KR20180078762A - Pharmaceutical composition comprising DAPAGLIFLOZIN L-PROLINE for the prevention or treatment of diabetes - Google Patents

Abstract

The present invention relates to a pharmaceutical composition comprising dapagliflozin L-proline. More specifically, the pharmaceutical composition comprising dapagliflozin L-proline has excellent elution characteristics even when d (0.9) of the dapagliflozin L-proline has a large particle size distribution of 60 μm or more, can be manufactured in a simple process, and has an advantage of less loss of active ingredients. Accordingly, the pharmaceutical composition of the present invention exhibits excellent elution rates and body absorption rates, thereby being useful as an agent for preventing or treating diabetes, diabetes-related diseases and diabetic complications.

Description

The present invention relates to a pharmaceutical composition for preventing or treating diabetes mellitus including dapagliflozin L-proline,

The present invention relates to a pharmaceutical composition comprising, as an active ingredient, dapagliflozin L-proline, which exhibits improved dissolution characteristics of the active ingredient and is simple in the production process and has little decomposition and loss of active ingredient.

Globally, diabetes has become one of the leading causes of adult death, and the number of diabetic patients is rapidly increasing as the obesity population grows, which is characterized by hyperglycemia due to excessive glucose production and peripheral insulin resistance. Plasma glucose is typically filtered in the renal glomeruli and is actively reabsorbed in the proximal tubules. SGLT-2 (sodium-glucose transporter 2) is considered to be a major transporter involved in glucose reabsorption at this site.

Thus selective inhibition of SGLT-2 in diabetic patients can normalize plasma glucose by increasing insulin sensitivity by delaying the onset of diabetic complications by increasing glucose excretion in the urine without significant gastrointestinal side effects. Thus, SGLT-2 inhibitors are attracting attention as a preventive or therapeutic agent for diabetes, diabetes-related diseases and diabetic complications.

(2S, 3R, 4R, 5S, 6R) -2- [4-chloro-3- (4- ethoxybenzyl) phenyl] -6- (hydroxymethylphenyl) Hydroxy-methyl) tetrahydro-2H-pyran-3,4,5-triol) is disclosed in U.S. Patent No. 6,515,117 as a compound of Formula 1 below.

Korean Patent No. 1493102 also discloses a process for the preparation of (S) -propylene glycol (PG), (R) -PG, ethanol, ethylene glycol (EG), 1: 2 L- L-proline hemihydrate, and 1: 1 L-phenylalanine.

Among these, D-phaglylofuro L-proline is excellent in its efficacy, but has problems such as a low dissolution rate in the production of pharmaceutical preparations. Therefore, it is necessary to improve the elution characteristics of the pharmaceutical preparation containing the above-mentioned polyglycolytic L-proline in order to increase the bioavailability of the dapagliflozin, but the development of a satisfactory pharmaceutical preparation has been made yet .

The particle size can be reduced to increase the surface area to have an improved dissolution rate. However, it is not always desirable to mill the compound as small as possible. An additional milling process for micronisation is required and may result in additional costs in capsule filling or tablet making since finely ground materials can form lumps inside the machine. In addition, physical heat and pressure may be generated in the milling process, which may lead to chemical modification of the compound, and loss may occur when the undifferentiated compound is recovered.

In order to improve the dissolution rate of dapagliflozed L-proline, instead of decreasing the particle size, it has been proposed to use a dapaglipro L-lysine having improved dissolution characteristics even in a large particle size distribution, ≪ RTI ID = 0.0 > proline. ≪ / RTI >

U.S. Patent No. 6,515,117, C-aryl glucoside SGLT2 inhibitors and method; And Korean Patent No. 1493102 discloses a method for the treatment of diabetes mellitus comprising administering to a patient in need of such treatment a composition comprising (1S) -1,5-anhydro-1-C- (3 - ((phenyl) Crystalline solvates and complexes of

The present inventors have studied a method for improving the elution characteristics of a pharmaceutical composition containing D-phaglyplated L-proline, and as a result, the present invention has been completed.

Although it is possible to find a method of improving the dissolution rate by increasing the surface area by reducing the particle size, this may require an additional milling step and complicate the manufacturing process, which may lead to an excessive cost. In the process of recovering the undifferentiated active ingredient Loss of the active ingredient may occur and this may lead to chemical denaturation of the active substance in the pulverization process.

Accordingly, an object of the present invention is to provide a polyparagraph (hereinafter, referred to as " polyparagraph ") which exhibits excellent elution characteristics even when dapaglyplloin L-proline has a large particle size distribution, Lt; / RTI > and a pharmaceutically acceptable carrier.

It is an object of the present invention to provide a pharmaceutical composition comprising multiparticulate L-proline, which exhibits excellent elution characteristics even when d (0.9) of dapagliflozed L-proline is 60 탆 or more.

Specifically, the present invention provides a pharmaceutical composition comprising multiparticulated L-proline as an active ingredient, wherein d (0.9) of the multipagraphy L-proline is 60 μm or more.

The d (0.9) of the above-mentioned polyglycolized L-proline can be 60 μm or more and 120 μm or less.

The polygalloglobulin L-proline may be contained in an amount of 0.1 to 20% by weight based on the total weight of the composition, and the polygalloglobulin L-proline may be contained in a concentration of 5 to 20 mg in terms of polyglycologlobin.

In addition, the pharmaceutical composition provided in the present invention may include one or more solubilizing agents, and preferably one or more solubilizing agents selected from the group consisting of Poloxamer 407, Polyoxyl 100 stearate and Polysorbate 65. The HLB value of the solubilizing agent is preferably from 5 to 25.

The solubilizing agent may be present in an amount of 0.1 to 20% by weight based on the total weight of the composition, preferably in a solid state at room temperature and may be contained in an amount of 0.1 to 10% by weight based on the total weight of the composition.

In addition, the pharmaceutical compositions provided herein may comprise one or more disintegrants, preferably one or more disintegrants selected from the group consisting of crospovidone, croscarmellose sodium and sodium starch glycolate have. The disintegrant may be included in an amount of 0.1 to 10% by weight based on the total weight of the composition.

In addition, the pharmaceutical composition may be formulated into an oral administration form, and the oral administration form may be a tablet.

According to Method 2 of the United States Pharmacopoeia Dissolution Test Item, the pharmaceutical preparation may have a dissolution rate of 80% or more of D-phaglyplated L-proline within 15 minutes upon dissolution test in pH 4.5 test solution, preferably within 10 minutes The dissolution rate of the dapagliflozed L-proline may be 80% or more. Also, the dissolution rate of D-fructooligosaccharide L-proline can be more than 90% within 30 minutes.

In addition, the pharmaceutical preparation may be for the prevention or treatment of diabetes, diabetes related diseases and diabetic complications.

The pharmaceutical composition containing the dapagliflozin L-proline according to the present invention has excellent dissolution characteristics of the active ingredient even when d (0.9) of the dapagliflozin L-proline is 60 m or more, The manufacturing process is easy, and the loss of the effective ingredient is small. Accordingly, the pharmaceutical composition of the present invention can be used as a preventive or therapeutic agent for diabetes, diabetes related diseases and diabetic complications which are excellent in quality and bioabsorbability.

FIG. 1 is a graph showing the dissolution rates of D-fructooligosaccharide L-proline in Example 1 and Comparative Examples 1 and 2. FIG.
FIG. 2 is a graph showing dissolution rates of D-fructooligosaccharide L-proline in Examples 1 to 3 and Comparative Examples 3 and 4. FIG.

Prophylaxis or treatment of diabetes mellitus, diabetes-related diseases and diabetic complications, the effect of SGLT-2 inhibitor, dapagliflozin L-proline, is excellent, but the dissolution rate should be improved I have a problem.

In order to improve the dissolution rate of the above-mentioned polygallylated L-proline, there is a method of finely pulverizing, but this is because of the complexity of the manufacturing process, the problem of the manufacturing process in which the finely pulverized material forms a lump in the machine, There is a problem in that loss of the active ingredient and chemical modification of the active ingredient due to generation of physical heat and pressure in the pulverization process may occur.

However, according to the study of the present inventors, it was surprisingly found that when the solubilizing agent of HLB 5 to 25 was used, the dissolution rate was remarkably improved even when d (0.9) of dapagliflozed L-proline was 60 탆 or more.

The present invention provides a pharmaceutical composition comprising multiparticulate L-proline, wherein d (0.9) of the multipagraphy L-proline is 60 탆 or more. At this time, d (0.9) of the dipalmitoyl L-proline can be 60 탆 or more and 120 탆 or less.

The polyparagraph L-proline used in the present invention is a crystalline complex of the following formula (2).

(In the above formula (2), x is 1 or 2 and y is 0 to 1)

Preferably, the multipagraphy L-proline of the present invention may be a 1: 2 crystalline complex.

In the present invention, the particle size of the drug is expressed based on the particle size distribution. In the present invention, d (0.9) means the particle diameter at the point where the particle size distribution of the drug obtained by measuring the particle diameter of the drug is accumulated in the order of smaller particle size and becomes 90% by weight when the particle size distribution is represented by the cumulative curve.

In the present invention, the particle size of the dipalmitoyl L-proline can be measured using a commercial apparatus according to the laser diffraction / scattering method based on the Mie theory. For example, it can be measured using a commercially available device such as HELOS (Helium-neon Laser for Optical Spectrometry, Sympatec) laser diffraction device. In this device, when a helium-neon laser beam is irradiated on a particle, scattering occurs, a light scattering pattern appears on the detector, and the light scattering pattern is analyzed according to the Mie theory to obtain the particle diameter distribution. The measurement method can be either a dry method or a wet method, but in the following examples, measurement results using a dry method are shown.

In the present invention, the pharmaceutical composition comprising the D-phaglyplated L-proline may comprise one or more solubilizing agents.

At this time, the solubilizing agent may be contained in an amount of 0.1 to 20% by weight, preferably 0.1 to 20% by weight based on the total weight of the composition.

The pharmaceutically acceptable solubilizing agent may be a solvent such as almond oil, castor oil, corn oil, cotton seed oil, ethanolate, glycerin, glyceryl monostearate, olive oil, peanut oil, polyethylene glycol, propylene glycol, soybean oil, Catechostearyl alcohol, cholesterol, diethanolamine, and the like which function to solubilize a poorly soluble substance by rapidly dissolving it in water through a hydrophilic group when the active ingredient is combined with one of the functional groups and the hydrophilic functional group is left, , Ethyleneglycol palmitostearate, glycerin, glyceryl monostearate, hydroxypropyl cellulose, isopropyl myristate, lecithin, medium chain glyceride, monoethanolamine, oleic acid, propylene glycol, polyoxyethylene alkyl Ether, polyoxyethylene castor oil distribution And the like, polyethylene sorbitan fatty acid esters, polyoxy ethylene stearates, propylene glycol carbonate know, sorbitan fatty acid esters, stearic acid, sunflower oil, triethanolamine.

The solubilizer used in the present invention may be provided as one or a mixture of two or more of them, preferably a solubilizer having an HLB value of 5 to 25, more preferably Poloxamer 407, Polyoxyl 100 stearate and Polysorbate 65 may be used as the solubilizing agent.

At this time, the HLB value is an abbreviation of 'hydrophile-lipophile balance' and is an index showing the balance between hydrophilicity and lipophilicity (hydrophobicity) of the solubilizing agent. The smaller the HLB value is, the stronger the lipophilic property is as a whole molecule, and the larger the hydrophilic property is, the stronger the hydrophilic property is.

The present inventors have found that when the solubilizing agent having an HLB value in the range of 5 to 25 is used, the dissolution rate is remarkably improved even when the particle size distribution of the D-paglyplloin L-proline is large.

In addition, the pharmaceutical compositions comprising the multipagraphy L-proline in the present invention may comprise one or more disintegrants. The disintegrant may be included in an amount of 0.1 to 10% by weight based on the total weight of the composition.

The disintegrant may be selected from the group consisting of crospovidone, pregelatinized starch, corn starch, methylcellulose, hydroxypropylmethylcellulose, sodium starch glyconate, sodium croscarmellose, low substituted hydroxypropylcellulose, sodium starch glycolate, starch, Alginic acid or a sodium salt thereof, or a combination thereof, but the present invention is not limited thereto.

Preferably, one or more selected from the group consisting of crospovidone, croscarmellose sodium and sodium starch glycolate can be selected.

The dosage of the above-mentioned polyglycolized L-proline may vary depending on the patient's age, sex, weight, degree of pathology, and route of administration. The pharmaceutical composition of the present invention comprises 0.1 to 20% by weight of the total weight of the composition of multipigraphy L-proline, and may be included as 5 to 20 mg of polyparagraph.

In addition, the multipargrapholin L-proline of the present invention can be used in combination with a diabetic therapeutic agent, a diabetic complication therapeutic agent, a hyperlipidemia therapeutic agent, a hypertension therapeutic agent, etc., having different action mechanisms.

Examples of therapeutic agents for diabetes and diabetic complications that can be used in combination include alpha-glucosidase inhibitor, biguanide, insulin secretagogue, insulin sensitizer, cannabinoid receptor -1 cannabinoid receptor 1 antagonist, DPP-IV inhibitor (DPP-IV inhibitor), and the like.

The following agents can be used as therapeutic agents that can be used in combination, but are not limited thereto.

Alpha-glucosidase inhibitors exhibit an action of delaying the absorption of carbohydrates from the organs and include agarbose, voglibose, emiglitate, miglitol, and the like.

Metformin is a representative benguinide drug, and buformin and phenformin belong to this group.

Insulin secretion promoters can be classified into sulfonylurea drugs and non-sulfonylurea drugs, including glybenclamide (glyburide), glipizide, glyclazide but are not limited to, gliclazide, glimepiride, tolazamide, tolbutamide, acetohexamide, carbutamide, chlorpropamide, glibornuride, Gliquidone, glisentide, glisolamide, glisoxepide, glyclopyamide, glycylamide, and glipentide. The term " glycoprotein " Etc. belong to the drug of the sulfonylurea structure, and repaglinide, nateglinide and the like belong to the drug of the non-sulfonylurea structure.

The cannabinoid receptor-1 antagonist is a relatively recently developed drug target, which inhibits the excessive activity of endogenous cannabinoids to control glucose and lipid metabolism as well as controlling body weight and energy balance, It acts on receptor-1 (cannabinoid receptor-1; CB1 receptor).

DPP-IV inhibitors rapidly cleave GLP-1, which stimulates glucose-dependent insulin secretion from pancreatic [beta] -cells and increases pancreatic [beta] -cell populations, and inhibits the release of GLP-1 from cells such as sitagliptin, valdagliptin, saxagliptin, Lipoglycans, lipoglycans, lipoglycans, lipoglycans, lipoglycans, lipoglycans, lipoglycans, and the like.

The multipargraphlodulin L-proline of the present invention is particularly useful for the treatment of one or more drugs selected from the group consisting of metformin, citagliptin, billagliptin, saxagliptin, linagliptin, anagliptin, allogliptin and gemigliptin Can be used together.

Examples of the therapeutic agent for hyperlipidemia and hypertension which can be used in combination include a hydroxymethylglutaryl coenzyme A reductase inhibitor, a fibrate compound, a squalene synthetase inhibitor, an acyl coenzyme A: cholesterol acyltransferase inhibitor, a low specific gravity lipoprotein receptor promoter, But are not limited to, one or more agents selected from the group consisting of triglyceride transfer protein inhibitors, appetite suppressants, calcium ion channel blockers, beta-adrenergic receptor blockers, angiotensin converting enzyme inhibitors and angiotensin receptor antagonists.

The pharmaceutical composition of the present invention contains multiparticulate L-proline as an active ingredient and may further contain conventional pharmaceutically acceptable carriers, excipients, binders, lubricants and the like. In addition, it can be formulated into preparations for oral administration or parenteral administration preparations such as tablets, capsules, beads, beads, granules, pills, troches, liquids and suspensions, which are customary in the pharmaceutical field .

In addition, the pharmaceutical preparation of the present invention may further contain a pH adjusting agent, a suspending agent, a preservative, a flavoring agent, a coloring agent, a sweetening agent, an absorbent and the like, if necessary. The content of such an additive is not particularly limited in the present invention and can be appropriately adjusted as needed.

When the pharmaceutical preparation containing the multipagraphy L-proline of the present invention is purified, the tablet is subjected to the dissolution test in the pH 4.5 test solution according to the second method of the US Pharmacopoeia dissolution test item, The dissolution rate of the crude L-proline may be 80% or more, and preferably the dissolution rate may be 80% or more within 10 minutes. Also, the dissolution rate may be over 90% within 30 minutes.

At this time, the second method of the US Pharmacopoeia dissolution test item means paddle method, and as the pH 4.5 test solution, a sodium acetate solution can be used.

In addition, when the pharmaceutical preparation of the present invention is a tablet, the tablet contains a step of mixing granular polyglycolized L-proline and a pharmaceutically acceptable additive, and tableting the granule And the like.

The granules can be prepared by a conventional wet granulation method or dry granulation method known in the art. In addition, the tablets may be prepared by a direct tableting method, and tableting may be carried out using a conventional tableting machine, for example, a rotary tableting machine.

For example, the tablet may be prepared by mixing first and second dry granules by mixing D-polylysine L-proline and a solubilizing agent; Mixing the first dry granule and the disintegrant to prepare a final granule; And tableting the resulting granules with a tablet. When the tablets are produced by such a production method, the efficiency of tableting is increased, securing a certain tablet hardness, preventing defects such as capping and laminating, and securing the effect of improving productivity, which is desirable.

Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are for further illustrating the present invention, and the scope of the present invention is not limited by these examples.

[Example]

Example  1 to 3: Da pagliprofrozen  Manufacture of tablets

Tablets containing the dapagliflozin L-proline 1: 2 crystalline complex (Hanmi Precision, Korea) were prepared with the composition shown in Table 1 below. The particle size distribution of the dapagliflozed L-proline is 60? D (0.9) <120, where the particle size unit is μm.

Dapagliflo L-proline was mixed with mannitol, lactose and microcrystalline cellulose and each solubilizing agent and compacted using a roller compactor (TF-1-A60, Freund vector, USA) To prepare primary dry granules.

Crospovidone, silicon dioxide and magnesium stearate were added to the prepared primary granules and mixed to prepare a final granule.

The final granules were tableted using a rotary tablet press (GRC-18, Sejong Machinery Co., Korea) and contained 15.6 mg (10 mg as dapagliflozin) as D-phaglyphrolated L-proline in one tablet The tablets containing paglyplloin L-proline were prepared.

Constituent Content (mg) Example 1 Example 2 Example 3 Primary dry granule Dapagliflozin L-proline 15.6 15.6 15.6 Mannitol 100.0 100.0 100.0 Microcrystalline cellulose 50.0 50.0 50.0 Lactose 50.0 50.0 50.0 Poloxamer 407 (HLB: 18-23) 10 - - Polyoxyl 100 stearate (HLB: 18.8) - 10 - Polysorbate 65 (HLB: 10.5) - - 10 Final granule Crospovidone 10.0 10.0 10.0 Silicon dioxide 3.4 3.4 3.4 Magnesium stearate 2.0 2.0 2.0 Gross weight (mg) 241.0 241.0 241.0

Comparative Example  1 and 2: Da pagliprofrozen  Tablet manufacture

A dipalmitoylpolygophyte was prepared in the same manner as in Example 1 with the composition shown in Table 2 below. The particle size distribution of the dapagliflozed L-proline is 60? D (0.9) <120, where the particle size unit is μm.

Constituent Content (mg) Comparative Example 1 Comparative Example 2 Primary dry granule Dapagliflozin L-proline 15.6 15.6 Mannitol 100.0 100.0 Microcrystalline cellulose 50.0 50.0 Lactose 50.0 50.0 Final granule Crospovidone - 10.0 Silicon dioxide 3.4 3.4 Magnesium stearate 2.0 2.0 Gross weight (mg) 221.0 231.0

Comparative Example  3 and 4: Da pagliprofrozen  Tablet manufacture

The tablets were prepared in the same manner as in Example 1 with the compositions shown in Table 3 below. The particle size distribution of the dapagliflozed L-proline is 60? D (0.9) <120, where the particle size unit is μm.

Constituent Content (mg) Comparative Example 3 Comparative Example 4 Primary dry granule Dapagliflozin L-proline 15.6 15.6 Mannitol 100.0 100.0 Microcrystalline cellulose 50.0 50.0 Lactose 50.0 50.0 Poloxamer 188 (HLB: 29) 10 - Brij 72 (HLB: 4.9) - 10 Final granule Crospovidone 10 10 Silicon dioxide 3.4 3.4 Magnesium stearate 2.0 2.0 Gross weight (mg) 241.0 241.0

Test Example  1: dissolution rate comparison evaluation

In accordance with the second method (Paddle) of the United States Pharmacopoeia (USP) dissolution test, 1000 ml of a pH 4.5 acetic acid salt solution was added to each of Examples 1 to 3 and Comparative Example 1 at a dissolution temperature of 37 ° C and a rotation number of 60 rpm To 4 were subjected to a dissolution test.

Samples of the dissolution test liquid were taken at 0, 5, 10, 15, 20 and 30 minutes after the start of the test, liquid chromatography was carried out under the following conditions, and the dissolution rate of the dapagliflozin was calculated and shown in the following Table 4, Respectively.

&Lt; Liquid chromatography conditions >

- Column: A column (Zorbax SB-C8, Agilent Zorbax) packed with octadecylsilylated silica gel for liquid chromatography having a particle diameter of 4.2 탆 was inserted into a stainless steel tube having an inner diameter of about 4.6 mm and a length of 15 cm,

- Column temperature: 25 ° C

- Sample injection amount: 10 μL

- Mobile phase: pH 7.2 Phosphate / acetonitrile = 60/40 (v / v)

- Flow rate: 1.0 mL / min

- Detector: Ultraviolet absorptiometer (measuring wavelength 240 nm)

Elution time (min) 0 5 10 15 20 30 Dissolution rate (%) Example 1 0 61 89 95 98 99 Example 2 0 57 85 95 99 100 Example 3 0 69 87 97 100 100 Comparative Example 1 0 19 43 66 78 80 Comparative Example 2 0 35 54 69 80 83 Comparative Example 3 0 41 66 79 83 88 Comparative Example 4 0 21 55 78 88 89

In the results of Table 4, in the case of Examples 1 to 3 in which the solubilizing agent having d (0.9) of 60 to 120 占 퐉 and HLB value of 5 to 25 of the dapaglyplloin L-proline was used, It can be confirmed that the dissolution rate is 85% or more, indicating excellent dissolution characteristics. On the other hand, in the case of Comparative Example 2 in which the particle size distribution of the same multi-paglyplloinized L-proline was shown but the solubilizing agent was not used, the dissolution rate in the 10 minutes was 54% and the dissolution rate in the 15 minutes was 69% And showed significantly lower dissolution characteristics than the case

In addition, in Comparative Example 1 in which the particle size distribution of the same dipalmitinized L-proline was shown but the crospovidone was not used as a disintegrant, the dissolution rate in 43 minutes was 15% and the dissolution rate in 15 minutes was 66% Was lower than that of Comparative Example 2 in which the surfactant was added.

Referring to FIG. 1, it can be seen that when d (0.9) of the dipalmitoyl L-proline is the same, when the disintegrant is added and when the solubilizing agent is added, it shows excellent elution characteristics.

Comparing Examples 1 to 3 and Comparative Examples 3 and 4 in order to compare the elution characteristics according to the HLB value of the solubilizing agent, Comparative Examples 3 and 4 with a solubilizing agent having a high HLB value of 29 and a low HLB of 4.9 In Comparative Example 4 using the solubilizing agent, the dissolution rate was less than 70% in 10 minutes and the dissolution rate was less than 80% in 15 minutes. As compared with Examples 1 to 3 using the solubilizing agent having an HLB value of 5 to 25, .

Referring to FIG. 2, when the solubilizing agent having an HLB value in the range of 5 to 25 is used, it can be seen that the dissolution characteristics are better.

When the d (0.9) of the d-phaglyplated L-proline is 60 탆 or more, the elution characteristics are further improved in the pharmaceutical composition further comprising a solubilizer and a disintegrant having an HLB value of 5 to 25, Can increase the in vivo absorption rate of jeans, and can be used as a preventive or therapeutic agent for diabetes, diabetes related diseases and diabetic complications of excellent quality.

Claims (21)

Lt; RTI ID = 0.0 &gt; L-proline, &lt; / RTI &gt;
Wherein the d-paglylofro L-proline has a d (0.9) of 60 mu m or more. The pharmaceutical composition according to claim 1, wherein d (0.9) of the polygallylated L-proline is 60 쨉 m or more and 120 쨉 m or less. The pharmaceutical composition of claim 1, comprising at least one solubilizing agent. The pharmaceutical composition according to claim 3, wherein the solubilizing agent is contained in an amount of 0.1 to 20% by weight based on the total weight of the composition. 5. The pharmaceutical composition according to claim 4, wherein the solubilizing agent is solid at room temperature and comprises 0.1 to 10% by weight based on the total weight of the composition. The pharmaceutical composition according to claim 3, wherein the solubilizing agent has an HLB value of 5 to 25. The pharmaceutical composition according to claim 3, wherein the solubilizing agent is selected from the group consisting of Poloxamer 407, Polyoxyl 100 stearate and Polysorbate 65. 7. The pharmaceutical composition of claim 1 comprising at least one disintegrant. 9. The pharmaceutical composition according to claim 8, wherein the disintegrant is present in an amount of 0.1 to 10% by weight based on the total weight of the composition. 9. The pharmaceutical composition according to claim 8, wherein said disintegrant is selected from the group consisting of crospovidone, croscarmellose sodium and sodium starch glycolate. 2. The pharmaceutical composition according to claim 1, wherein the multipageletyl L-proline is present in an amount of 0.1 to 20% by weight based on the total weight of the composition. 2. The pharmaceutical composition according to claim 1, wherein the polygalloglobulin L-proline is contained in an amount of 5 to 20 mg by multipagraphy. 13. The pharmaceutical preparation according to any one of claims 1 to 12, wherein the composition is formulated in an oral administration form. 14. The pharmaceutical preparation according to claim 13, wherein the oral administration form is a tablet. 14. The pharmaceutical preparation according to claim 13, wherein the dissolution rate of the polygallylated L-proline is 80% or more within 15 minutes in the dissolution test in the pH 4.5 test solution according to the second method of the US Pharmacopoeia dissolution test item. 14. The pharmaceutical preparation according to claim 13, wherein the dissolution rate of the polygallylated L-proline is 90% or more within 30 minutes in the dissolution test in the pH 4.5 test solution according to the second method of the US Pharmacopoeia dissolution test item. 14. The pharmaceutical preparation according to claim 13, wherein the dissolution rate of the polygallylated L-proline is 80% or more within 10 minutes in the dissolution test in the pH 4.5 test solution according to the second method of the US Pharmacopoeia dissolution test item. 13. The pharmaceutical composition according to any one of claims 1 to 12, wherein the composition is for the prevention or treatment of diabetes, diabetes related diseases and diabetic complications. 13. The pharmaceutical composition according to any one of claims 1 to 12, further comprising at least one medicament selected from the group consisting of a diabetes remedy, a diabetic complication remedy, a hyperlipidemia remedy and a hypertension remedy. 20. The pharmaceutical composition according to claim 19, wherein the medicament is at least one therapeutic agent for diabetes or a therapeutic agent for diabetic complications. 21. The pharmaceutical composition according to claim 20, wherein said medicament is at least one selected from the group consisting of metformin, citagliptin, billagliptin, saxagliptin, linagliptin, anagliptin, allogliptin and gemigliptin A pharmaceutical composition.

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