KR101533286B1 - Oral pharmaceutical compositions comprising choline alfoscerate and a method for preparing the same - Google Patents

Abstract

The present invention relates to an oral pharmaceutical composition containing choline alfoscerate, which is characterized in that the preparation method of the choline alfoscerate preparation is simple, light in weight, and can be improved in compliance with a small tablet volume, By improving the stability against moisture, temperature, light and the like, long-term storage of medicines becomes longer than before, and it can be easily used for prevention and treatment of senile dementia and memory-related diseases, particularly prevention and treatment of Alzheimer's disease.

Description

The present invention relates to an oral pharmaceutical composition containing choline alfoscerate and a method for preparing the same,

The present invention relates to an oral pharmaceutical composition containing choline alfoscerate and a process for producing the same.

In recent years, as the world has entered a rapidly aging society, the number of elderly people suffering from diseases such as senile diseases, especially dementia and brain dysfunction has increased rapidly, and there is a great interest in the treatment of these diseases.

In connection with neurotransmission control mechanisms, one of the treatments for dementia, cholinergic precursors, anticholinergic agents, nicotinic receptor agonists and muscarinic receptor antagonists are used as agents to increase cholinergic neurotransmission Choline alfoscerate, a cholinergic precursor of these drugs, has been reported to be effective in the treatment of dementia even with few side effects (Doqqrell SA and Evans S., Treatment of dementia with neurotransmission modulation, Expert oipin investiq drugs, 2003 , 12 (10), 1633-54).

Choline alfoscerate, which is an active ingredient in the present invention, is a compound also referred to as L-α-glycerylphosphorylcholine (α-GPC, GPC) .

Choline alfoscerate is a compound that performs a precursor function to provide choline in the biosynthesis of the neurotransmitter acetylcholine, but also has a higher rate of passage of the blood brain barrier (BBB) than conventional drugs, Or as a brain function improver. Specifically, it is a drug used for the treatment of secondary symptoms and degeneration secondary to cerebral vascular damage or degenerative brain syndrome. It is used for the treatment of senile cognitive disorders such as memory loss, confusion, loss of directional sensation and concentration, Affecting feelings and behaviors such as hypersensitivity, and senile depression.

Currently, most of the choline alfoscerate formulations are commercially available as formulations in which the liquid form of choline alfoscerate is contained in soft capsules. However, in the case of a soft capsule preparation, a separate soft capsule manufacturing facility is required at the time of manufacture, and there is a possibility that the pharmacologically active ingredient is converted into a water-soluble gelatin capsule according to storage conditions and time, Which may lead to changes in properties and disruption (acceleration or retardation). In addition, due to problems such as the possibility of microbial alteration of the soft capsule preparation, the preservative agent used to reduce it, the stickiness due to the gelatin ingredient, and the possibility of causing gastrointestinal side effects, the elderly patient taking a long- .

Thus, there is a need to develop choline alfoscerate as an oral solid preparation in order to improve storage stability and ease of administration. In fact, many researchers have developed a technique for preparing choline alfoscerate by powdering it in the form of powder or tablet to compensate for the disadvantages of soft capsules. However, it has been reported that choline alfoscerate, which is a pharmacologically active ingredient, And it is difficult to suppress the change of the formulation depending on the time that occurs due to moisture at a normal room temperature condition (25 캜, relative humidity 60%), and thus it is difficult to develop the technology as a solid preparation agent.

Korean Patent Laid-Open Publication No. 2009-0088564 discloses a pharmaceutical preparation using colloidal silicon dioxide as an excipient for adsorbing choline alfoscerate as a liquid, but it is also possible to formulate the liquid choline alfoscerate into a solid form There is a problem of using an excessive amount of excipients in order to increase the weight of the formulation and the possibility of increasing the purification volume. In Korean Patent No. 1172699, it is confirmed that choline alfoscerate is solidified using magnesium aluminosilicate, but the stability is not remarkably increased. In addition, Korean Patent No. 1257919 and Korean Patent No. 1257918 disclose various methods for pretreating choline alfoscerate. However, in order to granulate choline alfoscerate in liquid form, Since it uses a complicated manufacturing method, it takes a lot of manufacturing cost and time.

Korean Patent No. 1257919 (Oral solid preparation containing choline alfoscerate or a pharmaceutically acceptable salt thereof, registered on Apr. 31, 1983) Korean Registered Patent No. 1257918 (a sustained-release pharmaceutical composition containing choline alfoscerate or a pharmaceutically acceptable salt thereof, registered on Apr. 31, 2013) Korean Patent No. 1172699 (pharmaceutical preparation containing choline alfoscerate, and a method for producing the same, August 3, 2012) Korean Patent Publication No. 2009-0088564 (pharmaceutical preparation containing choline alfoscerate, published on August 20, 2009) European Patent No. 217765 (Process for preparation of L-α-glycerylphosphorylcholine, L-α-glycerylphosphorylethanolamine from crude and / or deoleated lecithins, registered on August 16, 1990) U.S. Patent No. 5,250,719 (registered as L-α-glycerylphosphorylcholine and L-α-glycerylphosphorylethanolamine, Oct. 5, 1993)

Doqqrell SA, and Evans S., Treatment of dementia with neurotransmission modulation, Expert oipin investiq drugs, 2003, 12 (10), 1633-54. Baer, E. and Kates, M., L-α-glycerylphosphorylcholine, J. Am. Chem. Soc., 1948, 70 (4), 1394-1399.

It is an object of the present invention to provide an oral pharmaceutical composition containing choline alfosate and a process for producing the same.

The present invention relates to an oral pharmaceutical composition containing choline alfoscerate and a process for producing the same.

The oral pharmaceutical composition containing choline alfoscerate of the present invention comprises choline alfoscerate as an active ingredient and calcium silicate as an excipient.

The oral pharmaceutical composition may further comprise microcrystalline cellulose, copovidone, croscarmellose sodium, anhydrous calcium hydrogen phosphate, and sodium stearyl fumarate as excipients.

The content of the calcium silicate may be 6 to 25 parts by weight based on 100 parts by weight of choline alfoscerate.

Wherein the oral pharmaceutical composition comprises 6 to 25 parts by weight of calcium silicate, 5 to 25 parts by weight of microcrystalline cellulose, 1 to 15 parts by weight of copovidone, and 1 to 15 parts by weight of croscarmellose sodium based on 100 parts by weight of choline alfoscerate 1 to 15 parts by weight of anhydrous calcium hydrogen phosphate, and 1 to 15 parts by weight of stearyl fumarate can be mixed.

The formulations of the oral pharmaceutical compositions may be powders, granules, capsules, tablets, coated tablets, or a combination of one or more thereof.

According to another aspect of the present invention, it is preferable that the oral pharmaceutical composition is a coated tablet, in which the compressed tablet is coated with a film coating agent.

Wherein the film coating agent comprises at least one polymer substrate selected from the group consisting of polyvinyl alcohol, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, methacrylic acid copolymer and cellulose, and at least one polymeric substrate selected from the group consisting of polyethylene glycol, glyceryl mono It may be composed of at least one additive selected from the group consisting of stearate, sodium lauryl sulfate, maltodextrin, dextrose, sodium citrate, lecithin, talc, sodium bicarbonate, triethyl citrate, titanium oxide, stearic acid, .

The coating tablet may be coated with a film coating agent in a form of a single film or a multilayer film in an amount of 1 to 12% by weight based on the total weight of the coating.

Further, according to another aspect of the present invention, there is provided a process for producing an oral pharmaceutical composition containing choline alfoscerate,

(a) mixing choline alfoscerate and calcium silicate in a mixer in a ratio of 6 to 25 parts by weight of calcium silicate to 100 parts by weight of choline alfoscerate;

(b) adding and mixing pharmaceutically acceptable excipients to the mixture obtained in step (a);

(c) titrating the mixture obtained in step (b) with an oral tablet while applying pressure; And

(d) coating the tableted compressed tablet with the film coating agent in the step (c).

Hereinafter, the present invention will be described in more detail.

The oral pharmaceutical composition of the present invention is characterized by containing choline alfoscerate as an active ingredient and calcium silicate as an excipient.

In preparing the pharmaceutical composition for oral use of the present invention, calcium silicate is used as an excipient in silicone-based materials to stabilize the water-absorbing property of choline alfoscerate as an active ingredient and to improve the flowability, , Tablet volume, and the like.

The pharmaceutical composition of the present invention preferably contains 6 to 25 parts by weight of calcium silicate in the excipient based on 100 parts by weight of choline alfoscerate. When the content of calcium silicate is less than 6 parts by weight or more than 25 parts by weight The effect of suppressing the water absorption of choline alfoscerate is lowered, or the bulk density is low when it is prepared in the form of powders, granules, capsules or tablets, and thus it is not preferable for the weight reduction and small volume oral solid preparation of the present invention .

In the oral pharmaceutical composition of the present invention, diluents, disintegrants, binders, lubricants, and the like which are commonly used in oral preparations can be used. More specifically, microcrystalline cellulose (MCC) It is preferable to use a mixture of Copovidone, Croscarmellose sodium, Di-basic calcium phosphate anhydrous (DCPA), and Sodium stearyl fumarate.

At this time, the excipients are excipients which do not significantly affect the content or elution of the active ingredient. However, the proportion of these composition components is preferably 6 to 25 parts by weight, based on 100 parts by weight of the active ingredient choline alfoscerate, 5 to 25 parts by weight of microcrystalline cellulose, 1 to 15 parts by weight of copovidone, 1 to 15 parts by weight of croscarmellose sodium, 1 to 15 parts by weight of anhydrous calcium hydrogen phosphate and 1 to 15 parts by weight of sodium stearyl fumarate desirable.

The pharmaceutical composition for oral use of the present invention can be prepared in the form of powders, granules, capsules, tablets or coated tablets, or a combination of at least one thereof.

In a preferred embodiment of the present invention, the pharmaceutical composition for oral use can be prepared by coating tablets coated with a film coating agent with compressed tablets under pressure in the form of a mixture of an active ingredient and an excipient.

At this time, the coated tablets may be coated by using a film coating agent in the form of a single film or a multilayer film. The film coating agent constituting the coating film may contain at least one polymeric substance such as polyvinyl alcohol, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, methacrylic acid copolymer or cellulose, and at least one of polyethylene glycol, glyceryl Stabilizers and pigments such as monostearate, sodium lauryl sulfate, maltodextrin, dextrose, sodium citrate, lecithin, talc, sodium bicarbonate, triethyl citrate, titanium oxide and stearic acid, Depending on the substrate, it is possible to use a solvent in the form of a flowable, aqueous or semi-aqueous system.

The amount of the coating agent to be used is preferably in the range of 1 to 12% by weight of the compressed tablet produced by directly compressing and mixing the active ingredient choline alfoscerate and the excipient on the basis of the entire single membrane or multilayer film. It is also preferred that the coating amount is in the range of 1 to 12% by weight, more preferably 2 to 10% by weight of the compressed tablet, There is an effect that can be maintained.

If the amount of the coating agent used is less than 1% by weight of the compressed tablet, the properties of the coating may change during long-term storage, which is undesirable, and even if it exceeds 12% .

Next, a method for producing an oral pharmaceutical composition containing choline alfoscerate of the present invention comprises: (a) mixing choline alfoscerate and calcium silicate in a mixer with calcium silicate 6-25 By weight; (b) adding and mixing pharmaceutically acceptable excipients to the mixture obtained in step (a); (c) titrating the mixture obtained in step (b) with an oral tablet while applying pressure; And (d) coating the pressed compressed tablet with the film coating agent in step (c).

The pharmaceutical composition of the present invention can be prepared by adding to the active ingredient choline alfosate an excipient, calcium silicate and other pharmaceutically usable excipients, more preferably microcrystalline cellulose, copovidone, croscarmellose sodium, anhydrous calcium hydrogen phosphate and stearyl fumarate After mixing the sodium, the compressed tablet is produced by a tabletting method in which a direct pressure is applied to the mixture.

That is, in the production method of the present invention, it is possible to stabilize the water absorbency of choline alfoscerate with calcium silicate as an excipient, and to combine the optimal excipient to provide choline alfoscerate in purified form thereto, It is possible to manufacture the pharmaceutical composition for general oral use which can be used by those skilled in the art without using the expensive production equipment such as the fluidized bed granulator and the wet granulator, thereby reducing the production cost and the production time.

The pharmaceutical composition of the present invention can be prepared according to a conventional formulation method, for example, a general dry granulation method or a direct compression tablet manufacturing method, and the direct tableting method is most preferable .

In addition, the pharmaceutical composition containing choline alfoscerate of the present invention may contain additional ingredients to enhance the characteristics of the solid dosage form, to maintain the particle state of the active substance during the formulation process, or to increase the safety of the composition. can do.

The additional ingredient may be mixed with other ingredients of the oral pharmaceutical composition containing the choline alfoscerate of the present invention and may not adversely affect the properties of the drug. As additional components that may be used in oral pharmaceutical composition formulations containing the choline alfoscerate of this invention, for example, diluents, binders, lubricants, lubricants, colorants, disintegrants, flavoring agents, pH adjusting agents, functional polymers or waxes And the pharmaceutical composition of the present invention is not limited thereto.

The pharmaceutical composition containing choline alfoscerate of the present invention can be used for the prevention and treatment of senile dementia, especially for the prevention and treatment of Alzheimer's disease. The specific form and dosage of the pharmaceutical composition administration of the present invention may be selected according to the characteristics of the patient, in particular the age, weight, lifestyle, level of symptoms, and the judgment of the expert depending on the case.

According to the present invention, an oral pharmaceutical composition containing choline alfoscerate with improved storage stability can be obtained. The oral pharmaceutical composition of the present invention is improved in stability against moisture, temperature, light, and the like, so that the stability of the drug can be maintained even in long-term storage, thereby preventing and treating senile dementia and memory-related diseases, particularly prevention and treatment of Alzheimer's disease .

In addition, compared to the conventional method for producing choline alfoscerate, the method for producing tablets is simple, so that the production cost can be reduced and the production time can be shortened. Further, the preparation can be made lightweight and purified with small volume, It is possible to obtain an effect of improving drug compliance.

1 is a photograph showing changes in properties of powder of Example 1, Test Example 1 (choline alfoscerate powder as an active ingredient) and Comparative Examples 1 to 3 with time.
FIGS. 2 and 3 are graphs showing the results of comparative dissolution tests of Example 18 and a comparative preparation (manufacture / import: Daewoong Pharma, product name: glyatorin soft capsules).

Hereinafter, preferred embodiments of the present invention will be described in detail. However, the present invention is not limited to the embodiments described herein, but may be embodied in other forms. Rather, the disclosure is thorough and complete, and is provided to enable those skilled in the art to fully understand the spirit of the invention.

1. Preparation and evaluation of mixed compositions containing choline alfoscerate

Choline alfoscerate, calcium silicate, and other oral excipients were mixed under the conditions shown in the following [Table 1] to prepare a mixed composition containing the choline alfosate of Example 1 in powder form. same.

Example  One: Choline alfoscerate  ≪ / RTI >

(Manufactured at 1,000 times the amount of [Table 1]).

1) After weighing each main ingredient and excipient, apples (30mesh).

2) 400 g of choline alfoscerate as an active ingredient and 100 g of calcium silicate are placed in a universal mixer for wrapping and mixed at 15 rpm for 10 minutes.

3) 60 g of microcrystalline cellulose, 20 g of copovidone and 30 g of croscarmellose sodium are added to the mixture produced in the step 2) in a universal mixer for wrapping and mixed at 15 rpm for 10 minutes.

4) 20 g of sodium stearyl fumarate is added to the mixture produced in the step 3) in a universal manufacturing machine mixer for wrapping, followed by final mixing at 15 rpm for 5 minutes.

Comparative Example  1 to 4: Choline alfoscerate  ≪ / RTI >

In addition, a mixed composition containing choline alfoscerate was prepared by the same method and under the same conditions as in Example 1, except that microcrystalline cellulose silicified under the conditions shown in Table 1 below, magnesium metasilicate aluminate, colloidal silica The choline alfoscerate preparations of Comparative Examples 1 to 4 were prepared by mixing the germicidal silicon dioxide.

Condition Choline
Alpoh
Cere
It
(mg) Silicic acid
calcium
(mg) Silicification
Microcrystalline cellulose
(mg) Magnesium metasilicate aluminate
(mg) Colloidal silicon dioxide
(mg) Microcrystalline cellulose
(mg) COPO
Scare
(mg) cross
Sodium camellose
(mg) Sodium stearyl fumarate
(mg) total
( mg ) Example 1 400 100 0 0 0 60 20 30 20 630 Comparative Example 1 400 0 100 0 0 60 20 30 20 630 Comparative Example
2 400 0 0 100 0 60 20 30 20 630 Comparative Example 3 400 0 0 0 100 60 20 30 20 630 Comparative Example 4 400 150 0 0 0 30 20 15 15 630

Experimental Example  One: Choline alfoscerate  ≪ / RTI >

<Experimental Example 1-1. Property evaluation of mixed composition >

As the mixed composition of Example 1 and Comparative Examples 1 to 4 and the powdered choline alfoscerate as Test Example 1, the mixture was allowed to stand for 12 hours, 1 day and 10 days at a relative humidity of 55 to 65% and 26 ° C, And the comparative example were compared and confirmed, and the results are shown in Fig. In the above [FIG. 1], the evaluation criteria of the properties of the mixed composition are as follows.

Property evaluation criteria of mixed composition A  Stable state without change of property B  If less than 20% of the total amount is hygroscopic to moisture C  About 50% to 60% of the total amount is due to water absorption, D  Less than 30% of the total amount is in the form of a powder, and liquid is visible due to moisture absorption E  When 100% of the total amount is visible as a completely transparent liquid due to moisture absorption in the air

Referring to the results of [Figure 1], it was confirmed that the preparation of Example 1 maintained the powder state not only on the first day but also after 10 days or more. On the other hand, in the case of the preparations of Comparative Examples 1 and 2, after 1 day, the water absorbed and the flowability of the powder was lowered, and water droplets were observed visually. In Comparative Example 3, the property change was the fastest among the comparative examples. In Comparative Example 4, the water stability was excellent. However, due to the excessive volume increase of the mixture due to the low bulk density, Lt; RTI ID = 0.0 &gt; oral &lt; / RTI &gt; pharmaceutical compositions.

<Experimental Example 1-2. Measurement of moisture content change>

Loss on drying (LOD) was measured for the mixed composition of Example 1 and Comparative Examples 1 to 4 and Test Example 1 (choline alfoselate in powder form) for 72 hours immediately after the preparation, The results are shown in Table 3 below.

LOD  change
(60 ° C, 10 min , 5g) start 30 minutes 1 hours 2 hours 12 hours 24 hours 72 hours Example 1 0.83% 0.90% 1.05% 1.32% 1.52% 1.67% 1.69% Test Example 1 ^* 0.50% 1.30% water drop
formation Semi-solid phase Conversion to liquid form Conversion to liquid form Conversion to liquid form Comparative Example 1 0.77% 0.80% 1.55% 1.83% 2.84% 4.84% 6.84% Comparative Example 2 0.82% 0.95% 1.42% 2.27% 3.05% 5.05% 7.34% Comparative Example 3 0.52% 0.72% 1.14% 1.50% 2.84% 6.84% 8.84% Ambient conditions (26 ℃, relative humidity 55 ~ 65%)
* Test 1: powdery Choline alfoscerate active ingredient
Measuring instrument (manufacturer): Precisa (SWISS), Type: XM10SE, Heating method: Halogen lamp
Sampling / temperature: 60 ℃, sample amount 5g, measuring time 10 minutes

The results are shown in Table 1. The water content change (LOD) was measured in the same manner as in Example 1 using choline alfosate and calcium silicate, and in Test Example 1 using only choline alfoscerate main component in powder form and Comparative Examples 1 to 3 using other silicone- As a result of confirming the degree of hygroscopicity of the active ingredient from moisture in the air according to the type of each excipient when exposed to general room temperature conditions, as shown in the above [Table 3] and [Figure 1] The effect of blocking the inflow of water into the mixed composition was superior to that of the comparative example using other excipients even after a lapse of a certain time.

2. Mixing of excipient ingredients By rate Choline alfoscerate  Preparation and evaluation of containing tablets

The mixed composition containing choline alfoscerate at a relative humidity of 55 to 65% and 26 DEG C was mixed by using a tablet machine under the conditions of the following production process and conditions of Table 4 under the conditions of varying the ratio of calcium silicate and various excipients, The tablets of Examples 2 to 13 and Comparative Examples 5 to 7 were prepared by compression and tableting.

Example  2 to 13 and Comparative Example  5 to 7: Choline alfoscerate  Manufacture of Containing Tablets

(Prepared at 10,000 times the amount of [Table 4]).

1) Weigh apples of main ingredient and each excipient and apples (30 mesh).

2) Add 4,000 g of choline alfoscerate as an active ingredient and calcium silicate into a mixer and mix at 15 rpm for 10 minutes.

3) Microcrystalline cellulose, copovidone, croscarmellose sodium and anhydrous calcium hydrogen phosphate are added to the mixture obtained in the step 2), and the mixture is mixed in a mixer at 15 rpm for 10 minutes.

4) Sodium stearyl fumarate is added to the mixture produced in the step 3) in a mixer, followed by final mixing at 15 rpm for 10 minutes.

5) The mixture produced in the step 4) is compressed and purified in a rotary tablet press to a pre-pressurization of 3 KN and a main pressure of 4 KN, followed by demineralization using demineralization.

6) Process inspection was carried out with the fixture obtained in the step 5) (Experiment 2)

Condition Colleen Alpo
Serrate
(mg) Calcium silicate
(mg) Pending
cellulose
(mg) Co-povidone
(mg) cross
Camelos
salt
(mg) Sodium stearyl fumarate
(mg) Anhydrous calcium hydrogen phosphate
(mg) total
(mg) Example 2 400 100 30 25 30 15 5 605 Example 3 400 90 40 25 30 15 5 605 Example 4 400 80 50 25 30 15 5 605 Example 5 400 70 60 25 30 15 5 605 Example 6 400 60 70 25 30 15 5 605 Example 7 400 50 80 25 30 15 5 605 Example 8 400 40 90 25 30 15 5 605 Example 9 400 30 100 25 30 15 5 605 Example 10 400 65 60 25 30 15 10 605 Example 11 400 65 50 25 30 15 20 605 Example 12 400 65 40 25 30 15 30 605 Example 13 400 65 30 25 30 15 40 605 Comparative Example 5 400 120 20 25 25 10 5 605 Comparative Example 6 400 20 50 35 60 35 5 605 Comparative Example 7 400 0 50 45 60 45 5 605

Experimental Example  2: Choline alfoscerate  Evaluation of Containing Tablets

<Experimental Example 2-1. Properties of tablets, hardness, disintegration, weight, and margin inspection>

The properties, hardness, disintegration and weight loss of the tablets according to calcium silicate and various excipients in the choline alfoscerate preparations of Examples 2 to 13 and Comparative Examples 5 to 7 were examined and the results are shown in Table 5 .

How to measure

Ten tablets of each of the examples were taken as average values after evaluation and measured according to the following apparatus and method.

- Thickness, Diameter, Hardness: Automatic hardness tester (ERWEKA)

- Masondo: Masson pottery (Labfine), 25 rpm, 4 minutes

- Disintegration time: Disintegration tester, Korean Pharmacopoeia 10 revision

Condition Thickness (mm) Diameter (mm) Hardness (KP) Disintegration (minute) Weight (mg) friction loss
(Within 0.5%) Example 2 5.6 15 11-12 15 minutes 605 fitness Example 3 5.6 15 10-12 15 minutes 605 fitness Example 4 5.6 15 9-13 13 minutes 605 fitness Example 5 5.5 15 10 to 13 11 minutes 605 fitness Example 6 5.5 15 10 to 13 9 minutes 605 fitness Example 7 5.5 15 10 to 13 8 minutes 605 fitness Example 8 5.5 15 8-10 7 minutes 605 fitness Example 9 5.4 15 9-12 7 minutes 605 fitness Example 10 5.5 15 8-10 8 minutes 605 fitness Example 11 5.5 15 8-10 7 minutes 605 fitness Example 12 5.5 15 8 ~ 11 7 minutes 605 fitness Example 13 5.5 15 8-12 6 minutes 605 fitness Comparative Example 5 5.1 15 1-4 2 minutes 605 fail Comparative Example 6 Sticking during tableting due to moisture absorption
Failure - - Comparative Example 7

Referring to the results in Table 5, it was confirmed that the formation of tablets was good in the range of 6 to 25 parts by weight of the calcium silicate mixed ratio with respect to 100 parts by weight of choline alfoscerate as the main ingredient. In addition, the excipient to be used in the present invention is preferably 1 to 25 parts by weight based on 100 parts by weight of choline alfoscerate as a main ingredient, and is preferably in the form of compactness, hardness, Respectively.

However, when the mixing ratio of calcium silicate was added at a ratio exceeding 25 parts by weight, it was found that when the tablets were formed (Comparative Example 5), the bulkiness increased due to the low bulk density, . In addition, it was confirmed that the composition containing choline alfoscerate as a main ingredient in the tablets tableted at a ratio of calcium silicate mixing ratio of less than 5 parts by weight was poor in stability from water.

3. Manufacture and evaluation of single or multi-layer coated coatings

Example  14: Single membrane Coating  Produce

The compressed tablet of Example 13 was placed in a coater (high-coater automatic coating machine), and the coating liquid prepared by using the coating agent and solvent of the composition shown in Table 6 was coated on the tablet surface at a rotation speed of 4 to 6 rpm, The coated tablets of Example 14 were prepared by a single film coating under the conditions of a temperature of 40 to 45 캜.

Example  15 to 18: Multilayer film Coating  Produce

Using the tableted compressed tablet of Example 13, coating was carried out by the same method as the preparation method of Example 14 using a coating solution prepared by using the coating agent of the composition shown in [Table 6] and a solvent, To 18 were prepared.

Example Floor / coating agent menstruum Mud  Contrast wt% Example 14 Hydroxypropylmethylcellulose, polyethylene glycol, cellulose, stearic acid, coloring matter Half water system Single 3%
Example 15 1-layer hydroxypropyl methylcellulose, polyethylene glycol (Opadry YS)
2-layer sodium carboxymethylcellulose, dextrose, sodium citrate, lecithin, maltodextrin (Opagros)

Semi-aquatic water system
7%
(2%, 5%)
Example 16 1-layer hydroxypropyl methylcellulose, polyethylene glycol (Opadry YS)
2-layer hydroxypropyl methylcellulose, cellulose, stearic acid,

Semi-aquatic water system
7%
(2%, 5%)

Example 17 1-layer hydroxypropyl methylcellulose, polyethylene glycol (Opadry YS)
2-layer polyvinyl alcohol, titanium oxide, talc, methacrylic acid polymer, sodium lauryl sulfate, sodium bicarbonate, pigment (Opadry 200F)

Semi-aquatic water system
7%
(2%, 5%)


Example 18 1-layer hydroxypropyl methylcellulose, polyethylene glycol (Opadry YS)
2-layer polyvinyl alcohol, titanium oxide, talc, methacrylic acid polymer, sodium lauryl sulfate, sodium bicarbonate, pigment (Opadry 200F)
3-carboxymethylcellulose sodium, dextrose, sodium citrate, lecithin, maltodextrin (Opagros)


Semi-aquatic water system


9%
(2%, 5%, 2%)

Experimental Example 3: Evaluation of coating definition

<Experimental Example 3-1. Coating definition property evaluation>

[Table 8] shows the result of confirming the stability of the coating of Examples 14 to 18 after coating.

How to measure

- Appearance: According to the following evaluation criteria, the property is evaluated.

Coating definition  Property evaluation reference list Great  The coating surface is smooth and glossy. Good  Coated surface is smooth but matte usually  Coated surfaces are rough and uneven incongruity  Coating surface rough and part of coating film peeling off

Example Immediately after coating  Property evaluation Example 14 Good fit Implementation 15 Good fit Example 16 Good fit Example 17 Good fit Example 18 Good fit

As a result of the tests of Example 14 which is a single film film coating type and Examples 15 to 17 which are a double film film coating type, no property change was observed and it was evaluated that the property was good.

In Example 18 of the three-layer coating type showing the best properties among the examples of the present invention, excellent properties were maintained even immediately after coating and stability test.

<Experimental Example 3-1. Packaged coating definition Long term preservation and stability test evaluation>

Examples 17 and 18 of the present invention were subjected to a long-term storage and accelerated stability test for 6 months, and the final results were summarized as follows in Tables 9 and 10.

Stability test

(Stability, content) of long-term storage (0, 1, 3, and 6 months) and accelerated storage (0, 1, 3, and 6 months) were carried out using the coating tablets of Examples 17 to 18.

- Equipment: Stability Tester FLT-700D (Labfine)

- Condition: long-term storage condition (25 ℃, relative humidity 60%), acceleration condition (40 ℃, relative humidity 75%)

- Content: Liquid chromatographic method (detector: RI, mobile phase: 60% acetonitrile, column: amide 5 μm), standard 95 to 105%

Example                    Long-term storage conditions (25 ℃, relative humidity 60%) Early 1 month 3 months 6 months content
(95 ~ 105%) content
(95 ~ 105%) content
(95 ~ 105%) content
(95 ~ 105%) Example 17 100.4 99.5 101.2 99.0 Example 18 100.1 99.9 101.0 100.3

Example                      Acceleration condition (40 ℃, relative humidity 75%) Early 1 month 3 months 6 months content
(95 ~ 105%) content
(95 ~ 105%) content
(95 ~ 105%) content
(95 ~ 105%) Example 17 100.4 100.0 99.8 98.5 Example 18 100.1 99.8 100.3 99.7

As shown in [Table 9] and [Table 10], in Examples 17 to 18, there was no significant change in property and content until 6 months of long-term storage and accelerated storage conditions, and the three-layer coating type tended to be more stable But all of them were in accordance with the content standards.

< Experimental Example  4: Dissolution test of oral pharmaceutical composition and reference drug of the present invention>

The coated tablets of Example 18 and the commercially available choline alfoscerate soft capsules were prepared as a comparative preparation (manufactured / imported by Daewoong Pharma, product name: glyatorin soft capsule, component name: choline alfoscerate 400 mg) A second dissolution test of the disintegration test method in General Test Methods of the Korean Pharmacopoeia 10th Edition) was conducted under the conditions of a temperature of 37 DEG C, a paddle II method, a rotation speed of 50 rpm, and an eluate of 900 mL. The eluate was collected from 12 samples at the elapsed time of 5 minutes, 10 minutes, 15 minutes, 30 minutes, and 45 minutes. After filtration, the eluate was analyzed by liquid chromatography (detector: RI, mobile phase: 60% acetonitrile, 5 탆), and the results of the tests are shown graphically in [Fig. 2] and [Fig. 3].

Claims (9)

A choline alfoscerate as an active ingredient, and calcium silicate as an excipient. The method according to claim 1,
Wherein said oral pharmaceutical composition further comprises microcrystalline cellulose, copovidone, croscarmellose sodium, anhydrous calcium hydrogen phosphate, and sodium stearyl fumarate as an excipient. The method according to claim 1,
Wherein the content of the calcium silicate is 6 to 25 parts by weight based on 100 parts by weight of choline alfoscerate. 3. The method of claim 2,
Wherein the oral pharmaceutical composition comprises 6 to 25 parts by weight of calcium silicate, 5 to 25 parts by weight of microcrystalline cellulose, 1 to 15 parts by weight of copovidone, and 1 to 15 parts by weight of croscarmellose sodium based on 100 parts by weight of choline alfoscerate 1 to 15 parts by weight of anhydrous calcium hydrogen phosphate, and 1 to 15 parts by weight of stearyl fumarate are mixed together. 5. The method according to any one of claims 1 to 4,
Wherein the oral pharmaceutical composition is in the form of a powder, granules, capsules, tablets, coated tablets or a combination of at least one of them. 6. The method of claim 5,
Wherein the coated tablet is in the form of compressed tablets in which an active ingredient and an excipient are mixed and coated with a film coating agent. The method according to claim 6,
Wherein the film coating agent comprises at least one polymer substrate selected from the group consisting of polyvinyl alcohol, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, methacrylic acid copolymer and cellulose, polyethylene glycol, glycerylmono Characterized in that it consists of at least one additive selected from the group consisting of stearate, sodium lauryl sulfate, maltodextrin, dextrose, sodium citrate, lecithin, talc, sodium bicarbonate, triethyl citrate, titanium oxide and stearic acid Oral pharmaceutical composition. The method according to claim 6,
Characterized in that the coating tablet is coated in the form of a single film or a multilayer film with a film coating of 1 to 12% by weight of the compressed tablet weight. A method for producing an oral pharmaceutical composition containing choline alfoscerate,
(a) mixing choline alfoscerate and calcium silicate in a mixer in a ratio of 6 to 25 parts by weight of calcium silicate to 100 parts by weight of choline alfoscerate;
(b) adding and mixing pharmaceutically acceptable excipients to the mixture obtained in step (a);
(c) titrating the mixture obtained in step (b) with an oral tablet while applying pressure; And
(d) coating the tableted compressed tablet with the film coating agent in step (c). &lt; Desc / Clms Page number 19 &gt;

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