KR20200033751A - Pharmaceutical Composition comprising Choline alfoscerate - Google Patents

Abstract

The present invention provides a pharmaceutical composition capable of securing a sustained-release or moisture-proof effect, by containing choline alfoscerate, and a sustained-release base or a coating base. The problem to be solved by the present invention is to provide a pharmaceutical composition containing choline alfoscerate, which has excellent the sustained-release or moisture-proof effect and has improved dosage convenience by miniaturization of a formulation.

Description

Pharmaceutical Composition comprising Choline alfoscerate

The present invention relates to a pharmaceutical composition comprising choline alfoscerate, and more particularly, to a pharmaceutical composition capable of securing a sustained or moisture-proof effect, including choline alfoscerate and a sustained release or coating base.

Choline alfoscerate has the effect of restoring damaged brain cells and increasing the amount of acetylcholine secretion. Choline alfoscerate has a very high blood brain barrier (BBB) penetration rate of 45%, and crosses the blood intestinal wall to be separated into choline and alfoscerate. After that, choline becomes acetylcholine to maintain brain function, and alfoscerate can restore damaged brain cells because it is a cell membrane component. Currently, choline alfoscerate is provided in the form of soft capsules, and is administered orally to 400 mg once or twice a day for adults.

The choline alfoscerate soft capsule agent is a formulation containing a liquid choline alfoscerate in a soft capsule, and there is a possibility that the active ingredient may migrate to a water-soluble soft gelatin coating over time. Is necessary. In addition, preservatives are often used to reduce the possibility of microbial deterioration of the soft capsule preparation, and gelatin capsules are weak to moisture and heat, which may cause delay in disintegration during storage, and the size of the soft capsule is larger than that of tablets. There is a disadvantage in that it is inconvenient for the elderly to fall.

In addition, choline alfoscerate has a problem of showing deliquescence, which changes to a liquid phase due to its high hygroscopic properties during long-term storage. To improve this, Korean Patent Registration No. 1499533 discloses a formulation containing choline alfoscerate adsorbed on colloidal silicon dioxide, but using too many excipients to formulate liquid choline alfoscerate in a solid phase form. There is a problem in that the size of the tablet is too large and the patient's compliance with medication is reduced. In addition, Korean Registered Patent No. 1257919 discloses a pharmaceutical composition comprising coated particles obtained by particle coating of choline alfoscerate as a water-soluble base, but since choline alfoscerate is single coated, choline alfosce is stored for a long time. Since the rate of deliquescent appears and the water-soluble base is coated up to 50 parts by weight, dissolution of the drug is remarkably slowed due to the high content of the water-soluble base, so that the pharmacological effect of the drug is not obtained. In addition, the patent discloses a technique for manufacturing a pharmaceutical composition including choline alfoscerate using a fluidized bed granulator, but the technique requires a special facility such as a fluidized bed granulator, so the manufacturing process is complicated and the processing time is long. Not only does it take, but manufacturing costs are high, making it difficult to apply in production.

The problem to be solved by the present invention is to provide a pharmaceutical composition comprising choline alfoscerate, which has excellent sustained or moisture-proof effects and has improved dosage convenience by miniaturization of the formulation.

The present inventors have studied the improvement of the sustained-release or moisture-proof effect of choline alfoscerate and the miniaturization study of the formulation in various ways. As a result, the combination of the sustained-release base is excellent in the sustained-release effect, and the double coating has excellent moisture-proof effect and simple production. The present invention was completed by preparing a miniaturized formulation in a process.

In one embodiment of the present invention, a pharmaceutical comprising two or more mixed sustained release bases selected from ionic bases, swellable bases and hydrophobic bases as choline alfoscerate or a pharmaceutically acceptable salt thereof and sustained release bases as active ingredients. Composition.

In one embodiment of the present invention, the mixed sustained release base comprises 10 to 30 parts by weight compared to 100 parts by weight of choline alfoscerate.

In one embodiment of the present invention, the ionic base comprises at least one selected from carbomer and sodium alginate.

In one embodiment of the invention, the swellable base comprises one or more selected from hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, methylcellulose and carrageenan.

In one embodiment of the invention, the hydrophobic base is glyceryl behenate, Hardened castor oil, hardened vegetable oil and stearic acid.

In one embodiment of the present invention, the pharmaceutical composition is one or more selected from hydroxypropylmethylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose and ethylcellulose as the first coating base and calcium silicate, magnesium metaaluminate and colloidal Polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol copolymer, hydroxypropyl starch, dimethylaminoethyl methacrylate, methyl methacrylate copolymer, ethyl methacrylate, chlorotrimethyl methacrylate, as one or more and second coating bases selected from silicon dioxide At least one selected from ammonium ethyl copolymer, methacrylic acid and ethyl acrylate copolymer, hydroxypropyl methylcellulose acetate succinate and hydroxypropylmethylcellulose phthalate, and mannitol, pregelatinized starch, erythritol, isomalt, xylitol, sorbitol and maltitol on These include one or more.

In one embodiment of the present invention, the first coating base comprises 0.5 to 10.0 parts by weight relative to 100 parts by weight of choline alfoscerate. In one embodiment of the present invention, the first coating base comprises 1.0 to 5.0 parts by weight relative to 100 parts by weight of choline alfoscerate.

In one embodiment of the invention, the second coating base comprises 1 to 25 parts by weight relative to 100 parts by weight of choline alfoscerate. In one embodiment of the present invention, the second coating base comprises 3.0 to 20.0 parts by weight relative to 100 parts by weight of choline alfoscerate. For example, it may be 5.0 to 20.0 parts by weight relative to 100 parts by weight of alfoscerate.

In one embodiment of the present invention, one or more components selected from calcium silicate, magnesium metaaluminate, and colloidal silicon dioxide among the second coating base may include 0.01 to 0.80 parts by weight relative to 100 parts by weight of choline alfoscerate. In addition, it may be 0.01 to 0.5 parts by weight compared to 100 parts by weight of choline alfoscerate. For example, when calcium silicate is selected, it may include that 0.01 to 0.80 parts by weight compared to 100 parts by weight of choline alfoscerate.

In one embodiment of the present invention, choline alfoscerate or a pharmaceutically acceptable salt thereof is 30 to 50% in 2 hours, 50 to 70% in 3 hours, and 12 hours in 12 hours using purified water as an eluent at a rotation speed of 50 rpm. This includes eluting more than 85%.

In one embodiment of the invention, the formulation of the pharmaceutical composition is characterized in that the tablets, capsules, granules.

In one embodiment of the invention, the size of the tablet is characterized in that 800 to 1,000 mm ³ .

The pharmaceutical composition of choline alfoscerate or a pharmaceutically acceptable salt thereof according to the present invention is excellent in sustained release effect by a combination between sustained release bases, has excellent moisture-proofing effect with a double coating, and is formulated without a separate special equipment when manufacturing a pharmaceutical composition It is possible to provide a sustained-release preparation of choline alfoscerate, which can be administered once a day by miniaturization of.

Figure 1 shows the size of the tablets prepared in Example 5-8 and the glycatirin soft capsule of Comparative Example 1 (Purchaser: Baekje Pharmaceutical, manufacturer: Chong Kun Dang).
Figure 2 shows the size of the tablets prepared in Example 5-8 and the comparative example 3, gliatamine fast release tablet (Purchaser: Baekje Pharmaceutical, manufacturer: Daewoong Bio).

[Pharmaceutical composition]

The pharmaceutical composition according to an embodiment of the present invention comprises two or more sustained-release bases selected from ionic bases, swellable bases and hydrophobic bases as choline alfoscerate or a pharmaceutically acceptable salt thereof and sustained-release bases as active ingredients. do.

Choline alfoscerate

In one embodiment of the present invention, choline alfoscerate refers to L-α-glyceryl phosphoryl choline (GPC).

In one embodiment of the present invention, choline alfoscerate or a pharmaceutically acceptable salt thereof may include pharmaceutically acceptable hydrates, solvates, isomers, polymorphs, esters or prodrugs, and the like.

In one embodiment of the invention, a solvate means a complex or aggregate formed by one or more molecules of a solute, ie a compound according to the invention or a pharmaceutically acceptable salt thereof, and one or more solvents. The solvates are usually crystalline solids with a fixed molar ratio of solutes and solvents. Representative solvents include water, ethanol, and isopropanol.

In one embodiment of the invention, an isomer refers to a compound having the same molecular formula but not the same connection method or spatial arrangement of members in the molecule.

In one embodiment of the invention, polymorph refers to a material that crystallizes in one or more crystal lattice arrangements.

In one embodiment of the invention, the ester means that the organic radical is substituted at the site of the hydrogen molecule of the acid.

In one embodiment of the invention, a prodrug means a compound that is transformed into a desired compound in vivo after administration.

In one embodiment of the present invention, the daily dose of choline alfoscerate or a pharmaceutically acceptable salt thereof may be determined in consideration of a dosage, bioavailability and toxicity that sufficiently exerts a pharmacological effect and does not cause side effects, Preferably it may be included in 400 to 1200 mg. In one embodiment of the invention, choline alfoscerate may be 600 mg. When the content of the choline alfoscerate is less than 400 mg, the concentration of choline alfoscerate is small, so that a sufficient pharmacological effect cannot be exhibited, and when it exceeds 1200 mg, the concentration of choline alfoscerate is high, and excessive pharmacological action may occur.

Westernization mechanism

The pharmaceutical composition according to an embodiment of the present invention includes a sustained release base to have a sustained release effect of choline alfoscerate.

In one embodiment of the present invention, the sustained release base is used in combination of two or more mixed sustained release bases selected from ionic bases, swellable bases and hydrophobic bases. When the sustained-release base is used alone, that is, the initial drug release is slow when using the ionic base alone, there is a problem that the drug does not elute more than 85% within 12 hours, and the initial drug release is fast when using the swellable base alone, or The definition hardness is less than 15kP, the physical stability is low, the initial drug release is fast when using a hydrophobic base alone, and a large amount of drugs over 90% is already released in 6 hours, resulting in the problem of not being able to exert the sustained-release effect of the drug for a long time. .

In one embodiment of the present invention, the ionic base refers to a pharmaceutically acceptable base that controls the release of the drug through ionic bonding with the drug, and includes one or more selected from carbomer and sodium alginate.

In one embodiment of the present invention, the swellable base refers to a pharmaceutically acceptable base that is instantaneously swollen in an aqueous solution to control the release of the drug through reduction of pores, hydroxypropelmethylcellulose, hydroxypropylcellulose, hydroxy Ethylcellulose, methylcellulose and carrageenan.

In one embodiment of the present invention, the hydrophobic base does not dissolve in the aqueous solution, refers to a pharmaceutically acceptable base that controls the release of the drug through pore blocking, glyceryl behenate, hard castor oil, hardened plant oil and stearic acid It contains one or more selected from.

In one embodiment of the present invention, the mixed sustained release base is 10 to 30 parts by weight, 11 to 30 parts by weight, 12 to 30 parts by weight, 13 to 30 parts by weight, 14 to 30 parts by weight compared to 100 parts by weight of choline alfoscerate Or 15 to 30 parts by weight. When the mixed sustained-release base is 10 to 30 parts by weight, the sustained-release base alone may have an effect of reaching optimal blood concentration with excellent drug release control and proper choline alfoscerate release rate compared to the initial component.

In one embodiment of the present invention, when two types of ionic base, swellable base or hydrophobic base of mixed sustained release base are selected (for example, ionic base and swellable base, ionic base and hydrophobic base and swellable base and hydrophobic base) ) 2 types of mixing ratio is 5: 1 to 1: 5, 4: 1 to 1: 4 weight ratio or 2: 1 to 1: 2, and when 3 types are selected (ionic base, swellable base and hydrophobic base) 5: 1: 1 to 1: 5: 1 to 1: 1: 5 weight ratio, 3: 1: 1 to 1: 3: 1 to 1: 1: 3 weight ratio or 2: 1: 1 to 1: 2: 1 to 1 It is a 1: 1 to 2 weight ratio.

Specifically, it is as follows.

The ionic base: swellable base is 1: 0.2 to 5 weight ratio, 1: 0.3 to 3 weight ratio or 1: 0.5 to 1 weight ratio, the ionic base: hydrophobic base is 1: 0.2 to 5 weight ratio, 1: 0.25 to 1 weight ratio Or 1: 0.3 to 1 weight ratio, the swellable base: hydrophobic base = 1: 0.2 to 5 weight ratio, 1: 0.25 to 1 weight ratio or 1: 0.3 to 1 weight ratio, the ionic base: swellable base: hydrophobic base 1: 0.2 It is 5 to 0.2 to 5 weight ratio, 1: 1 to 0.2 to 5 weight ratio, or 1: 0.2 to 5 to 1 weight ratio.

Within the mixed weight ratio of the sustained-release base 2 or 3, it has better drug release control than the sustained-release base alone, and has an optimal sustained-release effect for a long time.

In one embodiment of the present invention, the sustained release base is 15 to 25 kP, 17 to 23 kP or 19 to 21 kP hardness by using two or more mixed sustained release bases selected from ionic bases, swellable bases and hydrophobic bases. It is secured and has excellent wear resistance of tablets, so it has stable physical properties.

Excipient

The pharmaceutical composition according to an embodiment of the present invention may further include an excipient to secure long-term storage stability and have a sustained sustained release effect. In the present invention, excipients are understood as components that are distinct from lubricants and coating agents.

In one embodiment of the invention, the excipients include one or more selected from anhydrous calcium phosphate, calcium phosphate monohydrate, calcium phosphate dihydrate, isomalt, gelatin and corn starch.

In one embodiment of the invention, the excipient is 5 to 30 parts by weight, 6 to 28 parts by weight or 8 to 25 parts by weight relative to 100 parts by weight of choline alfoscerate. Within the above weight range, proper release control of the pharmacologically active ingredient and preparation of the formulation are easy, as well as excellent form retention. In addition, since the total mass of the formulation is not significantly increased, there is an effect that the problem of dysphagia does not occur in the patient or the elderly.

Coating base

The pharmaceutical composition according to an embodiment of the present invention may further include a coating base to prevent the deliquescent problem of choline alfoscerate generated when stored for a long time.

In one embodiment of the invention, the coating base comprises a first coating base and a second coating base. When both the first coating base or the second coating base is used, the choline alfoscerate formulation according to the present invention does not have a deliquescent problem, but a phenomenon in which moisture is formed on the surface of the final formulation and a drug is not generated Does not show excellent formulation effect.

The pharmaceutical composition according to an embodiment of the present invention is a first coating base selected from hydroxypropyl methyl cellulose, polyvinylpyrrolidone, hydroxypropyl cellulose and ethyl cellulose, at least one first coating main component and calcium silicate, metaaluminic acid Polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol copolymer, hydroxypropyl starch, dimethyl aminoethyl methacrylate, methyl methacrylate copolymer as one or more first coating auxiliary components and second coating base selected from magnesium and colloidal silicon oxide , One or more of the second coating main component selected from ethyl methacrylate, chlorotrimethylammonium methacrylate copolymer, methacrylate, ethylacrylate copolymer, hydroxypropyl methylcellulose acetate succinate and hydroxypropylmethylcellulose phthalate, mannitol, Comprises at least one second coating auxiliary component selected from starch, erythritol, iso malteu, xylitol, sorbitol and maltitol. By performing a double coating using the first coating base and the second coating base, choline alfoscerate is prevented from being deliquescent, so it is more effective in maintaining stability of the final formulation than a single coating.

In one embodiment of the present invention, the first coating base includes a first coating auxiliary component to adsorb moisture originating from the inside of the formulation, and promotes property stability such as prevention of drug derivation.

In one embodiment of the present invention, the second coating base includes a second coating auxiliary component to prevent moisture penetrating from the outside, thereby enhancing moisture resistance.

In one embodiment of the present invention, the first coating base is 0.5 to 10 parts by weight, 1 to 8 parts by weight or 1.5 to 6 parts by weight relative to 100 parts by weight of choline alfoscerate.

In one embodiment of the present invention, one or more components selected from calcium silicate, magnesium metaaluminate, and colloidal silicon dioxide among the first coating base may include 0.01 to 0.80 parts by weight compared to 100 parts by weight of choline alfoscerate. In addition, it may be 0.01 to 0.50 parts by weight relative to 100 parts by weight of choline alfoscerate. For example, when calcium silicate is selected, it may include that the choline alfoscerate is 0.01 to 0.8 parts by weight compared to 100 parts by weight.

In one embodiment of the present invention, the second coating base is 1 to 25 parts by weight, 3 to 20 parts by weight, or 5 to 18 parts by weight relative to 100 parts by weight of choline alfoscerate.

In one embodiment of the present invention, within the range of the first coating base and the second coating base, the problem of deliquescent of choline alfoscerate does not occur, and the phenomenon that water is formed on the surface of the final formulation and the drug is derived An excellent formulation that does not occur is realized.

The pharmaceutical composition according to an embodiment of the present invention is choline alfoscerate or a pharmaceutically acceptable salt thereof in a water eluate and a rotation speed of 50 rpm in 30 to 50% within 2 hours, 50 to 70% in 3 hours, and within 12 hours It elutes more than 85%. If it is eluted below the above range, there is a problem in that the drug expression rate of the initial patient is slowed down. As inappropriate.

The pharmaceutical composition according to an embodiment of the present invention may be formulated into tablets, capsules, granules, and the like.

As shown in FIGS. 1 and 2, the size of the currently available commercially available Gliatilin soft capsule (Comparative Example 1) is 1,077 mm ³ , and the rapid release of Glyamine (Comparative Example 3) is 982 mm ³ , whereas Tablet size according to one embodiment 800 to 1,000 mm ³ , 850 to 980 mm ³ , 900 to 960 mm ³ . That is, in general, the esophageal diameter of a person is about 2 cm, and a large number of dementia patients occur in the elderly people over 65 years of age. have.

In addition, the tablet according to an embodiment of the present invention contains a sustained release mechanism additionally compared to the above-mentioned glycamine fast-release tablet, and is faster than the rapid-release tablet even though it has increased by 150% by weight compared to choline alfoscerate (400 mg) of the product currently on sale. Provided are miniaturized tablets.

Therefore, the pharmaceutical composition according to one embodiment of the present invention is a sustained-release preparation that can be taken once a day, but is also a soft capsule of Gliatilin (Comparative Example 1) and fast release of Gliatamine (Comparative Example 1) that should be taken 2-3 times a day. Example 3) By providing a smaller sized preparation, the patient's convenience in taking can be promoted.

[Method for preparing pharmaceutical composition]

The method of manufacturing a pharmaceutical composition according to an embodiment of the present invention may use a direct tableting method or a roller pressing method.

In one embodiment of the present invention, the direct tableting method comprises: (a) mixing choline alfoscerate with a sustained release base, an excipient and a lubricant, and (b) tableting the mixture obtained in step (a) to form a tablet. Step (c) and coating the uncoated tablet obtained in step (b).

In one embodiment of the present invention, the roller compaction method comprises: (a) mixing choline alfoscerate with a sustained release base, an excipient, a lubricant, and (b) granulating a mixture obtained in step (a) by roller compaction. The step of making, (c) tableting the granules obtained in step (b) to form a tablet, and (d) coating the tablets obtained in step (c).

The manufacturing method of the pharmaceutical composition according to an embodiment of the present invention reduces the production cost by using a simple manufacturing process such as a direct tableting method or a roller pressing method without special facilities such as a soft capsule filling machine, a fluidized bed granulator, or a high shear granulator. It is suitable for commercial production.

The method of manufacturing a pharmaceutical composition according to an embodiment of the present invention can manufacture a formulation excellent in compressibility and hardness using a direct compression method or a roller compaction method. In addition, the above-described manufacturing method can produce a miniaturized formulation using a dense excipient.

Hereinafter, the present invention will be described in detail based on the following examples. However, the following examples are only for illustrating the present invention and the scope of the present invention is not limited thereto.

Example 1: Preparation and evaluation of miniaturized sustained release formulations

Example 1-1

With the ingredients and contents shown in Table 1, tablets were prepared using a direct tableting method according to the following method.

Calcium anhydrous calcium phosphate, carbomer, hydroxyethylcellulose, and hardened castor oil were mixed with choline alfoscerate, and the resulting mixture was lubricated with talc and magnesium stearate passed through a 40 mesh sieve, and then 16 mm x 8 mm. The target hardness was set to 15-25 kP with a rectangular punch. All processes were carried out in a laboratory dehumidified below 35% relative humidity.

Example 1-2

With the ingredients and contents listed in Table 1 below, a tablet was prepared using a roller compaction method according to the following method.

Calcium hydrogen phosphate anhydride, carbomer, hydroxyethylcellulose, and hardened castor oil are mixed with choline alfoscerate, and the obtained mixture is roller speed 1.5 to 2.5 rpm, screw speed 8 to 8 using a roller compactor (Seoul Hi-Tech, RC80). A compact was prepared by compacting the mixture at 10 rpm and pressure 8-12 MPa. The compact was passed through 20 mesh to prepare granules having an average particle diameter of 100 to 850 μm. This granule was lubricated with talc and magnesium stearate passed through a 40 mesh sieve, and then compressed into a target hardness of 15 to 25 kP with a 16 mm x 8 mm rectangular punch. All processes were performed in a laboratory dehumidified with a relative humidity of 35% or less.

Ingredient (mg / tablet) Example 1-1 1-2 Choline alfoscerate 600 600 Calcium hydrogen phosphate anhydrous 105 105 Carbomer (ionic base) 25 25 Hydroxyethyl cellulose (swellable base) 25 25 Cured castor oil (hydrophobic base) 25 25 Talc 20 20 Magnesium stearate 20 20 Gross weight 820 820 Maximum hardness (kP) 23 25 Screw thickness (mm) 6.40 6.35 Flowability Good Good

As a result of comparing Examples 1-1 and 1-2, the maximum hardness and thickness were excellent in Example 1-2, and the flowability was excellent in both Examples.

In addition, when comparing the volume of Examples 1-1 to 1-2 tablets with Comparative Example 1, the soft capsule of Gliatilin (Purchaser: Baekje Pharmaceutical, manufacturer: Chong Kun Dang, containing 400 mg of cholyl alphosate) It was confirmed that 1-2 tablets had 23.96% and 24.51% volume reductions, respectively, than the soft capsules.

division Comparative Example 1 Example 1-1 Example 1-2 a (Long axis length, mm) 14.9 16.0 16.0 b (shortened length, mm) 8.5 8.0 8.0 c (height, mm) 8.5 6.40 6.35 V (volume, mm ³ ) 1077 819 813

That is, the formulation according to the present invention, compared to the commercially available choline alfoscerate soft capsule, despite the API dose increased by 150% by weight, the volume is significantly reduced, providing a more convenient taking feeling for elderly patients with swallowing discomfort There is an excellent point.

Test Example 1.

Test method

Comparative dissolution test was performed as follows according to the content test method of the soft capsule term of Choline Alfoscerate of the Korean Pharmacopoeia.

<Dissolution test conditions>

Elution solution: purified water

Elution temperature: 37 ℃

Paddle rotation speed: 50rpm

<High performance liquid chromatography (HPLC) analysis conditions>

Column: Kromasil NH ₂ Column

Mobile phase: 60% ACN

Detector: refractive index detector

Flow rate: 1.5 ml / min

Injection volume: 50 μl

In the dissolution test conditions, the eluate was taken at 10 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes, 120 minutes, 180 minutes, 360 minutes, 720 minutes, and filtered to obtain a test solution.

Separately, 33 mg of choline alfoscerate standard was precisely weighed and placed in a 100 mL volumetric flask, followed by aligning the mark with the solution mixed with the mobile phase to prepare a standard solution. And it was analyzed by the HPLC analysis conditions with the sample solution and the standard solution.

The comparative dissolution test results are shown in Table 3 below.

time Dissolution rate (% by weight) Example 1-1 1-2 30 minutes 22 19 60 minutes 31 29 120 minutes 45 46 180 minutes 62 63 360 minutes 84 83 720 minutes 100 100

As shown in Table 3, it was confirmed that there was almost no difference in dissolution rate according to the direct compression method and the roller compression method, and both manufacturing methods were 30-50% within 2 hours, 50-70% within 3 hours, and 85 within 12 hours. It was satisfied to elute more than%. From the results of Tables 1 to 3, it was confirmed that it is possible to secure pharmacokinetic equivalence with the reference drug, and to prepare a sustained-release preparation with a small size.

Example 2. Evaluation of sustained-release effect according to the sustained-release base alone and mixed use

The sustained-release effect was studied according to the sustained-release base alone and mixed use.

Examples 2-1 to 2-10 and Comparative Examples 2-1 to 2-3

With the ingredients and contents described in Tables 4 to 5 below, tablets were prepared in the same manner as in Example 1-2.

Ingredient (mg / tablet) Comparative example Example 2-1 2-2 2-3 2-1 2-2 2-3 2-4 2-5 2-6 2-7 Choline alfoscerate 600 600 600 600 600 600 600 600 600 600 Calcium hydrogen phosphate anhydrous 105 105 105 105 105 105 105 105 105 105 Carbomer (ionic base) 105 - - 52.5 - 52.5 84.0 84.0 - 21.0 Hydroxyethyl cellulose (swellable base) - 105 - 52.5 52.5 - 21.0 - 84.0 84.0 Cured castor oil (hydrophobic base) - - 105 - 52.5 52.5 - 21.0 21.0 - Talc 30 30 30 30 30 30 30 30 30 30 Magnesium stearate 20 20 20 20 20 20 20 20 20 20 Gross weight 860 860 860 860 860 860 860 860 860 860 Hardness (kP) 24.2 13.3 19.9 19.1 17.2 21.8 22.4 22.7 15.5 16.1

Ingredient (mg / tablet) Example 2-8 2-9 2-10 2-11 2-12 2-13 2-14 2-15 2-16 Choline alfoscerate 600 600 600 600 600 600 600 600 600 Calcium hydrogen phosphate anhydrous 105 105 105 105 105 105 105 105 105 Carbomer (ionic base) 21.0 - 70 17.5 17.5 43.75 17.5 43.75 35 Hydroxyethyl cellulose (swellable base) - 21.0 17.5 17.5 70 43.75 43.75 17.5 35 Cured castor oil (hydrophobic base) 84.0 84.0 17.5 70 17.5 17.5 43.75 43.75 35 Talc 30 30 30 30 30 30 30 30 30 Magnesium stearate 20 20 20 20 20 20 20 20 20 Gross weight 860 860 860 860 860 860 860 860 860 Hardness (kP) 20.2 19.4 22.5 19.5 16.8 19.4 18.5 21.1 18.9

(* If the hardness is less than 15kP, the tablet is easily broken, and if the hardness is more than 25kP, there is a problem of cracking when tableting.)

Test Example 2.

Comparative dissolution tests were performed according to the test method of Test Example 1, and the comparative dissolution test results of Comparative Examples 2-1 to 2-3 and Examples 2-1 to 2-10 are shown in Tables 6 and 7 below.

time Dissolution rate (% by weight) Comparative example Example 2-1 2-2 2-3 2-1 2-2 2-3 2-4 2-5 2-6 2-7 30 minutes 5 20 28 13 20 17 8 10 21 17 60 minutes 12 28 37 20 30 25 18 19 30 25 120 minutes 26 42 54 35 47 40 35 38 45 42 180 minutes 39 55 72 54 63 57 53 51 59 54 360 minutes 64 73 90 69 79 75 66 68 75 71 720 minutes 82 87 100 87 97 94 86 87 91 88

time Dissolution rate (% by weight) Example 2-8 2-9 2-10 2-11 2-12 2-13 2-14 2-15 2-16 30 minutes 23 25 11 23 19 15 21 17 18 60 minutes 32 34 20 31 27 23 29 25 26 120 minutes 48 49 38 48 41 37 45 40 41 180 minutes 65 66 51 64 55 52 60 57 56 360 minutes 81 83 69 80 74 71 77 74 74 720 minutes 101 102 87 99 89 88 94 93 92

The dissolution of Comparative Example 2-1, in which the total amount of ionic base was added, was slow in initial drug release, and the dissolution in 12 hours did not exceed 85%, and the dissolution of Comparative Example 2-2, in which the total amount of swellable base was added, was rapid in initial drug release. , It showed a low hardness (less than 15kP), it was confirmed that the dissolution of Comparative Example 2-3 in which a hydrophobic base was injected in a large amount, the initial drug release was fast, and the drug eluted more than 90% within 6 hours.

On the other hand, in Examples 2-1 to 2-16, two or three mixed sustained-release bases selected from ionic, swellable and hydrophobic bases were introduced, and the initial drug release control and dissolution rate within 12 hours were 85. In addition to satisfactory dissolution results in% or more, it showed stable physical properties with a hardness of 15 kP or more.

Example 3: Evaluation of sustained-release effect according to the mixed sustained-release base content

The sustained-release effect was studied according to the content of the mixed sustained-release base.

Examples 3-1 to 3-4

With the ingredients and contents shown in Table 8, tablets were prepared in the same manner as in Example 1-2.

Ingredient (mg / tablet) Example 3-1 3-2 3-3 3-4 Choline alfoscerate 600 600 600 600 Calcium hydrogen phosphate anhydrous 105 105 105 105 Carbomer (ionic base) 30 40 50 60 Hydroxyethyl cellulose (swellable base) 30 40 50 60 Cured castor oil (hydrophobic base) 30 40 50 60 Talc 20 20 20 20 Magnesium stearate 20 20 20 20 Gross weight 820 880 760 820

Test Example 3.

Comparative dissolution test was performed according to the test method of Test Example 1, and the comparative dissolution test results of Examples 3-1 to 3-4 are shown in Table 9 below.

time Dissolution rate (% by weight) Example 3-1 3-2 3-3 3-4 30 minutes 19 17 16 15 60 minutes 28 25 23 22 120 minutes 43 41 39 36 180 minutes 59 55 53 51 360 minutes 78 70 66 63 720 minutes 98 90 88 86

As shown in Table 9, the mixed sustained release base of Examples 3-1 to 3-4 is 30-50% within 2 hours and 50 within 3 hours within 10 to 30 parts by weight compared to 100 parts by weight of choline alfoscerate. It was confirmed that the sustained-release effect eluting at least 85% within -70% and 12 hours.

Example 4: Preparation of coating tablets and evaluation of moisture resistance

The moisture proof evaluation of the choline alfoscerate coated tablet according to the present invention was performed.

With the ingredients and contents shown in Table 10 below, a coated tablet was prepared according to the following method.

A first coating dispersion was prepared by adding and stirring the first coating base into 80% ethanol, and a second coating dispersion was prepared by adding the second coating base into purified water. After putting the tablets prepared in Example 1-2 into a coating machine, the first coating dispersion was sprayed at a supply temperature of 40 to 50 ° C, a product temperature of 33 to 37 ° C, a spray rate of 3 rpm, and a spray pressure of 3.2 bar to coat the tablets. A first coated tablet was prepared. After drying the first coating tablet for 10 minutes at a supply temperature of 60 ° C, the second coating tablet is sprayed with a second coating dispersion at a supply temperature of 50 to 60 ° C, a product temperature of 35 to 40 ° C, a spray rate of 3 rpm, and a spray pressure of 3.2 bar. Was coated. After the coating was completed, it was cured at a supply temperature of 60 ° C for 2 hours.

division Ingredient (mg / tablet) 4-1 4-2 4-3 4-4 Example 1-2 820 820 820 820
1st
coating
Mechanism Opadry 03K19229 * 16.0 16.0 13.3 13.3 Calcium silicate - - 2.7 2.7 ethanol q.s q.s q.s q.s Purified water q.s q.s q.s q.s 2nd
coating
Mechanism Opadry 88A620001 ** 64.0 48.0 64.0 48.0 Mannitol - 16.0 - 16.0 Purified water q.s q.s q.s q.s Gross weight (mg / tablet) 900 900 900 900

* 03K19229: Coating base containing about 85% of hydroxypropylmethylcellulose

** 88A620001: Coating agent containing about 40% polyvinyl alcohol

Test Example 4.

Examples 4-1 to 4-4 were exposed to air for 14 days in an unpacked condition at room temperature storage conditions (25 ° C., 60% RH) to perform a hygroscopicity test, and the results are shown in Table 11. Table 4 shows the properties of Example 4-4.

time Hygroscopicity (%) Example 4-1 4-2 4-3 4-4 3 days 1.26 0.67 1.01 0.38 7 days 4.52 1.96 3.46 0.92 14 days 6.85 3.52 5.28 2.48

time Example 4-4

14 days

As a result of observation for 2 weeks, Examples 4-1 to 4-4 exhibited a hygroscopicity of less than 10%, and Examples 4-4 exhibited a hygroscopicity of less than 3%, as well as a tablet surface when observing the 14th day properties. No moisture condensation and no drug-derived phenomenon were found.

Example 5. Moisture evaluation of double coated coating tablets according to various content combinations of primary and secondary coating bases

From the results of Example 4, in order to optimize the moisture-proof coating composition showing the optimum moisture-proofing power, a study was conducted on various content combinations of the coating base.

Examples 5-1 to 5-9

With the ingredients and contents shown in Table 13, a double coated coated tablet was prepared in the same manner as in Example 4 above.

division Ingredient (mg / tablet) Example 5-1 5-2 5-3 5-4 5-5 5-6 5-7 5-8 5-9 Example 1-2 820 820 820 820 820 820 820 820 820
1st
coating
Mechanism Opadry 03K19229 24.6 8.2 8.2 24.6 8.2 24.6 24.6 24.6 24.6 Calcium silicate 1.64 1.64 4.92 4.92 4.92 4.92 1.64 1.64 4.92 ethanol q.s q.s q.s q.s q.s q.s q.s q.s q.s Purified water q.s q.s q.s q.s q.s q.s q.s q.s q.s 2nd
coating
Mechanism Opadry 88A620001 73.8 73.8 73.8 73.8 73.8 24.6 24.6 73.8 73.8 Mannitol 24.6 24.6 8.2 24.6 24.6 8.2 8.2 8.2 8.2 Purified water q.s q.s q.s q.s q.s q.s q.s q.s q.s Gross weight (mg / tablet) 944.64 928.24 915.12 947.92 931.52 882.32 879.04 928.24 931.52

Test Example 5.

In Examples 5-1 to 5-9, the hygroscopicity test was performed by exposing for 31 days in air without packaging at room temperature storage conditions (25 ° C, 60% RH), and the hygroscopicity test and the results of observation of properties were respectively Tables 14 and 16 are shown below.

The double coated coated Example 3, Daewoong Bio Gliatamine Sokbangjeong (Purchaser: Baekje Pharmaceutical, related patent KR1556568) was compared with the moisture resistance evaluation of the double coated coated tablet of the present invention.

time Hygroscopicity (%) Comparative example Example 3 5-1 5-2 5-3 5-4 5-5 5-6 5-7 5-8 5-9 14 days 3.7 0.8 0.9 1.2 0.8 0.8 2.3 2.3 0.9 1.0 31 days 7.0 1.7 2.1 3.4 1.7 1.7 4.8 6.9 2.0 2.2

time Constellation Comparative example Example 3 5-1 5-2 5-3 5-4 5-5 5-6 5-7 5-8 5-9 14 days

31 days

time Constellation Example 5-1 5-8
98 days

Examples 5-15 to 5-9 double-coated with a first coating base comprising hydroxypropylmethylcellulose and calcium silicate having various mixing weight ratios and a second coating base comprising polyvinyl alcohol and mannitol for 31 days As a result of the observation, relatively low moisture absorption and excellent properties were confirmed. The lowest moisture absorption and the best properties were observed in Examples 5-1 and 5-8 on a 98-day basis, as shown in Table 16 above.

On the other hand, the comparative example 3, the glycamine fast-release tablet was double coated, but as shown in Tables 14 and 15, it was confirmed that the hygroscopicity at 31 days and the unstable properties of the edges of the tablets spread.

Test Example 6.

Comparative dissolution test was performed according to the test method of Test Example 1, and the comparative dissolution test results of Examples 5-1 and 5-8 are shown in Table 17 below.

time Dissolution rate (% by weight) Example 5-1 5-8 30 minutes 15 13 60 minutes 25 24 120 minutes 43 45 180 minutes 60 62 360 minutes 81 82 720 minutes 97 100

As shown in Table 17, the dissolution rates of the double coated tablets of Examples 5-1 and 5-8 obtained results similar to those of Example 1-2 tablets, and the double coated choline alfoscerate sustained-release tablet according to the present invention exhibited property stability. At the same time, it was confirmed that it was possible to control the miniaturization of tablets and the excellent drug release of choline alfoscerate.

Claims (10)

Choline alfoscerate as an active ingredient or a pharmaceutically acceptable salt thereof; And
A pharmaceutical composition comprising two or more mixed sustained release bases selected from ionic bases, swellable bases and hydrophobic bases as sustained release bases. According to claim 1,
The ionic base is at least one selected from carbomer and sodium alginate;
The swellable base is at least one selected from hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, methyl cellulose and carrageenan; or
The hydrophobic base is a pharmaceutical composition comprising at least one selected from glyceryl behenate, hydrogenated castor oil, hydrogenated vegetable oil and stearic acid. According to claim 1,
The mixed sustained release base pharmaceutical composition comprising 10 to 30 parts by weight compared to 100 parts by weight of choline alfoscerate. The method of claim 3,
The mixed sustained release base is a pharmaceutical composition comprising 11 to 30 parts by weight compared to 100 parts by weight of choline alfoscerate. The pharmaceutical composition according to any one of claims 1 to 4, wherein the pharmaceutical composition is a double coated tablet. The method of claim 5,
The pharmaceutical composition may include at least one selected from hydroxypropylmethylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose and ethylcellulose as the first coating base, and at least one selected from calcium silicate, magnesium metaaluminate, and colloidal silicon dioxide; And
As the second coating base, polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol copolymer, hydroxypropyl starch, dimethylaminoethyl methacrylate, methyl methacrylate copolymer, ethyl methacrylate, chlorotrimethylammonium ethyl methacrylate copolymer, and methacrylic acid ㆍ Containing at least one selected from ethyl acrylate copolymer, hydroxypropyl methylcellulose acetate succinate and hydroxypropylmethylcellulose phthalate and at least one selected from mannitol, pregelatinized starch, erythritol, isomalt, xylitol, sorbitol and maltitol Pharmaceutical composition. The method of claim 6,
The first coating base is 0.5 to 10.0 parts by weight compared to 100 parts by weight of choline alfoscerate or
The second coating base is a pharmaceutical composition comprising 1 to 25 parts by weight compared to 100 parts by weight of choline alfoscerate. The method of claim 6,
At least one component selected from calcium silicate, magnesium metaaluminate and colloidal silicon dioxide among the first coating base is 0.01 to 0.80 parts by weight compared to 100 parts by weight of choline alfoscerate. According to claim 1,
The choline alfoscerate or a pharmaceutically acceptable salt thereof contains 30 to 50% in 2 hours, 50 to 70% in 3 hours, and 85% or more in 12 hours using purified water as an eluent at a rotation speed of 50 rpm. Pharmaceutical composition. The method of claim 5,
The size of the tablet is a pharmaceutical composition, characterized in that 800 to 1,000 mm ³ .

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