KR101118866B1 - Pulsatile drug delivery system and producing method thereof - Google Patents

Abstract

The present invention provides an internally releasing compartment comprising nicolandil and a stabilizer; A release inhibiting compartment surrounding said internally releasing compartment and not containing nicorandil; And an external release-releasing compartment surrounding the release-suppressing compartment and comprising nicolandil and a stabilizer, and a method of manufacturing the same.

The pulsatile releasing preparation of the present invention is easy to manufacture, and it is not only possible to make wet preparation methods such as wet granules and coatings, but also to reduce the number of doses of the drug and improve medication compliance, while having an advantage of being small in size and easy to take.

Nicolandil, Pulsatile Release Formulations

Description

Pulsatile drug delivery system and producing method

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to pulsatile releasing preparations containing nicolandil, and more particularly, to languid-containing pulsatile releasing preparations which are easy to manufacture and a method for producing the same.

Nicorandil is an effective drug for the treatment of angina with vasodilation, but side effects such as headaches occur frequently at high doses, and ulcers occur in various parts of the body such as the anus, genitals and lower extremities when taken for a long time. (European journal of gastroenterology & hepatology, Vol. 19 (5), 2007: pp 395-398).

In order to avoid the risk of taking high doses, it is necessary to take the medicine divided into several times a day, but in this case, there is a problem such as poor compliance, and when formulated as a persistent drug to reduce the number of doses, side effects occur due to high blood concentration. There is a fear that the period will be shorter or more frequent.

International Publication No. WO 99/059552 describes the preparation of pulsed preparations using drugs such as nicorandil, nifedipine, propranolol, to reduce the worsening of symptoms caused by non-compliance, and the side effects of conventional sustained-release preparations (headaches). , Chills) and the like, the inner core portion containing the drug to be controlled for release, the release control layer containing no drug to be controlled for release, and the drug to be controlled to release. Disclosed is a pulsed formulation comprising a drug release layer containing.

However, the international patent discloses a method for producing a pulsed preparation of nicolandil, a nuclear tablet including a drug is prepared, and coated with a controlled release layer to prepare an inner nuclear tablet, and the inner nuclear tablet as a nuclear tablet It is based on the method of repeating the process of coating again with an emitting layer comprising a. To this end, it is difficult to use a specially manufactured device or to repeatedly perform at least two unit processes in order to prepare one unit formulation.

In addition, fumaric acid, which is disclosed as the main release control substrate constituting the release control layer disclosed in the above International Patent Publication, may cause renal gastrointestinal disorders and flushing with excessive doses, resulting in thickening of the release control layer due to excessive use. As a result, the size of the pulsed preparation may be increased.

The inventors of the present invention have completed the present invention as a result of studying nicolandyl-containing pulsatile preparations that are easy to manufacture, and have high safety and effectiveness.

The technical problem to be achieved by the present invention is to provide a nicorandil-containing pulsatile formulation that is easy to manufacture and has a small size while improving medication compliance by reducing the number of doses of the drug.

In addition, the technical problem to be achieved by the present invention is to provide a method for producing a nicolandyl-containing pulsatile preparation.

The present invention provides an internally releasing compartment comprising nicolandil and a stabilizer; A release inhibiting compartment surrounding said internally releasing compartment and not containing nicorandil; And an outward-releasing compartment surrounding the release-inhibiting compartment and comprising nicolandil and a stabilizer.

The nicolandil preferably contains 5 to 60 mg in an amount corresponding to an adult daily dose for one unit of the pulsatile release agent. Nicorandil contained in one unit of this formulation can be released according to the planned time in units of 2.5 to 20 mg per single release, depending on the purpose of the formulation design.

The pulsatile release preparation of the present invention provides a pulsatile release preparation having a release-suppressing compartment and an immediate release compartment in order to the outer layer in sequence, and the number of pulsatile releases can be adjusted according to the added number.

Stabilizers included in the pulsatile release formulation of the present invention are for increasing the stability of nicorandil, and are fumaric acid, oxalic acid, and / or sodium stearyl fumarate, and the like, preferably sodium stearyl fumarate. Stabilizing agent is 0.25 to 1 part by weight with respect to 1 part by weight of nicorandil in the formulation, the role of the stabilizer may be insufficient if less than 0.25 part by weight, it may affect the release rate of the drug when more than 1 part by weight There is.

The inward release compartment and / or the outward release compartment may be prepared by dissolving or suspending nicorandil, and / or stabilizer in anhydrous ethanol. Specifically, a stabilizer insoluble in nicolandyl on anhydrous ethanol is suspended, and the soluble stabilizer is dissolved and prepared by a method such as preparing tablets by preparing granules or the like with an appropriate excipient or forming a coating layer with a coating solution. It is possible. Nicorandil and stabilizer may be added to anhydrous ethanol simultaneously or sequentially.

The inward release compartment and the outward release compartment may comprise a general pharmaceutically acceptable excipient for formulation, and an excipient with a controlled water content is preferred for the stability of nicolandil. For example, sugars such as mannitol, spray dried mannitol, maltose, spray dried maltose, xylitol, spray dried xylitol, maltitol, spray dried maltitol, sorbitol, and / or spray dried sorbitol, starch As the pregelatinized starch and the like, but is not limited thereto. These excipients may be used in admixture with the stabilizer and nicorandil, or may be prepared in granular form by addition to anhydrous ethanol solution of nicorandil and stabilizer.

In addition, pharmacologically acceptable disintegrants for rapid release of the drug can be used sodium starch glycolate, croscarmellose sodium, cross-linked polyvinylpyrrolidone, ion exchange resins, etc., to control the water of these disintegrants One is preferable.

In addition, a film coating base may be used to form a film coating layer, and for example, thickeners such as hydroxypropylmethyl cellulose, ethyl cellulose, and / or polyvinyl alcohol; Or / and polyethylene glycol; And / or plasticizers such as castor oil.

The release-suppressing compartment serves to suppress the release of the drug for a predetermined time to the coating layer of the inner-release-releasing compartment, and preferably suppresses the release of nicolandil of the inner-releasing compartment for at least 4 hours.

The release inhibiting compartment is composed of a pH-dependent enteric base, a water insoluble polymer, or a water-soluble polymer, and the like, and further includes pharmaceutically acceptable additives such as disintegrants, binders, excipients, and the like. The release inhibiting compartment is prepared by preparing a coating solution and coating the coating liquid using a coating machine, or by coating the powder or granular mixture dry using a tableting machine.

The pH-dependent enteric base may be polyvinylacetate phthalate, methacrylic acid copolymer, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose succinate, shellac, cellulose acetate phthalate, cellulose propionate phthalate, poly (methacrylate). -Methyl methacrylate) copolymers, and / or poly (methacrylate-ethylacrylate) and the like, wherein the water-insoluble polymer is polyvinyl acetate, polymethacrylate copolymer, cellulose acetate, or / and ethylcellulose Or the like, and the polymethacrylate copolymer is a poly (ethylacrylate-methyl methacrylate) copolymer, and / or a poly (ethylacrylate-methylmethacrylate-trimethylaminoethyl methacrylate) copolymer, or the like. .

In addition, the water-soluble polymer is hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, methyl cellulose, carboxymethyl cellulose sodium, hydroxypropyl methyl cellulose acetate succinate, polyvinylpyrrolidone, Or / and polyvinyl alcohol and the like.

The pulsatile releasing agent of the present invention may further include a coating layer containing no drug prepared using a film coating agent on the outermost layer for the properties and stability of the formulation.

The pulsatile releasing agent of the present invention can be taken once or twice a day, and thus can be conveniently administered, and can prevent headaches that may occur when taking high doses through pulsatile release.

In addition, the present invention comprises the steps of (a) producing an internal flux release compartment for compressing nicolandil and stabilizer; (b) at least one selected from the group consisting of a pH-dependent enteric base, a water-insoluble polymer, and a water-soluble polymer, the release inhibiting compartment manufacturing step covering the internally-releasing compartment; (c) preparing a coating solution by dissolving or suspending nicolandyl and a stabilizer in anhydrous ethanol; And (d) provides a pulsatile release agent manufacturing method comprising the step of manufacturing the outer flux release compartment for coating the coating liquid on the outer layer of the release inhibitor compartment.

The stabilizer is fumaric acid, oxalic acid, and / or sodium stearyl fumarate, and the like, preferably sodium stearyl fumarate.

Looking at the manufacturing method in detail as follows.

In the step (a), in addition to the nicolandil and stabilizer, excipients may be mixed and compressed into tablets as needed to prepare tablets, or after dissolving nicolandyl in anhydrous ethanol, an insoluble stabilizer is suspended and soluble in stability. The topical agent may be prepared using a method such as dissolving and associating with an appropriate excipient to prepare granules and then tableting and tableting.

In the step (b), the coating liquid is prepared by coating the coating liquid with one or more selected from the group consisting of a pH-dependent enteric base, a water-insoluble polymer, and a water-soluble polymer, or coating the powder or granular mixture using a tableting machine. Release control compartments can be prepared by coating or the like, and can be prepared by mixing pharmaceutically acceptable additives such as disintegrants, binders, excipients and the like.

Step (c) is a step of preparing a coating solution by dissolving or suspending nicorandil and a stabilizer in anhydrous ethanol, the components of which are not very soluble are suspended in anhydrous ethanol, and the components of high solubility are dissolved in anhydrous ethanol coating solution To prepare, a film coating base may be used if necessary.

In the step (c) nicorandil and stabilizer may be added to anhydrous ethanol at the same time, or may be added sequentially.

In step (d), the coating solution prepared in step (c) is coated on the outer surface of the release inhibiting section prepared in step (b), and a known coating machine may be used.

The present invention also provides a method for preparing an internal release compartment for compressing nicolandil and a stabilizer; (b) at least one selected from the group consisting of a pH-dependent enteric base, a water-insoluble polymer, and a water-soluble polymer, the release inhibiting compartment manufacturing step covering the internally-releasing compartment; And (c) it provides a method for producing a pulsatile release agent comprising the step of producing an external flux release compartment for compressing the nicorandil and stabilizer outside the release inhibitor compartment.

The stabilizer is fumaric acid, oxalic acid, and / or sodium stearyl fumarate, and the like, preferably sodium stearyl fumarate.

The nicorandil and stabilizer of step (c) may be granular, prepared by dissolving or suspending in anhydrous ethanol and associated with an excipient.

Looking at the manufacturing method in detail as follows.

Steps (a) and (b) are the same as in the above-described manufacturing method.

In the step (c), by adding an excipient, a disintegrant, and the like, in addition to the nicolandil and the stabilizing agent, compressing the external velocity in the form of an outer layer of the tablet including the inner flux release compartment and the release control compartment as the inner core. Emissive compartments can be prepared.

Furthermore, nicorandil and a stabilizer are dissolved or suspended in anhydrous ethanol to form a binding solution, and the binder is added by adding an excipient, a disintegrating agent, and the like. Externally releasing compartments may be prepared in the form of an outer layer of tablets containing internally releasing compartments and release control compartments as internal nuclei.

The compression can use a known nucleating tablet press.

In the production method of the present invention, a highly stable nicorandil-containing pulsatile release formulation can be prepared by using a stabilizer, and wet preparation such as wet granules and coating can be performed by using ethanol anhydride.

The pulsatile formulations of the present invention are easy to manufacture, and are not only capable of wet manufacturing methods such as wet granules and coatings, but also have a reduced number of times of drug administration, while improving drug compliance, while being small in size, easy to take, and the preparation of the present invention. It can be manufactured easily by the method.

Hereinafter, although this invention is demonstrated concretely based on an Example, this invention is not limited to a following example.

Example 1 Preparation of a Pulsating Release Agent 1

(1) Preparation of internal flux release compartment

5 g of nicorandil (RPG Life Science, India.) And 2.5 g of stearyl sodium fumarate (JRS Pharma, Pruv) were sieved through a No. 35 sieve and mixed. 40.5 g of D-mannitol (Roquette, Pearitol.) Sieved through a No. 35 sieve and 1.5 g of cross-linked polyvinylpyrrolidone (BASF, Kollidon) were mixed, and again, sodium stearyl fumarate sieved through No. 35 sieve ( 0.5 g of JRS Pharma, Pruv) was added and finally mixed. The mixture was compressed into tablets with a diameter of 5 mm using a tableting machine to prepare tablets.

(2) the manufacture of release inhibitory compartments

140 g of ethyl cellulose (Hercules, Ethylecellulose) and 9.7 g of polyvinylpyrrolidone (BASF, Kollidon) were mixed, followed by final mixing of 0.3 g of magnesium stearate. Using a nucleated tableting machine (Killian, RUD-1), the tablet prepared in the above (1) was used as the inner core and the mixture was compressed and coated.

(3) Manufacture of externally releasing compartments

5 g of nicorandil was completely dissolved in 60 g of anhydrous ethanol (Duksan Chemical, Ethanol anhydrous), followed by further dissolving 5 g of hydroxypropylmethylcellulose (Hercules, Klucel.) And 1 g of polyethylene glycol 6000 (BASF, Lutrol 6000). A coating solution was prepared by suspending 2.5 g of sodium stearyl fumarate (JRS Pharma, Pruv) in this solution. The tablets made in (2) were coated with a coating machine (SFC-30F, Sejong Pharmatech).

Example 2 Preparation of Pulsating Release Agent 2

(1) Preparation of internal flux release compartment

Tablets were prepared in the same manner as in Example (1), except that spray-dried sorbitol (Solbitab SD250, Espia Pharma, USA) was used instead of mannitol.

(2) the manufacture of release inhibitory compartments

Eudragit S100 (Methacrylic acid copolymer Type B, Degussa, Germany) 14.0g, polyethylene glycol 400 2g dissolved in ethanol (Duksan Chemical, 95% Ethanol) and a coating solution prepared by suspending 1g of talc, (1 The tablet prepared in the) was coated with a coating machine (SFC-30F, Sejong Machinery) to prepare a coated tablet.

(3) Manufacture of externally releasing compartments

2.5 g of croscarmellose sodium (Ac-di-Sol, FMC Biopolymer) and 190.5 g of spray-dried sorbitol (Solbitab SD250, Spiaipama, USA) were placed in a high speed mixer (Lab. Pharm Mixer P, Diosna) for 10 minutes. Mixed. 5 g of nicorandil and 5 g of stearyl sodium fumarate (JRS Pharma, Pruv) were dissolved in anhydrous ethanol to prepare a binding solution, and the combined binding solution was gradually added to the mixed powder to prepare granules. A speed mixer was used. After drying, the granules were sieved through a No. 20 sieve, and 0.5 g of sodium stearyl fumarate was added thereto, followed by final mixing. This mixture and the coated tablet prepared in (2) were compressed using a nucleus tableting machine (Killian, RUD-1).

Example 3 Preparation of Pulsating Release Agent 3

(1) Preparation of internal flux release compartment

Preparation was carried out in the same manner as in Example (1), except that spray-drying xylitol (xylitol T, DHW-Ecogreen, Germany) was used instead of mannitol.

(2) the manufacture of release inhibitory compartments

14.0 g of Ethyl cellulose T10 (Aqualon EC, Aqualon, Germany), 2 g of polyethylene glycol 400 and 1 g of talc were prepared in anhydrous ethanol, and the tablet prepared in (1) was coated with a coating machine (SFC-30F, Sejong Pharmatech).

(3) Manufacture of externally releasing compartments

5 g of nicorandil was completely dissolved in 60 g of anhydrous ethanol, and then 5 g of hydroxypropylmethylcellulose and 1 g of polyethylene glycol 6000 were further dissolved, and 2.5 g of fumaric acid was further dissolved to prepare a coating solution. The tablets prepared in (2) were coated with the coating solution (SFC-30F, Sejong Pharmatech).

Example 4 Preparation of a Pulsating Release Agent 4

(1) Preparation of internal flux release compartment

It was prepared according to the preparation method of Example 1 (1), except that spray-dried maltose (Advantose 100, Espiaipama, USA) was used instead of mannitol.

(2) the manufacture of release inhibitory compartments

100 g of hydroxypropyl methyl cellulose (Methocel E 100M, Colorcon) and 29.7 g of Carbopol (Carbopol 934P, Lubrizol) were mixed, and magnesium stearate was added thereto and finally mixed. Using the nucleated tableting machine (Killian, RUD-1), the tablet manufactured in the above (1) was used as the inner core, and the mixture was compressed into tablets.

(3) Manufacture of externally releasing compartments

5 g of nicorandil, 5 g of stearyl fumarate, 2.5 g of croscarmellose sodium and 250.5 g of maltose were added to a double cone mixer, followed by mixing, and 0.5 g of stearyl fumarate was added thereto and finally mixed. Using a nucleated tableting machine (Killian, RUD-1), the tablet prepared in (2) above was used as the inner core, and the final mixture was compressed to dry coating.

Example 5 Preparation of Multiple Pulsatile Release Agent 1

The pulsatile release formulation prepared in Example 2 was prepared again according to the release inhibition compartment manufacturing method of Example 2 (2), and coated using a coater. The coated tablet was again coated with a coating solution prepared according to the preparation method of Example (3) to prepare a multi-pulsatile release formulation.

Example 6 Preparation of a Multi-Pulsatile Release Agent 2

The pulsatile release formulation prepared in Example 1 was prepared again and coated with a coating solution according to Example 3 (2). The coated tablet was again coated with a coating solution according to Example 3 (3) to prepare a multi-pulsatile release agent.

Example 7 Preparation of Multiple Pulsatile Release Formulations 3

The pulsatile releasing formulation prepared in Example 3 was again coated by preparing a coating solution according to Example 2 (2). The coated tablet was compressed again using a nucleus tablet press (Killian, RUD-1) together with the mixture prepared according to the preparation method of Example 2 (3) to prepare a multi-pulsatile release agent.

Example 8 Preparation of a Pulsating Release Agent 5

(1) Preparation of internal flux release compartment

Tablets were prepared in the same manner as in Example 2, except that fumaric acid (KIC Chemical, Fumaric acid NF / FCC) was used instead of sodium stearyl fumarate.

(2) the manufacture of release inhibitory compartments

Eudragit S100 (Methacrylic acid copolymer Type B, Degussa, Germany) 14.0g, polyethylene glycol 400 2g dissolved in ethanol (Duksan Chemical, 95% Ethanol) and a coating solution prepared by suspending 1g of talc, (1 The tablet prepared in the) was coated with a coating machine (SFC-30F, Sejong Machinery) to prepare a coated tablet.

(3) Manufacture of externally releasing compartments

2.5 g of croscarmellose sodium (Ac-di-Sol, FMC Biopolymer) and 190.5 g of spray-dried sorbitol (Solbitab SD250, Spiaipama, USA) were placed in a high speed mixer (Lab. Pharm Mixer P, Diosna) for 10 minutes. Mixed. 5 g of nicorandil and 5 g of fumaric acid (KIC Chemical, Fumaric acid NF / FCC) were dissolved in anhydrous ethanol to prepare a binding solution, and the combined binding solution was gradually added to the mixed powder to prepare granules. A high speed mixer was used. After drying, the granules were sieved through a No. 20 sieve, and then 0.5 g of sodium stearyl fumarate (JRS Pharma, Pruv) was added and finally mixed. Using a nucleated tableting machine (Killian, RUD-1), the coated tablet prepared in (2) was used as the inner core, and the final mixture was compressed.

Experimental Example 1 Dissolution Test

The dissolution test was carried out under the following conditions in order to confirm the pulsatile release properties of the formulations prepared in Examples 1 to 3 and 5 to 7.

Dissolution test basis: Dissolution test method of General Test Method

Test method: Paddle method, 50 revolutions / min

Test solution: water, 900mL

Analysis method: liquid chromatograph method (detection wavelength = maximum 230nm)

The results are shown in FIGS. 1 and 2. 1 and 2, the time {Time (hr)} is shown on the X axis, and the drug release rate {Drug Release (%)} is shown on the Y axis.

As shown in FIG. 1, the pulsatile releasing agent prepared in Examples 1 to 3 has a release inhibition time of 4 to 6 hours after the first release of the drug, and the release is completed within 1 hour after the start of the secondary release. Can be.

In addition, as shown in FIG. 2, the multi-pulsatile release agent prepared in Examples 5 to 7 has a release inhibition time of 4 to 6 hours after the first release of the drug, and the release is completed within 1 hour after the start of the secondary release. And again has a release suppression time of 4-6 hours, the third release is started again and the release is completed within 1 hour.

These results indicate that the pulsatile release agent prepared according to the manufacturing method of the present invention may have a desired number of release times, a release time, and a release pattern.

Experimental Example 2 Stability Experiment

In order to determine the stability of nicolandil contained in the inner and outer flux of the formulation, the change of content at 60 ° C storage condition was analyzed using HPLC (Agilient1200, Agilient, detection wavelength = maximum 230 nm). Measured.

Sample 1 was a tablet manufactured in the same manner as in the production method of Example 1 (1) to contain 5 mg of nicolandil per tablet.

Sample 2 is a tablet prepared by preparing and tableting the final mixture in the same manner as in the preparation method of Example 2 (3), but by compressing only the final mixture so as not to contain the internally-releasing compartment and the release inhibiting compartment therein. It was to contain 5 mg of nicolandil per tablet.

Sample 3 is a tablet prepared by preparing and tableting the final mixture in the same manner as in Preparation Method (3) of Example 8, but by compressing only the final mixture so as not to include the internally releasing compartment and the release inhibiting compartment therein. It was to contain 5 mg of nicolandil per tablet.

Comparative samples were prepared from commercially available Sigmat tablets (Nicolandil 5mg, Sino Pharmaceutical).

The results are shown in Table 1 below.

time
Nicolandil content (% by weight) Comparative Sample Sample 1 Sample 2 Sample 3 Date of manufacture 97.8 97.6 99.8 97.4 1 day 82.4 91.5 92.1 92.2 3 days 40.8 78.1 85.5 81.8 7 days 5.8 11.8 79.5 74.6

As a result, it was confirmed that the nicorandil stability of the sample 2 and the sample 3, which was prepared by mixing the nicolandil and the stabilizer in powder form, and preparing the compressed tablet 1 and the nicolandil and the stabilizer in granular form, compared to the comparative sample. Can be.

These results indicate that the stability of nicolandil in the inner-release compartment and the outer-releasing compartment of the present invention is excellent, and as a result, the stability of the nicorandil in the pulsatile release agent of the present invention is excellent.

In addition, Sample 2 (sodium stearyl fumarate as stabilizer) and Sample 3 (fumaric acid as stabilizer) prepared by the wet method using anhydrous ethanol showed excellent stability. It shows excellent manufacturing.

       1 is a graph showing the dissolution curve of the tablets prepared in Examples 1 to 3.

Figure 2 is a graph showing the dissolution curve of the tablets prepared in Examples 5-7.

Claims (19)

Internal compartments including nicorandil, including nicorandil and sodium stearyl fumarate; Surrounding the internal compartment containing nicorandil, and comprises at least one selected from the group consisting of ethyl cellulose, hydroxypropyl methyl cellulose (HPMC), methacrylic acid copolymer and polyvinylpyrrolidone, and includes nicolandil Inner compartment coating layer; And A pulsatile release formulation surrounding said inner compartment coating layer and comprising an outer compartment comprising nicolandil comprising nicolandyl and sodium stearyl fumarate. The method of claim 1, wherein the ethyl cellulose, hydroxypropyl methyl cellulose (HPMC), methacrylic acid copolymer, and polyvinylpyrrolidone without addition of nicorandil in addition to the nicorandil-containing outer compartment of the pulsatile release formulation A pulsatile releasing agent having a coating layer comprising at least one selected from the group consisting of and a nicolandil containing compartment surrounding the coating layer in sequence. delete delete The pulsatile releasing preparation according to claim 1, wherein the sodium stearyl fumarate is 0.25 to 1 part by weight based on 1 part by weight of nicolandil. delete The pulsatile releasing preparation according to claim 1, wherein the inner compartment coating layer delays the release of nicolandil of the inner compartment including the nicolandil by at least 4 hours. delete delete delete delete The method of claim 1, wherein the pulsatile release agent A pulsatile release preparation that is taken once a day or twice a day. (a) compressing a mixture comprising nicolandyl and sodium stearyl fumarate to produce a nicolandil containing internal compartment; (b) preparing an inner compartment coating layer surrounding the nicolandyl-containing inner compartment with at least one material selected from the group consisting of ethyl cellulose, hydroxypropyl methyl cellulose (HPMC), methacrylic acid copolymer and polyvinylpyrrolidone; Doing; (c) dissolving or suspending nicolandyl and sodium stearyl fumarate in anhydrous ethanol to prepare a solution; And (d) coating the solution on the inner compartment coating layer to prepare an outer compartment including nicolandil. delete delete (a) compressing a mixture comprising nicolandyl and sodium stearyl fumarate to produce a nicolandil containing internal compartment; (b) preparing an inner compartment coating layer surrounding the nicolandyl-containing inner compartment with at least one material selected from the group consisting of ethyl cellulose, hydroxypropyl methyl cellulose (HPMC), methacrylic acid copolymer and polyvinylpyrrolidone; Doing; And (c) coating a mixture comprising nicolandyl and sodium stearyl fumarate on the outer layer of the inner compartment coating layer to prepare an outer compartment containing nicolandyl, the method of producing a pulsatile releasing agent. delete delete The method according to claim 16, wherein the mixture of step (c) is granules prepared by dissolving or suspending nicolandyl and sodium stearyl fumarate in anhydrous ethanol and in association with an excipient.

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