KR20230148924A - Sustained-release coated soft capsule containing choline alfoscerate and the preparation method thereof - Google Patents

Abstract

The present invention relates to a sustained-release coated choline alfoscerate soft capsule formulation made by coating a sustained-release coating layer on a soft capsule containing choline alfoscerate. Choline alfoscerate is a drug used for the treatment of patients with brain diseases, but soft capsules containing the same require 2 to 3 doses per day due to the rapid release of choline alfoscerate. The sustained-release coated choline alfoscerate soft capsule formulation made by coating a sustained-release coating layer achieves effective drug delivery with only one dose per day through sustained release that releases a certain amount of drug after administration. This will be an effective treatment agent that increases medication compliance for dementia and Alzheimer's patients who have difficulty taking medications.

Description

Sustained-release coated soft capsule containing choline alfoscerate and the preparation method thereof {Sustained-release coated soft capsule containing choline alfoscerate and the preparation method thereof}

It relates to a sustained-release coated soft capsule containing choline alfoscerate.

Choline alfoscerate is a precursor of acetylcholine and is used as a treatment for cognitive impairment, a major symptom of Alzheimer's disease. Choline alfoscerate passes through the blood-brain barrier and enters the brain, becoming choline, a precursor to the brain neurotransmitter acetylcholine. Acetylcholine normalizes neurotransmission functions that have deteriorated due to cranial nerve damage.

Choline alfoscerate has the characteristic of deliquescence, meaning it absorbs moisture from the surrounding environment and easily dissolves. Choline alfoscerate dissolved in a water-soluble base solvent (e.g., concentrated glycerin) is placed in a soft gelatin capsule. It has been marketed in the form of soft capsules obtained by filling. However, in the case of soft capsule formulations, there is a risk of property deformation due to the nature of gelatin capsules, which are sensitive to moisture and heat.

Therefore, research has recently been conducted on solid formulations in which choline alfoscerate is adsorbed on an adsorbent, and there are cases where it is actually sold on the market in the form of film-coated tablets.

Currently, choline alfoscerate is marketed as a formulation contained in soft capsules instead of general granules or mixing methods due to its highly hygroscopic and extremely water-soluble properties. However, in the case of commercially available soft capsule preparations, the drug is released quickly and the time to reach the highest blood concentration is only 3 hours. For this reason, administration is recommended 2-3 times a day (choline alfoscerate soft capsule, Cosmax Bio Co., Ltd.) , refer to the Ministry of Food and Drug Safety’s drug information system test results). The sustained-release coating layer used in the present invention solves the problem of rapid drug release in soft capsules and improves medication compliance. Sustained-release coating soft capsules coated with such a sustained-release coating layer exhibit a sustained-release effect that releases the drug over a long period of time, and through improved medication compliance, the same effect can be achieved with just one administration per day compared to two to three administrations per day for conventional commercial products. This could be a more effective dosage for patients suffering from senile dementia and Alzheimer's disease who require acetylcholine.

However, there are no sustained-release preparations on the market yet. By developing a formulation that can be taken once a day through sustained-release, it is expected that medication compliance will improve.

In order to solve this problem, the inventors of the present invention formed a sustained-release coating layer whose release is controlled by osmotic pressure on a soft capsule containing choline alfoscerate, thereby reducing the pharmacokinetic delay time and minimizing the amount of added excipients. It was possible to minimize the increase in size or volume of the dosage form and achieve sustained release with gradual release over 24 hours, thereby improving the convenience of administration.

One purpose of the present invention is to

To provide a pharmaceutical formulation containing choline alfoscerate with a sustained-release coating layer formed.

Another object of the present invention is to

In the soft capsule formulation containing choline alfoscerate, a pharmaceutical formulation with a sustained-release coating layer formed on the surface of the soft capsule and a method for manufacturing the same are provided.

In order to solve the above problems,

In one aspect, the present invention

Soft capsules containing choline alfoscerate or a pharmaceutically acceptable salt thereof; and

It includes a sustained-release coating layer coated on the outside of the soft capsule,

The sustained-release coating layer provides a pharmaceutical formulation containing a sustained-release coating polymer, a water-soluble film former, a plasticizer, a pore former, and a lubricant.

In another aspect, the present invention

Comprising: forming a coating layer containing a sustained-release coating polymer, a water-soluble film former, a plasticizer, a pore former, and a lubricant on a soft capsule containing choline alfoscerate or a pharmaceutically acceptable salt thereof.

A method for manufacturing pharmaceutical preparations is provided.

The pharmaceutical preparation according to the present invention can minimize the increase in size or volume of the formulation by minimizing the amount of excipients added compared to sustained-release tablets and achieve sustained-release, thereby improving the convenience of administration.

Figures 1a and 1e are scanning electron micrographs of the coating layer before elution of Examples 1 to 4 and 7.
Figures 2a and 2e are scanning electron micrographs of the coating layer after elution of Examples 1 to 4 and 7.
Figure 3 is a graph showing the dissolution test results of Examples 1 to 7.
Figure 4 is a graph showing the bursting strength test results of Examples 1 and 7.
Figure 5 is a graph showing the dissolution test results of Example 2 and Examples 8 to 10.
Figure 6 is a graph showing the results of a dissolution test according to the ratio of polyvinyl acetate dispersion and hydroxypropyl methylcellulose.
Figure 7 is a graph showing dissolution test results according to dissolution test rpm.

Hereinafter, the present invention will be described in detail.

Meanwhile, the embodiments of the present invention may be modified into various other forms, and the scope of the present invention is not limited to the embodiments described below. Additionally, the embodiments of the present invention are provided to more completely explain the present invention to those with average knowledge in the relevant technical field. Furthermore, “including” a certain element throughout the specification means that other elements may be further included, rather than excluding other elements, unless specifically stated to the contrary.

In one aspect, the present invention

Soft capsules containing choline alfoscerate or a pharmaceutically acceptable salt thereof; and

It includes a sustained-release coating layer coated on the outside of the soft capsule,

The sustained-release coating layer provides a pharmaceutical formulation containing a sustained-release coating polymer, a water-soluble film former, a plasticizer, a pore former, and a lubricant.

Choline alfoscerate is a natural choline compound found in the brain. Choline alfoscerate is a brain function improver that acts directly on damaged brain cells. Choline alfoscerate passes through the blood-brain barrier and enters the brain, where it is separated into choline and glyceryl phosphate dehydrogenase. Choline is a precursor to acetylcholine, a brain neurotransmitter that plays a central role in memory and learning, and acetylcholine normalizes neurotransmission functions that have deteriorated due to damage to cranial nerves. In addition, glyceryl phosphate dehydrogenase is metabolized into phospholipids, a component of cell membranes, and normalizes damaged nerve cell function. Since patients with Alzheimer's disease or dementia have lower levels of acetylcholine than normal people, the patient's symptoms can be expected to improve by increasing the production of acetylcholine through intake. Choline alfoscerate is used for secondary symptoms caused by cerebrovascular defects, such as memory loss, confusion, disorientation due to decreased motivation and spontaneity, decreased concentration, and symptoms of degenerative or degenerative brain organic mental syndrome. You can. It is also used for emotional and behavioral changes such as emotional anxiety, irritability, indifference to those around you, and geriatric pseudodepression.

Choline alfoscerate can be used in various forms, such as pharmaceutically acceptable salts, optical isomers, racemates, hydrates, and solvates, as long as equivalent pharmacological activity is maintained. The pharmaceutically acceptable salts include salts derived from pharmaceutically acceptable acids or bases. In particular, in the present invention, “pharmaceutically acceptable salt” refers to any salt at a concentration that is non-toxic and harmless to patients and has an effective effect, and the side effects caused by the salt do not reduce the beneficial efficacy of the pharmacologically active ingredient. .

The choline alfoscerate preparation of the present invention has the form of a soft capsule, and choline alfoscerate or a pharmaceutically acceptable salt thereof is included as a liquid content to form the soft capsule contents, and is composed of a soft capsule layer surrounding the contents. It can be.

To improve the deformation and stability of the capsule, choline alposcerate is packaged in an aluminum bag, or by adsorbing choline alposcerate to an excipient as described in Korean Patent Nos. 10-1499533 and 10-1172699. Any method may be used, but is not limited thereto.

In the present invention, the contents of the soft capsule may include choline alfoscerate and concentrated glycerin, and the soft capsule may contain 10 to 15 parts by weight of concentrated glycerin based on 100 parts by weight of choline alfoscerate.

In the present invention, the “film layer” of the soft capsule includes, but is not limited to, gelatin, concentrated glycerin, and purified water. The shell layer refers to the layer surrounding the contents of the soft capsule. In the present invention, the shell layer may include 20 to 30 parts by weight of concentrated glycerin based on 100 parts by weight of gelatin, and 1 part by weight of purified water per 100 parts by weight of gelatin. It may contain from 5 parts by weight.

Additionally, in the production of the film layer, other additives may be included as long as they do not impair the property stability, disintegration rate, and formulation homogeneity of the soft capsule. For example, the film layer may be manufactured by adding glycerin, sugar alcohol, and/or purified water to gelatin, the soft capsule base, and may further include a colorant to improve the properties of the soft capsule, but is not limited thereto.

The gelatin used in the present invention may be gelatin manufactured using pig skin, cow skin, or gelatin substituted with succinic acid, but is not limited thereto, and all gelatins that can be used in the production of food or medicine are included within the scope of the present invention.

The sugar alcohol used in the present invention is an alcohol obtained by hydrogen reduction of the aldehyde group of sugars. For example, solutions of sorbitol, mannitol, maltitol, lactitol, palatinate, xylitol, erythritol, sugar alcohols can be prepared from cornstarch, i.e. mixtures of sorbitol, sorbitan, mannitol and hydrogenated starch hydrolysates, hydrogenated maltose starch syrup, i.e. It may be derived from a mixture of maltitol, sorbitol and oligosaccharide alcohols. Specifically, the sugar alcohol may include, but is not limited to, a sugar alcohol solution derived from sorbitol, maltitol, corn starch, and hydrogenated maltose starch syrup.

The amount of sugar alcohol used to prepare the soft gelatin capsule shell layer of the present invention is not particularly limited as long as the physical properties of the resulting capsule are not deteriorated. For example, the amount of the sugar alcohol plasticizer may be 10 to 50 parts by weight, specifically 20 to 40 parts by weight, per 100 parts by weight of gelatin.

The sustained-release coating layer according to the present invention includes polyvinyl acetate, hydroxypropyl methylcellulose, triethyl citrate, propylene glycol, and talc,

At this time, the mixing ratio of the ingredients is not particularly limited, but

Preferably, based on 100 parts by weight of polyvinyl acetate, 30 to 40 parts by weight of hydroxypropyl methylcellulose, 12 to 17 parts by weight of triethyl citrate, 50 to 60 parts by weight of propylene glycol, and 30 to 40 parts by weight of talc,

More preferably, based on 100 parts by weight of polyvinyl acetate, it may be 33 to 38 parts by weight of hydroxypropyl methylcellulose, 13 to 16 parts by weight of triethyl citrate, 53 to 57 parts by weight of propylene glycol, and 32 to 36 parts by weight of talc. there is.

The total weight of the soft capsule according to the present invention including the contents may be 600 to 1000 mg or 700 to 900 mg, but is not particularly limited thereto and may be appropriately selected depending on the content of choline alfoscerate as an active ingredient.

In the soft capsule according to the present invention, the active ingredient choline alfoscerate or a pharmaceutically acceptable salt thereof may be included in an amount of 300 to 500 mg, or 350 to 450 mg.

In the pharmaceutical preparation according to the present invention, the sustained-release coating layer coated on the soft capsule may have a thickness of 0.1 mm to 0.4 mm, or 0.15 mm to 0.35 mm.

The sustained-release coating layer may be formed at 12 to 18 parts by weight, or 14 to 16 parts by weight, based on 100 parts by weight of the soft capsule including the contents.

The sustained-release coating layer may be included in an amount of 100 to 140 mg or 110 to 130 mg.

If necessary, the sustained-release coating layer may further include one or more of PEG (eg, PEG-6000) and mannitol (eg, D-mannitol).

The sustained-release coating solution is composed of pharmaceutically acceptable substances within a range that does not reduce the effect of choline alfoscerate, the active ingredient, for the purpose of further enhancing the sustained-release effect. The material may include, but is not limited to, a sustained-release coating polymer, a water-soluble film former, a plasticizer, a pore former, and a lubricant. In addition, all materials acceptable for the composition of the sustained-release coating solution to be described later may be described as examples, but are not limited to the described list.

Sustained-release coating polymer refers to a pharmaceutically acceptable water-insoluble material that controls the release of drugs, and includes polyvinyl acetate, methyl methacrylate-ethyl acrylate copolymer, methyl methacrylate-ethyl acrylate-trimethylaminoethyl meth. Crylic acid copolymer, ammoniomethacrylic acid copolymer, ethylcellulose, cellulose ester, cellulose ether, cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, hydroxypropylmethyl Examples include cellulose phthalate, glyceryl palmitostearate, glyceryl stearate, glyceryl behenate, cetyl palmitate, and glyceryl monooleate, and polyvinyl acetate is preferred.

Water-soluble film former refers to a polymer that has high absorption capacity, strong water retention capacity, and has the property of swelling and gelling instantaneously in water. It refers to a viscous polymer that is soluble in pharmaceutically acceptable water and controls the release of drugs. , hydroxypropyl methylcellulose, polyvinyl alcohol, hydroxypropylcellulose, hydroxypropyl methylcellulose phthalate, polyalkylene oxide, polyvinyl acetate-polyvinylpyrrolidone, sodium alginate and chitosan, preferably may be hydroxypropyl methylcellulose. The water-soluble film former may be used in an amount of 10 to 60, 20 to 50, and preferably 30 to 40 parts by weight based on 100 parts by weight of the sustained-release coating polymer.

The plasticizer increases the plasticity of the polymer coating to increase coating efficiency and promotes decomposition of the coating polymer. Examples of the plasticizer include triethyl citrate, butyryl-n-hexyl citrate, and fatty acid citrate derivatives, and are preferably used. may be triethyl citrate. It may be 5 to 20, 6 to 17, preferably 12 to 17 parts by weight based on 100 parts by weight of the sustained-release coating polymer.

Pore formers may include propylene glycol and D-mannitol, and one or more of these may be used. The pore former may be used in an amount of 5 to 60, 10 to 60, and preferably 50 to 60 parts by weight based on 100 parts by weight of the sustained-release coating polymer.

Commonly used lubricants include talc, stearic acid, magnesium stearate, calcium stearate, sodium lauryl sulfate, hydrogenated vegetable oil, sodium benzoate, sodium stearyl fumarate, magnesium aluminometasilicate, glyceryl behenate, and glyceryl mono. Examples include stearate, glyceryl palmitostearate, colloidal silicon dioxide, and mixtures thereof, and preferably talc. The amount of lubricant may be 15 to 40 parts by weight, preferably 30 to 40 parts by weight, based on 100 parts by weight of the sustained-release coating polymer.

In another aspect, the present invention

Provides a method for manufacturing a sustained-release coated soft capsule formulation, which includes:

It includes forming a coating layer containing a sustained-release coating polymer, a water-soluble film former, a plasticizer, a pore former, and a lubricant on a soft capsule containing choline alfoscerate or a pharmaceutically acceptable salt thereof.

At this time, the step of forming the coating layer may include spraying and drying an aqueous solution containing a sustained-release coating polymer, a water-soluble film former, a plasticizer, a pore former, and a lubricant.

In the manufacturing method, the sustained-release coating soft capsule preparation refers to the sustained-release coating soft capsule preparation described above, and the details described for the sustained-release coating soft capsule preparation equally apply to the manufacturing method.

The types and contents of choline alfoscerate, soft capsule, coating layer, sustained-release coating layer, sustained-release coating polymer, water-soluble film former, plasticizer, pore former, and lubricant are as described above.

Hereinafter, the present invention will be described through examples.

Materials and Methods

reagent part

Choline Max soft capsules (Choline alfoscerate) were purchased from Cosmax pharma co., Ltd. (Cheongju, Korea).

Polyvinyl acetate dispersion (Kollicoat SR 30D) was purchased from BASF Corporation (Ludwigshafen, Germany) and used as a sustained-release coating polymer, and hydroxypropyl methylcellulose (Pharmacoat 645) was purchased from Shin-Etsu Chemical Co., Ltd (Chiyoda, Japan). ) and used as a water-soluble film former. Triethyl citrate was used as a plasticizer purchased from Sigmaaldrich (St. Louis, MO, USA). As a pore former, propylene glycol was purchased from Dow chemical (Midland, USA), D-mannitol was purchased from Tokyo chemical industries co., ltd (Saitama, Japan), and polyethylene glycol 6000 was purchased from Sanyo chemical industries, ltd (Nagoya, Japan). ) was purchased and used. Talc was used as a lubricant purchased from Nippon talc co., ltd (Osaka, Japan). Acetonitrile was provided by Honeywell Burdick & Jackson (Muskegon, MI, USA) and was high-performance liquid chromatography (HPLC) grade. Water was purified using a filter in the laboratory.

<General coating method>

Preparation of sustained-release coating solution:

1) Manufacture of sustained-release coating solution #1

It was prepared by dissolving 26.9 mg of hydroxypropyl methylcellulose (PHARMACOAT ^® 645) in 180 mg of distilled water. The dosage is per tablet, and for the convenience of the manufacturing process, 26.9 g of hydroxypropyl methylcellulose and 180 g of distilled water, equivalent to 1000 tablets, were accurately weighed.

2) Manufacture of sustained-release coating solution #2

19.2 mg of talc was prepared by mixing 60 mg of distilled water and homogenizing it. The above capacity is per tablet, and for the convenience of the manufacturing process, it was manufactured by accurately weighing 19.2 g of talc and 60 g of distilled water, equivalent to 1,000 tablets.

3) Manufacture of sustained-release coating solution #3

It is prepared by uniformly mixing 166.7 mg of polyvinyl acetate dispersion (Kollicoat ^® SR 30D) (50.0 mg as solid content), 8.3 mg of triethyl citrate, and 15.6 mg of propylene glycol. The above dosage is per tablet, and for the convenience of the manufacturing process, it is manufactured by accurately weighing 166.7 g of polyvinyl acetate dispersion (50.0 g as solid content), 8.3 g of triethyl citrate, and 15.6 g of propylene glycol, equivalent to 1000 tablets. do.

The prepared sustained-release coating solutions #1# to #3 were mixed in a set ratio to prepare a sustained-release coating solution for forming a sustained-release coating layer.

Formation of sustained-release coating layer:

The mixed sustained-release coating solution was sprayed on the prepared soft capsules under the following coating conditions to obtain soft capsules with a sustained-release coating layer formed.

Coating conditions:

- Flow rate: 3 ml/min;

- Spray gun nozzle diameter: 0.8 mm;

- Pan speed: 18rpm;

- Bed temperature: 42℃;

<Examples 1 to 7>

Prepare a sustained-release coating solution according to the mixing ratio of each component to form a sustained-release coating layer as shown in Tables 1 and 2 below,

A sustained-release coating layer was formed under the coating conditions described above.

Example 1
Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Polyvinyl acetate (solids) (mg) 50.0 53.7 56.7 62.3 52.2 54.7 50.2 Hydroxypropyl methylcellulose 26.9 23.3 20.2 15.3 28.1 29.5 17.9 triethyl citrate 8.3 8.3 8.3 8.2 8.7 9.1 7.4 propylene glycol 15.6 15.6 15.6 15.3 10.9 5.7 27.6 Talc 19.2 19.2 19.2 18.9 20.1 21.0 17.0 total 120.0 120.1 120.0 120.0 120.0 120.0 120.0

Example 8 Example 9 Example 10 Polyvinyl acetate (solids) 35.8 71.6 107.3 Hydroxypropylmethylcellulose 15.5 31.0 46.5 triethyl citrate 5.5 11.1 16.6 propylene glycol 10.4 20.8 31.1 Talc 12.8 25.6 38.4 total 80.0 166.1 239.9

<Experimental Example 1> Photographing before and after dissolution

Examples 1 to 4 and 7 were compared for coating layers before and after elution using a scanning electron microscope (SEM). FIGS. 1A and 1E are photographs taken of the coating layer before dissolution in the above examples, and FIGS. 2A and 2E are photographs taken of the coating layer after dissolution in the above examples.

As shown in Figures 1 and 2, it was confirmed that minute holes existed in the coating layer after elution in the remaining examples except Example 1. It was found that this was caused by aggregation in the coating solution due to changes in the amount of hydroxypropylmethylcellulose.

<Experimental Example 2> Dissolution test

1. Preparation of sample solution

The eluate was taken from the soft capsules coated in Examples 1 to 7 and used as a sample. A dissolution test was conducted at pH 6.8, 37°C and 50 rpm according to the Korean Pharmacopoeia Dissolution Test Method 2. After 0.5, 1, 2, 4, 6, 8, 10, 12, 16, and 24 hours, 3 ml of the eluate was taken and filtered through a membrane filter with 0.45 μm pores, and the filtrate was used as the sample solution.

2. Preparation of standard solution

Exactly 400.0 mg of choline alfoscerate standard was taken and placed in a 100 ml volumetric flask. 50 ml of mobile phase was added and ultrasonic shaking was performed for 10 minutes to completely dissolve, then cooled to room temperature and the mobile phase was added to bring the total amount to 100 ml. Afterwards, it was diluted with an appropriate amount of mobile phase to prepare standard solutions of 400, 200, 100, 50, 25, and 12.5 μg/ml.

3. HPLC analysis conditions

HPLC was measured using a product from Agilent (CA, USA) under the following conditions.

Mobile phase: 3:7 (v/v) mixture of distilled water and acetonitrile

Column: 4.6mm x 250mm; 5μm NH2 column

Column temperature: 28℃

Detector: RI detector

Flow rate: 1.5ml/min

Injection volume: 50μl

4. Dissolution test results

The dissolution test graph of Examples 1 to 7 is shown in Figure 3. The following table shows the dissolution rate by time.

Dissolution rate
(%) Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7
2 hours 5.2 0.0 0.0 0.0 11.2 0.0 0.0
6 hours 88.5 51.5 2.5 0.0 82.4 75.5 2.6 12 hours 97.7 94.1 66.5 0.0 99.3 101.3 68.4 16 hours - 98.3 88.9 0.0 - - 92.0 24 hours - 98.1 95.8 14.6 97.5 - 97.0

As shown in the table above, Examples 3 and 7 had lower dissolution rates at 12 hours compared to other examples, showing a good sustained release effect. Additionally, when comparing the two examples, Example 7 showed a more effective dissolution rate for administration as all of the samples were dissolved within 24 hours.

<Experimental Example 3> Measurement of bursting strength of coated tablets

The eluates of Examples 1 and 7 were taken according to the dissolution test method performed in Test Example 2, and after a set sampling time, a sustained-release soft capsule whose release was controlled by osmotic pressure was obtained using a texture analyzer (TAXT plus). The physical properties of coated tablets were analyzed. The test was conducted using the compression method. The results are shown in Figure 4 and Table 4.

Bursting Strength (N) Example 1 Example 7 Mean ± standard deviation Mean ± standard deviation Initial 155.0±12.8 154.7 ± 18.3 4 hours 3.5 ± 1.48 119.7 ± 30.3 8 hours 1.69 ± 0.3 5.6 ± 2.1 16 hours 1.5 ± 0.6 3.8 ± 0.4

As shown in the table above, the bursting strength after 16 hours was 1.9N or less in Example 1, in which the coating layer was torn during dissolution, and 1.9N or more in Example 7, in which the coating layer was maintained. Example 7 is expected to persist in the human gastrointestinal tract for 16 hours without dose dumping.

(1.5 - 1.9N = bursting strength that would cause the tablet to break in the human gastrointestinal tract)

<Experimental Example 4> Measurement of dissolution change according to coating weight

In order to measure the change in dissolution depending on the coating weight, the dissolution of Example 2 and Examples 8 to 10 was measured. The results are shown in Figure 5 and Table 5.

Example 8 Example 2 Example 9 Example 10 Zeroth order rate constant 17.27 13.14 7.83 7.22

As shown in Figure 5 and Table 5, as the coating weight increased, the sustained release effect increased and the release rate decreased.

<Experimental Example 5> Measurement of dissolution change according to composition

In order to measure the change in dissolution as the composition changed, the dissolution of Examples 1 to 3 was measured. The results are shown in Figure 6 and Table 6.

Example 1 Example 2 Example 3 Zeroth order rate constant 18.85 13.14 8.23

As shown in Figure 6 and Table 6, it was confirmed that the sustained release effect increased as the ratio of polyvinyl acetate dispersion / hydroxypropyl methylcellulose in the coating solution increased.

<Experimental Example 6> Measurement of dissolution change according to rpm

In order to measure the dissolution change according to the rpm change in the dissolution test method (see step 1 of Test Example 2 above), the dissolution was measured in Example 7 while changing the dissolution test rpm. The results are shown in Figure 7 and Table 7.

Example 7 (50rpm) Example 7 (100rpm) Example 7 (150rpm) Zeroth order rate constant 9.14 9.38 9.17

As shown in Figure 7 and Table 7, when the dissolution test was conducted under three conditions with the paddle rotation speed of 50, 100, and 150 rpm, there was no difference in the dissolution profile depending on the paddle rotation speed. Through this, it was confirmed that stable drug release can occur regardless of the hydrodynamic conditions in the body.

Claims (16)

Soft capsules containing choline alfoscerate or a pharmaceutically acceptable salt thereof; and
It includes a sustained-release coating layer coated on the outside of the soft capsule,
The sustained-release coating layer is,
Containing a sustained-release coating polymer, a water-soluble film former, a plasticizer, a pore former, and a lubricant,
Pharmaceutical preparations.
According to clause 1,
The sustained-release coating layer is,
For 100 parts by weight of the water-soluble film former, 30 to 40 parts by weight of the sustained-release coating polymer, 12 to 17 parts by weight of the plasticizer, 50 to 60 parts by weight of the pore former, and 30 to 40 parts by weight of the lubricant.
Pharmaceutical preparations.
According to paragraph 1,
The sustained-release coating layer is,
For 100 parts by weight of the water-soluble film former, 33 to 38 parts by weight of the sustained-release coating polymer, 13 to 16 parts by weight of the plasticizer, 53 to 57 parts by weight of the pore former, and 32 to 36 parts by weight of the lubricant.
Pharmaceutical preparations.
According to paragraph 1,
The soft capsule is a pharmaceutical preparation of 600 to 1000 mg.
According to paragraph 1,
A pharmaceutical formulation comprising 300 to 500 mg of choline alfoscerate or a pharmaceutically acceptable salt thereof.
According to paragraph 1,
The sustained-release coating layer has a thickness of 0.1 mm to 0.4 mm.
According to paragraph 1,
The sustained-release coating layer is 12 to 18 parts by weight based on 100 parts by weight of the soft capsule.
According to paragraph 1,
The sustained-release coating layer is a pharmaceutical formulation of 100 to 140 mg.
According to paragraph 1,
The soft capsule is a pharmaceutical preparation containing gelatin.
According to paragraph 1,
The sustained-release coating polymer is polyvinyl acetate, methyl methacrylate-ethyl acrylate copolymer, methyl methacrylate-ethyl acrylate-trimethylaminoethyl methacrylic acid copolymer, ammoniomethacrylic acid copolymer, ethylcellulose, cellulose ester, cellulose ether. , cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, hydroxypropylmethylcellulose phthalate, glyceryl palmitostearate, glyceryl stearate, glyceryl behenate, A pharmaceutical preparation characterized in that it is one of cetyl palmitate and glyceryl monooleate.
According to paragraph 1,
The water-soluble film former is one of hydroxypropyl methylcellulose, polyvinyl alcohol, hydroxypropylcellulose, hydroxypropyl methylcellulose phthalate, polyalkylene oxide, polyvinyl acetate-polyvinylpyrrolidone, sodium alginate, and chitosan. A pharmaceutical preparation, characterized in that.
According to paragraph 1,
A pharmaceutical preparation, characterized in that the plasticizer is one of triethyl citrate, butyryl-n-hexyl citrate and fatty acid citrate derivatives.
According to paragraph 1,
A pharmaceutical preparation, characterized in that the pore forming agent is one of propylene glycol and D-mannitol.
According to paragraph 1,
The lubricant includes talc, stearic acid, magnesium stearate, calcium stearate, sodium lauryl sulfate, hydrogenated vegetable oil, sodium benzoate, sodium stearyl fumarate, magnesium aluminometasilicate, glyceryl behenate, glyceryl monostearate, A pharmaceutical preparation, characterized in that it is one of glyceryl palmitostearate and colloidal silicon dioxide.
Comprising: forming a coating layer containing a sustained-release coating polymer, a water-soluble film former, a plasticizer, a pore former, and a lubricant on a soft capsule containing choline alfoscerate or a pharmaceutically acceptable salt thereof.
Method for producing a pharmaceutical preparation according to paragraph 1.
According to clause 15,
The step of forming the coating layer includes spraying and drying an aqueous solution containing a sustained-release coating polymer, a water-soluble film former, a plasticizer, a pore former, and a lubricant.