JP7383320B2 - Extended release formulation containing limaprost - Google Patents

Description

Detailed description of the invention

〔Technical field〕
The present invention relates to a sustained-release preparation containing limaprost, and more specifically, it is capable of not only improving the stability of limaprost, but also maintaining an appropriate drug concentration of limaprost even with twice-daily dosing therapy. The present invention relates to a limaprost-containing sustained release formulation that can exhibit significant therapeutic effects.

[Background technology]
Limaprost ((E)-7-[(1R,2R,3R)-3-hydroxy-2-[(3S,5S)-(E)-3-hydroxy-5- Methyl-1-nonenyl]-5-oxocyclopentyl]-2-heptanoic acid) is a prostaglandin E1 derivative and is used as a prophylactic or therapeutic agent for peripheral circulation disorders. (Buerger's disease), lumbar spinal canal stenosis, etc.

Limaprost alfadex represented by the following chemical formula 2 is a compound in which limaprost is clathrated with α-cyclodextrin.

Limaprost is primarily formulated as an oral preparation using the limaprost alphadex form. The oral preparation on the market is an immediate-release preparation that is orally administered three times a day at a dose of 166.67 μg limaprost alfadex (5 μg as limaprost), and is available under the trade names Toa Opalmon (Toa ST) and Limamon Tablets. (Kanmi Yakuhin) and Opasto tablets (Yongjin Yakuhin) have been approved.

Limaprost and limaprost alphadex have a problem in that they are difficult to handle because they are relatively unstable at temperatures above room temperature or in the presence of small amounts of acids, bases, or moisture. Accordingly, research into formulations containing limaprost or limaprost alfadex has focused primarily on improving the stability of the drug.

Korean Patent No. 10-1504862 discloses a tablet with improved stability containing a mixture of limaprost alphadex and β-cyclodextrin in an amount of 30 to 99% by weight based on 100% by weight of the entire tablet. . However, the tablets are immediate-release preparations that are orally administered three times a day, and after the blood concentration is high at the time of administration, the blood concentration rapidly decreases over time due to its short half-life. patients may become irritated quickly by the drug and exhibit side effects such as decreased sensitivity. Furthermore, the tablets are manufactured using a freeze-drying method, which complicates the manufacturing process and is not efficient in terms of cost.

Therefore, not only can the stability of limaprost be improved, but also the drug concentration of limaprost can be properly maintained even in twice-a-day dosing therapy to improve patient compliance and dosing convenience. There is a need for the development of sustained release formulations that can exhibit therapeutic efficacy.

[Summary of the invention]
[Problem to be solved by the invention]
The purpose of the present invention is to provide a limaprost-containing drug that can not only improve the stability of limaprost, but also maintain the drug concentration of limaprost appropriately even with twice-daily dosing therapy and exhibit sustained therapeutic effects. The objective is to provide a release formulation.

[Means to solve the problem]
On the other hand, the present invention provides one or more active ingredients selected from the group consisting of limaprost and limaprost alphadex, ethyl cellulose as a sustained release agent, hydroxypropyl betadex as a first stabilizer, and a second stabilizer. Provides a sustained release formulation containing glyceryl behenate.

A sustained release preparation according to an embodiment of the present invention includes one or more active ingredients selected from the group consisting of limaprost and limaprost alfadex in an ethylcellulose matrix as a sustained release agent and as a first stabilizer. A sustained release granule in which hydroxypropyl betadex is dispersed; and glyceryl behenate as a second stabilizing agent.

In one embodiment of the present invention, the sustained release granules include one or more active ingredients selected from the group consisting of limaprost and limaprost alphadex and hydroxypropyl betadex as a first stabilizer dissolved in a solvent; It may be formed by kneading a mixture of ethyl cellulose as a sustained release agent and hydroxypropyl betadex as a first stabilizer.

In one embodiment of the present invention, the sustained release preparation may be formed by compressing the sustained release granules together with glyceryl behenate as a second stabilizer.

In one embodiment of the present invention, the active ingredient may be included in an amount of 0.001 to 1% by weight based on 100% by weight of the entire sustained release preparation.

In one embodiment of the present invention, the hydroxypropyl betadex may be included in an amount of 5 to 30% by weight based on 100% by weight of the entire sustained release formulation.

In one embodiment of the present invention, the ethylcellulose may be included in an amount of 30 to 65% by weight based on 100% by weight of the entire sustained release preparation.

In one embodiment of the present invention, the weight average molecular weight of the ethylcellulose may be 65,000 to 215,000.

In one embodiment of the present invention, the glyceryl behenate may be included in an amount of 1 to 20% by weight based on 100% by weight of the entire sustained release preparation.

When the sustained-release preparation according to one embodiment of the present invention was subjected to a dissolution test in water at 50 rpm according to the Korean Pharmacopoeia dissolution test method 2 (paddle method), the active ingredient was 20 to 40% in 1 hour. It may exhibit a release profile of 45-65% dissolution in 2 hours, 60-80% dissolution in 4 hours, and 80% or more in 8 hours.

On the other hand, the present invention
(i) obtaining a binding solution by dissolving one or more active ingredients selected from the group consisting of limaprost and limaprost alfadex and hydroxypropyl betadex as a first stabilizer in a solvent;
(ii) obtaining sustained release granules by kneading the binding liquid with a mixture of ethyl cellulose as a sustained release agent and hydroxypropyl betadex as a first stabilizer; and (iii) obtaining sustained release granules; Provided is a method for producing a sustained-release formulation, comprising the step of tabletting the same with glyceryl behenate as a second stabilizer.

In one embodiment of the invention, the solvent in step (i) may be water.

〔Effect of the invention〕
The limaprost-containing sustained-release preparation according to the present invention can provide a sustained delayed release of limaprost for 8 hours or more, and maintains an appropriate drug concentration of limaprost even with twice-daily dosing therapy, resulting in sustained therapeutic effects. can be shown. Therefore, the sustained-release preparation according to the present invention can improve a patient's compliance with taking medication and the convenience of taking it.

Furthermore, the limaprost-containing sustained-release preparation according to the present invention has the advantage of being able to improve the temperature and/or moisture stability of limaprost and being able to be manufactured more efficiently and economically.

[Brief explanation of the drawing]
[FIG. 1] A graph showing the dissolution patterns in water of sustained release preparations of Examples 8 to 9 and Comparative Example 5.

[FIG. 2] A graph showing the results of pharmacokinetic evaluation using animals of the limaprost-containing sustained release preparation of Example 9 (test drug) and Toa Opalmon tablets of Toa ST (control drug).

[Form for carrying out the invention]
The present invention will be explained in more detail below.

One embodiment of the present invention includes one or more selected from the group consisting of limaprost and limaprost alphadex as an active ingredient, ethyl cellulose as a sustained release agent, hydroxypropyl betadex as a first stabilizer, and a second stabilizer. The present invention relates to a sustained release formulation containing glyceryl behenate as an agent.

A sustained release preparation according to an embodiment of the present invention includes one or more active ingredients selected from the group consisting of limaprost and limaprost alfadex in an ethylcellulose matrix as a sustained release agent and as a first stabilizer. A sustained release granule in which hydroxypropyl betadex is dispersed; and glyceryl behenate as a second stabilizing agent.

A sustained-release preparation according to an embodiment of the present invention comprises dispersing an active ingredient and hydroxypropyl betadex as a first stabilizer in an ethyl cellulose matrix as a sustained-release agent to form sustained-release granules; By compressing the sustained release granules together with glyceryl behenate as a second stabilizer, limaprost can not only be released continuously for more than 8 hours, but also have stability against temperature and/or moisture. It can be improved.

In one embodiment of the present invention, the sustained release granules are prepared by dissolving the active ingredient and hydroxypropyl betadex as the first stabilizer in a solvent, ethyl cellulose as the sustained release agent, and hydroxypropyl betadex as the first stabilizer. It may be formed by kneading it into a mixture with propyl betadex.

In one embodiment of the present invention, limaprost is a drug used as an active ingredient to treat thromboangiitis obliterans (Buerger's disease) or lumbar spinal canal stenosis, or to improve symptoms of these diseases.

The limaprost may be used in the form of free base, pharmaceutically acceptable salt, racemate, enantiomer, polymorph, hydrate, solvate, clathrate, etc. The pharmaceutically acceptable salts include salts of inorganic acids such as hydrochloride, bromate, hydrobromide, hydroiodide, sulfate, nitrate, phosphate; and maleate; Salts of organic acids include fumarates, salicylates, succinates, citrates, acetates, lactates, tartrates, benzoates, methanesulfonates, and the like. The clathrate compound includes limaprost alphadex. Preferably, limaprost free base or limaprost alfadex may be used.

The content of limaprost (based on free base) may be used in the range of 0.005 mg to 0.03 mg, preferably in the range of 0.005 mg to 0.015 mg. In particular, for twice-daily dosing, each tablet may contain an amount of 0.0075 mg to 0.015 mg, such as 0.015 mg.

In one embodiment of the present invention, the active ingredient may be included in an amount of 0.001 to 1% by weight based on 100% by weight of the entire sustained release preparation.

In one embodiment of the present invention, the hydroxypropyl betadex is included in the binding solution and the mixture together with the active ingredient as a first stabilizer, and serves to primarily stabilize the active ingredient.

The hydroxypropyl betadex may be included in an amount of 5 to 30% by weight, preferably 10 to 25% by weight based on 100% by weight of the entire sustained release preparation. If the hydroxypropyl betadex is contained in an amount less than 5% by weight, the effect of improving stability may be insignificant, and if it is contained in an amount exceeding 30% by weight, it may be difficult to manufacture granules. .

The solvent may be water, for example purified water. By using water as the solvent, safety in administration can be ensured.

In one embodiment of the invention, the ethylcellulose serves as a sustained release agent for delayed release of limaprost.

The weight average molecular weight of the ethylcellulose may be 65,000 to 215,000, preferably 65,000 to 120,000. If the weight average molecular weight of the ethyl cellulose is less than 65,000, the viscosity may be low and the sustained release effect may be reduced; if it exceeds 215,000, the viscosity may be high and the sustained release effect may be excessively increased. Adjustment of elution rate may be difficult.

The ethylcellulose may be included in an amount of 30 to 65% by weight, preferably 40 to 55% by weight based on 100% by weight of the entire sustained release preparation. If the ethylcellulose is contained in an amount less than 30% by weight, the sustained release effect may be insignificant, and if it is contained in an amount exceeding 65% by weight, the sustained release effect may be excessive and dissolution rate adjustment may be difficult. It can be difficult.

In one embodiment of the present invention, the sustained release preparation may be formed in the form of a tablet by compressing the sustained release granules together with glyceryl behenate as a second stabilizer.

In one embodiment of the present invention, the glyceryl behenate is a second stabilizer and plays a role of secondarily stabilizing the active ingredient that is primarily stabilized in the sustained release granules. do.

The glyceryl behenate may be included in an amount of 1 to 20% by weight, preferably 1 to 15% by weight, based on 100% by weight of the entire sustained release preparation. If the glyceryl behenate is contained in an amount less than 1% by weight, the effect of improving stability may be insignificant, and if it is contained in an amount exceeding 20% by weight, a sustained release effect will be exhibited and the dissolution rate will be reduced. may affect.

The sustained release formulation according to one embodiment of the present invention may further include a pharmaceutically acceptable additive.

The pharmaceutically acceptable additives include diluents, binders, lubricants, disintegrants, fluidizing agents, and the like.

The diluent serves to improve the ease of tabletting and maintain the shape of the sustained release preparation. As the diluent, mannitol, microcrystalline cellulose, betadex, lactose, glucose, etc. may be used alone or in combination of two or more, and in particular, mannitol, microcrystalline cellulose, or a mixture thereof may be used.

The diluent may be included in an amount of 40% by weight or less, for example, 10 to 40% by weight, based on 100% by weight of the entire sustained-release preparation. If the diluent is contained in an amount exceeding 40% by weight, the proportion of sustained release agent added may be relatively low, resulting in a decreased sustained release effect.

The binder serves to increase the binding strength of the sustained release formulation. Examples of the binder include povidone; cellulose derivatives such as hydroxypropylcellulose and hydroxypropylmethylcellulose; gums such as xanthan gum, alginate, and gum arabic; saccharides such as starch, pregelatinized starch, and sucrose; or mixtures thereof. In particular, povidone may be used.

The binder may be included in an amount of 1 to 10% by weight, preferably 1 to 5% by weight, based on 100% by weight of the entire sustained release preparation. If the binder is included in an amount less than 1% by weight, granule formation may become difficult, and if the binder is included in an amount exceeding 10% by weight, the density of the granules may become high.

The lubricant improves the fluidity of the powder and granules, increasing the filling property into the die, which is the lower part of the tablet press, and also increases the filling properties between the powder and granules and between the powder and the tablet press. It serves to reduce the friction between the upper part of the punch and the die, making it easier to compress and release the tablet.

As the lubricant, hydrogenated castor oil, sodium stearyl fumarate, magnesium stearate, talc, etc. may be used, particularly hydrogenated castor oil.

The lubricant may be included in an amount of 0.5 to 10% by weight based on 100% by weight of the entire sustained release preparation. If the lubricant is contained in an amount less than 0.5% by weight, tableting may become difficult, and if it is contained in an amount exceeding 10% by weight, disintegration of the preparation may be delayed and the dissolution rate may be reduced. be.

When the sustained-release preparation according to one embodiment of the present invention was subjected to a dissolution test in water at 50 rpm according to the Korean Pharmacopoeia dissolution test method 2 (paddle method), the active ingredient was 20 to 40% in 1 hour. It may exhibit a release profile of 45-65% dissolution in 2 hours, 60-80% dissolution in 4 hours, and 80% or more in 8 hours.

By exhibiting the above-mentioned release profile, the sustained-release preparation according to one embodiment of the present invention can exhibit a sustained therapeutic effect even when administered only twice a day (Experimental Example 4, FIG. 1).

Furthermore, the sustained-release preparation according to one embodiment of the present invention has a limaprost content retention rate of 50% or more after open storage for two weeks under accelerated conditions (40°C/75% RH), and has an Alu- The generation rate of related substances can be reduced in an accelerated test (40° C./75% RH) using Alu packaging, and it has excellent stability against temperature and/or moisture (Experimental Examples 1 to 3, Tables 5 to 8).

One embodiment of the present invention relates to a method for manufacturing a sustained release preparation, and the manufacturing method of the present invention includes:
(i) obtaining a binding solution by dissolving one or more active ingredients selected from the group consisting of limaprost and limaprost alfadex and hydroxypropyl betadex as a first stabilizer in a solvent;
(ii) obtaining sustained release granules by kneading the binding liquid with a mixture of ethyl cellulose as a sustained release agent and hydroxypropyl betadex as a first stabilizer; and (iii) obtaining sustained release granules; with glyceryl behenate as a second stabilizer.

In one embodiment of the present invention, step (i) is a step of obtaining an active ingredient-containing binding liquid for forming sustained release granules.

A binder may further be used in step (i) above.

Detailed explanations regarding the active ingredient, first stabilizer, solvent, and binder are the same as those described above in connection with the sustained release formulation.

In one embodiment of the present invention, step (ii) is a step of kneading the active ingredient-containing binding liquid into a mixture of a sustained release agent and a first stabilizer to obtain sustained release granules.

Step (ii) may be performed using a high speed mixer.

In one embodiment of the present invention, step (iii) is a step of compressing the sustained release granules together with a second stabilizer, and may be carried out using a conventional tableting method.

In said step (iii), pharmaceutically acceptable additives, such as lubricants, may further be used with the granules.

A method for producing a sustained release preparation according to an embodiment of the present invention includes kneading a binding liquid containing limaprost and a first stabilizer into a mixture of a sustained release agent and a first stabilizer, as described above. After forming sustained release granules, the sustained release granules are compressed together with a second stabilizer through a wet granulation and tabletting process, which enables delayed release of limaprost and stability against temperature and/or moisture. Improved sustained release formulations can also be manufactured more easily and efficiently.

Hereinafter, the present invention will be explained more specifically using Examples, Comparative Examples, and Experimental Examples. Note that these Examples, Comparative Examples, and Experimental Examples are merely for illustrating the present invention, and it is obvious to those skilled in the art that the scope of the present invention is not limited thereto.

Example 1 and Comparative Examples 1 to 3: Production of limaprost sustained-release preparations based on the type of cyclodextrin Limaprost sustained-release preparations were produced according to the following method with the composition shown in Table 1 below (unit: weight %).

After preparing a binding solution by dissolving limaprost alphadex clathrate compound in purified water with povidone as a binding agent and betadex, hydroxypropyl betadex or gammadex as a first stabilizer, the binding solution is mixed with high speed stirring. Wet granules were obtained by putting the mixture into a high speed mixer and kneading it into a mixture of a diluent, a first stabilizer, and a sustained release agent. The obtained wet granules were dried at 50° C. using a fluidized bed dryer, and then a second stabilizer and a lubricant were added and tableted.

Examples 2 to 4: Manufacture of limaprost sustained release preparations according to the content of hydroxypropyl betadex.Limaprost sustained release preparations were prepared using the same method as in Example 1 with the composition shown in Table 2 below and varying the content of hydroxypropyl betadex. A formulation was manufactured (unit: weight %).

Examples 5 to 7 and Comparative Example 4: Manufacture of limaprost sustained release preparations according to the content of glyceryl behenate. A limaprost sustained release formulation was manufactured (unit: weight %).

Examples 8 to 9 and Comparative Example 5: Manufacture of limaprost sustained-release preparations according to the content of ethylcellulose.Limaprost sustained-release preparations were prepared according to the composition shown in Table 4 below and according to the same method as in Example 1, with different contents of ethylcellulose. manufactured (unit: weight %).

Experimental Example 1: Stability test depending on the type of cyclodextrin For the stability test depending on the type of cyclodextrin as the first stabilizer, the sustained release formulations of Example 1 and Comparative Examples 1 to 3 were subjected to accelerated conditions ( The content retention rate of limaprost after open storage at 40° C./75% RH was analyzed.

Limaprost content analysis was performed using high performance liquid chromatography (HPLC). Agilent 1200 series was used for HPLC, the column was C18 (5 μm, 4.6 x 150 mm), and the mobile phase was prepared with 0.02 M potassium dihydrogen phosphate buffer/acetonitrile/isopropanol (50/25/10). Detection was performed using a UV detector at 215 nm.

The results are shown in Table 5 below.

From Table 5, Example 1 in which hydroxypropyl betadex was added showed a significantly superior stabilizing effect, and Comparative Example 1 and Comparative Example 2 in which betadex or gammadex was added, and a comparison in which no stabilizer was added. It can be seen that Example 3 has poor stability.

Experimental Example 2: Stability test according to the content of hydroxypropyl betadex For the stability test according to the content of hydroxypropyl betadex as the first stabilizer, sustained release formulations of Examples 2 to 4 and two commercially available The limaprost content retention rate after open storage of the formulation under accelerated conditions (40° C./75% RH) was analyzed. Limaprost content analysis was performed in the same manner as described in Experimental Example 1 above.

The results are shown in Table 6 below.

From Table 6, it can be seen that as the content of hydroxypropyl betadex increases, the stability of the tablet against heat and moisture improves.

Additionally, an accelerated test (40°C/75% RH) in Alu-Alu packaging was conducted for Example 4 and commercially available formulation 1, which showed the results with the most improved stability. The rate of change of the 11-deoxy form of chemical formula a was measured using UPLC.

The results are shown in Table 7 below.

From Table 7, it was confirmed that Example 4 had a lower change rate of the related substance 11-deoxy than Commercial Preparation 1, and had better stability.

Experimental Example 3: Stability test based on the content of glyceryl behenate For a stability test based on the content of glyceryl behenate as the second stabilizer, the sustained release formulations of Examples 5 to 7 and Comparative Example 4 were tested. The content retention rate of limaprost after open storage under accelerated conditions (40° C./75% RH) was analyzed. Limaprost content analysis was performed in the same manner as described in Experimental Example 1 above.

The results are shown in Table 8 below.

From Table 8, it can be seen that as the content of glyceryl behenate increases, the stability of the tablet against heat and moisture improves.

Experimental Example 4: Dissolution rate test depending on the content of ethyl cellulose In order to investigate the change in dissolution rate depending on the content of ethyl cellulose as a sustained release agent, a dissolution test in water of the sustained release formulations of Examples 8 to 9 and Comparative Example 5 was conducted. went.

The dissolution test was conducted according to the Korean Pharmacopoeia dissolution test method 2 (paddle method) under the conditions of an eluent of 900 ml (water), a paddle rotation speed of 50 rpm, and a temperature of 37±0.5°C. After 1 hour, 2 hours, 4 hours, and 8 hours from the start of the test, the mixture was filtered through a 0.45 μm filter and analyzed using high performance liquid chromatography (HPLC).

The results are shown in Figure 1.

From Figure 1, it can be seen that as the content of ethyl cellulose as a sustained release agent increases, the increase in dissolution rate over time decreases, and that sustained release properties are not exhibited when ethyl cellulose as a sustained release agent is not contained. I understand.

Experimental Example 5: Pharmacokinetic evaluation using Beagle dogs The above Example 9 was used as a test drug, and Toa ST's Toa Opalmon Tablets (limaprost α-cyclodextrin clathrate compound) was used as a control drug. Pharmacokinetic studies were conducted as follows.

A total of 12 healthy beagle dogs were divided into two groups of 6 dogs each, and a cross-over experiment was conducted using oral drug administration. For accurate evaluation, animals were fasted from food for 12 hours before drug administration, and then experiments were conducted. Six tablets each of the test drug and control drug were orally administered with 20 to 30 mL of water. Venous blood was collected at predetermined time intervals after administration, and the blood was immediately centrifuged to collect plasma, which was then stored frozen. Limaprost in plasma was quantitatively analyzed using a liquid chromatography mass spectrometer (LC-MS/MS). The maximum blood concentration (Cmax) and the time to reach the maximum blood concentration (Tmax) were calculated from the blood concentration calculated based on the quantitative analysis results, and the relationship between the blood concentration of the administered drug and time was shown through this. A graph (AUCt) was obtained. The pharmacokinetic evaluation was finally evaluated based on the pharmacokinetic parameters (Cmax, Tmax, AUCt) calculated for the commercially available formulation (control drug) and sustained release formulation (test drug).

The results are shown in FIG.

From FIG. 2, the maximum blood concentration (Cmax) of the control drug and the test drug were 9.89 pg/mL and 13.26 pg/mL, respectively, and the time to reach the maximum blood concentration (Tmax) was 0.6 hr and 0.6 hr, respectively. 74 hr., and the AUCt of the control drug and test drug were 15.38 hr. each. pg/mL and 29.02hr. It can be seen that it shows pg/mL.

As a result of pharmacokinetic evaluation, the ratio of AUCt between the test drug and the control drug was approximately 1.26 when converted to administration of the control drug and test drug three times a day and twice a day, The ratio of Cmax was 1.34, which was an approximate value and showed similar results, and in the case of Tmax, it was confirmed that the test drug increased 0.14 hr more than the control drug. Through this, it was found that the drug release was delayed in the formulation according to the present invention, and it was confirmed that the drug was detected for up to 8 hours after administration, thereby exhibiting sustained release properties.

Although specific parts of the present invention have been described in detail above, those skilled in the art will understand that such specific descriptions are merely preferred embodiments and should not be construed as limiting the scope of the present invention. It is clear that there is no such thing. Those skilled in the art will be able to make various applications and modifications within the scope of the present invention based on the above content.

Therefore, it can be said that the substantial scope of the invention is defined by the claims and their equivalents.

3 is a graph showing the dissolution patterns in water of sustained release formulations of Examples 8 to 9 and Comparative Example 5. FIG. 3 is a graph showing the results of pharmacokinetic evaluation using animals of the limaprost-containing sustained release preparation of Example 9 (test drug) and Toa ST's Toa Opalmon tablets (control drug). FIG.

Claims (12)

Contains one or more selected from the group consisting of limaprost and limaprost alphadex as an active ingredient, ethyl cellulose as a sustained release agent, hydroxypropyl betadex as a first stabilizer, and glyceryl behenate as a second stabilizer. , sustained release formulation. Sustained-release granules, in which one or more active ingredients selected from the group consisting of limaprost and limaprost alphadex and hydroxypropyl betadex as a first stabilizer are dispersed in an ethylcellulose matrix as a sustained-release agent; and glyceryl behenate as a second stabilizer. The sustained release granules are prepared by dissolving one or more active ingredients selected from the group consisting of limaprost and limaprost alphadex and hydroxypropyl betadex as a first stabilizer in a solvent, and ethyl cellulose as a sustained release agent. The sustained release preparation according to claim 2, which is formed by kneading into a mixture with hydroxypropyl betadex as a first stabilizer. The sustained release preparation according to claim 2, wherein the sustained release preparation is formed by compressing the sustained release granules together with glyceryl behenate as a second stabilizer. The sustained-release preparation according to claim 1, wherein the active ingredient is contained in an amount of 0.001 to 1% by weight based on 100% by weight of the entire sustained-release preparation. The sustained-release preparation according to claim 1, wherein the hydroxypropyl betadex is contained in an amount of 5 to 30% by weight based on 100% by weight of the entire sustained-release preparation. The sustained-release preparation according to claim 1, wherein the ethylcellulose is contained in an amount of 30 to 65% by weight based on 100% by weight of the entire sustained-release preparation. The sustained release preparation according to claim 1, wherein the ethylcellulose has a weight average molecular weight of 65,000 to 215,000. The sustained-release preparation according to claim 1, wherein the glyceryl behenate is contained in an amount of 1 to 20% by weight based on 100% by weight of the entire sustained-release preparation. When a dissolution test was conducted in water at 50 rpm according to Korean Pharmacopoeia dissolution test method 2 (paddle method), the active ingredient was 20-40% in 1 hour, 45-65% in 2 hours, and 60-80% in 4 hours. %, the sustained release formulation according to claim 1, exhibiting a release profile of 80% or more dissolution in 8 hours. (i) obtaining a binding solution by dissolving one or more active ingredients selected from the group consisting of limaprost and limaprost alfadex and hydroxypropyl betadex as a first stabilizer in a solvent;
(ii) obtaining sustained release granules by kneading the binding liquid with a mixture of ethyl cellulose as a sustained release agent and hydroxypropyl betadex as a first stabilizer; and (iii) obtaining sustained release granules; A method for producing a sustained-release formulation, comprising the step of tabletting with glyceryl behenate as a second stabilizer. The manufacturing method according to claim 11, wherein the solvent in step (i) is water.