingredient and the sustained-release agent are physically contacted to prevent deterioration by interaction, and to prevent adhesion by dissolving in the moisture of gelatin. A coating layer may be further formed. In this case, the separation coating layer may include a separator that is one or a mixture of two or more selected from the group consisting of hyproxypropylmethylcellulose, povidone, and polyvinyl alcohol. In addition, the separation coating layer made of the separator serves to uniformly form the coating layer during the sustained-release base coating process.

The sustained-release bases included in the sustained-release coating layer mainly use a water-soluble solvent when preparing the coating solution. Therefore, as a component included in the separation coating layer, the above separation bases having low reactivity to both the sustained-release base and the active ingredient and excellent in water barrier properties may be selectively used. Among the above separators, hydroxypropylmethylcellulose may be most preferably used, and the weight ratio of the separator included in the separation coating layer and the sustained-release agent in the sustained-release coating layer is preferably 1:5 to 1:10. If the content of the separation coating layer is too low, the stability of the formulation may be reduced due to the interaction of the soft capsule film and the sustained-release base, and if it is too high, the tablet formulation becomes large, which may negatively affect the ease of use and inferior economy.

Claims (29)

As a pharmaceutical composition containing choline alfoscerate or a pharmaceutically acceptable salt thereof as an active ingredient, and comprising a sustained-release agent and an adsorbent, Based on the total weight of the pharmaceutical composition, The active ingredient is 30 to 40% by weight, The sustained-release base agent is 30 to 50% by weight, A pharmaceutical composition comprising 2 to 4% by weight of the adsorbent. The method of claim 1, The sustained-release base is one or a mixture of two or more selected from the group consisting of hydroxypropylmethylcellulose, sodium alginate, polyethylene oxide, polyvinyl alcohol, ethyl methacrylate/ethacrylic acid chlorotrimethylammonium ethyl copolymer, and hydroxypropylcellulose Pharmaceutical composition, characterized in that. The method of claim 1, The adsorbent is a pharmaceutical composition, characterized in that one or a mixture of two or more selected from the group consisting of calcium silicate, meglumine, and colloidal silicon dioxide. The method of claim 1, The pharmaceutical composition is a pharmaceutical composition, characterized in that the total weight of 30 to 40mg tablets. As a pharmaceutical composition containing choline alfoscerate or a pharmaceutically acceptable salt thereof as an active ingredient, A purification layer containing an active ingredient, an excipient, and an adsorbent, and a sustained-release agent, and A pharmaceutical composition comprising a sustained-release coating layer containing a sustained-release agent. The method of claim 5, A pharmaceutical composition, characterized in that the content of the sustained-release agent in the tablet layer is 10 to 20% by weight based on the total weight of the pharmaceutical composition. The method of claim 5, A pharmaceutical composition, characterized in that the content of the sustained-release agent in the sustained-release coating layer is 5 to 15% by weight based on the total weight of the pharmaceutical composition. The method of claim 5, Pharmaceutical composition, characterized in that the sustained-release base of the tablet layer is hydroxypropylmethylcellulose. The method of claim 5, The sustained-release base of the sustained-release coating layer, A pharmaceutical composition comprising one or two or more selected from the group consisting of ethyl methacrylate and chlorotrimethylammonium ethyl acrylate copolymer, ethyl cellulose, and polyvinyl acetic acid. The method of claim 5, The active ingredient is a pharmaceutical composition, characterized in that it contains 35 to 45% by weight based on the total weight of the pharmaceutical composition. The method of claim 5, A pharmaceutical composition, characterized in that the total weight of the pharmaceutical composition is 55 to 65mg. As a pharmaceutical composition containing choline alfoscerate or a pharmaceutically acceptable salt thereof as an active ingredient, Active ingredients are filled inside the soft capsule film, The soft capsule is a pharmaceutical composition comprising a capsule base, a plasticizer, and a sustained-release base. The method of claim 12, The sustained-release base is a pharmaceutical composition, characterized in that it contains 10 to 30% by weight based on the total weight of the pharmaceutical composition. The method of claim 12, The sustained-release base is one or a mixture of two or more selected from the group consisting of hydroxypropylmethylcellulose, sodium alginate, polyethylene oxide, polyvinyl alcohol, ethyl methacrylate/ethacrylic acid chlorotrimethylammonium ethyl copolymer, and hydroxypropylcellulose Pharmaceutical composition, characterized in that. The method of claim 12, A pharmaceutical composition, characterized in that the plasticizer is contained in an amount of 7 to 20% by weight based on the total weight of the capsule base. The method of claim 12, The plasticizer is a pharmaceutical composition, characterized in that one or a mixture of two or more selected from the group consisting of concentrated glycerin, propylene glycol, sorbitol, and polyethylene glycol. It contains choline alfoscerate or a pharmaceutically acceptable salt thereof as an active ingredient, Pharmaceutical composition, characterized in that consisting of a single-layer soft capsule formulation of a seamless method. The method of claim 17, The pharmaceutical composition further comprises a gelling agent, a curing agent, and a sustained-release agent. The method of claim 18, The gelling agent is one or two or more selected from the group consisting of carbomer, gelatin, agar, pectin, poloxamer, xanthan gum, carrageenan, and starch. The method of claim 18, The curing agent is a pharmaceutical composition, characterized in that one or two or more selected from the group consisting of a silicon-based compound or a cellulose derivative. The method of claim 18, The curing agent is a pharmaceutical composition, characterized in that one or a mixture of two or more selected from the group consisting of magnesium aluminate, calcium silicate, microcrystalline cellulose, colloidal silicon dioxide, and light anhydrous silicic acid. The method of claim 18, The sustained-release base is one or a mixture of two or more selected from the group consisting of hydroxypropylmethylcellulose, sodium alginate, polyethylene oxide, polyvinyl alcohol, ethyl methacrylate/ethacrylic acid chlorotrimethylammonium ethyl copolymer, and hydroxypropylcellulose Pharmaceutical composition, characterized in that. The method of claim 18, A pharmaceutical composition, characterized in that the curing agent is contained in an amount of 30 to 80% by weight based on the total weight of the gelling agent. The method of claim 18, A pharmaceutical composition, characterized in that the sustained-release base is contained in an amount of 30 to 60% by weight based on the total weight of the pharmaceutical composition. As a pharmaceutical composition containing choline alfoscerate or a pharmaceutically acceptable salt thereof as an active ingredient, Active ingredients are filled inside the soft capsule film, A pharmaceutical composition, characterized in that a sustained-release coating layer containing a sustained-release base is formed on the surface of the soft capsule film. The method of claim 25, The soft capsule is a pharmaceutical composition, characterized in that one or two or more selected from the group consisting of carbomer, gelatin, agar, pectin, poloxamer, xanthan gum, carrageenan, and starch. The method of claim 25, The sustained-release base is a pharmaceutical composition, characterized in that one selected from the group consisting of ethyl methacrylate-chlorotrimethylammonium ethyl acrylate copolymer, ethyl cellulose, and polyvinyl acetic acid. The method of claim 25, A separation coating layer is formed between the soft capsule film and the sustained-release coating layer, comprising a separator selected from the group consisting of hydroxypropylmethylcellulose, povidone, and polyvinyl alcohol, A pharmaceutical composition, characterized in that the weight ratio of the separator and the sustained-release agent is 1:5 to 1:10. The method of claim 25, The sustained-release base is a pharmaceutical composition, characterized in that it contains 5 to 15% by weight based on the total weight of the pharmaceutical composition.

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