KR20160005971A

KR20160005971A - Solid preparations containing choline alfoscerate and preparing method thereof

Info

Publication number: KR20160005971A
Application number: KR1020140085171A
Authority: KR
Inventors: 최연웅; 민병구; 기도형; 전형준; 최은정; 조상민; 하대철; 박희찬; 송희용
Original assignee: 한국유나이티드제약 주식회사
Priority date: 2014-07-08
Filing date: 2014-07-08
Publication date: 2016-01-18
Also published as: WO2016006862A1; KR101631846B1; PH12016500414B1; PH12016500414A1

Abstract

The present invention relates to a solid preparation comprising choline alfoscerate and calcium silicate and a method for producing the same, which enables calcium silicate to be formulated in solid form by adsorbing choline alfoscerate. The solid preparations comprising choline alfoscerate and calcium silicate of the present invention are advantageous in that they are less likely to be deteriorated by microorganisms or lower in stability due to moisture than the soft capsule formulations, .
In addition, the present invention improves the initial dissolution rate of the solid preparation by mixing two or more disintegrants to exhibit the same level of dissolution profile as that of the conventional soft capsule formulation, so that there is no difference in the appearance of the drug efficacy.

Description

[0001] Solid preparations containing choline alfoscerate and their preparation [

The present invention relates to a solid preparation comprising choline alfoscerate and calcium silicate and a method for producing the same, which enables calcium silicate to be formulated in solid form by adsorbing choline alfoscerate.

L-α-glyceryl phosphorylcholine (L-GPC), ie, choline alfoscerate, is a cholinesterase precursor compound that stimulates the production of acetylcholine, a neurotransmitter.

Originally, choline alfoscerate exists naturally in all cells of the body. As the aging progresses, its amount gradually decreases, leading to memory loss, perceived weakness, neurodegeneration and dementia. Therefore, chemically synthesized choline alfoscerate can be used as a brain function improver or a treatment for dementia by normalizing brain, nerve cell and cholinergic neuronal transmission system.

As a result, researchers have made efforts to develop a medicament containing choline alfoscerate, which is effective for improving brain function, etc. As a result, it has been found that the present invention can provide a pharmaceutical composition containing glycine soft capsules, glyceryl soft capsules, glial top soft capsules, Soft capsule formulations are being sold.

However, soft capsules containing choline alfoscerate have the disadvantages that the active ingredient is likely to migrate to a water-soluble soft gelatin capsule over time, which results in poor stability, requires a separate soft capsule manufacturing facility at the time of manufacture, There is a problem that can be. In addition, gelatin capsules have drawbacks in that they are difficult to keep because they are weak against moisture and heat, and they are inconvenient to take in the case of elderly patients whose swallowing ability is poor due to the large size of the preparation compared to tablets.

In relation to a preparation comprising choline alfoscerate or a method for producing the same, Patent Document 1 discloses a pharmaceutical preparation characterized by choline alfoscerate adsorbed on colloidal silicon dioxide and granulated, and Patent Document 2 Discloses a pharmaceutical preparation which is adsorbed on magnesium aluminosilicate so as to be able to formulate a solid form. Patent Document 3 discloses a sustained-release pharmaceutical composition comprising a coated portion formed on the outer surface of choline alfoscerate and a sustained-release base formed on the outer surface of the coated portion. However, since Patent Documents 1 and 2 require the use of a large amount of adsorbent, there is a problem in that the size of the prepared solid preparation increases and the cost increases. Patent Document 3 describes a sustained-release preparation containing choline alfoscerate, And technical features.

Therefore, the inventors of the present invention have made efforts to reduce the size of the solid preparation using a small amount of the adsorbent while solving the problems associated with the stability and convenience of the conventional soft capsule formulation. As a result, when the choline alfoscerate and calcium silicate are mixed, It is possible to prepare solid preparations of choline alfoscerate satisfying the conditions, and the present invention has been completed.

Korean Patent Publication No. 10-2009-0088564 Korean Patent No. 10-1172699 Korea Patent No. 10-1257918

It is an object of the present invention to provide a solid preparation comprising choline alfoscerate and calcium silicate, which is more stable and convenient to use than conventional liquid formulations.

Another object of the present invention is to provide a solid preparation comprising choline alfoscerate and calcium silicate, wherein the initial dissolution rate of the solid preparation is improved by mixing two or more disintegrants.

It is another object of the present invention to provide a method for preparing a solid preparation by mixing choline alfoscerate and calcium silicate.

In one aspect, the invention provides solid formulations comprising choline alfoscerate and calcium silicate.

In the present invention, the choline alfoscerate is also called L-alpha-glyceryl phosphoryl choline (L-GPC), and is a precursor compound of the cholinergic system, which produces the neurotransmitter acetylcholine It is a promoting drug. Therefore, the choline alfoscerate can be used as a brain function improver or a dementia treatment agent by normalizing brain, nerve cell and cholinergic neuronal transmission system.

In the present invention, the calcium silicate refers to a compound in which silicon dioxide and calcium oxide are bound in various ratios and is a kind of silicate compound.

The silicate compound is a substance containing silicic acid in the compound, and examples thereof include sodium silicate, colloidal silicon dioxide, potassium silicate, magnesium silicate, magnesium aluminosilicate and calcium silicate. In order to prepare a solid preparation containing choline alfoscerate, the above-mentioned silicate compound may be used singly or in combination of two or more, but calcium silicate is most preferable in consideration of stability and ease of use.

When the calcium silicate is mixed with choline alfoscerate, the choline alfoscerate can be made into a solid preparation by adsorbing choline alfoscerate. Since choline alfoscerate itself is unstable in temperature and humidity, it is important to solve the stability problem of raw materials in the case of solid preparations containing choline alfoscerate. In the present invention, by using calcium silicate as an adsorbent, stability of raw material against moisture can be assured due to the water-absorbing function of calcium silicate.

In one specific implementation, solid formulations were prepared by mixing calcium silicate, colloidal silicon dioxide, and magnesium aluminosilicate, respectively, with choline alfoscerate. As a result, in the case of solid formulations prepared using calcium silicate as an adsorbent, And the generation of fine powder was small, and it was found to be economical even though there was almost no deviation between the prepared solid preparations.

When a solid preparation containing choline alfoscerate is prepared using a silicate compound other than calcium silicate as an adsorbent, calcium silicate should be used in an amount of 5 to 20 times or more as compared with the case of using calcium silicate The same effect can be obtained. Therefore, when calcium silicate is used as an adsorbent, it is possible to produce a solid preparation having improved stability even when a relatively small amount is used as compared with other silicate compounds. Therefore, the size of the prepared solid preparation is small, .

The choline alfoscerate and the calcium silicate are preferably mixed at a weight ratio (w / w) of 1: 0.01 to 1: 0.5 by weight to choline alfoscerate. More preferably 1: 0.05 to 1: 0.15, and most preferably 1: 0.1. When the weight ratio (w / w) of choline alfoscerate and calcium silicate is less than 1: 0.01, calcium silicate has a weak effect of adsorbing choline alfoscerate, and has a high degree of grinding and is not economical, Deviations may occur between solid formulations. When the weight ratio (w / w) of choline alfoscerate to calcium silicate is more than 1: 0.5, there is almost no difference in the adsorption effect between the case and the case where the weight ratio (w / w) is less than 0.5, but the strength of the prepared solid preparation becomes high and the disintegration time becomes long The time for generating the medicinal effect may be delayed.

In one specific implementation, calcium silicate was mixed so that the choline alfoscerate weight ratio (w / w) was 1: 0.025, 0.05, 0.075, 0.01, 0.125, 0.15 and 0.175, When the weight ratio of calcium silicate to silicate weight is 1: 0.05 to 1: 0.15, the hardness of the prepared solid preparation is not too hard or too low, the degree of grinding is low and it is economical, Was not observed.

The calcium silicate is preferably contained in an amount of 1 to 20% by weight based on the total weight of the preparation. More preferably 1 to 15% by weight, and most preferably 3 to 10% by weight. When the calcium silicate is contained outside the above range, the hardness of the prepared solid preparation is too hard or too soft, and the degree of grinding is high, which is uneconomical.

In the present invention, the solid preparation is a formulation having a solid state, and examples thereof include, but are not limited to, tablets, pills, powders, coatings, granules or chewable tablets.

The tablet refers to a medicament made by compressing a medicament to a certain shape, and the medicament is a spherical medicament. The medicament refers to a finely divided drug, a chemical substance, or a dry mixture of both. Also, the coating agent refers to a preparation that is coated with a coating agent to improve the stability of the tablet or pill, and the chewing tablet refers to a preparation which chews in the oral cavity and hardens the hardness so that it does not need to be taken with water.

In the present invention, the solid preparation can be used as a prophylactic or therapeutic agent for a symptom or disease that may occur due to the lack of acetylcholine. Specifically, examples include symptoms due to cerebral vascular defects, degenerative brain mellitus syndrome, dementia, memory impairment, delirium, decreased motivation and spontaneity, decreased concentration, emotional anxiety, irritable hypersensitivity, and senile depression. But the kind is not limited thereto.

In another embodiment, the present invention provides a solid formulation comprising choline alfoscerate and calcium silicate, characterized in that the disintegrant is mixed with one or more, more preferably two or more, disintegrants.

In the present invention, the disintegrant absorbs moisture when the solid preparation is taken to promote the disintegration of the solid preparation. Particularly, in the present invention, by using two or more disintegrants in combination, an initial dissolution rate of the solid preparation can be improved as compared with the case where the disintegrant alone is used, so that a dissolution profile equivalent to that of conventional soft capsules can be obtained.

The disintegrant is not limited in its kind as long as it is pharmaceutically acceptable, and examples thereof include croscarmellose sodium, sodium starch glycolate, microcrystalline cellulose, crospovidone, polyvinylpyrrolidone, low substituted hydroxypropylcellulose, alginic acid, powder Cellulose, starch, sodium alginate, and the like. Preferably croscarmellose sodium, crospovidone, sodium starch glycolate or the like, or a mixture of two or more thereof, most preferably a mixture of croscarmellose sodium and crospovidone.

Preferably, the disintegrant is used in an amount of 1 to 15% by weight based on the total weight of the solid preparation regardless of whether the disintegrant is a single component or a mixture of two or more components. More preferably 1 to 10% by weight, and most preferably 3 to 5% by weight. When the disintegrant is less than 1 wt% based on the total weight of the tablets, the initial elution of the solid preparation is delayed and the efficacy is slower than that of conventional soft capsule preparations. When the disintegrant is more than 15 wt% The solid content of the prepared solid preparation can be increased, which is uneconomical.

When two or more, especially two, of the above-mentioned disintegrants are mixed, it is preferable to mix the disintegrants in a weight ratio of 1: 0.2 to 5. More preferably in a weight ratio of 1: 0.5 to 2. When the disintegrant is mixed out of the above range, the effect of improving the initial dissolution rate is not as effective as using the disintegrant alone, which is inefficient.

In one specific implementation, a solid formulation was prepared by adding a mixture of crospovidone, croscarmellose sodium, and sodium starch glycolate, and two components, respectively, to the choline alfoscerate as a disintegrant, , The dissolution profile was comparable to that of the conventional soft capsule when the two components were mixed.

In another aspect, the present invention provides a method for preparing a solid preparation by mixing choline alfoscerate and calcium silicate.

Specifically,

(a) adding choline alfoscerate and calcium silicate into a high-speed coagulation unit and mixing to adsorb choline alfoscerate on calcium silicate to produce an adsorbate;

(b) combining the adsorbent of (a) with an excipient to produce a conjugate;

(c) adding a disintegrant and a lubricant to the associate of (b) to prepare a mixture;

(d) preparing a tablet by pressing the mixture of (c) using a tableting machine; And

(e) a step of adding opacifying agent to the tablet of (d) and coating the mixture with choline alfoscerate and calcium silicate to prepare a solid preparation.

In the present invention, the above-mentioned choline alfoscerate, calcium silicate, and disintegrants are as described above.

The excipient serves to increase the volume so that a solid preparation having a desired size can be prepared. The excipient is not limited as long as it is pharmaceutically acceptable. Examples of the excipient include lactose hydrate, starch, sandalwood, mannitol, sorbitol, glucose, dextrin, sucrose, Microcrystalline cellulose, and the like. Lactose hydrate, microcrystalline cellulose or a mixture thereof.

The lubricant improves the fluidity of the powder, increases the filling property of the die, which is the lower part of the tablet machine, and increases the friction between the powder and the punch-die at the upper part of the tablet. To facilitate compression and release of the solid tablet, and the kind thereof is not limited as long as it is pharmaceutically acceptable. Examples thereof include silicon dioxide, talc, stearic acid, stearate, carnauba wax, colloidal silicon dioxide, magnesium silicate, magnesium stearate and sodium stearyl fumarate, preferably stearyl sodium fumarate.

In the present invention, it is preferable that the choline alfoscerate and the calcium silicate are mixed at a weight ratio (w / w) of 1: 0.01 to 1: 0.5. More preferably 1: 0.05 to 1: 0.15, and most preferably 1: 0.1.

In the present invention, it is preferable that the disintegrant is used in an amount of 1 to 15% by weight based on the total weight of the solid preparation regardless of whether the disintegrant is a single component or a mixture of two or more components. More preferably 1 to 10% by weight, and most preferably 3 to 5% by weight. Further, it is preferable to use a mixture of two or more components as the disintegrating agent in view of the improvement of the initial dissolution rate.

When a solid preparation containing choline alfoscerate is prepared using calcium silicate as an adsorbent as in the present invention, it is possible to prepare a stable preparation without granulation, and owing to omission of the granulation process, the production process is shortened It is economical to increase production efficiency.

The solid preparations comprising choline alfoscerate and calcium silicate produced by the above method can be used for the treatment or prevention of symptoms caused by lack of acetylcholine, symptoms due to cerebrovascular deficiency, degenerative brain syndrome, dementia, Delirium, hypersensitivity and spontaneous abortion, loss of concentration, emotional disturbance, irritability, irritability, senile depression, and the like.

The solid preparations comprising choline alfoscerate and calcium silicate of the present invention have higher stability than liquid formulations such as conventional soft capsules and are less likely to be contaminated or altered by microorganisms or the like. In addition, since the volume is smaller than that of the liquid preparation, convenience of taking is improved, and storage is easy.

In addition, by using a disintegrant capable of improving the initial dissolution rate, a dissolution profile almost equal to that of a conventional soft capsule preparation can be obtained, so that an equivalent effect can be obtained, and a manufacturing apparatus is not required and cost can be reduced.

Hereinafter, the present invention will be described in more detail with reference to Examples. It will be apparent to those skilled in the art that these embodiments are for illustrative purposes only and that the scope of the present invention is not limited by these embodiments in accordance with the gist of the present invention.

Example 1: Preparation of solid preparations comprising choline alfoscerate and silicic acid compounds

The choline alfoscerate powder and the silicate compound were put in a high speed coalescing machine and mixed to adsorb the choline alfoscerate powder to the silicate compound. Then, the microcrystalline cellulose and lactose hydrate, which are excipients, were added to the adsorbed product and then combined. Then, crospovidone, croscarmellose sodium and sodium stearyl fumarate were added and mixed, and the mixture was compressed by a tablet machine. Thereafter, Opadry was added and coated to prepare a solid preparation containing choline alfoscerate and a silicic acid compound. The solid preparation is characterized by being used for the treatment of cerebrovascular diseases.

Example 2: Comparison of properties of solid preparations containing choline alfoscerate and silicic acid compounds according to kinds of silicate compounds

2-1. Preparation of solid preparation using silicate compound as adsorbent

In order to compare the properties of the solid preparations containing choline alfoscerate according to the kinds of the silicic acid compounds, the solid preparations were prepared by using the method of Example 1 so that each component had the contents shown in Table 1 below.

Ingredient (mg) Usage A B C Choline alfoscerate chief ingredient 400 400 400 Calcium silicate
absorbent 40 - - Colloidal silicon dioxide - 40 - Magnesium silicate aluminate - - 40 Microcrystalline cellulose
Excipient 100 100 100 Lactose baggage 80 80 80 Crospovidone
Disintegration 20 20 20 Croscarmellose sodium 10 10 10 Sodium stearyl fumarate Lubricant 10 10 10 Gross weight 660 660 660

2-2. Comparison of the properties of solid preparations according to kinds of silicate compounds

In order to compare the properties of the prepared choline alfoscerate-containing solid preparation according to the type of silicic acid compound, the thickness, hardness, degree of shrinkage and disintegration time of the solid preparation prepared in Example 2-1 were measured, Are shown in Table 2 below.

Thickness (mm) Hardness (kPa) Marson (%) Disintegration time (min) A 6.1 10.5 0.1 10 B 6.3 10.2 1.0 6 C 6.1 10.5 1.2 10

As a result of the experiment, it was observed that the calcium silicate group had better adsorption power than the other groups.

In the case of the group using colloidal silicon dioxide and magnesium aluminosilicate, the mixture before sticking was sticky and sticking problem was caused, and it was difficult to be tattooed. Also, it was predicted that the degree of grinding was 1.0 or more in the measurement of the degree of abrasion, and the amount of dust was more than 10 times that of the calcium silicate group.

Example 3: Comparison of the properties of solid preparations containing choline alfoscerate and calcium silicate according to the amount of calcium silicate

3-1. Preparation of solid preparations according to the amount of calcium silicate

In order to compare the properties of the solid preparations containing choline alfoscerate according to the amount of calcium silicate, the solid preparations were prepared by using the method of Example 1 so that each component had the contents shown in Table 3 below.

Ingredient (mg) Usage D E F G H I J Choline alfoscerate chief ingredient 400 400 400 400 400 400 400 Calcium silicate absorbent 10 20 30 40 50 60 70 Microcrystalline cellulose Excipient 130 120 110 100 90 80 70 Lactose baggage 80 80 80 80 80 80 80 Crospovidone Disintegration 20 20 20 20 20 20 20 Croscarmellose sodium 10 10 10 10 10 10 10 Sodium stearyl fumarate Lubricant 10 10 10 10 10 10 10 Gross weight 660 660 660 660 660 660 660

3-2. Comparison of the properties of prepared solid formulations according to the amount of calcium silicate

In order to compare the properties of the solid preparations containing choline alfoscerate according to the amount of calcium silicate, the thickness, hardness, degree of shrinkage and disintegration time of the solid preparation prepared in Example 3-1 were measured, Are shown in Table 4 below.

Thickness (mm) Hardness (kPa) Marson (%) Disintegration time (min) D 5.8 Not measurable 1.5 5 E 5.9 5.1 1.3 8 F 6.0 7.0 1.1 9.5 G 6.1 10.5 0.1 10 H 6.3 14 0.1 15 I 6.4 17 0.1 18 J 6.5 Not measurable 0.05 25

The experimental results showed that the hardness of the prepared solid preparation increased as the amount of calcium silicate increased. In particular, in the case of mixing 10 mg of calcium silicate, the hardness was not measured because the mixture was too thick during the preparation of the solid preparation, resulting in a sticking problem during tableting, which made tablet molding difficult. In the case of the group obtained by mixing 70 mg of calcium silicate, the hardness was not measured because the tablets were pressed without being broken when measuring the hardness.

In the case of Marxondo, the amount of calcium silicate decreased, and the degree of scratching increased. In the case of the group of calcium silicate mixed with 40 mg or more, the produced solid preparation had a loss of less than 0.1% in the preparation of the solid preparation, and the hardness of the solid preparation was low and the coating was also hardly produced. However, in the case of 10 mg of calcium silicate mixed, the loss of raw material was observed to be 15 times or more as compared with that of the mixture of 40 mg or more in the masness degree of 1.5%.

The disintegration time tended to increase as the amount of calcium silicate increased. Particularly, in the case of the group in which 70 mg of calcium silicate was mixed, the disintegration time of the prepared solid preparation was 25 minutes, and the disintegration degree was later than that of the other groups.

3-3. Comparison of the stability of prepared solid preparations according to the amount of calcium silicate

In order to compare the stability of choline alfoscerate-containing solid preparations according to the amount of calcium silicate, the solid preparation prepared in Example 3-1 was stored for 6 months in long-term storage (25 ° C, 60% relative humidity) After storage under the conditions of the test (40 ± 2 ° C., 75 ± 5% relative humidity), the results are shown in Table 5 below.

D E F G H I J Appearance (white rectangular tablet) incongruity Suitable Suitable Suitable Suitable Suitable Suitable Content (95% ~ 105%) Suitable Suitable Suitable Suitable Suitable Suitable Suitable Elution (30 minutes 80% or more (water)) Suitable Suitable Suitable Suitable Suitable Suitable incongruity

As a result of the experiment, it was observed that the amount of calcium silicate in the group containing 10 mg of calcium silicate was so small that the tablet did not maintain its original shape and was easily broken and the color changed to yellow. In the case of the group containing 70 mg of calcium silicate, it was observed that the prepared solid preparation hardened due to too much calcium silicate and did not elute.

Example 4: Comparison of dissolution rates of solid preparations containing choline alfoscerate and calcium silicate according to the type and amount of disintegrant

4-1. Preparation of solid preparations according to kind and amount of disintegrant

In order to compare the properties of the solid preparations containing choline alfoscerate according to the type and amount of the disintegrant, the solid preparations were prepared by using the method of Example 1 so that each component had the contents shown in Table 6 below.

Ingredient (mg) Usage K L M N O P Q R S Choline alfoscerate chief ingredient 400 400 400 400 400 400 400 400 400 Calcium silicate absorbent 40 40 40 40 40 40 40 40 40 Microcrystalline cellulose Excipient 100 100 100 100 100 100 100 100 100 Lactose baggage 80 80 80 80 80 80 80 80 80 Crospovidone Disintegration 30 - - 10 10 20 - 20 - Croscarmellose sodium - 30 - 20 - 10 10 - 20 Sodium starch glycolate - - 30 - 20 - 20 10 10 Sodium stearyl fumarate Lubricant 10 10 10 10 10 10 10 10 10 Gross weight 660 660 660 660 660 660 660 660 660

4-2. Elution test of solid preparation according to kind and amount of disintegrant

In order to compare the dissolution rate of the solid preparation prepared in Example 4-1 with that of the conventional soft capsule type glycitalin soft capsule (Daewoong Pharma), the dissolution test was carried out under the following conditions, Respectively.

[Exam conditions]

Eluent: water 900 ml

Temperature: 37 ± 0.5 ° C

Test method: Korean Pharmacopoeia dissolution test, Method 2 (paddle method)

Paddle rotation speed: 50 rpm

Test solution
(water) Average dissolution rate (%) 5 minutes 10 minutes 15 minutes 30 minutes Treaty 0 58.6 91.0 97.6 K 25.3 54.2 70.1 96.3 L 28.2 66.6 68.5 96.3 M 26.3 61.5 78.2 95.1 N 10.2 70.2 88.2 96.5 O 54.1 68.8 89.2 97.3 P 18.5 62.1 89.5 95.6 Q 58.2 70.2 95.6 96.5 R 52.1 66.5 78.5 94.6 S 41.2 74.5 87.3 94.6

As a result of the experiment, the dissolution rate of the disintegrant alone was 70 to 80% after 15 minutes compared with the case where the disintegrant alone was used and the dissolution pattern was different from the control drug. In addition, the dissolution pattern of the group treated with the disintegrant was faster than that of the group treated alone, and the elution pattern was similar to that of the control.

Claims

A solid preparation comprising choline alfoscerate and calcium silicate.

The method according to claim 1,
Wherein the calcium silicate adsorbs the choline alfoscerate.

The method according to claim 1,
Wherein the weight ratio of the choline alfoscerate to the calcium silicate is 1: 0.01 to 1: 0.5.

The method of claim 3,
Wherein the weight ratio of the choline alfoscerate to the calcium silicate is 1: 0.05 to 1: 0.15.

The method according to claim 1,
Wherein the calcium silicate is present in an amount of 1 to 20% by weight based on the total weight of the preparation.

The method according to claim 1,
Wherein the formulation further comprises a disintegrant.

The method according to claim 6,
The disintegrant may be selected from the group consisting of Croscamellose sodium, Sodium starch glycolate, Microcrystalline cellulose, Crospovidone, Cross-linked povidone, Polyvinylpyrrolidone, (PVP), low substituted hydroxypropyl cellulose, low substituted, alginic acid, powdered cellulose, starch and sodium alginate. A solid formulation characterized by:

The method according to claim 6,
Wherein the disintegrant is selected from the group consisting of croscarmellose sodium, sodium starch glycolate, and crospovidone.

9. The method of claim 8,
Wherein the disintegrant is mixed in a weight ratio of 1: 0.2 to 5.

The method according to claim 1,
Wherein the solid preparation is a tablet, pill, powder, coating, granule or chewable tablet.

11. The method according to any one of claims 1 to 10,
Wherein the solid preparation is used for the treatment of cerebrovascular diseases.

(a) adding choline alfoscerate and calcium silicate into a high-speed coagulation unit and mixing to adsorb choline alfoscerate on calcium silicate to produce an adsorbate;
(b) combining the adsorbent of (a) with an excipient to produce a conjugate;
(c) adding a disintegrant and a lubricant to the associate of (b) to prepare a mixture;
(d) preparing a tablet by pressing the mixture of (c) using a tableting machine; And
(e) adding opaque to the stamp of (d) and coating
&Lt; / RTI > wherein the choline alfoscerate and calcium silicate are mixed to produce a solid formulation.