KR20190027987A - Oral Administration Citrulline Malate Composition for supplying energy and preventing myasthenia - Google Patents

Abstract

The present invention relates to a citrulline malate solid formulation composition for oral administration containing a citrulline malate compound as an active component. According to the present invention, it is possible to provide a composition of a solid formulated form such as tablets or capsules by solving problems caused by madescent properties and summertime deliquescence of citrulline malate and the citrulline malate solid formulation composition, in which medication compliance is improved by shielding unpleasant tastes such as a sour taste of citrulline malate.

Description

BACKGROUND OF THE INVENTION 1. Field of the Invention [0001] The present invention relates to a citrulline malate composition for oral administration for prevention and improvement of energy supply and myasthenia gravis,

The present invention relates to a composition for oral administration of citrulline malate for the prophylaxis and amelioration of energy supply and myasthenia, and more particularly to a composition for oral administration of citrulline malate for oral administration, High content of active ingredient of Citrulline malate which treats muscular atrophy through energy supply such as fatigue and lethargic symptoms due to deterioration of muscles and organs during work, before and after exercise, etc. Oral solid ≪ / RTI >

The conventional liquid agent has a relatively poor physico-chemical stability and may cause microbial propagation. It is bulky and inconvenient to carry, and it is inconvenient to be diluted due to a strong acidity. In addition, when a solid preparation such as tablets or capsules is to be formulated, it is very difficult to form tablets or capsules because of high customization of the active ingredient and stickiness due to deliquescence found in summer, There is no commercially available solid preparation.

Currently, drugs containing citrulline malate are marketed in Korea as a liquid (styme) in Palm Biote Co., Ltd., and have a specific irritating sour taste, and their compliance is lowered. In order to alleviate this irritation, There is an inconvenience. As a result, other liquid products that alleviate acidity (eg, Viggus Ace, NexPam Korea, etc.) are being introduced. In addition, a Korean patent (registered patent No. 10-1486534) discloses a gallic acid formulation which is improved in viscosity to improve the problem of citrulline malate solution. However, such a liquid or gel preparation is not easy to carry and carry due to its large volume and its load, and has a limitation in shielding a fundamentally unpleasant taste.

In addition, in the item of overseas health functional food which is not currently imported to the domestic market, the solid formulations of citrulline malate have been commercialized as exercise supplements, but the tablets are very bulky and the neck turn is uncomfortable and the disintegration time is more than 40 minutes There is a problem in that it can not have any characteristics as a drug such as delayed.

Disclosure of Invention Technical Problem [8] Accordingly, the present invention has been made keeping in mind the above problems occurring in the prior art, and it is an object of the present invention to provide a solid formulated composition such as tablets or capsules by solving the problems caused by the tolerance and deliquescence of citrulline malate.

Another object of the present invention is to provide a citral malate solid preparation composition which shields an unpleasant taste such as sour taste of citral malate and improves adherence compliance.

Furthermore, since the daily dose of citrulline malate is 1 g, it is important to design a small dosage form that is easy to swallow when tableted. The present invention is characterized by the production of tablets which can range from 55% to 86% of the main component.

In order to achieve the above object, the present invention provides a citrulline malate solid preparation composition for oral administration comprising citrulline malate compound as an active ingredient.

Further, the composition is characterized in that it comprises granules prepared by adding a binding solution in which a binder is dissolved in a solvent to citrulline maleate and an adsorbent.

The binder may be selected from the group consisting of povidone, polyvinylpyrrolidone, polyvinyl alcohol, carbol, hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, carboxymethylcellulose sodium, hydroxyethylcellulose, fluoran, carboxyvinyl Polymer polyethylene glycol or a derivative thereof.

The composition is also characterized in that it is prepared by dissolving citrulline maleate in purified water and then adding an adsorbent to the adsorbed granules to include an additive comprising a disintegrant.

Further, the adsorbent is a mixture of at least one selected from silicon dioxide, colloidal silicon dioxide, calcium silicate, and magnesium aluminosilicate.

Further, the disintegrant is characterized in that it is at least one selected from the group consisting of croscarmellose sodium, crospovidone, carboxymethylcellulose calcium, sodium starch glycolate, and cornstarch.

The composition may further comprise at least one lubricant selected from the group consisting of magnesium stearate, zinc stearate, calcium stearate, stearic acid, talc, paraffins, lead, glyceryl behenate, sodium stearyl fumarate and stearyl fumarate .

The composition may further comprise at least one fluidizing agent selected from the group consisting of starch, talc, silicon dioxide, calcium silicate, magnesium carbonate, and magnesium oxide.

According to another aspect of the present invention, there is provided a method of manufacturing a bonding liquid, comprising the steps of: preparing a bonding liquid by mixing a binder and a solvent; Adding the binding solution to a mixture of a citrate malate compound and an adsorbent to produce a wet granule; Drying the wet granules; Mixing the dried granules with an additive comprising a disintegrant; And a step of titrating the post-mixed mixture. The present invention also provides a method for preparing a citrulline maleate solid preparation for oral administration.

The present invention also provides a method for purifying a citrate maleate compound, comprising the steps of: dissolving a citrate maleate compound in purified water; Mixing the solution with an adsorbent; Drying the mixture, post-mixing the dried composition with an additive comprising a disintegrant; And a step of titrating the post-mixed mixture. The present invention also provides a method for preparing a citrulline maleate solid preparation for oral administration.

According to the present invention, there is solved the problem caused by the exacerbation of citrulline malate and the deliquescence in summer, and it is possible to prevent the unpleasant taste such as the composition of solid formulated form such as tablets or capsules and the sour taste of citrulline malate, Maleate solid formulation compositions can be provided.

Brief Description of the Drawings Fig. 1 is an image photograph showing a phase change when citral malate was exposed in air. Fig.
FIG. 2 is an image photograph showing the results of the deliquescence and moisture protection experiments. FIG.
FIG. 3 is a photograph showing the degree of adsorption in a state after 12 hours from the result of FIG. 2 as a result of the deliquescence and moisture protection experiments.
Fig. 4 is an image photograph showing the result of inhibition prevention after granule production. Fig.

The present invention relates to a citrulline malate solid formulation composition for oral administration comprising a citrulline malate compound as an active ingredient.

BRIEF DESCRIPTION OF THE DRAWINGS The invention will be described in detail with reference to the accompanying drawings.

The present invention relates to an oral solid preparation comprising Citrulline malate, which is a therapeutic agent for the treatment of muscular endurance through energy supply, in a high content as an active ingredient.

In the present invention, in order to solve the above difficulties, a technology for forming a solid preparation such as tablets or capsules on a mass scale was developed through a number of experiments, and at the same time, citrulline malate A solid preparation is provided. Furthermore, since the daily dose of citrulline malate is 1 g, it is important to design a small dosage form that is easy to swallow when tableted. The present invention is characterized by the production of tablets which can range from 55% to 86% of the main component.

Citrullin malate is C10H19N3O8, and the formula is as follows.

[Chemical Formula 1]

 Citrulline malate (CAS 54940-97-5) is an adjuvant treatment of nourishing tonic or dysfunctional energy through energy supply. Citrulline is the precursor amino acid of arginine, which is involved in the Urea cycle, which converts to arginine in the body. Malic acid is involved in the TCA cycle. Thus, ATP production is promoted and waste materials such as lactic acid and ammonia are rapidly released to help recover fatigue quickly and to enhance immunity.

It is also involved in nitrate metabolism and induces vasodilation and is effective in controlling blood pressure, which is effective in normalizing arterial hypotensive dystonia and other muscle diseases symptoms and muscle fatigue.

The most preferred tablets of medicines are easy to carry and can discomfort the taste. They are the most preferred formulation as anti-tampering agent because of its high compliance with dosage. However, due to the physicochemical properties of citrulline maleate, it is very sensitive to moisture, sticking: a phenomenon in which the tablets stick to the punches and dies that are sticking to the tablets and become difficult to release), and thus the tablet is severely impaired, and in particular, it is a phase state that changes rapidly in the summer air and is opaque or has a very high viscosity And it is very difficult to formulate into a solid form. Fig. 1 is an image photograph showing a phase change when humid summer citrulline maleate is exposed to air.

The present invention provides a formulation for oral solid preparations to complement the inconvenient dosing and processing disadvantages of existing citrulline malate liquid formulations. First, by using the wet granulation method, the fluidized bed granulation method, the pellet coating method and the combination with the appropriate adsorbent, it is possible to improve uniformity by preventing conventionality and delusion, and at the same time, to provide a high content Citrulline maleate solid preparation.

In a preferred embodiment of the present invention, it is preferred that citrulline malate be included in the range of about 500 mg to about 1000 mg per tablet.

One embodiment of the present invention is to prepare a binding solution by dissolving a binding agent having binding and coating properties in a solvent and then preparing a fine particle granule prepared by adding citral malate as a main ingredient to a mixture of various additives desirable. The granules prepared by adding the adsorbent do not show melting upon drying at a temperature of 60 ° C or higher, and deliquescence can be delayed or prevented even when exposed to a high humidity of 50% or more.

In one embodiment of the present invention, the binder is selected from the group consisting of povidone, polyvinylpyrrolidone, polyvinyl alcohol, carbopol, hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, microcrystalline cellulose, carboxymethylcellulose sodium, Ethyl cellulose, pluran, carboxyvinyl polymer polyethylene glycol, or a derivative thereof.

As the solvent, low-priced alcohol such as methanol and ethanol, ketone such as acetone, water and the like can be used as a solvent, but it is preferable to use ethanol in consideration of safety and the like.

Another embodiment of the present invention may include a granule prepared by dissolving citral malate as a main component in purified water, adding the adsorbent to adsorb it, and mixing the adsorbent with the additive.

As the adsorbent, silicon dioxide, colloidal silicon dioxide, calcium silicate, magnesium aluminosilicate and the like can be used, and calcium silicate is most preferably used as an adsorbent.

As an embodiment of the present invention, the additive may include a disintegrant.

The disintegrant may be croscarmellose sodium, crospovidone, carboxymethylcellulose calcium, sodium starch glycolate, cornstarch, and the like, which may be included in one of the pre-granulation and post-granulation processes, .

In one embodiment of the present invention, the fluidizing agent and the glidant may be added to the granules after the granulation, followed by tableting by mixing.

The lubricant may be at least one selected from magnesium stearate, zinc stearate, calcium stearate, stearic acid, talc, paraffins, lead, glyceryl behenate, sodium stearyl fumarate and stearyl fumarate.

The fluidizing agent may be at least one selected from the group consisting of starch, talc, silicon dioxide, calcium silicate, magnesium carbonate, and magnesium oxide. In particular, the fluidizing agent may be used for enhancing the stability or protecting the active ingredient from moisture (starch, Silica, etc.).

In one aspect of the present invention, a method for preparing a citrulline maleate solid preparation for oral administration may comprise the following steps.

(a) Mixing the binder and the solvent to prepare a binding solution;

(b) Adding the binding solution to a mixture of a citrate malate compound and an adsorbent, etc. to prepare a wet granule;

(c) Drying the wet granules;

(d) Mixing the dried granules with an additive comprising a disintegrant; and

(e) The step of titrating the after-

In another aspect of the present invention, a method for preparing a citrulline maleate solid preparation for oral administration may include the following steps.

(a) Dissolving a citrulline maleate compound in purified water;

(b) Mixing the solution with an adsorbent;

(c) Drying the mixture;

(d) Mixing the dried composition with an additive comprising a disintegrant; and

(e) The step of titrating the after-

The method for preparing the composition of the present invention may include (1) a pre-addition step (2) a granule manufacturing and drying step, (3) a post-addition step, (4) And (5) coating processes, and (3) granules and pellet coating processes for other solid formulations.

A small amount of a lubricant and a disintegrant may be added to the active ingredient in the above (1) pre-addition process. The binder may also be incorporated into the active ingredient as a powder, or (2) added in liquid form during the granulation step.

In the step (2) of granulating the granules, the granules are granulated using a sieving machine (No. 14 to No. 18) after the granulation is combined and dried, and dried in a drier set at a temperature of 40 ° C to 60 ° C. More specifically, it is preferable to dry until the loss on dry (LOD) value becomes less than 1.5% at 105 캜 for 10 minutes. The granules obtained in the above-described manufacturing process may be sieved with the same mesh, or they may be sieved with a larger or smaller diameter. This process is the same as the process for producing pellets.

In the above (3) purification, at least one of the above-described disintegrant and lubricant is added to the granules obtained in the previous addition step (1) and mixed appropriately.

In the (4) tableting process, tablets of appropriate hardness are prepared by using a rotary compressor.

In (5) film coating process, 1) seal coating and 2) moisture-proof coating may be sequentially carried out with a double coating, and only moisture-proof coating may proceed.

The coating agent may be at least one selected from the group consisting of polyvinyl alcohol, hydroxypropylmethylcellulose, glyceryl behenate, glycerol distearate, nonwax, paraffin, carnauba wax, stearic acid, stearyl alcohol, glyceryl stearate, ethylcellulose , Polyethylene, polymethacrylate, silicone, cellulose nitrate, and the like, and may be granules or tablets containing single to multiple film coatings.

All the manufacturing processes are conducted in a humidity condition of RH 50% or less, more preferably 40% or less, and a temperature of about 20 캜 in order to prevent convention during manufacturing.

In the solid preparation composition for oral administration according to the embodiment of the present invention, the solid preparation is intended to have a disintegration time of not more than 20 minutes.

The solid preparation for oral administration according to the embodiment of the present invention may be used as an oral pharmaceutical preparation (OTC) or a food supplement.

The medicinal oral preparations may be used as an adjuvant for treating insomnia and as a nourishing medicament.

Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these embodiments are only for describing the present invention in more detail 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. Manufacturing Process Study

Silica is blended with citrulline maleate, and a binding solution prepared according to the following example is added thereto, followed by granulation with a 14-18 sieve to prepare granules.

Dried at a temperature of 40 ° C to 60 ° C in a drier containing silica gel, and then formed into a sieve of the same or smaller mesh as the sieved product. The dried granules have an LOD of preferably 1.5% or less. To the contents, the selected one of an adsorbent, a lubricant and a disintegrant is added.

When the contents are sufficiently mixed, silicon dioxide, magnesium stearate, talc, and the like are blended to a given volume, and a tablet of 580 mg to 700 mg is prepared using a rotary compressor. The prepared nail was prepared by adding hydroxypropylmethylcellulose to which a plasticizer with a plasticizer was added by 2% by weight or less of the tableting agent and 3 to 6% by weight of a coating solution in which polyvinyl alcohol was dissolved by moisture- Prepare the tablets and store them with silica gel in sealed containers.

[Examples 1 to 7]

[Comparison of the adsorbent and the production example of the tumbler]

Usage ingredient Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Active ingredient Citrulline Malate 500 500 500 500 500 500 500 absorbent Siloid AL-1FP 50 Starch 1500 50 Silloid 244FP 50 Avicel PH 112 50 Aerosil 50 NOYCILIN US2 50 Siloid XDP3150 50 Binder HPMC 10 10 10 10 10 10 10 Disintegration Cross camelose sodium 40 40 40 40 40 40 40 Fluidizing agent Silloid 244FP 15 15 15 15 15 15 15 Lubricant Magnesium stearate 10 10 10 10 10 10 10 Total 625 625 625 625 625 625 625

(Unit: mg)

Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Adsorption test ○ ○ △ ○ △ ○ ○ Tablet thickness (mm) 5.90 6.21 6.62 6.12 6.68 5.72 6.72

○: Appropriate △: Absorbent but ambiguous X: Not appropriate

[Evaluation of tablets]

The above experiments of Examples 1-7 are experiments to find an adsorbent suitable for tableting. Preliminary experiments were conducted by screening the groups that can be used as adsorbents such as Siloid Al-1FP, Starch 1500, Siloid 244FP, Avicel PH112, Aerosil, Noicilin US2, Silyloid XDP 3150 (Figs. 2 and 3) To select the appropriate adsorbent.

Figures 2 and 3 are images of the adsorbent selected for the moisture and moisture protection experiments and performed the preceding experiments. (3) Citrulline Malrate: Silyloid AL-1FP = 1,000 mg of citrulline malate (500 mg of citrulline malate, 1000 mg of citrulline malate) at the same humidity of 75% 1: 1, (4) Citrullin Malate: Siloid 244FP = 1: 1, (5) Citrullin Malate: Aerosil = 1: 1, (6) Citrullin Malate: Avicel PH112 = Citrulline maleate: stachy 1500 = 1: 1. Neociline and Siloid XDP 3150 were additional experiments and were not included in the figure. Syloid 244 FP and aerosil are not visibly adsorbed compared to the other comparative groups, which can be visually confirmed in FIG. 3 after 12 hours of exposure at 75% humidity.

As a result, the adsorbent used in Examples 1, 2, 4, 5, and 7 exhibited relatively good adsorption performance to the naked eye, and the small tablets were preferred in terms of liposomal treatment. Thus, bulky silyloids 244FP, Tablets containing aerosil have not been preferred in the invention.

[Examples 8 to 10]

[Preparation example of tablet according to binder type having binding and coating function]

Usage ingredient Example 8 Example 9 Example 10 Active ingredient Citrulline Malate 500 500 500 absorbent NOYCILIN US2 50 50 50 Binder HPMC 10 Binder PVP 10 Binder Kollidon VA64 10 absorbent NOYCILIN US2 50 50 50 Disintegration Calcium carboxymethylcellulose 40 40 40 Lubricant Magnesium stearate 10 10 10 Coating agent HPMC + PEG 6.5 6.5 6.5 Coating agent Polyvinyl alcohol 20.5 20.5 20.5 Total 687 687 687

(Unit: mg)

Table 4 shows the tablets evaluation results of Examples 8 to 10.

Disturbance and refinement 5 days 10 days 15th open
Room temperature 20 ° C,
Humidity Less than 40% Example 8 Granule X X X refine X X X Example 9 Granule X X X refine X X X Example 10 Granule X X X refine X X X open
Acceleration condition
40 [deg.] C, 75% Example 8 refine X X X Example 9 refine X X ○ Example 10 refine X X ○

[Experiment result]

In Examples 8, 9 and 10, experiments were conducted to examine the effect of the polymer binder having a coating function with a binder solution of granules in order to help prevent conventions according to the composition of the present invention. All of the tablets using this polymer were adequately tableted at room temperature and in practice, but HPMC was favorable in comparison with open accelerated conditions.

FIG. 4 shows images of tablets that did not develop deliquescence and tablets that developed deliquescence inside the film coating.

[Examples 11 to 13]

The main component, citrulline maleate, is dissolved in purified water as a solvent and then adsorbed by mixing with calcium silicate as an adsorbent.

Thereafter, it is dried until the moisture becomes 1.5% by weight or less for about 3 hours.

After drying, the disintegrant, the excipient, and the lubricant are mixed, and the tablets are manufactured through tableting and coating processes.

Usage ingredient Example 11 Example 12 Example 13 Active ingredient Citrulline Malate 500 500 500 absorbent Calcium silicate 200 150 110 solvent Purified water 250 250 250 Disintegration Crospovidone 70 70 70 Disintegration Croscarmellose sodium 70 70 70 Excipient Anhydrous calcium dihydrogen phosphate 100 100 100 Lubricant Magnesium stearate 16 16 16 Lubricant Colloidal silicon dioxide 5 5 5 Total 961 911 871

Example 13 Sample weight (mg) Concentration at the calibration curve (mg / L = ppm) content(%) Disintegration test Early 871.3 254.11 101.61 1 minute 871.7 252.85 101.06 871.0 253.68 101.47 1 month long 871.2 249.97 99.97 2 minutes 30 seconds 871.1 250.93 100.36 871.4 245.90 98.32 Accelerated 1 month 871.7 247.45 98.91 2 minutes 15 seconds 871.3 247.60 99.01 871.5 250.23 100.03

In the case of the adsorption processes of Examples 11 to 13, there is an advantage in that the convenience of administration due to the complete masking effect due to the adsorption of the active ingredient is enhanced, and rapid drug efficacy is achieved due to shortening of the disintegration time. As can be seen from Tables 5 and 6 above, Examples 11 to 13 all exhibit excellent stability and disintegratability.

Claims (10)

A citrulline malate solid formulation composition for oral administration comprising a citrulline malate compound as an active ingredient.
The method according to claim 1,
Wherein the composition comprises granules prepared by adding a binding solution in which a binder is dissolved in a solvent to citrulline malate and an adsorbent.
3. The method of claim 2,
Wherein the binder is selected from the group consisting of povidone, polyvinylpyrrolidone, polyvinyl alcohol, carbol, hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, carboxymethylcellulose sodium, hydroxyethylcellulose, fluoran, carboxyvinylpolymer polyethylene Or a mixture of at least one selected from the group consisting of glycols, glycols, and derivatives thereof.
The method according to claim 1,
Wherein the composition is prepared by dissolving citrulline maleate in purified water and then adding an adsorbent to the adsorbed granules to include an additive comprising a disintegrant.
5. The method according to any one of claims 2 to 4,
Wherein the adsorbent is a mixture of at least one selected from silicon dioxide, colloidal silicon dioxide, calcium silicate, and magnesium aluminosilicate.
5. The method of claim 4,
Wherein the disintegrant is at least one selected from the group consisting of croscarmellose sodium, crospovidone, carboxymethylcellulose calcium, sodium starch glycolate, and cornstarch.
5. The method according to any one of claims 2 to 4,
Wherein the composition further comprises at least one lubricant selected from the group consisting of magnesium stearate, zinc stearate, calcium stearate, stearic acid, talc, paraffins, lead, glyceryl behenate, sodium stearyl fumarate and stearyl fumarate ≪ RTI ID = 0.0 > citrulline < / RTI > maleate solid pharmaceutical composition for oral administration.
5. The method according to any one of claims 2 to 4,
Wherein the composition further comprises at least one fluidizing agent selected from the group consisting of starch, talc, silicon dioxide, calcium silicate, magnesium carbonate, and magnesium oxide.
Mixing the binder and the solvent to prepare a binding solution;
Adding the binding solution to a mixture of a citrate malate compound and an adsorbent to produce a wet granule;
Drying the wet granules;
Mixing the dried granules with an additive comprising a disintegrant; and
The step of titrating the after-
≪ / RTI > or a pharmaceutically acceptable salt thereof.
Dissolving a citrulline maleate compound in purified water;
Mixing the solution with an adsorbent;
Drying the mixture;
Mixing the dried composition with an additive comprising a disintegrant; and
The step of titrating the after-
≪ / RTI > or a pharmaceutically acceptable salt thereof.

Images