WO2013069897A1

WO2013069897A1 - Stabilised sustained-release preparation of sarpogrelate

Info

Publication number: WO2013069897A1
Application number: PCT/KR2012/008306
Authority: WO
Inventors: 이홍우; 최재승; 박종수; 남경태; 김지태
Original assignee: 근화제약주식회사
Priority date: 2011-11-08
Filing date: 2012-10-12
Publication date: 2013-05-16
Also published as: KR101534606B1; KR20130050877A

Abstract

The present invention relates to a sustained-release preparation comprising sarpogrelate or a pharmaceutically acceptable salt of sarpogrelate as a pharmaceutically active ingredient, wherein the sustained-release preparation comprises one or more hydrophilic macromolecular polymer, selected from hydroxypropyl methylcellulose, polyethylene oxide or a carbomer, in an amount of between 10 and 50 percent by weight with respect to the total weight of the preparation. Even when administered once a day, the sustained-release preparation has the same therapeutic effect as a fast-release tablet that is administered 3 times a day and thus the sustained-release preparation can substantially improve patient drug-taking compliance, and the preparation has an advantageous effect in long term storage in that the preparation is stable even when produced by a general wet granulation method.

Description

General specifications

The name of the foot

Stabilized Sustained-Release Formulations of Safoacrylate

Technical Field

The present invention is directed to a stabilized sustained release formulation of safoglylate or a pharmaceutically acceptable salt thereof.

Background

Hydrochloric acid sapogrelate (Sarpogrelate HC1), ie, (±) 2- (dimethylamino) -l-{[0- (m-methoxyphenethyl) phenoxy] methyl} ethylhydrogen succinate hydrochloride, 5 ᅳ HT2A serotonin receptor inhibitors are known to inhibit vasoconstriction, inhibit platelet formation, and inhibit vascular smooth muscle proliferation. Products that improve the ischemic symptoms such as pain and cold sensations have been commercially available.

Currently available commercially available safoglylate hydrochloride formulations are prescribed to take 100 mg three times a day, which is inconvenient for medication. In addition, safoglylate is an adjuvant drug mainly administered in combination with a diabetic agent, and in the case of a patient administered in combination with a diabetic agent administered once a day, there is a problem in that the adjuvant drug should be taken three times a day. Therefore, there is a demand for the development of a sustained release formulation of safoglylate that has the same effect as three doses once daily.

On the other hand, the technology for sustained release of rapid-release preparation is already widely used in the art. Republic of Korea Patent Publication No. 10-2007-0021565 relates to a sustained-release tablet metformin and a method for manufacturing the same, and to release the sustained-release preparation by slugizing the composition containing the sustained-release polymer at a pressure of a predetermined condition and then compressed according to the dry granulation method Methods of making are described. U. S. Patent No. 3,458, 622 also describes the preparation of a sustained release tablet using a combination of povidone and carbomer.

However, there are some difficulties in applying safograte hydrochloride to such general sustained release techniques. The first is that the group of safoglylate hydrochloride is very short at 0.8 hours, and in the case of fast-release tablets it is absorbed very quickly at this 0.4 hour, reaching the maximum blood concentration. The second is the stability of the main component, and safoglylate hydrochloride is represented by the following structural formula when exposed to moisture, such as BP-984 (l- (Dimethylamino) 3- [2- [2- (3-met hoxypheny 1) ethyl] -2 -propanol hydrochloride) or a flexible substance called Ml is produced, Excessive generation of these analogs in tablets can lower the active ingredient content of the drug and cause problems in quality control.

Moreover, in order to have the same effect as three doses once a day, it is necessary to develop a formulation having both rapid and sustained-release tablet properties. In general, a sustained release formulation is designed with a bilayer tablet of a rapid release layer and a sustained release worm. In the case of a matrix sustained release formulation, the drug is released at a constant rate at a substantially constant rate from the beginning to the end of the release to a blood concentration at which the drug can be expressed. This is because it takes a long time to increase the initial blood concentration by adding an immediate layer. In particular, drugs with shorter half-lives (e.g., 7 hours), such as safoglylate, may have a longer time to reach the efficacious blood levels when the initial release rate is low, which may lead to failure to reach effective blood concentrations. The preparation of safoglylate monolayer tablets in sustained release formulations is very difficult. In order to solve the above problems, the inventors of the present invention conducted a simulation to secure a blood concentration pattern suitable for once-a-day administration in consideration of the pharmacokinetic characteristics of safoglylate hydrochloride and its metabolite Ml. In spite of its short half-life, we have developed a single-dose safoacrylate sustained-release monolayer formulation that can be used once daily to provide continuous pharmacological effects in the human body. In addition, the long-term stability of the product was secured by adding an appropriate stabilizer to compensate for the unstable disadvantages of water and alkali. Detailed description of the invention

Technical challenge

It is an object of the present invention to provide a sustained release formulation of safoglylate which can be administered once daily and has improved stability. Technical solution

The present invention provides a sustained release formulation comprising safoglylate or a pharmaceutically acceptable salt of safoglylate as a pharmacologically active ingredient, wherein the hydrophilic polymer is one or more of hydroxypropylmethylcellose, polyethylene oxide, or carbomer. It provides a sustained release formulation comprising 10 to 50% by weight relative to the total weight of the formulation.

According to one embodiment of the invention, the preparation is citric acid, citric acid anhydride, succinic acid, It may further comprise a stabilizer of at least one of L- glutamic acid, L- malic acid, boric acid, tartaric acid, lactic acid or fumaric acid.

According to another embodiment of the present invention, the preparation may further comprise a lubricant of at least one of stearic acid, magnesium stearate, talc or colloidal silicon oxide.

According to another embodiment of the present invention, the pharmaceutically acceptable salt may be a hydrochloride salt.

According to another embodiment of the present invention, the dissolution rate of the sustained release formulation may be 20-50% at 4 hours, and 60-100% at 24 hours. Favorable effect

The safoglylate sustained release formulation of the present invention has a therapeutic effect equivalent to that of the rapid release tablet administered three times a day even once a day, and can greatly improve patient compliance. In addition, it is stable in manufacturing by general wet granulation method, which is advantageous for long term storage. Brief description of the drawings

1 is a graph showing the dissolution test results of the preparation prepared in Comparative Example 2.

Figure 2 is a graph showing a comparison of the dissolution test results of the formulations prepared in Examples 2-12 and Comparative Example 3.

Figure 3 is a graph showing the dissolution test results of the formulations prepared in Examples 2-1 to 2-3.

Figure 4 is a graph showing a comparison of the dissolution test results of the formulations prepared in Examples 2-3 to 2-5.

Figure 5 is a graph showing the amount of change of BP-984 over time of the formulations prepared in Examples 2-3 and 2-6 to 2-11.

FIG. 6 is a graph showing sarpogrelate concentrat ion at the time of reference and test. FIG. FIG. 7 is a graph showing Ml blood concentration (active metabolite concentrat ion) at the time of reference and test (test).

8 is a graph showing the blood concentration of safoglylate at the time of the control agent and the test agent.

9 is a graph showing the Ml blood concentration at the time of the control agent and the test agent. Best Mode for Carrying Out the Invention The present invention relates to sustained release formulations comprising, as pharmacologically active ingredients, safoglylate or pharmaceutically acceptable salts of safoglylate, specifically the total weight of the formulation By including 10 to 50% by weight relative to the sustained release formulation that is continuously eluted in the body for 1 day even when prepared in a monolayer formulation. Sustained-release preparations of the present invention include safoglylate or a pharmaceutically acceptable salt of safoglylate as a pharmacologically active ingredient.

The sustained release formulation of the present invention is an additive for delayed release, which includes a hydrophilic polymer, and the hydrophilic polymer includes acacia rubber, tragacanth rubber, locust bean rubber, guar rubber, karaya gum, agar, pectin, cara Long, soluble or insoluble alginic acid salt, methyl cellulose, hydroxypropyl methyl sulfide, carbomer, polyethylene oxide, hydroxy propyl cellulose, hydroxyethyl cellulose, sodium carboxymethyl cellulose, carboxypoly Methylene, gelatin, casein, zein, bentonite, natural or synthetic anionic or nonionic hydrophilic rubbers, modified cellulose based materials and protein based materials, preferably hydroxypropylmethylcell. One selected from the group consisting of rose, polyethylene oxide and carbomer The material may be.

The hydrophilic polymer is preferably one having a viscosity of 5 ~ 1,000,000cps more preferably more preferably has a viscosity of 4,000 ~ 100,000cps. If 4,000cps US polymer is used, the durability of the tablet is lowered after administration, which may lead to rapid drug release. If the polymer exceeds l, 000,000cps, the release is too late and it is difficult to expect a therapeutic effect. The hydrophilic polymer may be added in an amount of 10 to 50% by weight based on the total weight of the preparation, and more preferably 20 to 40% by weight. If less than 10% by weight, drug release is fast, and continuous release control is difficult. If it exceeds 50% by weight, release of the active ingredient is too slow to reach a blood concentration that exhibits a therapeutic effect. In addition, the sustained-release preparation of the present invention may further comprise a stabilizer, the stabilizer is an acidic material that maintains the stability of sapoglylate which is unstable to alkali and moisture, preferably a pharmaceutically acceptable acidifying agent. Do. Specifically, the stabilizer may be one or more of citric acid, citric anhydride, succinic acid, L- glutamic acid, L- malic acid, boric acid, tartaric acid, lactic acid or fumaric acid, but is not limited thereto. The stabilizing agent contains 0.1 to 10% by weight relative to the total weight of the formulation, and may be good. If less than 0.1% of the acidifying agent is used, the stabilizing effect of the acidifying agent may be less. May be acidified more than necessary to indicate an adverse reaction with other additives. Sustained release formulations of the present invention may further comprise a glidant, which may be one or more of stearic acid, stearic acid magnesium, talc or colloidal silicon oxide. In addition, the lubricant is preferably in the form of a powder. The lubricant is preferably included 0.1 to 8% by weight relative to the total weight of the formulation, more preferably 0.5 to 3% by weight may be included. Pharmaceutically acceptable salts of the safoglylate include acid addition salts and quaternary ammonium salts. Acid addition salts include inorganic acid salts such as hydrochloride, hydrobromide salt, iodide hydrochloride sulfate, and phosphate salts, oxalate salts, maleic acid salts, fumaric acid salts, lactic acid salts, malic acid salts, succinic acid salts, tartaric acid salts, benzoic acid salts, and methanesulphate. Organic acid salts, such as a fon acid salt and a citric acid salt, are mentioned, As a quaternary ammonium salt, Lower alkylhalogenides such as methyl iodide, methyl bromide, ethal iodide, ethyl bromide, methylmethanesulfonate, and the like. Lower alkylsulfonates such as ethylmethanesulfonate, and lower alkylarylsulfonates such as methyl-p_luenesulfonate, and the like, and safoglylate hydrochloride is preferably used. In the following examples of the present invention, the safoglylate hydrochloride is mainly described, but the scope of the present invention is not limited to the safoglylate hydrochloride. Sustained release formulation of the present invention, elution 20 to 50% in 4 hours, 24 hours

It may be 60 to 100%, specifically 20 to 40¾ in 4 hours, 40 to 60% in 10 hours, 80 to 10 ° in 24 hours. The sustained release formulation according to the present invention is characterized in that it shows a continuous dissolution pattern of the pharmacologically active ingredient which can be achieved in a multilayer formulation even in a monolayer formulation.

Single-layer formulations have the advantage of significantly lower manufacturing costs than two-layer formulations. While the monolayer manufacturing process goes through granulation, tableting, and coating, the bilayer manufacturing process requires a separate preparation of granules in the immediate release layer and the sustained release layer. In addition, in order to tablet double-layer tablets, a double-layer tablet press is required. Since double-layer tablet presses have higher equipment prices than single-layer tablet presses, and the tableting speed is slower than that of single-layer tablet presses, it requires a lot of cost to tablet the same amount. Shall be. Therefore, the present invention has the advantage of maximizing the production efficiency by the single-layered tablet having the same effect as the two-layered tablet. The inventors of the present invention have shown that safoglylate is not used for fast-acting drugs such as cold medicine or painkillers, but is used for chronic diseases, and the pharmacological effect of the active metabolite Ml is 5 to 10 times higher than the parental sapoglylate. The literature review indicated that it was possible to design single-dose, sustained release formulations daily, and this was demonstrated through animal studies and clinical trials in humans. That is, the formulation of the present invention is characterized by being able to maintain the drug efficacy duration while maintaining the drug expression time of the pharmacologically active ingredient. Therefore, the preparation of the present invention can be prepared in an economical and easy way, compared with the case of preparing in a multi-layered formulation, and has the same therapeutic effect as the rapid-release tablet administered three times a day even once a day. Compliance can be greatly improved. Embodiment for Invention

Hereinafter, the present invention will be described in more detail through the following test. However, these examples are only for illustrating the present invention, and the present invention is not limited in any way by these examples. Example 1 Preparation of Safoacrylate Compositions Containing Stabilizers

In an aqueous solution of lOmg / ml safoglylate (purchaser, manufacturer: Hanseochem Co., Ltd.), citric acid (Samjeon Chemical),

Citric anhydride (samjeonchem), tartaric acid (samjeonchem), succinic acid (samjeonchem), lactic acid (samjeonchem), L-glutamic acid (samjeonchem), and fumaric acid (samjeonchem) to 0.5mg / ml Examples 1-1 to 1-7, which were safoglylate compositions containing stabilizers, were prepared by addition.

[Table 1]

Example 2: Preparation of Sustained-Release Formulations of Safoglycerate Hydrochloride

(1) Preparation of Examples 2-1 to 2-5

Safoglycerate hydrochloride (Hanseocam) hydroxypropylmethylcelose 2208 (75HD-100000, Shandong HEAD), carbomer according to the composition of Examples 2-1 to 2-5 of Table 2

934P (Carbopol 934P, Lubrizol), polyethylene oxide (PolyOX Coagulent,

Lor con), lactose monohydrate (200M, DMV) through a No. 30 sieve and mixed

Hydroxypropylmethylcellose 2910 (6 cps, Shinetsu) was associated with a binding solution dissolved in purified water (0.2 ml / tablet). The association was dried at 60 ^° C. and then lowered to No. 18 to form granules with a constant particle size distribution. Put stearic acid into granulator

After adding magnesium (FACI), the mixture was mixed for 3 minutes to obtain a final mixture. The mixture was compressed to prepare Examples 2-1 to 2-5.

Table 2

(Unit: mg / tablet) (2) Preparation of Examples 2-6 to 2-11

According to the composition of Table 3, safoglylate hydrochloride,

After hydroxypropyl methylcellulose 2208 was sieved through a No. 30 sieve,

Hydroxypropylmethylcellose 2910 and each stabilizer were associated with a binder solution dissolved in purified water (0.2 ml / tablet). The union was dried at 60 ^o C and then lowered into a sieve of No. 18 Granules with a particle size distribution were formed. The granules were placed in a mixer and stearic acid magnesium was added and mixed for 3 minutes to obtain a final mixture. The mixture was compressed to prepare Examples 2-6 to 2-11.

Table 3

(Unit: mg / tablet)

(3) Preparation of Examples 2-12

According to the composition of Table 4, safoglylate hydrochloride,

Hydroxypropylmethylcellose 2208 (75HD-100000 ， Shandong head),

Lactose hydrate (DMV) was sieved through a No. 30 sieve and mixed, and then hydroxypropylmethylcellose 2910 (6 cps, Shinetsu) was associated with a binder solution dissolved in purified water (0.2 ml / tablet). The association was dried at 60 ^° C. and then passed through a sieve of No. 18 to form granules with a constant particle size distribution. The granules were placed in a mixer and magnesium stearate (FACI) was added and then mixed for 3 minutes to obtain a final mixture. This mixture was compressed to prepare Example 2-12.

Table 4

Comparative Example 1: Preparation of Aqueous Solution of Safoglylate Hydrochloride

Safoglylate (Purchased, Manufacturer: Hanseo Chem) was dissolved in water to prepare a 10 _mg / ml solution. Comparative Example 2: Preparation of General Formulation of Safoglylate Hydrochloride

According to the composition of Table 5, safoglylate hydrochloride (Hanseochem),

Lactose hydrate (DMV) was sieved through a No. 30 sieve and mixed, and then hydroxypropylmethylcellose 2910 (606, Shinetsu) was combined with a binder solution dissolved in purified water (0.2 ml / tablet). this The union was dried at 60 ° C. and lowered into a sieve of No. 18 to form granules with a constant particle size distribution. The granules were placed in a mixer and magnesium stearate (FACI) was added and then mixed for 3 minutes to obtain a final mixture. The mixture was compressed to prepare Comparative Example 2.

Table 5

Comparative Example 3: Preparation of Safoacrylate Hydrochloride Formulation with Small Amount of Polymeric Polymer

Comparative Example 3 was prepared in the same manner as in Examples 2 to 12, except that the content of the hydrophilic polymer was changed.

Table 6

Experimental Example 1 Severity Test of Safograte

When safoglylate hydrochloride is exposed to a specific environment, a chemical change occurs and it becomes a flexible substance (ΒΡ-984). Since the change of the safoglylate to the flexible material (ΒΡ-984) in the tablet means that the impurities are increased, in order to confirm the stability of the safoglylate under the conditions of Table 7 (i) to (vii) The degree of formation of analog (BP-984) was determined under each condition.

That is, Comparative Example 1 was divided into 50 ml volumetric flasks each 10 ml, water (ii), 0.1 N hydrochloric acid solution (iii), 0.1 N sodium hydroxide solution (iv), 0.6% as shown in Table 7 below.

Hydrogen peroxide solution (V) was added and reacted under each storage condition. After completion of reaction, add 0.1 N hydrochloric acid solution and 0.1 N sodium hydroxide solution to the flask.

Sodium hydroxide and 0ΛΝ hydrochloric acid solution were neutralized by adding K l, and water was added to 5 (l) to adjust the content of the flexible substance by using the liquid chromatograph method. Only Comparative Example 1 was stored at room temperature for 24 hours. As control group (i), only Comparative Example 1 was stored at 100 ° C. for 3 hours to observe the effect of heat.

Analog (BP-984) was measured.

[Table 7]

Specifically, the flexible material (BP-984) included in each sample

The liquid chromatography (HPLC) was used under the following conditions.

Column ： C18, 4.6X150 匪， 5 / tii

Mobile phase ： Water / Acetonitrile / Trifluoroacetic acid = 1000/700/1

Flow rate: 1.2 ml / min The flexible substance measurement results are as shown in Table 8 below.

Table 8

Test Results As shown in Table 8, ^■ Safoglylate hydrochloride was very unstable as it was mostly changed to BP-984 in strong alkali environment (iv), and more than 50% of main component was BP-984 even under both water and heat effects (vii). It appears to be unstable enough to change to. The sample (Π) simply dissolved in water produced 0.6% of BP-984, and 0.3% of BP-984 was detected under acidic conditions (iii), which was the most stable among the test groups.

Based on these test results, it was judged that it would be advantageous to add an acidifying agent to ensure the stability of the drug containing safoglylate. Experimental Example 2 Stabilizer Evaluation Experiment

Example 1-1 to 1-7, and stored for 1 week at 60 ° C. The content change of BP-984 in the same manner as in Experimental Example 1 was measured. Comparative Example 1, an aqueous solution of safoglylate without stabilizer, was used as a control, and the results are shown in Table 9.

Indicated.

Table 9

Example 1-7 I L-Glutamine ^ 0.04 1.03 3.25 4.14 5.26 Test Results As shown in Table 9, the amount of BP-984 increased from the initial 0.05% to 15.14% for the control group, while Example 1- with the addition of a stabilizer. 1 to 1 to 7 was 4.2 to 8.2%, and about 30 to 50% of the flexible material was produced compared to the control. Experimental Example 3 Evaluation Test of Dissolution of Sustained-Release Formulation

The sapoglylate hydrochloride preparation of the present invention prepared in Example 2 was subjected to a dissolution test by the method 2 paddle method in the dissolution test section of the Korean Pharmacopoeia general test method, and the drug in the sample was measured at ultraviolet VIS at 260 nm. Measured. From the measured absorbance values, the dissolution rate of safoglylate hydrochloride was calculated from the following equation.

(1) Elution pattern of preparation without adding polymer

The dissolution test of the safoglylate hydrochloride preparation prepared in 2 was compared and the results are shown in Table 10 and FIG. 1.

TABLE 10

(unit : %)

Referring to Table 10 and FIG. 1, the preparation without the polymer polymer (hydroxypropylmethylcellulose) disintegrates tablets from the initial dissolution to rapidly release the drug and elutes at least 90% in 15 minutes. The release pattern was very different from the sample to which the polymer was added. Therefore, it was not possible to obtain a sustained release pattern with a formulation in which the polymer was not added.

(2) Comparison of elution patterns according to the polymer addition amount

The dissolution test of the safoglylate hydrochloride sustained release formulations prepared in Examples 2-1 to 2-3, Examples 2-12, and Comparative Example 3 was performed, and the results are shown in Tables 11, 12, and FIGS. 2 and 3 below. It was.

Table 11

Referring to Table 11 and Figure 3, prepared in Examples 2-1 to 2-3

As a result of the elution test of the safoacrylate hydrochloride sustained release formulation, all samples showed a sustained release dissolution pattern. Example 2-1 in which the amount of hydroxypropylmethylcellose of 100,000 cps was 20% and Example 2-2 in 25% showed similar dissolution rates. The elution was about 10% lower at 10 hours than the two samples. In addition, referring to Table 12 and FIG. 2, Comparative Example 3, in which 5% of the polymer is added, exhibits a delay effect of about 80% release in 6 hours, compared to Comparative Example 3, in which the polymer additive is not added. It is difficult to use as a dosage form to be taken once daily. On the other hand, as a result of the dissolution test of Example 2-12 with the addition of 10% of the polymer, the release delay effect of 85% was released in 12 hours, and this release pattern was sustained by the gastrointestinal retention time and metabolic process in the body. It is expected to be possible.

(3) Comparison of Dissolution Patterns According to Polymer Types

The dissolution test of the safogrelate hydrochloride sustained release formulations prepared in Examples 2-3 to 2-5 were performed, and the results are shown in Table 13 and FIG. 4.

Table 13

(Unit:%) Referring to Table 13 and FIG. 4, the dissolution rates of Example 2-3 using hydroxypropylmethylcellulose and Example 2-5 using polyethylene oxide are similar to each other. Example 2-4 using a carbomer showed a rapid dissolution until the first hour, but after the elution was slowed down, the dissolution rate was about 50% at 12 hours.

(4) Comparison of Dissolution Patterns by Stabilizer Type

The dissolution test of the safogrelate hydrochloride sustained release formulation prepared in Examples 2-6 to 2-11 was carried out, and the results are shown in Table 14 below.

Table 14

(Unit:) Experimental results showed no significant difference in dissolution rate of each sustained release formulation according to the type of stabilizer. Experimental Example 4 Stability Evaluation Experiment of Sustained-Release Formulation

Formulations of Examples 2-3 and 2-6 to 2-11 in High Density Polyethylene (HDPE) Bottles

After packaging and stored at 40 ^° C. and 75% humidity conditions, the production of BP-984 was observed for 6 months and the results are shown in Table 15 and FIG. 5.

Table 15

As a result of the test, in Example 2-3, BP # 984 was generated about 1.3% at 6 months, Example 2-6 using citric anhydride, Example 2-11 using fumaric acid, and tartaric acid. The BP-984 content of Example 2-7 was lower than 0.6%, Example 2-8 using succinic acid was 0.6%, Example 2-10 using L-glutamic acid and lactic acid showed 0.7% of Most of the examples in which BP-984 occurred and the acidifier was added showed more than 60% less BP-984 content than Example 2-3 without the acidifier. Experimental Example 5. Pharmacokinetic Test of Sapoglylate and Active Metabolite Ml in Animals (Beagle Dogs) Example 2 Using Anplag tablets (Yuhan Corporation), a immediate release formulation of safoglylate hydrochloride, as a control agent, Example 2 Pharmacokinetics for Beagle Dogs Using -6 As a Test Product Test was made. 12 healthy beagle dogs were divided into 2 groups of 6 dogs each. In the first group, the control agent was orally administered 3 times a day, 1 tablet (lOOmg as safoglylate hydrochloride) every 6 hours, and in the second group. There is a test preparation once a day, once

One tablet (300 mg as safoglycerate hydrochloride) was orally administered. After oral administration, test preparations were collected up to 24 hours post-dose and control preparations up to 28 hours, and the concentrations of sapoglylate and active metabolite Ml in plasma were quantified by LC—MS / MS. The results are shown in Table 16 and FIGS. 6 and 7.

Table 16

* 2 C _max : Maximum blood concentration

* 3 T _max : Time to reach peak blood concentration

* 4 T _1/2 : Disappearance Half-Life Test Results As shown in Table 16 and FIGS. 6 and 7, for AUC and C _max .

Based on the test / control ratio, sapoglylate and Ml were 0.44 ~ 0.65, which was about 50% lower than the _immediate release preparation.

The delay was 0.67 hours to 1.2 hours and the Ml was delayed from 0.8 hours to 3.8 hours. Lastly, the half-life T _1/2 was increased by 3.8 times in sapoglylate and 2.15 times in Ml. This blood concentration pattern can be said to prove the development of a safoacrylate sustained release formulation. Experimental Example 5. Pharmacokinetic Test of Safoglylate and Metabolite M-1 in Humans

A pharmacokinetic test was carried out on humans using Anflag tablets (Yuhan Corporation), a rapid-release preparation of commercially available safoglylate hydrochloride, as a control formulation and Example 2-6 as a test formulation. A total of 18 healthy adult male subjects were randomized and divided into 9 groups, each grouped into 9 groups, and the control and test agents were repeatedly administered for 4 days, and the sapoglylate and active metabolism Ml in plasma for 24 hours on the 4th day of repeated administration. Concentration

Quantification by LC-MS / MS. In addition, the control agent and the test agent were cross-administered after a period of inactivity. The results are shown in Table 17 and FIGS. 8 and 9.

Table 17

T _1/2 ⁴ (hr) 0.64 2.66 4.16 4.98 I 7.10 1 1.43

* 1 AUC ₀ -24, ss: Area under the blood concentration-time curve up to 24 hours after repeated administration

* 2 C _ma x, ss: Maximum blood concentration after repeated administration

* 3 T _max : Time to reach peak blood concentration

* 4 Ύ _{ι / 2} : Results of the disappearance half-life test As shown in Table 17 and FIGS. 8 and 9, the AUC at steady state after administration was 1.09, and the active metabolism was Safoglylate whose parental ratio was the ratio of the test drug to the control agent. The body Ml is 1.02, which means that three doses of immediate release and one sustained release formulation are equivalent in the amount absorbed by circulating blood. On the other hand, _Cmax , the maximum blood concentration at steady state, was found to occur at high blood levels when the immediate release product was lowered because the sustained-release product was about half of the immediate release product as the test / control ratio was 0.41 and Ml was 0.61. In addition, the time to reach the maximum blood concentration was delayed by 7 times for both safoglylate and Ml, and the half-life was increased by 4 times for safoglylate and 1.4 times for Ml, which resulted in sustained release. It shows a typical characteristic. Industrial availability

The safoglylate sustained release formulation of the present invention has a therapeutic effect equivalent to that of the rapid release tablet administered three times a day even with a once-daily administration, and can greatly improve the patient's medication route.

Claims

Claim

[Claim 1]

In the sustained release formulation comprising safoglylate or a pharmaceutically acceptable salt of safoglylate as a pharmacologically active ingredient,

A sustained release formulation comprising 10 to 50 weight percent of a hydrophilic polymer of at least one of hydroxypropylmethylcellose, polyethylene oxide or carbomer relative to the total weight of the formulation.

[Claim 2]

The method according to claim 1, ^"a sustained release preparation containing a citric acid, anhydrous citric acid, succinic acid, L- glutamic acid, L- malic acid, boric acid, tartaric acid, lactic acid or fumaric acid, addition of one or more stabilizers of the.

[Claim 3]

The method according to claim 1,

A sustained release formulation further comprising at least one lubricant of stearic acid, magnesium stearate, talc or colloidal silicon oxide.

[Claim 4]

The method according to any one of claims 1 to 3,

The pharmaceutically acceptable salt is a hydrochloride salt.

[Claim 5]

The method according to any one of claims 1 to 3,

A sustained release formulation having a dissolution rate of 20-50% in 4 hours and 60-100% in 24 hours.