KR101794573B1 - Immediate-release solid preparations comprising choline alfoscerate and preparing method thereof - Google Patents

Abstract

The present invention relates to an immediate-release solid preparation comprising choline alfoscerate and ethyl cellulose, which can be formulated into a solid form by controlling moisture absorbing properties through granulating choline alfoscerate, which is in a liquid or powder form, using ethyl cellulose; and to a preparing method thereof. According to the present invention, the moisture absorbing properties of a main component can be controlled without slowing down the elution of the preparation, the stability can be improved, and an appropriate small tablet size can be realized.

Description

TECHNICAL FIELD [0001] The present invention relates to an immediate-release solid preparation comprising choline alfoscerate and a preparation method thereof, and a method for producing the same. BACKGROUND ART < RTI ID = 0.0 >

The present invention relates to a formulation comprising choline alfoscerate.

Choline is a precursor to the neurotransmitter Acetylcholine, one of the most useful nutrients to improve brain metabolism or enhance mental abilities. Choline Alfoscerate (α-GPC), a phospholipid-conjugated cholinesterase, is a semisynthetic derivative of lecithin, a substance found naturally in the body, and L-alpha-glycerylphosphorylcholine (L- alpha glycerylphosphorylcholine). Choline alfoscerate helps in the conversion or synthesis of neurotransmitters important in the brain. Specifically, choline alfoscerate is absorbed into the body and decomposed into choline and glycerophosphate. After passing through the central nervous system (CNS) through the blood brain barrier (BBB), the neurotransmitter acetylcholine . ≪ / RTI > Choline alfoscerate contributes to the improvement of cognitive ability and helps to maintain memory for a long time. Choline alfoscerate also helps maintain neurons and neurons, and is involved in the formation of new cell membranes by binding to omega-3, which also enhances neural cell proliferation.

Choline alfoscerate is a compound that plays an important role in the production of new acetylcholine in the brain. It is naturally present in all cells of the body and is important for healthy body development or especially rapid brain development in neonates. And the reduction of choline alfoscerate results in a decrease in perceived ability, vascular dementia or neurodegeneration in Alzheimer's disease. Thus, choline alfoscerate is known to be effective not only in improving perceptual ability and brain function of elderly people but also in reducing concentration, emotional instability, irritability or depression, and is recently marketed as a medicinal product or a health functional food.

The present invention relates to pharmaceutical formulation of choline alfoscerate having the above pharmacological effect. Specifically, the present invention relates to a rapid-release solid preparation for oral administration of choline alfoscerate, which can form a solid form by controlling the hygroscopicity by granulating choline alfoscerate in liquid or powder form with ethylcellulose and And a method for producing the same. In one embodiment of the present invention, choline alfoscerate is mixed with a long fatty acid chain such as a lipid component and then granulated with an ethylcellulose binding liquid to produce a rapid-release oral solid for controlling the hygroscopicity of choline alfoscerate A preparation is obtained. In another embodiment according to the present invention, a solubilizing agent such as polysorbate or sodium lauryl sulfate (SLS) may be further added to supplement the drug delivery system of the immediate release. Technological considerations for supplementing other drug delivery systems other than the solubilized formulation may also be added to the present invention within the scope of not impairing the object of the present invention.

From a pharmaceutical point of view, further characterization of choline alfoscerate is sought.

Choline alfoscerate is a known substance having the structure of the following formula (1).

[Chemical Formula 1]

Choline alfoscerate has high hygroscopicity and water-solubility properties, so it is wet and liquefied by adsorbing moisture in the air when left in the air. However, it is difficult to block moisture with ordinary granules or mixing methods. Inevitably, A liquid soft capsule appeared. Such a commercial soft capsule of choline alfoscerate is recommended to take 400 mg of choline alfoscerate per day 2-3 times a day.

However, in the case of soft capsules, when the capsules are torn in the packaging line when packaging the drug in a pharmacy, or when the capsules are torn due to tearing of the gelatin film, And the like.

In addition, since the soft capsules of gelatin are weak to moisture and heat, they are difficult to be stored, and they are disadvantageous to take in the case of elderly patients whose swallowing ability is lower than that of tablets due to their large size, and the active ingredient is soft, There is a possibility of transition to a coating film, the uniformity of the content is low, a separate soft capsule manufacturing facility is required at the time of manufacturing, and there is a problem that it can be altered by microorganisms.

In order to solve the above problems of the conventional soft capsules, Korean Patent Registration No. 10-1257919 discloses a polyvinyl alcohol copolymer which is selected from the group consisting of hydroxypropyl, methylcellulose, hydroxypropylcellulose, polyvinyl alcohol, methacrylic acid copolymerization and polyethylene oxide Discloses a technique for preparing choline alfoscerate particles coated with one or more water-soluble polymers. However, the above technology is characterized in that the water-soluble polymer is coated to about 50 parts by weight, so that the release of the drug can be slowed due to the high content of the polymer.

Korean Patent Laid-Open Publication No. 10-2013-0121796 relates to a composition comprising a host and a guest, wherein the guest comprises an inclusion compound which is choline alfoscerate, wherein the choline alfoscerate: cyclodextrin is used in a weight ratio of 1: 0.005 to 0.5 A viscosity reducing agent, magnesium aluminosilicate, or the like is added to the composition to prepare a tablet, powder or granule formulation. However, the dissolution rate is insufficient.

Korean Patent Publication No. 10-1172699 discloses an example in which 400 mg of a main ingredient of a single dose or 50 mg of magnesium aluminosilicate in an amount of 50% is added to prepare a tablet core and then a single coated film tablet is prepared. However, since the weight of the tablet is about 800 mg and the coating is single coated, the dissolution of the drug is delayed after one month at the accelerated condition (40 ° C., 75% RH) When stored for a period of time, only a single coating layer will lose stability to moisture, resulting in delayed drug elution due to moisture entering the tablet core.

Korean Patent Publication No. 10-2013-0121796 Korean Patent Publication No. 10-1172699 Korean Patent Publication No. 10-1257918 Korean Registered Patent No. 10-1257919 Korean Patent Publication No. 10-2009-0088564 Korean Patent Publication No. 10-0904727 Korean Patent Publication No. 10-2009-0084194 Korean Patent Publication No. 10-2012-0083276 U.S. Published Patent Application No. 2009-0176740

The present inventors have made efforts to develop a small-sized solid preparation for oral administration using a small amount of excipient while solving the problems associated with the stability and convenience of the conventional soft capsule, and as a result, Granules of choline alfoscerate can be used to control the hygroscopicity of the main component without delaying the elution of the drug and improving the stability and can realize an appropriate small size of tablet, The present invention has been accomplished on the basis of confirming that the utilization rates can be expressed equally.

That is, the present invention provides a small-sized solid tablet for oral administration which is low in weight and easy to be taken by the elderly layer in a simple manufacturing process, and can be formulated through a general tablet preparation method, and can block the high hygroscopicity of choline alfoscerate , And also to develop tablets that exhibit bioavailability equivalent to commercially available soft capsules.

The present inventors have succeeded in controlling the hygroscopicity of the main component using ethylcellulose, which is mainly used in the implementation of the sustained-release drug delivery system by switching the conventional limiting idea, ensuring fast dissolution equality, Lt; RTI ID = 0.0 > capsule < / RTI >

Specifically, the present invention solves the above-mentioned problems by means of the following.

1. A rapid-release solid preparation comprising choline alfoscerate as an active ingredient, which comprises ethylcellulose as a hygroscopic agent.

2. The rapid-release solid preparation according to 1 above, further comprising a long chain fatty acid such as a lipid component as a hygroscopic agent.

3. The rapid-release solid preparation according to 1 or 2 above, wherein choline alfoscerate is combined with an ethylcellulose binding liquid and granulated.

4. The rapid-release solid preparation according to any one of 1 to 3 above, wherein the weight ratio of ethyl cellulose to the total weight of the solid preparation is from 0.005 to 0.03.

5. The method according to any one of 2 to 4 above, wherein the long chain fatty acid chains such as lipid components are selected from the group consisting of glyceryl monostearate, glyceryl monooleate, glyceryl palmitostearate, stearic acid, stearyl alcohol, Lt; RTI ID = 0.0 > (I) < / RTI > or glyceryl behenate.

6. The rapid-release solid preparation according to item 5, wherein the weight ratio of glyceryl behenate is 0.001 to 0.2 based on the total weight.

7. The rapid-release solid preparation according to any one of 1 to 6, further comprising at least one member selected from the group consisting of magnesium silicate, magnesium aluminosilicate, magnesium metasilicate alumina, and talc.

8. The pharmaceutical composition according to any one of the above 1 to 7, which is selected from the group consisting of Croscamellose sodium, Sodium starch glycolate, Microcrystalline cellulose, Crospovidone, cross-linked povidone, From the group consisting of polyvinylpyrrolidone (PVP), hydroxypropylcellulose (low substituted), alginic acid, powdered cellulose, starch and sodium alginate And further comprises at least one selected from the group consisting of the compound of formula (I).

9. The rapid-release solid preparation according to 8 above, further comprising croscamellose sodium.

10. The lubricant composition according to any one of 1 to 9 above, wherein at least one selected from the group consisting of colloidal silicon dioxide, magnesium stearate, talc, sodium stearyl fumarate, aluminum magnesium silicate, stearic acid, and sucrose fatty acid ester Wherein the solid preparation is further comprised of at least one compound of formula

11. The rapid-release solid preparation according to the above-mentioned 10, further comprising magnesium stearate or talc.

12. The rapid-release solid preparation according to any one of 1 to 11 above, further comprising a pharmaceutically acceptable solubilizing agent such as polysorbate or sodium lauryl sulfate.

13. The rapid-release solid preparation according to any one of 1 to 12, wherein the solid preparation is a tablet, a pill, a powder, a coating, a granule or a chewable tablet.

14. A method for producing a binding agent, comprising: (a) preparing a binding solution by mixing and dispersing choline alfoscerate and ethylcellulose in an ethanol or ethanol aqueous solution;

(b) combining the binding solution of (a) with a pharmaceutically acceptable additive;

(c) drying the association of (b);

(d) drying the dried material (c) and adding a pharmaceutically acceptable additive to prepare a final mixture;

(e) molding the final mixture of (d) using a tablet machine to produce a tablet;

(f) adding a film coating agent to the tablet of (e) and coating the same.

15. The method of producing a rapid-release choline alfoscerate-containing solid preparation according to 14 above, wherein the lipid component is further mixed in the step (a).

Since the present invention is a solid preparation, there is no disadvantage of soft capsules such as being altered by microorganisms as compared with conventional soft capsule formulations, and the hygroscopicity of choline alfoscerate is controlled more than that of solid preparations, There is less fear of deterioration, and the volume is small, which is advantageous in convenience of taking.

In addition, the present invention is characterized in that the initial dissolution rate is improved compared to the conventional solid preparations, thereby showing a dissolution profile equivalent to that of conventional soft capsules, so that the soft capsules do not differ from the conventional soft capsules in terms of drug efficacy.

Fig. 1 shows the initial state before the humidification test, and Fig. 2 shows the hygroscopic state after 24 hours.

In the present specification, choline alfoscerate is used to include a known main ingredient containing choline alfoscerate as an active ingredient, such as choline alfoscerate or a pharmaceutically acceptable salt thereof. For example, choline alfoscerate as used herein includes, without limitation, forms of crystalline polymorphs such as amorphous or crystalline forms, racemates, enantiomers, polymorphs, hydrates, anhydrides, and solvates.

Herein, the additives refer to pharmaceutically acceptable ingredients known to HANDBOOK OF PHARMACEUTICAL EXCIPIENTS and the like unless otherwise specified. Excipients, lubricants, disintegrating agents, solubilizing agents, and the like. Refers to any component commonly known in the pharmaceutical industry.

In the present specification, the weight refers to the relative weight of the entire solid preparation when the weight is 1. For example, when the preparation is tableted, it can be interpreted as a relative weight when the tablet weight is 1.

The present invention relates to a solid preparation for oral administration containing choline alfoscerate, which is an active ingredient used for the treatment of cerebrovascular disease, and is characterized in that it comprises tablets, pills, powders, coatings, granules Or < / RTI > That is, since the present invention relates to the formulation of choline alfoscerate, methods of obtaining raw materials of choline alfoscerate other than those from a pharmaceutical point of view, medicinal use, usage and dosage, and the like, are not limited to those known in the prior art. For example, in the solid preparation according to the present invention, the choline alfoscerate used as the active ingredient can be used as a therapeutically effective amount and can be used in amounts such as 200 mg or 400 mg per unit But are not limited thereto.

In addition, the drug delivery system of the solid preparation for oral administration has a rapid release, sustained release and delayed release, and the present invention relates to rapid release. In summary, the present invention is for the purpose of realizing a rapid-release solid preparation.

As described above, choline alfoscerate is hygroscopic, so when it is molded to be solid, the hardness is not secured and it is crushed and it is difficult to implement the solid agent. However, the inventors of the present invention contemplated that when choline alfoscerate is combined with ethyl cellulose, it is possible to block the aggregation of water to block moisture absorption and prevent the rapid release drug delivery system of choline alfoscerate So that the present invention can be completed. That is, the present invention aims at achieving a drug delivery system for interception and rapid release of choline alfoscerate by mixing with specific additives, and reducing the weight and volume of the final preparation. On the other hand, with the exception of the core principle of solving the above-described problems, the present invention can employ the usual solid formulation formulation techniques without limitation. The same is true for techniques for supplementing rapid release. Hereinafter, the characteristic features of the present invention will be described.

The present invention adopts ethyl cellulose as a hygroscopic agent. Ethylcellulose is an additive often listed as a controlled release agent for the implementation of a hydrophilic sustained release drug delivery system together with hydroxypropylmethylcellulose, sodium hydroxypropylcellulose, hydroxyethylcellulose, methylcellulose, carboxymethylcellulose or acrylic acid derivatives. For example, in Korean Patent Laid-Open Publication No. 10-2014-0094679, a water-insoluble polymer such as ethyl cellulose or the like has a coating agent for releasing drug of sustained release of choline alfoscerate so that the blood concentration of the drug can be maintained above the basal level for 10 hours or more Are listed as one type of additive used as. As such, ethylcellulose has been recognized as a matrix or coating agent for a sustained-release drug delivery system and has been recognized as an additive component that is not generally incorporated into a rapid-release solid preparation. However, We have combined cellulose with choline alfoscerate.

Unlike Korean Patent Laid-Open Publication No. 10-2014-0094679, the present inventors have combined ethylcellulose with choline alfoscerate in a liquid solvent such as ethanol or an aqueous ethanol solution as a hygroscopic agent instead of a coating agent. More particularly, the present invention relates to a method for preparing a binding liquid by mixing and dispersing ethylcellulose with choline alfoscerate in a solvent such as ethanol or an aqueous solution of ethanol, and then spraying the mixture with an enemy excipient and a disintegrating agent to form choline alfoscerate And granulated by wet granulation. As a result, the association with ethylcellulose effectively blocked the hygroscopicity of choline alfoscerate and also induced the rapid release of choline alfoscerate, thereby achieving bioequivalence with conventional soft capsules.

Moreover, the association with ethylcellulose can effectively block the hygroscopicity of choline alfoscerate without a large amount of excipients, and the total weight and volume of the final solid preparation can also be significantly reduced. Specifically, choline alfoscerate is administered orally 400 mg once or twice or three times a day for the treatment of secondary symptoms and degenerative or degenerative brain syndromes caused by cerebrovascular defects, Is a recommended drug. Therefore, when formulating choline alfoscerate, it is necessary to add a high-dose drug of 200 mg or 400 mg per unit dosage form. In the conventional solid preparations, since the adsorbent or the excipient is uniformly dispersed in each drug particle to control the moisture absorption, or the drug particle is coated with the coating agent to control the moisture absorption, the additive such as excipient, adsorbent or coating agent , The weight and volume of the final formulation were not desirable for convenience of administration. However, since the present invention enables effective hygroscopicity control by ethyl cellulose, an excessive amount of excipients such as an excipient, an adsorbent or a coating agent may not be mixed.

As described above, the present invention realizes further miniaturization than the conventional solid preparation, and can also improve convenience of taking. In particular, the technique employing a coating for blocking the hygroscopicity of choline alfoscerate, as disclosed in Korean Patent Publication No. 10-2014-0094679 or Korean Patent Publication No. 10-1257919, is not limited to a large amount of a coating agent, It is inevitably necessary to additionally add a binder and a plasticizer for smooth coating formation of the final formulation, so that the weight and volume of the final preparation are inevitably increased as a whole, and that such additional ingredients may adversely affect the drug release of the drug The effect of the present invention can be evaluated as a remarkable progress.

The ethylcellulose used as the hygroscopic agent in the present invention preferably has a solution viscosity of 10 (cP, mPas) or less and a viscosity of less than 7 (cP, mPas) .

Ethylcellulose is preferably contained in a weight ratio of 1: 0.005 to 1: 0.03 relative to the tablet weight, more preferably 0.005 to 0.01 in weight, more easily controlling the release of the drug, . If the amount of ethylcellulose used is more than 0.03 part by weight, the disintegration of tablets may be delayed and the release of the drug may be delayed, thereby lowering the absorption rate of the drug.

The present invention can further comprise a long fatty acid chain such as a lipid component for hygroscopicity blocking of choline alfoscerate. Long chain fatty acids, such as biodegradable lipid components, have been used as sustained release agents and acceptable ingredients are known. The present invention may employ any one or more of long chain fatty acids such as gastric lipid components, and preferably glyceryl monostearate, glyceryl monooleate, glyceryl palmitostearate, stearic acid, stearyl alcohol, Sodium stearyl fumarate or glyceryl behenate, and more preferably glyceryl behenate may be employed. Although the exact principle is not known, it has been found that when a lipid component having a long fatty acid chain is mixed with choline alfoscerate and has an unknown effect on each other, when the final solid preparation is obtained, when the preparation is coated, The inventors have found that the preparation exhibits long-term stability stability even after storage for a long period of time under severe conditions of moisture absorption.

When glyceryl behenate is compounded, it is preferably 1: 0.001 to 1: 0.2, more preferably 1: 0.001 to 1: 0.05, relative to the tableted parts by weight. If the glyceryl behenate exceeds 0.2 parts by weight based on the tableted parts by weight, the volume of the tablet becomes large and the tableting may be difficult, thereby preparing tablets of desired weight (i.e., 700 mg or less, preferably 650 mg or less) It can be difficult.

In addition to the above, the solid preparation according to the present invention may contain additives such as pharmaceutically acceptable excipients, disintegrants, lubricants or solubilizers commonly used in the pharmaceutical industry.

Pharmaceutically acceptable excipients are not limited, but at least one selected from the group consisting of magnesium silicate, magnesium aluminosilicate, magnesium metasilicate alumina and talc is preferable for achieving the object effect of the present invention.

Pharmaceutically acceptable disintegrants include, but are not limited to, croscarmellose sodium, sodium starch glycolate, microcrystalline cellulose, crospovidone, cross-linked povidone, In the group consisting of polyvinylpyrrolidone (PVP), low substituted hydroxypropyl cellulose (low substituted), alginic acid, powdered cellulose, starch and sodium alginate At least one selected is preferable in achieving the object effect of the present invention.

Pharmaceutically acceptable lubricants include, but are not limited to, at least one selected from the group consisting of colloidal silicon dioxide, magnesium stearate, talc, sodium stearyl fumarate, aluminum magnesium silicate, stearic acid, and sucrose fatty acid esters. It is preferable in achieving the object of the invention.

If desired, the solid preparations according to the invention may further comprise a pharmaceutically acceptable solubilizing agent such as polysorbate or sodium lauryl sulfate for immediate release.

The solubilizing agent is preferably 1: 0.001 to 1: 0.1, more preferably 1: 0.001 to 1: 0.05 based on the tableted parts by weight. When the solubilizer exceeds 0.1 part by weight based on the weight of the tablet, the long-chain fatty acid chain such as the lipid component of the tablet and the hygroscopic permeability of ethylcellulose may be increased to make tableting difficult. , Preferably about 650 mg) may be difficult to produce.

The rapid-release solid preparation of the present invention comprises the steps of: (a) preparing a binding solution by mixing and dispersing choline alfoscerate and ethylcellulose in a solvent such as ethanol or ethanol aqueous solution; (b) combining any of the excipients and disintegrants with the binding solution of (a); (c) drying the association of (b); (d) drying the dried material of (c), adding optional excipients, disintegrating agent and lubricant to prepare a final mixture; (e) molding the final mixture of (d) using a tablet machine to produce a tablet; And (f) adding an opaque or a film coating agent to the paint of (e) and coating. In step (a), a long fatty acid chain such as a lipid component may be further added.

The amount of the excipient, the disintegrant and the glidant to be used can be appropriately selected in consideration of the tablet having a size convenient for the patient and the elution characteristics such as rapid release. Further, the solubilizing agent may be appropriately compounded.

The combining step of steps (a) and (b) can be carried out through conventional wet granulation. For example, choline alfoscerate, a lipid component, and ethylcellulose are added to at least one excipient selected from the group consisting of pharmaceutically acceptable excipients magnesium silicate, magnesium aluminosilicate, magnesium aluminometasilicate, and talc, Alternatively, the wet granulation can be performed while mixing the binding liquid mixed and dispersed in the aqueous ethanol solution at a high speed in a high-speed coater.

The granules obtained by wet granulation can be dried and sieved by a conventional method.

Step (d) is performed by mixing the sized granules obtained in step (c) with a pharmaceutically acceptable additive, and then tableting and shaping the tablet. Herein, as the post-mixing additive, one or more excipients selected from the group consisting of magnesium silicate, magnesium aluminosilicate, magnesium metasilicate alumina and talc; Croscamellose sodium, sodium starch glycolate, microcrystalline cellulose, crospovidone, cross-linked povidone, polyvinylpyrrolidone (PVP), and starch glycol At least one disintegrant selected from the group consisting of hydroxypropylcellulose (low substituted), alginic acid, powdered cellulose, starch and sodium alginate; And at least one lubricant selected from the group consisting of colloidal silicon dioxide, magnesium stearate, talc, sodium stearyl fumarate, aluminum magnesium silicate, stearic acid, and sucrose fatty acid esters. no. Additives such as excipients, disintegrants, lubricants, and the like may be appropriately adjusted to obtain bioavailability equivalent to that of commercially available soft capsules.

Step (f) can be coated with a conventionally used film coating. In one embodiment, the method of manufacture of the present invention is carried out using one or more film coatings selected from the group consisting of hydroxypropelmethylcellulose, hydroxypropylcellulose, polyvinylalcohol, polyvinylpyrrolidone, methacrylic acid copolymer and polyethylene oxide Coating step.

Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples. However, the following examples and test examples are provided only for illustrating the present invention, but the scope of the present invention is not limited thereto.

[Comparative Example 1] Production of a solid preparation containing choline alfoscerate and a silicic acid compound

Tablets containing choline alfoscerate were prepared according to the ingredients and contents in Table 1 below. The content of Table 1 means the content (mg) per unit tablet.

An aqueous solution of ethanol was mixed and dispersed in 400 mg of choline alfoscerate as an active ingredient to prepare a binding solution.

Magnesium metasilicate aluminate, talc, and croscarmellose sodium were blended in a high speed coalescing machine, and granulation was carried out while injecting the abovementioned binding liquid. The resulting wet granules were dried and sized. Croscarmellose sodium, magnesium metasilicate alumina, talc and magnesium stearate were added to the resulting granules, mixed, and then tableted. The obtained tablets were coated with Opadry II85F92177 yellow coater and carnauba wax to prepare film-coated tablets.

[Example 1] Production of solid preparation containing choline alfoscerate and silicic acid compound

Tablets containing choline alfoscerate were prepared according to the ingredients and contents in Table 1 below. The content of Table 1 means the content (mg) per unit tablet.

400 mg of choline alfoscerate as an active ingredient is mixed and dispersed with glyceryl behenate, and an ethanol aqueous solution in which ethyl cellulose is dissolved is mixed and dispersed to prepare a binding solution.

Magnesium metasilicate alumimate, talc and croscarmellose sodium were mixed in a high-speed coalescing machine and granulated while the above-mentioned binding liquid was introduced. The resulting wet granules were dried and sized. Croscarmellose sodium, magnesium metasilicate alumina, talc and magnesium stearate were added to the resulting granules, mixed, and then tableted. The obtained tablets were coated with Opadry II yellow coating agent and carnauba wax to prepare film-coated tablets.

[Test Example 1] Comparative dissolution test

Example 1 and Comparative Example 1 were subjected to a dissolution test as described below.

As the eluate, 900 mL of water (purified water in the KIPPO General Test Methods) was used, the elution temperature was 37 ° C, and the rotational speed of the paddle was 50 rpm. The eluate was collected at 5, 10, 15 and 30 minutes with 6 samples, and filtered to prepare a sample solution. Separately, the corresponding amount of 44.4 mg of choline alfoscerate standard was precisely weighed, placed in a 100-mL volumetric flask, dissolved in water, and filtered to prepare a standard solution.

The test solution and standard solution were analyzed by liquid chromatography using the following conditions.

Column: APS-2 hypersil (NH-2) 4.6 * 250 mm, 5 占 퐉

Mobile phase: methanol: acetonitrile: water (3: 3: 4)

Detector: refractive index detector

Flow rate: 0.8 ml / min

Injection volume: 20 uL

The results of the dissolution test are shown in Table 2 below.

It was confirmed that the release of the drug in Example 1 was faster than 85% in 15 minutes as in Comparative Example 1.

 Drug release (%) 5 minutes 10 minutes 15 minutes 30 minutes Comparative Example 1 50.5 83.5 97.0 97.5 Example 1 43.8 78.9 96.1 101.8

[Test Example 2] Evaluation of bioavailability

The bioavailability of the tablets prepared in Example 1 was evaluated through bioequivalence studies.

Commercially available chondroitin glycyrrhizin soft capsules (chondogonadang) were also evaluated as comparative agents.

A total of 50 subjects were orally administered with 150 mL of water once with 1200 mg (Choline alfoscerate 400 mg x 3 tablets or 3 capsules) through a 2-group 2-fold cross-over test.

Blood sampling times were 0.5, 0.75, 1, 1.33, 1.67, 2, 3, 4, 6, 8 and 12 hr after dosing and tested according to the bioequivalence study schedule.

The drug kinetics parameters of blood drug concentration obtained by pre-administration blood sampling and post-administration blood sampling by choline alfoscerate endogenous substance were as shown in Table 3 below.

From the results of Table 3, it can be seen that the tablets of Example 1 prepared according to the present invention are biologically equivalent within the tolerance range of the comparative preparation.

Pharmacokinetic parameters Pharmacokinetic parameters Choline alfoscerate commercial soft capsule (comparative agent) Example 1 AUCt (ng · hr / mL) 1.91 + 0.83 1.82 + 1.02 Cmax (ng / mL) 0.39 + 0.17 0.38 + 0.12 Tmax (hr) 2.90 ± 2.72 2.66 ± 1.65

[Test Example 3] Humidity stability test

The tablets and commercially available tablets prepared in Example 1 and Comparative Example 1 were stored for 24 hours in an unpacked condition (40 ° C / 75% RH) at arbitrary conditions Respectively.

Fig. 1 shows the initial state before the humidification test, and Fig. 2 shows the hygroscopic state after 24 hours.

As can be seen from the results of Figs. 1 and 2, the tablets of Example 1 containing choline alfoscerate containing a long fatty acid chain such as ethylcellulose and a lipid component showed stable properties without changing the properties of the tablet (FIG. 2), and the tablets of Comparative Example 1 exhibited an appearance that the choline alfoscerate in the tablets was affected by humidity and cracked as the thickness was increased while receiving moisture.

Claims (9)

A solid preparation comprising choline alfoscerate as an active ingredient, comprising a granular dispersion of a composition comprising choline alfoscerate and a lipid component with a binding agent comprising ethyl cellulose, wherein the lipid component is glyceryl behenate, glyceryl Palmitostearate or sodium stearyl fumarate, wherein the content of the lipid component in the granule is 0.001 to 0.2 part by weight based on the weight of the solid preparation, and the content of ethyl cellulose in the binder is 0.005 to 0.03 part by weight based on the weight of the solid preparation ≪ / RTI > delete delete delete delete delete The solid preparation according to claim 1, further comprising polysorbate or sodium lauryl sulfate as a solubilizing agent. (a) preparing a binding solution by mixing and dispersing choline alfoscerate and ethylcellulose in an ethanol or ethanol aqueous solution;
(b) combining the binding solution of (a) with a pharmaceutically acceptable additive;
(c) drying the association of (b);
(d) sizing the dried material of (c) and adding a pharmaceutically acceptable additive to prepare a final mixture;
(e) molding the final mixture of (d) using a tablet machine to produce a tablet;
(f) adding a film coating agent to the tablet of (e) and coating the tablet,
Wherein the lipid component is glyceryl behenate, glyceryl palmitostearate or sodium stearyl fumarate and the content of the lipid component in the granule is 0.001 to 10 parts by weight, based on the weight of the solid preparation, 0.2 parts by weight, and the content of ethyl cellulose in the binder is 0.005 to 0.03 parts by weight, based on the weight of the solid preparation, of the solid preparation containing choline alfoscerate. delete

Images