KR20160054216A - Pharmaceutical tablet comprising Choline Alphoscerate and method for manufacturing the same - Google Patents

Abstract

A method for manufacturing a tablet comprising choline alphoscerate uses a partial wet granulation method minimizing an excipient, and removes tableting error by adjusting ratio of a slip modifier inside and outside a granule. The method comprises the following steps: (i) mixing about 5-20 wt% of a slip modifier and a water-insoluble excipient based on the tablet weight with choline alphoscerate; (ii) combining the mixture by about 60-90 wt% of an ethanol-contained aqueous solution or a combination solution having 0.2-5 wt% of a binder based on total weight of the tablet; (iii) drying and tableting the combined product; (iv) mixing a pharmaceutically usable excipient and the water-insoluble excipient with the tableted product with 1-15 wt% of a slip modifier; (v) forming a tablet by putting a lubricant into the mixture, and compressing the same; (vi) primarily coating the tablet obtained from step (v) with a hydroxylpropyl methyl cellulose-contained solution; and (vii) secondarily coating the tablet obtained in step (vi) with a polyvinyl alcohol-contained solution.

Description

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a tablet containing choline alfoscerate,

Choline is one of the most useful nutrients to improve brain metabolism or enhance mental abilities. Choline alfoscerate is a substance found naturally in the body and is known as alpha-glycerylphosphorylcholine. Choline alfoscerate (a-GPC) aids in the conversion or synthesis of important neurotransmitters in the brain. It breaks down into cholinesin the body and through the blood-brain barrier (BBB) system (CNS) into the production of the neurotransmitter acetylcholine. a-GPC plays a role in improving cognitive ability and helps to make long-term memory. In addition, choline alfoscerate helps maintain nerves and neurons, and is involved in the formation of new cell membranes by binding to omega-3 and enhances the spread of nerve cells. The method for producing choline alfoscerate-containing tablets of the present invention is characterized in that choline alfoscerate as a main component is partially granulated by a wet process to prepare tablets, then primary coated with an aqueous solution of hydroxypropylmethylcellulose ethanol, (Or methacrylate polymer) aqueous solution, and a method for producing the same.

L-a-glycerylphosphorylcholine (GPC) is a known substance and has a structure represented by the following formula (1).

[Chemical Formula 1]

Choline alfoscerate is an important compound for the production of new acetylcholine in the brain. It is known to exist naturally in all cells of the body and is important for the healthy development of the newborn, especially for rapid brain development, As the aging process progresses, it decreases, resulting in a decrease in perceived ability, vascular dementia, and neurodegeneration in Alzheimer's disease. Therefore, choline alfoscerate is known to be useful for improving perception, brain function and treatment of elderly people, as well as for reducing concentration, emotional instability, irritability and depression, and has recently been marketed as a health food.

Currently, choline alfoscerate is recommended to take 2 to 3 times daily 400 mg soft capsules. In the case of soft capsules, in the case of the multi-drug use of the elderly patients, the capsules tearing on the packing line in the packaging of the drug pills in the pharmacy, or when the capsules are torn and the gelatin capsule is torn, And the like.

In order to solve the problems of the conventional soft capsule as described above, Korean Patent No. 1257919 discloses a soft capsule comprising at least one selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylalcohol, methacrylic acid copolymerization and polyethylene oxide Discloses a technique for preparing choline alfoscerate particles coated with a water-soluble polymer. It is characterized in that it is coated up to about 50 parts by weight of the water-soluble polymer, so that the release of the drug may be delayed due to the high content of the polymer.

Korean Patent Laid-Open Publication No. 2013-121796 relates to a preparation made in the form of a pharmaceutical preparation comprising a host and a guest, wherein the guest is an inclusion compound which is choline alfoscerate, wherein the choline alfoscerate: cyclodextrin is dissolved in a ratio of 1: 0.005 To 0.5 wt.%, And adding a viscosity reducing agent, magnesium aluminosilicate or the like to prepare tablets, powders and granules.

In addition, in Korean Patent No. 10-1172699, a single-coated film tablet was prepared by adding 400 mg of the main ingredient and 50% of magnesium aluminosilicate to the tablet core, and the tablet weight was about 800 mg (40 ° C., 75% RH), the release of the drug was delayed after one month, and because of the high water content of the main component, Resulting in a delay in elution of the drug due to moisture entering the tablet core.

KR 2013-0121796 A KR 10-1172699 B KR 10-1257918 B KR 10-1257919 B KR 2009-0088564 A KR 10-2009-0088564 A KR 10-0904727 B KR 2009-0084194 A GB 2012-0083276 A US 20090176740 A1

Accordingly, the present inventor has been working to produce tablets of a low weight to facilitate the taking of the elderly in a simple manufacturing process.

Another object of the present invention is to improve the granular forming ability by solving the problem of the dyspepsia and to improve the water stability by minimizing the surface of the main component exposed to the moisture of the outside air.

In order to achieve the above object, the present invention uses a partial wet granulation method capable of minimizing the excipient and solves the problem of the tableting problem by adjusting the ratio of the lubricant inside and outside the granule. When the granules are formed, the fraction of the main component sticking to the surface of the tableting machine is lower than that of the main ingredient powder, thereby solving the problem of sticking trouble such as sticking or picking. In addition, by applying the lubricant to the formed granules at an appropriate ratio, the contact of the lubricant with the lubricant surface is minimized, thereby minimizing the contact between the surface of the tablet and the main component, minimizing the penile disorder and minimizing the surface of the main component exposed to moisture in the outside air Water stability can be improved. In the preparation of granules, water and ethanol mixture were used as a binding agent to increase the granule forming ability. When necessary, the binder could be dissolved in the binding solution to produce harder granules. The tablet core is first coated with a polymer dissolved in ethanol, and then coated with a polymer aqueous solution effective for water blocking to produce a pharmaceutical tablet containing choline alfoscerate having water stability even under accelerated conditions.

The present invention is characterized in that the content of choline alfoscerate main component is high so that it is excellent in ease of taking by low-weight refining and provides more stable film-coated tablets under storage conditions. In addition, the film-coated tablets can be easily manufactured according to the general tablet manufacturing method, and the tablets having a low weight of about 650 mg are improved in stability and storage stability by the partial wet granulation and double coating process.

The present invention provides a more stable film-coated tablet under storage conditions while increasing the content of choline alfoscerate as a main ingredient. The present invention is a tablet comprising choline alfoscerate wherein the active ingredient is present in an amount of 55 to 70% of the total tablet weight and comprises about 8 to 25% by weight of glidant based on the total weight of the tablet. In order to prepare a low-weight tablet, a small amount of excipient can be used. Partial granulation method is used in the present invention. The purpose of this study was to solve the problem of cardiovascular problems by adjusting the ratio of internal and external lubricants. In the preparation of granules, a mixture of water and ethanol may be used as a binding liquid in order to increase the granulating ability. If necessary, the binding agent may be dissolved in the binding liquid to produce harder granules. When the granules are formed, the fraction of the main component sticking to the surface of the tableting machine is lower than that of the active ingredient powder, thereby solving the problem of sticking trouble such as sticking or picking. In addition, the lubricant efficiently encloses the surface of the lubricant by adding the lubricant to the formed granules in an appropriate ratio, thereby minimizing the contact discomfort by reducing the contact between the tablet surface and the active ingredient, and minimizing the surface of the active ingredient exposed to moisture in the outside air Thereby enhancing water stability. By appropriately adjusting the ratio of the lubricant contained in the granules containing the active ingredient, it is possible to efficiently use the minimum lubricant lye to prevent the tableting disorder and the disintegration delay, and also to have the minimum tablet size, .

The tablet core was first coated with a polymer dissolved in ethanol, and then coated with a polymer aqueous solution effective for blocking moisture to obtain a tablet having water stability even under accelerated conditions.

The lubricant in the present invention is about 8 to 25% by weight based on the weight of the tablet, and includes magnesium aluminosilicate, colloidal silicon dioxide, magnesium oxide, or a mixture thereof, and about 1 to 40% Water, and the binder may contain about 0.2 to 5% by weight based on the weight of the tablet, and polyvinyl pyrrolidone, polyvinyl alcohol, cellulose derivatives, gums or a mixture thereof may be used.

The formulations of the present invention can be formulated using additives such as pharmaceutically acceptable disintegrants, water-insoluble excipients, and lubricants within the scope of not impairing the effects of the present invention. Crospovidone, croscarmellose sodium or a mixture thereof may be used as the disintegrant, and calcium phosphate, calcium dihydrogenphosphate, microcrystalline cellulose or a mixture thereof may be used as the water-insoluble excipient. Magnesium stearate, sodium stearyl fumarate, or the like may be mixed as a lubricant during tableting.

The primary coating serves as a protective separation layer to prevent contact of the tablet core containing active ingredients that are susceptible to moisture with the secondary coating aqueous solution, and about 1 to 2% by weight of hydroxypropylmethylcellulose is dissolved in ethanol . At this time, ethanol may contain about 1 to 40% by weight of water, which is conventionally used for explosion prevention.

The secondary coating is coated with an aqueous solution containing polyvinyl alcohol, methyl methacrylate, butyl, dimethylaminoethyl copolymer or the like capable of imparting moisture blocking ability in an amount of about 3 to 5 wt% based on the weight of the tablet.

Hereinafter, the manufacturing process of the present invention is as follows.

i) mixing choline alfoscerate with about 5 to 20% by weight of lubricant and water insoluble excipients by weight of the tablet,

(ii) incorporating from about 60% to about 90% by weight of an ethanol-containing aqueous solution or binder in an amount of from 0.2% to 5% by weight based on the total weight of the tablet,

(iii) drying and sizing the association,

(iv) admixing the formulation with a pharmaceutically acceptable excipient and a water-insoluble excipient together with 1 to 15% by weight of a lubricant,

(v) adding a lubricant to the mixture and pressing to form tablets,

(vi) first coating the tablets obtained in v with a solution containing hydroxypropylmethylcellulose,

(vii) secondarily coating the tablets obtained in vi with a polyvinyl alcohol-containing solution,

To prepare choline alfoscerate tablets.

Examples and comparative examples of the present invention are as follows.

1. Selection of tablet weight and amount of lubricant

Purified cores containing 400 mg of choline alfoscerate were prepared in the same manner as described in the following table to determine whether granular flowability and tableting properties were satisfactory. To determine the tablet disintegration time in water, Respectively. For rapid evaluation of the water stability of the tablets, the whole mixture immediately before tableting was left in a desiccator at 80% relative humidity for 1 day, and the weight gain was measured and compared (position change).

division
Ingredients Comparative Example 1 Comparative Example Comparative Example 3 Example 1 Example 2 Lubricant (5%)
The main ingredient (75%) Lubricant (30%)
The main ingredient (51%) Lubricant (8%)
The main ingredient (67%) Lubricant (8%)
The main ingredient (67%) Lubricant (14%)
The main ingredient (60%)
and
Lip
of mine
Choline alfoscerate 400 400 400 400 400 Silicate aluminate
Magnesium (lubricant) 13.3 117 112.5 24 45 Microcrystalline cellulose 20.2 23.5 5.5 31 32.5 Polyvinylpyrrolidone 9.4 10 2 10 2.5

and
Lip
outside
Silicate aluminate
Magnesium (lubricant) 13.3 117 112.5 24 45 Calcium phosphate 36.7 57.9 10.4 69 79.5 Croscarmellose sodium 26.5 39 8.5 30 32.5 Sodium stearyl fumarate 10.6 15.6 3.6 12 13 Total refined weight 530 780 655 600 650 Granule formation
Carr's index (CI)
Want
TD: 0.89 mg / ml
CI: 21% Poor flow
TD: 0.58 mg / ml
CI: 31% Poor flow
TD: 0.52 mg / ml
CI: 33% Want
TD: 0.72 mg / ml
CI: 20% Want
TD: 0.76 mg / ml
CI: 19%
Unparalleled Incapacitation
(Sticking, picking) Incapacitation
(Laminating)
(Weight deviation occurred) Incapacitation
(Laminating)
(Occurrence of mass deviation) I want to eat
(Sticking, picking lamination
none) I want to eat
(Sticking, picking, laminating
none) Refined disintegration
(Water, minute) 13 minutes 18 minutes 19 minutes 11 minutes 11 minutes Water stability
(80% RH, left for 1 day)
Moisture increase) High Conventional
49% High Conventional
38% High Conventional
33.2% Relatively
Low Conventional
29% Relatively
Low Conventional
28%

According to the above Table 1, when the weight of the tablet is less than 550 mg, sticking or picking occurs in the preparation of the tablet due to the high moisture content of the active ingredient, and when the tablet weight is 800 mg or more, It seems uncomfortable for the elderly to take their patients. When the content of the lubricant is less than 8% by weight, the water stability of the tablet deteriorates and the lubricant is picked and sticked. When the lubricant is more than 30% by weight, The disintegration was delayed.

2. Percentage of internal and external lubricants

In order to set the ratio of the inner and outer lubricants, the purified core containing 400 mg of choline alfoscerate was prepared as described in the following table, and the granular flowability and the stability of the granules were examined. The disintegration time of the tablet in water was determined according to the Korean Pharmacopoeia Respectively. For rapid evaluation of the water stability of the tablets, the whole mixture immediately before tableting was left in the desiccator at 80% relative humidity for 1 day, and the weight increase rate was measured and compared.

division
Comparative Example 4 Comparative Example 5 Example 3 Example 4 Example 5 Percentage of lubricant granules inside and outside 1: 0 1: 3.5 1: 0.5 1: 1 1: 2


In the granule


Choline alfoscerate 400 400 400 400 400 Magnesium silicate aluminate
(Lubricant) 100 - 67 - 33 Colloidal silicon dioxide
(Lubricant) - 22.2 - 45 - Microcrystalline cellulose 47 47 40 52 47 Polyvinylpyrrolidone 3 3 3 3 3


Granule et al

Magnesium silicate aluminate
(Lubricant) 0 - 33 - 67 Colloidal silicon dioxide
(Lubricant) - 77.8 - 45 - Calcium phosphate 54.5 54.5 61.5 59.5 55 Croscarmellose sodium 32.5 32.5 32.5 32.5 32.5 Sodium stearyl fumarate 13 13 13 13 13 Total refined weight 650 650 650 650 650
Carr's index (CI) TD: 0.84 mg / ml,
CI: 22% TD: 0.61 mg / ml
CI: 28% TD: 0.72 mg / ml
CI: 18% TD: 0.68 mg / ml
CI: 19% TD: 0.65 mg / ml
CI: 21%

Unparalleled Incapacitation
(Sticking, picking) Incapacitation
(Laminating)
(Weight deviation occurred) I want to eat
(Sticking, picking lamination
none) I want to eat
(Sticking, picking lamination
none) I want to eat
(Sticking, picking lamination
none) Refined disintegration (water, minute) 13 minutes 12 minutes 10 minutes 9 minutes 9 minutes Water stability
(80% RH, increase in moisture upon standing for 1 day) 38.4% 30.2% 26.8% 26.6% 25.7%

According to the above Table 2, when no lubricant was added in addition to the granules, the active ingredient exposed on the granule surface could not be surrounded by the hydrophobic lubricant, In the case of a high amount, the amount of the extra-granular lubricant was too large to cause the tablet weight deviation, and the flowability was deteriorated.

3. Ethanol content test in binding solution

In order to determine the mixing ratio of ethanol and water which can be used as a binding solution in the production of granules, the granules were prepared by varying the ethanol content of the formulation of Example 1 as shown in the table below.

The flowability of the granules and the recovery of the granules were measured together with the ability to form granules and the occurrence of lumps after granule production.

division Example 6 Example 7 Example 8 Example 9 Ethanol content 20 wt% 60 wt% 80 wt% 80 wt% Presence or absence of granules Good Good Good Bad Whether or not lumps occur Small amount Does not occur Does not occur Does not occur Granule flowability TD: 0.85 mg / ml
CI: 18% TD: 0.77 mg / ml
CI: 19% TD: 0.72 mg / ml
CI: 20% TD: 0.59 mg / ml
CI: 25% Granule recovery rate 85% 95% 97% 98%

According to Table 3, when the ethanol content in the binding liquid composition was about 40% by weight or less, the active ingredient soluble in water was formed into a hard lump with a large amount of water, so that it was difficult to granulate, and the ethanol content in the binding liquid was 100% In the case of ethanol alone, the binding force was not sufficient and the granules were broken after drying and the granulation ability was not good.

4. Test for stability of coating layer

In order to evaluate the stability according to the coating, the tablet cores prepared according to Example 1 of the present invention were first and second coated as follows. The primary coating was prepared by coating a coating solution in which hypromellose 2910, titanium oxide, polyethylene glycol, and talc were dissolved and dispersed in a mixed solvent of ethanol and water (8: 2), and then coated with about 1 to 2% by weight based on the weight of the tablet. The secondary coating was prepared by coating a solution of polyvinyl alcohol, titanium oxide, polyethylene glycol, talc, and yellow iron oxide in water, followed by coating with about 3 to 5 wt% of the tablet weight.

The unstained tablet cores and the single coated tablets with the first and second coatings coated with the double coated tablets and the second coated tablets were evaluated for stability at room temperature for 4 months.

When left for 4 months at room temperature, the tablet cores that were not coated as compared to the first prepared tablet cores were swollen with the moisture in the air to melt the surfaces and swell. In addition, in the case of the single coated tablet, the film coating layer peeled off when left for 4 months, whereas the double coated tablet like the present invention was confirmed to have a uniform tablet shape as shown in [Figure 1].

[Figure 1]

Claims (12)

Wherein the active ingredient choline alfoscerate is from 55 to 70% by weight of the total weight and the lubricant is from 8 to 25% by weight and the lubricant has a lubricant content of 0.2 to 1 By weight of the choline alfoscerate tablet. The method according to claim 1,
Wherein the lubricant is any one of magnesium aluminosilicate, colloidal silicon dioxide, magnesium oxide, or mixtures thereof. The method according to claim 1,
Characterized in that the active ingredient is wet granulated with ethanol containing from 1 to 40% by weight of water or with a binding liquid in which 0.2 to 5% by weight of binder is dissolved in the total weight of the tablet, Rate purification. The method of claim 3,
Wherein the binding agent is any one of polyvinylpyrrolidone, polyvinyl alcohol, cellulose derivative, gum, or a mixture thereof. The method according to claim 1,
Wherein said tablets are double coated with a protective coating layer containing hydroxypropylmethylcellulose dissolved in an ethanol-containing solution and a water barrier coating layer containing polyvinyl alcohol dissolved in water. A composition comprising choline alfoscerate as an active ingredient,
(i) the lubricant contains the lubricant in an amount of 8 to 25% by weight based on the weight of the tablet, and the content of the lubricant in the lubricant is in the range of 0.2 to 1 based on the lubricant in the granule,
ii) a choline alfoscerate film-coated tablet comprising a protective coating layer containing hydroxypropylmethylcellulose dissolved in ethanol as a film coating layer and a water barrier coating layer containing polyvinyl alcohol dissolved in water. (i) mixing choline alfoscerate with about 5 to 20 wt% of a lubricant and a water insoluble excipient by weight of the tablet,
(ii) combining the aqueous solution containing about 60 to 90% by weight of ethanol with a solvent in which the binder is dissolved in an amount of 0.2 to 5% by weight,
(iii) drying and sizing the association,
(iv) admixing the formulation with a pharmaceutically acceptable disintegrant and a water-insoluble excipient together with from 1 to 15% by weight of a lubricant,
(v) adding a lubricant to the mixture, mixing and compressing to form a tablet,
(vi) first coating the tablets obtained in v with a solution containing hydroxypropylmethylcellulose,
(vii) secondarily coating the tablets obtained in vi with a polyvinyl alcohol-containing solution,
≪ / RTI > wherein the cholinesterase inhibitor is selected from the group consisting of: 8. The method of claim 7,
Wherein the lubricant is any one of magnesium aluminosilicate, colloidal silicon dioxide, magnesium oxide or a mixture thereof. 8. The method of claim 7,
Wherein the water-insoluble excipient is any one of calcium phosphate, calcium dihydrogenphosphate, microcrystalline cellulose, and mixtures thereof. 8. The method of claim 7,
Wherein the binding agent is any one of polyvinylpyrrolidone or polyvinyl alcohol or a cellulose derivative or gum or a mixture thereof. 8. The method of claim 7,
Wherein the disintegrant is any one of crospovidone, croscarmellose sodium, or a mixture thereof. 8. The method of claim 7,
Wherein the lubricant is any one of magnesium stearate, sodium stearyl fumarate or a mixture thereof.