WO2011126327A2

WO2011126327A2 - Pharmaceutical composition with controlled-release properties comprising mosapride or levodropropizine, and preparing method thereof

Info

Publication number: WO2011126327A2
Application number: PCT/KR2011/002458
Authority: WO
Inventors: Ho-Seong Jeon; Yong-Kwan Shin; Dae-Woong Ko; Su-Bin Im; Kang-Min Kim; Jae-Keol Rhee; Sung-Hoon Kam
Original assignee: Hyundai Pharm Co., Ltd.
Priority date: 2010-04-09
Filing date: 2011-04-07
Publication date: 2011-10-13
Also published as: WO2011126327A3

Abstract

Disclosed is a sustained-release pharmaceutical composition comprising mosapride or levodropropizine as an active ingredient, a method of preparing the same, and a pharmaceutical composition with dual release property comprising a sustained-release part and an immediate release part respectively comprising the active ingredient. The sustained-release pharmaceutical composition may constantly release drugs despite change in internal organ movement state of a subject, and it may constantly release the active ingredient even if a long time passes after administration, and thus, it may sufficiently deliver drugs only with single dose or two doses per day. And, since the pharmaceutical composition with dual release property has an immediate part and a sustained-release part exhibiting independent release properties, it may simultaneously increase rapid pharmaceutical effect and convenience for internal use, and improved treatment effect may also be expected due to improved the dissolution stability.

Description

TITLE OF THE INVENTION

PHARMACEUTICAL COMPOSITION WITH CONTROLLED-RELEASE PROPERTIES COMPRISING MOSAPRIDE OR LEVODROPROPIZINE, AND PREPARING METHOD THEREOF

BACKGROUND OF THE INVENTION

(a) Field of the Invention

This disclosure relates to a sustained-release pharmaceutical composition comprising mosapride or levodropropizine as an active ingredient, a method of preparation thereof, and a pharmaceutical composition with dual release property comprising a sustained-release part and an immediate release part,

(b) Description of the Related Art

Mosapride (4-Amino-5-chloro-2-ethoxy-N-((4-(4-fluorobenzyl)-2- morpholinyl)methyl)benzamide, mosapride) is a world's first selective serotonin 5-HT4 receptor agonist, and is known to have strong actions of promoting movement and emptying of digestive tract. The mosapride is represented by the following Chemical Formula 1.

[Chemical Formula 1 ]

The mosapride has been introduced in the country under a drug name of

Gasmotin, and it is known as a drug for treating gastrointestinal tract for markedly improving gastric emptying and improving upper gastrointestinal symptoms of chronic gastritis.

Meanwhile, levodropropizine, which is ' named as levo-3-(4-phenyl-l-piperazinyl)-l,2-propandiol, has one asymmetric carbon atom, and is represented by the following Chemical Formula 2. mical Formula 2]

The levodropropizine is a peripheral antitussive agent with an action mechanism distinguished from a central antitussive agent such as dihydrocodeine and dextromethorphan, and it has remarkably lowered appearance of central nervous system side effects (sleepiness). And, it is known as a drug that may be safely administered without interactions with other drugs such as a β-blocker, methyl xanthine, a mucoregulator, corticosteroid, antibiotics, antihistamines, while inhibiting inflammation and bronchoconstriction, and mucus hypersecretion.

However, the existing pharmaceutical composition comprising mosapride or levodropropizine may not secure constant pharmaceutical effects to a subject due to change in dissolution properties according to body conditions, and it should be administered several times a day because the pharmaceutical effects may not be lasted for a long time.

Therefore, in accordance with the progress of the present preparation technique, technologies for sustained release of various drugs are under development with the purpose of improving convenience of a patient. A sustained-release preparation may effectively elicit potential effects of drugs and simultaneously decrease the number of administration by maintaining the pharmaceutical effects, compared to common immediate release preparations, and it has a lot of advantages to lower appearance of toxicity and side effects on effectiveness and safety.

Meanwhile, for a disease significantly requiring rapid action property too, a rapid action property that effective blood concentration may be rapidly reached after administration so as to exhibit effects of drugs is also required. Thus, there is a demand for a development of a preparation with advantages on both sides of therapeutic effects and convenience for internal use by having rapid manifestation of pharmaceutical effects and durability of pharmaceutical effects, together with a development of a sustained-release preparation. SUMMARY OF THE INVENTION

Accordingly, the inventors prepared a sustained-release pharmaceutical composition comprising mosapride or levodropropizine, which has constant pharmaceutical effect despite change in the internal organ movement state of a subject and exhibits constantly continued pharmaceutical effect for a long time, and a pharmaceutical composition with dual release property, which comprises a sustained-release part and an immediate release part exhibiting independent release properties, and thus may increase rapid pharmaceutical effect and convenience for internal use, and exhibit improved pharmaceutical effect due to improved dissolution stability, and completed the invention.

Therefore, it is an object of the present invention to provide a sustained-release pharmaceutical composition that may constantly dissolute active ingredients despite change in the internal organ movement of a subject, releases active ingredients at a constant rate for 12 hours to 24 hours so as to sufficiently deliver drugs with single dose or two doses per day, and a pharmaceutical composition with dual release property simultaneously having rapid action property and durability.

To achieve the above object, the present invention provides a sustained-release pharmaceutical composition comprising (i) an active ingredient comprising mosapride or levodropropizine; (ii) a release controller; (iii) a release control aid comprising at least one selected from the group consisting of alginate, alginate derivatives, and a salt thereof; and, (iv) a sustained-release base.

The present invention also provides a method of preparing a sustained-release tablet comprising: (a) mixing (i) an active ingredient comprising mosapride or levodropropizine, (ii) a release controller, (iii) a release control aid comprising at least one selected from the group consisting of alginate, alginate derivatives, and a salt thereof, and (iv) a sustained-release base; (b) forming granules from the mixture prepared in step (a) and controlling the size; and, (c) tableting the granules.

The present invention also provides a pharmaceutical composition with dual release property, which comprises an immediate release part comprising an active ingredient comprising mosapride or levodropropizine, and a pharmaceutically acceptable excipient; and, a sustained-release part comprising the active ingredient, a sustained-release base, and a pharmaceutically acceptable excipient.

Hereinafter, the present invention will be explained in detail.

According to one embodiment of the invention, the sustained-release pharmaceutical composition comprises (i) an active ingredient comprising mosapride or levodropropizine; (ii) a release controller; (iii) a release control aid comprising at least one selected from the group consisting of alginate, alginate derivatives, and a salt thereof; and, (iv) a sustained-release base.

The pharmaceutical composition comprises (i) mosapride or levodropropizine as an active ingredient. The content of the active ingredient may be easily determined by one of ordinary knowledge in the art according to age, gender, disease severance, body weight, etc. of a patient, but preferably 3 wt% to 60 wt%, based on the total weight of unit dosage form. If the content is less than the above range, an active ingredient may be contained in a very small amount, and thus pharmaceutical effect may not be effectively delivered in body, and if the content exceeds the above range, it may be uneconomical.

The (ii) release controller may be preferably selected from the group consisting of microcrystalline cellulose, lactose, mannitol, cellulose acetate, ethylcellulose, polymethacrylate, and a combination thereof, but not limited thereto.

The (ii) release controller may be preferably contained in the content of 10 wt% to 90 wt%, based on the total weight of unit dosage form, but not limited thereto. The release controller allows constant dissolution of active ingredients despite change in the internal organ movement state of a subject, and allows the pharmaceutical composition to release active ingredients at a constant rate for 12 hours so as to deliver pharmaceutical effect with single dose or two doses per day. And, if the content is less than the above range, the above effects may not be obtained, and if the content exceeds the above range, it may be uneconomical and cause inconvenience for internal use due to increased total weight of unit dosage form.

Particularly, the cellulose acetate, ethyl cellulose, and polymethacrylate may be preferably used together with microcrystalline cellulose, lactose and/or mannitol, but not limited thereto. The cellulose acetate, ethyl cellulose, and polymethacrylate may be preferably contained in the content of 10 wt% to 90 wt% based on the total weight of unit dosage form, but not limited thereto. If the content exceeds the above range, dissolution rate may be varied according to the state of the internal organ movement of a subject, and if the content is less than the above range, release controller effect may be insufficient.

The sustained-release pharmaceutical composition may constantly release the active ingredient despite change in the internal organ movement state of a subject, by comprising the (ii) release controller.

Specifically, the dissolution rate of the sustained-release pharmaceutical composition at a rotation speed of 75 rpm may be 130% or less of the dissolution rate at a rotation speed of 50 rpm, when measured in 900ml of water or a dissolution medium of pH 4,0 or pH 6.8 at 37 ^°C using second method of Korean pharmacopoeia dissolution test (a paddle method). The rotation speed may reflect the degree of the internal organ movement state of a subject.

Thus, as can be seen from the dissolution property, the sustained-release pharmaceutical composition may constantly release active ingredients despite change in the internal organ movement state of a subject, which is reflected in the difference in the rotation speed.

The (iii) release control aid may be selected from the group consisting of alginate, alginate derivatives, and a salt thereof, and the alginate may be preferably sodium alginate, but not limited thereto.

The (iii) release control aid may be preferably comprised in the content of 1 wt% to 20 wt%, based on the total weight of unit dosage form, but not limited thereto. The release control aid allows the pharmaceutical composition of the present invention to release active ingredients at a constant speed for 12 hours to 24 hours so as to deliver pharmaceutical effect with single dose or two doses per day. If the content is less than the above range, the above effects may not be obtained, and if the content exceeds the above range, it may be uneconomical and cause inconvenience for internal use due to increased total weight of unit dosage form. Therefore, the sustained-release pharmaceutical composition may constantly release active ingredients for a long time, and thus, it may sufficiently deliver drugs with single dose or two doses per day because pharmaceutical effect may be secured for maximum 12 hours to 24 hours, by comprising the (iii) release control aid selected from the group consisting of alginate, alginate derivatives, and a salt thereof.

The (iv) sustained-release base may be easily selected by one of ordinary knowledge in the art as long as it may be used in the preparation of a sustained-release pharmaceutical composition, but it may be preferably selected from the group consisting of polymethacrylate, polyox, glyceryl behenate, solid fat, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, ethylcellulose, cellulose acetate, gum, and a combination thereof. The gum may be selected from the group consisting of xanthan gum, guar gum, acacia gum, arabia gum, gelan gum, locust bean gum, and a combination thereof, but not limited thereto.

The sustained-release pharmaceutical composition may further comprise various ingredients commonly used in pharmaceutical compositions besides the (i) active ingredient, (ii) release controller, (iii) release control aid comprising at least one selected from the group consisting of alginate, alginate derivatives, and a salt thereof, and (iv) sustained-release base. For example, it may further comprise at least one selected from the group consisting of a polymer, a carrier, a filler, a lubricant, a flow control agent, a crystallization retarding agent, a solubilizer, a coloring agent, a pH control agent, a surfactant, and an emulsifier commonly used in the preparation of pharmaceutical compositions. The polymer may be Kollidone, and the lubricant may be preferably aerosil and/or magnesium stearate (St-Mg), but not limited thereto.

The pharmaceutical composition may be preferably formulated in a dosage form suitable for oral administration, but not limited thereto. It may be preferably provided in the form of a solid oral preparation considering productivity and convenience for internal use and portability of a patient.

The solid oral preparation may include a multi-layered tablet such as a dual tablet, a triple tablet, etc., a cored tablet, a single tablet, a coated tablet, or a capsule, but not limited thereto. Each preparation may be obtained by commonly known methods. And, the solid oral preparation may be administered once or twice a day

As explained, the sustained-release pharmaceutical composition of the present invention may constantly release active ingredients despite change in the state, specifically internal organ movement state of a subject, by comprising the (ii) release controller, and it may constantly release active ingredients for a long time, and thus, sufficiently deliver drugs with single does or two doses per day because pharmaceutical effects may be secured for maximum 12 hours to 24 hours, by comprising the (iii) release control aid comprising at least one selected from the group consisting of alginate, alginate derivatives, and a salt thereof.

Meanwhile, according to another embodiment of the invention, a method of preparing the sustained-release tablet comprises (a) mixing (i) an active ingredient comprising mosapride or levodropropizine, (ii) a release controller, (iii) a release control aid comprising at least one selected from the group consisting of alginate, alginate derivatives, and a salt thereof, and (iv) a sustained-release base; (b) forming granules from the mixture prepared in step (a) and controlling the size; and, (c) tableting the granules.

The (ii) release controller, (iii) release control aid comprising at least one selected from the group consisting of alginate, alginate derivatives, and a salt thereof, and (iv) sustained-release base used in the preparation of the sustained-release tablet are as explained above.

In step (b), the granule may be preferably formed by a dry granulation method, but not limited thereto.

The sustained-release tablet prepared by forming granules by dry granulation may have improved dissolution property due to small difference in dissolution rate according to the internal organ movement state of a subject, compared to the tablet prepared by forming granules by wet granulation.

The dry granulation may be performed by a commonly known method, but preferably, granules may be formed by introducing the mixture prepared in step (a) in a commonly used roller compactor.

The method of preparing a sustained-release table may further comprise additional mixing a sustained-release base, after controlling the size of the granule in step (b), but not limited thereto.

The additional mixing may be performed by mixing the sustained-release base in the content of 50 wt% to 150 wt%, based on total weight of the sustained-release base mixed in step (a), but not limited thereto.

The sustained-release tablet prepared by the method further comprising additional mixing may have much improved dissolution rate due to small difference in dissolution rate according to the internal organ movement state of a subject.

According to yet another embodiment of the invention, provided is a pharmaceutical composition with dual release property, which comprises an immediate release part comprising an active ingredient comprising mosapride or levodropropizine, and a pharmaceutically acceptable excipient; and, a sustained-release part comprising the active ingredient, a sustained-release base, and a pharmaceutically acceptable excipient.

As results of experiments, it was confirmed that an immediate release preparation should be administered over several doses because pharmaceutical effect may not be lasted long, and it does not properly shows therapeutic effect due to the low compliance. And, it was also confirmed that although a sustained-release preparation may reduce the number of administration to once or twice a day and effectively elicit potential effects of drugs, convenience for internal use, and stability such as reduction of side effect, in the case of a disease requiring rapid action or patients with severe cough, symptom relief effect through rapid antitussive action within a short time may not be obtained, and there is a problem in bioavailability if dissolution rate changes according to change in body condition such as pH change.

Therefore, it was confirmed that by providing a pharmaceutical composition with dual release property, comprising an immediate release part and a sustained-release part respectively comprising mosapride or levodropropizine and exhibiting independent release properties, rapid pharmaceutical effects and convenience for internal use may be simultaneously increased, and difference in dissolution rate according to pH change may be decreased thus minimizing deviation of bioavailability to pH change in gastrointestinal tract according to administration before and after meal, and thus, remarkably improved therapeutic effect may be expected.

The content of an active ingredient included in the pharmaceutical composition with dual release property may be easily determined by one of ordinary knowledge in the art according to age, gender, severance of disease, body weight, etc. of a patient, but preferably, it may be 10 to 70 wt% based on the total weight of unit dosage form. Preferably, a dosage form comprising 80 to 200mg of the active ingredient may be administered once or several times a day, more preferably, a dosage form comprising 80 to lOOmg may be administered twice a day.

If the content of the active ingredient is less than the above range, manifestation of drug effect may not reach an effective level, and if the content exceeds the above range, side effect due to excessive administration may be caused, and mass of the composition itself increases to render the administration difficult, and thus, it may not be available as a pharmaceutical composition.

The active ingredient is divided and included respectively in the immediate release part and the sustained-release part, and the initial release amount and continued release amount of the active ingredient of mosapride or levodropropizine may be easily controlled by controlling the ratio of the active ingredient of the immediate release part and the sustained-release part.

Preferably, the active ingredient may be included in the immediate release part and the sustained-release part in the weight ratio of 1 : 0.5 to 1 : 2, more preferably 1 : 0.5 to 1 : 1. If the content is less than the above range, effects due to inclusion of the sustained-release part may not be properly obtained, and if it exceeds the above range, deviation of dissolution rate according pH change may increase.

The pharmaceutically acceptable excipient that may be included in the immediate release part and the sustained released part may include various pharmaceutically acceptable excipients useful for formulation as long as it does not adversely affect the effect of the present invention. And, the content may be determined according to solubility and chemical property of the active ingredient, selected administration route, and standard pharmaceutical practice. More specifically, a diluent may include starch, microcrystalline cellulose, lactose, glucose, mannitol, alginate, alkali earth metal salt, clay, polyethylene glycol, or dicalcium phosphate, and the like, and a binder may include microcrystalline cellulose, high dispersible silica, sugar such as mannitol, lactose, polyethylene glycol, polyvinyl pyrrolidone derivatives such as polyvinyl pyrrolidone (povidone), polyvinyl alcohol, copovidone, and the like, natural gum synthetic gum, or gelatin, and the like, and a lubricant may include light anhydrous silicic acid, talc, stearic acid, magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, sodium lauryl sulfate, hydrogenated vegetable oil, sodium benzoate, glyceryl monostearate, glyceryl palmitostearate, glyceryl behenate, sodium stearyl fumarate, polyethylene glycol, and the like, but not limited thereto.

The excipient may be preferably included in the content of 10 to 90 wt% based on the total weight of unit dosage form, but not limited thereof. The excipient enables the immediate release pharmaceutical composition to form a preparation of suitable form. Thus, if the content is less than the above range, the above effect may not be sufficiently obtained, and if it exceeds the above range, it may be uneconomical and cause inconvenience for internal use due to increased weight of unit dosage form.

In addition, various ingredients commonly used in pharmaceutical compositions may be further comprised. For example, at least one selected from the group consisting of a polymer, a carrier, a filler, a lubricant, a flow control agent, a crystallization regarding agent, an antioxidant, a solubilizer, a coloring agent, a flavoring agent, a preservative, a taste masking agent, a pH control agent, a surfactant, and an emulsifier may be used in commonly used amount. The polymer may be Kolidon, the lubricant may be preferably aerosil and/or magnesium stearate (St-Mg), but not limited thereto.

The immediate release part may further comprise a disintegrating agent.

The disintegrating agent may include starch or modified starch such as sodium starch glycolate, corn starch, potato starch, pregelatinized starch, and the like, clay such as bentonite, montmorillonite, veegum, and the like, crosslinked cellulose such as hydroxypropyl cellulose, carboxymethyl cellulose, croscarmellose sodium and the like, an effervescent agent such as crospovidone, sodium bicarbonate, citric acid, and the like, or a combination thereof. In case the disintegrating agent is included, it may be preferably included in the content of 0.1 to 70 wt%, more preferably 5 to 20 wt%, based on total weight of unit dosage form.

The disintegrating agent allows more rapid disintegration of the immediate release pharmaceutical composition so as to release active ingredients and deliver pharmaceutical effects. Thus, if the content is less than the above range, the above effects may not be sufficiently obtained, and if it exceeds the above range, it may be uneconomical and cause inconvenience for internal use due to increased total weight of unit dosage form. Thus, the immediate release pharmaceutical composition may further improve immediate action property by comprising the disintegrating agent.

Relatively large amount of drugs should be released within a short time so that the active ingredient may exhibit significant pharmaceutical effect for a patient with severe cough. It may be appropriate that the active ingredient of the immediate release part is released in an amount exceeding 30mg within 1 hour, more preferably within 30 minutes, when dissolution test of the pharmaceutical composition is performed in 900ml of water or a dissolution medium of pH 1.2, pH 4.0 or pH 6.8 at 37 ^°C ± 0.5 ^°C , at 50rpm to 75rpm, using a paddle method according to Korean Pharmacoopoeia. Thereby, rapid pharmaceutical effect may be obtained and inconvenience of the patient with severe cough may be effectively improved.

The immediate release pharmaceutical composition may be consisted of with the composition as described in the following Table 1, but not limited thereto.

[Table 1 ]

And, the pharmaceutical composition with dual release property may exhibit dissolution rate of the active ingredient of 85% or more after 10 hours, when dissolution test is performed in 900ml of water or a dissolution medium of pH 1.2, pH 4.0 or pH 6.8 at 37 ^°C ± 0.5 ^°C , 50rpm to 75rpm using a paddle method according to Korean Pharmacopoeia, by comprising a sustained-release part that comprises the active ingredient, a sustained-release base, and a pharmaceutically acceptable excipient, together with the immediate release part. Therefore, when the pharmaceutical composition is administered in a body, it may exhibit preferable pharmaceutical effect even with reduced administration number of for example twice a day. Thus, the pharmaceutical composition with dual release property may be used to improve convenience for internal use of a patient.

The sustained-release base included in the sustained-release part may be preferably the same as used in the sustained-release pharmaceutical composition according to one embodiment of the invention, and preferably, at least one selected from the release controller and release control aid included in the sustained-release pharmaceutical composition may be further comprised.

The pharmaceutical composition with dual release property may be formulated into a dosage form suitable for oral administration, and preferably, it may be provided in the form of a solid oral preparation considering productivity and convenience for internal use and portability of a patient.

The solid oral preparation may be a multi-layered preparation such as a dual tablet or a triple tablet, a cored tablet, a single tablet, a coated tablet, or a capsule, but not limited thereto. Each preparation may be obtained by a commonly known method. For example, each composition of the sustained-release part and the immediate release part may be combined in the separated form to obtain a preparation in the form of a dual tablet or a triple tablet by a common method, or each composition of the sustained-release part and the immediate release part may be respectively formed in the form of granules, and then, a single tablet or a capsule may be obtained using the granules. And, a cored tablet wherein a composition of the immediate release part surrounds a composition of the sustained-release part may be obtained by a common method. And, preferably, the solid oral preparation may be administered once or twice a day.

If the sustained-release pharmaceutical composition according to one embodiment of the invention or the pharmaceutical composition with dual release property according to another embodiment of the invention comprises mosapride as an active ingredient, it may be preferably used for promoting gastrointestinal mobility, and it may be useful for prevention or treatment of a gastroesophageal reflux disease, postgastrectomy syndrome, and other various gastrointestinal symptoms. And, if it comprises levodropropizine as an active ingredient, it may be preferably used for prevention or treatment of a disease selected from the group consisting of acute bronchitis, chronic bronchitis, bronchoconstriction, cough, and mucus hypersecretion.

The sustained-release pharmaceutical composition of the present invention may constantly release drugs despite change in the internal organ movement state of a subject, and it may constantly release an active ingredient even if a long time passes after administration, and thus, sufficiently deliver drugs with single dose or two doses a day.

And, the pharmaceutical composition with dual release property may simultaneously increase rapid pharmaceutical effect and convenience for internal use by comprising an immediate release part and a sustained-release part exhibiting independent release properties, and it may decrease deviation of dissolution rate according to pH change to minimize deviation of bioavailabilities according to administrations before and after meal, and thus, remarkably improved pharmaceutical effect may be expected.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph measuring dissolution rates of the sustained-release tablets comprising release control aid only of Comparative Example 1 according to difference in rotation speed (rpm). FIG. 2 is a graph comparing the dissolution properties of the sustained-release tablet comprising a release controller only of Comparative Example 2 and the sustained-release tablet of the present invention (prescription 6) at a rotation speed of 50 rpm.

FIG. 3 is a graph measuring the dissolution properties of the sustained-release tablets of the present invention (prescription 3 and prescription 5) at rotation speeds of 50 rpm, 75 rpm.

FIG. 4 shows the result of dissolution test of the immediate release tablet comprising levodropropizine of Comparative Example 3.

FIG. 5 shows the result of dissolution test of the dual-layered tablet having weight ratio of levodropropizine of the immediate release part and the sustained-release part of 1 : 0.5 according to Example 3.

FIG. 6 shows the result of dissolution test of the dual-layered tablet having weight ratio of levodropropizine of the immediate release part and the sustained-release part of 1 : 1 according to Example 4.

FIG. 7 shows the result of dissolution test of the dual-layered tablet having weight ratio of levodropropizine of the immediate release part and the sustained-release part of 1 : 2 according to Example 5.

FIG. 8 shows the result of dissolution test of the dual-layered tablet having weight ratio of levodropropizine of the immediate release part and the sustained-release part of 1 : 1 according to Example 6.

DETAILED DESCRIPTION OF THE EMBODIMENTS

Hereinafter, the present invention will be explained in detail with reference to the following Examples.

However, these Examples are only to illustrate the present invention, and the scope of the present invention is not limited thereto.

Dissolution property of a sustained-release tablet comprising a release control aid only A sustained-release tablet containing sodium alginate as a release control aid was prepared according to the composition described in the following Table 2, and the dissolution property was examined.

Specifically, the sustained-release tablet was prepared using mosapride as drug, HPMC (hydroxypropyl methylcellulose), xanthan gum, and locust bean gum as a sustained-release base, and Kollidone as a polymer, aerosil 200 and magnesium stearate (St-Mg) as a lubricant.

More specifically, the ingredients 1 to 9 in the following Table 2 were mixed, and granules were formed by a dry granulation method using a roller compactor. The formed granules were sieved to control the size, and then, the ingredients 10 and 11 were additionally mixed and tableted to prepare a sustained-release tablet.

[Table 2]

The dissolution properties of the prepared sustained-release tablet was examined in 900ml dissolution medium of pH4.0, at 37 ^°C , at 50 rpm and 75 rpm, using second method of Korean Pharmacopoeia dissolution test (paddle method), and the results are described in Table 3 (results after 16 hours) and FIG. 1.

[Table 3]

As described in the above Table 3, it can be seen that the sustained-release tablet which does not comprise a release controller shows remarkable difference in dissolution rates of maximum 45 to 60% or more according to external condition, i.e., rotation speed. Furthermore, as shown in FIG. 1 , it can be seen that the difference much increase over time.

At this time, the rotation speed reflects the degree of the internal organ movement state of subject. Therefore, the result of the dissolution property shows that in case the above prepared sustained-release tablet is administered, dissolution rate may be varied according to the internal organ movement state of a subject and thus constant pharmaceutical effect may not be secured.

Dissolution property of a sustained-release tablet comprising a release controller only

A sustained-release tablet containing lactose as a release controller was prepared according to the composition described in the following Table 4, and the dissolution property was examined.

Specifically, the ingredients 1 to 6 of the following Table 4 were mixed, and granules were formed by a dry granulation method using a roller compactor. The formed granules were sieved to control the size, and then, the ingredient 7 was additionally mixed and tableted to prepare the sustained -release tablet. iTable 4]

The dissolution property of the sustained-release tablet prepared according to the above Table 4 was tested under the same conditions as the <Comparative Example 1>, and the results are shown in FIG. 2.

As shown in FIG. 2, it can be seen that the sustained-release tablet comprising a release controller only does not constantly deliver drugs over time, and thus the release pattern shows a curve shape. <Example l>

Dissolution property of a mosapride sustained-release tablet comprising a release control aid and a release controller

Based on the results of the <Comparative Example 1> and <Comparative Example 2>, a sustained-release tablet comprising sodium alginate as a release control aid and lactose as a release controller was prepared and the dissolution property was confirmed.

Specifically, a sustained-release tablet with the composition of the following Table 5 was prepared, and more specifically, the ingredients 1 to 6 of the following Table 5 were mixed and granules were formed by a dry method using a roller compactor. The formed granules were sieved to control the size, and then, the ingredients 7 to 9 were additionally added and tableted to prepare the sustained-release tablet.

[Table 5]

The dissolution property of the sustained-release tablet prepared according to Table 5 was tested under the same condition as the <Comparative Example 1>, and the results are described in Table 6 (results after 16 hours), and in FIG. 2 and FIG. 3.

Particularly, comparison of the prescription 6 of the present invention with <Comparative Example 2> in FIG. 2 shows that linear dissolution property is shown by comprising a release control aid.

[Table 6]

The Table 6 and FIG. 3 compare the dissolution properties of the sustained-release tablet of this Example at rotation speeds of 50 rpm and 75 rpm, and they show that the sustained-release tablet of the present invention may constantly release drugs despite change of the internal organ movement state of a subject by using a release controller.

It can be also seen that dissolution property may be much improved if a sustained-release base is additionally mixed after forming granules as prescription 5.

Dissolution property of a levodropropizine sustained-release tablet comprising a release control aid and a release controller

A sustained-release tablet comprising levodropropizine with the composition of the following Table 6 was prepared. More specifically, the ingredients 1 to 6 of the following Table 7 were mixed and granules were formed by a dry method using a roller compactor. The formed granules were sieved to control the size, and then, the ingredient 7 was additionally mixed and tableted to prepare the sustained-release tablet of the present invention.

[Table 7]

The dissolution property of the sustained-release tablet prepared according to the Table 7 was tested in 900ml of a dissolution medium of pH 6.8, at 37 ^°C , at 50 rpm and 75 rpm, using second method of Korean Pharmacopoeia dissolution test (paddle method), and the results are described in Table 8 (results after 8 hours). [Table 8]

The results of the Table 8 show that the sustained-release tablet prepared in this Example may constantly release drugs even if a long time passes by using a release control aid.

Preparation of an immediate release tablet comprising levodropropizine

According to the composition described in the following Table 9, levodropropizine, lactose, microcrystalline cellulose, sodium starch glycolate were mixed, and compressed using a roller compactor to form granules by s dry method. The granules were sieved to control the size. And, magnesium stearate was added thereto, and the mixture was tableted with a tableting machine to prepare an immediate release tablet.

[Table 9]

Preparation of a dual-layered tablet comprising levodropropizine

Immediate release granules were prepared according to the composition described in the following Table 10, and sustained-release granules were prepared according to the composition described in the following Table 1 1 , so that weight ratio of levodropropizine of the immediate release part and the sustained release part may be 1 : 0.5 (Example 3), 1 : 1 (Example 4) and 1 : 2 (Example 5). The prepared granules were tableted to dual-layered tablets. Specific preparation process is as follows.

< a. Preparation of immediate release granules>

Levodropropizine, lactose, microcrystalline cellulose, and sodium starch glycolate were mixed according to the composition described in the following Table 10, and compressed with a roller compactor to form granules by a dry method. The granules were sieved to control the size. Magnesium stearate was mixed to prepare immediate release granules.

< b. Preparation of sustained-release granules>

According to the composition described in the following Table 1 1 , Levodropropizine, xanthan gum, hydroxypropyl methylcellulose, lactose, sodium alginate, and 1/2 amount of magnesium stearate were mixed, and compressed with a roller compactor to form granules by a dry method. The granules were sieved to control the size. The rest 1/2 amount of magnesium stearate was mixed to prepare sustained-release granules.

< c. Preparation of a dual-layered tablet>

The prepared immediate release granules and sustained-release granules were tableted ith a tableting machine with varying the content ratio of levodropropizine.

The levodropropizine content ratio of the immediate release part : sustained-release part

- Example 1 → 1 : 0.5

- Example 2 → 1 : 1

- Example 3 → 1 : 2 [Table 10]

Preparation of a dual-layered tablet comprising levodropropizine

A dual-layered table was prepared by the same method as Examples 3 to 5, except that immediate release granules were prepared according to the composition described in the following Table 12, and sustained-release granules were prepared according to the composition described in the following Table 13, so that the weight ratio of levodropropizine of the immediate release part and the sustained release part may be 1 : 1. [Table 12]

Preparation of a dual-layered tablet comprising levodropropizine

Immediate release granules were prepared according to the composition described in the following Table 14, and sustained-release granules were prepared according to the composition described in the following Table 15, so that the weight ratio of levodropropizine of the immediate release part and the sustained-release part may be 1 : 1.

The immediate release granules were prepared by the same method as Examples 3 to 5, and the sustained- release granules were prepared by mixing levodropropizine, ethylcellulose, glyceryl behenate, and the 1/2 amount of magnesium stearate,, compressing with a roller compactor to form granules by a dry method, and then, sieving the granules to control the size, and mixing the rest 1/2 amount of magnesium stearate.

The prepared immediate release granules and the sustained-release granules were tableted with a tableting machine to prepare a dual-layered tablet.

[Table 14]

Experimental Example>

Dissolution test

For the above preparations, dissolution test was performed under the following conditions by a paddle method according to Korean Pharmacopoeia, and dissolution rate of the active ingredient levodropropizine was measured over time. To confirm difference according to pH condition of the dissolution medium, a dissolution test was performed for the preparation of Comparative Example 3 respectively in water, dissolution media of pH 1.2, pH 4.0 and pH 6.8. The results show that difference in dissolution rate is largest when using water and using a dissolution medium of pH 1.2. Thus, dissolution tests of Examples 3 to 6 were performed with water and a dissolution medium of pH 1.2.

Dissolution medium :

Comparative Example 3 : Korean Pharmacopoeia dissolution medium water, pH 1.2, pH 4.0, pH 6.8

Examples 3 ~ 6 : Korean Pharmacopoeia dissolution medium water, pH

1.2

Temperature of dissolution medium : 37 ^°C ± 0.5 ^°C

Amount of dissolution medium : 900 mL

Agitation speed : 50 rpm

Sample taking : A dissolution medium was taken, filtered with a 0.2 ιη filter and determined as a test solution. After taking the dissolution medium, new dissolution medium was compensated with the equal amount. The dissolution rate of the active ingredient was analyzed from the test solution obtained in the dissolution test. The dissolution rate was analyzed using HPLC, and the dissolution rate test results are shown in FIG. 5 (Comparative Example 3), FIG. 5 (Example 3), FIG. 6 (Example 4), FIG. 7 (Example 5), and FIG. 8 (Example 6).

As shown in FIG. 4, although the immediate release tablet shows no difference in dissolution rate according to pH, the active ingredient is released too rapidly to lower durability of pharmaceutical effect to some degree, and thus, there are dangers on effectiveness, safety, etc. such as side effects including increase in the number of administration or toxicity, and the like. Meanwhile, as shown in FIG. 5 to FIG. 8, the dual-layered tablet releases the active ingredient in an effective amount for exhibiting rapid action property while preventing too rapid dissolution of the active ingredient, and it maintains high dissolution rate even at 12 hours, thus confirming that it has the rapid action property of the immediate release tablet and the durability of the sustained-release tablet, and it shows small difference in dissolution rate according to pH, and in the case of Example 3 (FIG. 5) wherein the ratio of levodropropizine of the immediate release part and the sustained-release part is 1 : 0.5, and Example 4 and Example 6 with 1 : 1 (FIG. 6, FIG. 8), difference in dissolution rate is remarkably small and thus dissolution stability is very excellent.

As explained, the pharmaceutical composition with dual release property of the present invention may simultaneously increase rapid pharmaceutical effect and convenience for internal use by comprising an immediate release part and a sustained-release part exhibiting independent release properties, and dissolution stability to pH change may be remarkably improved, and thus, improved therapeutic effect may be expected.

Claims

WHAT IS CLAIMED IS;

1. A sustained-release pharmaceutical composition comprising

(i) an active ingredient comprising mosapride or levodropropizine;

(ii) a release controller;

(iii) a release control aid comprising at least one selected from the group consisting of alginate, alginate derivatives, and a salt thereof; and,

(iv) a sustained-release base.

2. The sustained-release pharmaceutical composition of claim 1 , wherein the release controller is selected from the group consisting of microcrystalline cellulose, lactose, mannitol, cellulose acetate, ethylcellulose, polymethacrylate, and a combination thereof.

3. The sustained-release pharmaceutical composition of claim 1 , wherein the alginate is sodium alginate.

4. The sustained-release pharmaceutical composition of claim 1 , wherein the sustained-release base is selected from the group consisting of hydroxypropyl methylcellulose, gum, and a combination thereof.

5. The sustained-release pharmaceutical composition of claim 1, wherein the dissolution rate of the sustained-release pharmaceutical composition at a rotation speed of 75 rpm is 130% or less of the dissolution rate at a rotation speed of 50 rpm, when measured in 900ml of water or dissolution medium of pH 4,0 or pH 6.8 at 37 ^°C using second method of Korean Pharmacopoeia dissolution test (a paddle method).

6. The sustained-release pharmaceutical composition of claim 1 , wherein the sustained-release pharmaceutical composition is provided in the form of a solid oral preparation.

7. The sustained-release pharmaceutical composition of claim 6, wherein the solid oral preparation is a multi-layered tablet, a cored tablet, a single tablet, a coated tablet, or a capsule.

8. A method of preparing a sustained-release tablet comprising:

(a) mixing (i) an active ingredient comprising mosapride or levodropropizine, (ii) a release controller, (iii) a release control aid comprising at least one selected from the group consisting of alginate, alginate derivatives, and a salt thereof, and (iv) a sustained-release base;

(b) forming granules from the mixture prepared in step (a) and controlling the size; and

(c) tableting the granules.

9. The method of claim 8, wherein the release controller is selected from the group consisting of microcrystalline cellulose, lactose, mannitol, cellulose acetate, ethylcellulose, polymethacrylate, and a combination thereof.

10. The method of claim 8, wherein the alginate is sodium alginate.

1 1. The method of claim 8, wherein the sustained-released base is selected from the group consisting of hydroxypropyl methylcellulose, gum, and a combination thereof.

12. The method of claim 8, wherein in step (b), the granule is formed by a dry granulation method.

13. The method of claim 8, wherein further comprising additional mixing a sustained-release base, after controlling the size of the granules in step (b).

14. The method of claim 13, wherein the additional mixing comprises mixing the sustained-release base in the content of 50 wt% to 150 wt%, based on the total weight of the sustained-release base mixed in step (a).

15. A pharmaceutical composition with dual release property comprising

an immediate release part comprising an active ingredient comprising mosapride or levodropropizine, and a pharmaceutically acceptable excipient; and

a sustained-release part comprising the active ingredient, a sustained-release base, and a pharmaceutically acceptable excipient.

16. The pharmaceutical composition of claim 15, wherein the active ingredient is comprised in the amount of 80 to 200mg.

17. The pharmaceutical composition of claim 15, wherein the active ingredients of the immediate release part and the sustained-release part are comprised in the weight ratio of 1 : 0.5 to 1 : 2.

18. The pharmaceutical composition of claim 16, wherein the pharmaceutical composition releases the active ingredient of the immediate release part in an amount exceeding 30 mg within 1 hour, when dissolution test is performed in 900ml of water or dissolution medium of pH 1.2, pH 4.0 or pH 6.8 at 37 ^°C ± 0.5 ^°C , at 50rpm to 75rpm, using second method of Korean Pharmacopoeia dissolution test (paddle method).

19. The pharmaceutical composition of claim 15, wherein the pharmaceutical composition exhibits dissolution rate of the active ingredient of 85% or more after 10 hours, when dissolution test is performed in 900ml of water or dissolution medium of pH 1.2, pH 4.0 or pH 6.8 at 37 ^°C ± 0.5 ^°C , at 50rpm to 75rpm, using second method of Korean Pharmacopoeia dissolution test (paddle method).

20. The pharmaceutical composition of claim 15, wherein the pharmaceutical composition is provided in the form of a solid oral preparation.

21. The pharmaceutical composition of claim 20, wherein the solid oral preparation is a multi-layered tablet, a cored tablet, a single tablet, a coated tablet, or a capsule.