KR101190708B1 - Sustained-release pharmaceutical composition comprising mosapride or salt thereof - Google Patents

Abstract

The present invention relates to a sustained release pharmaceutical composition comprising mosaprid or a salt thereof, wherein the composition of the present invention initially meets the effective blood concentration of mosapride by satisfying a unique two-phase dissolution profile (immediate release phase and delayed release phase). It can be reached quickly, and in the late period, the effective blood concentration can be continuously maintained to increase the efficacy of mosapride by taking a single dosage form once a day, as well as to improve medication compliance.

Description

Sustained-release pharmaceutical composition comprising mosapride or salt thereof}

The present invention relates to a sustained release pharmaceutical composition comprising mosaprid or a salt thereof having a controlled dissolution profile.

Mosapride of formula 1, 4-amino-5-chloro-2-ethoxy-N-((4- (4-fluorobenzyl) -2-morpholinyl) methyl) benzamide) is EP 243959 And US 4870074 as gastrointestinal motility promoters.

Mosaprid is a selective serotonin (5-hydroxytrytamine, 5-HT) receptor agonist that selectively acts on the serotonin (5-HT) receptor on the gut cholinergic neuron to promote the release of acetylcholine at the nerve endings. In addition, the acetylcholine promotes digestive tract smooth muscle movement, thereby promoting strong digestive tract movement and gastric emptying. Mosaprid has no dopamine D2 receptor blocking action and therefore has no side effects such as extrarapyramidal symptoms, hyperprolactinemia (milk secretion, feminized breast), QT prolongation and deep vein.

Mosapride is generally taken three times a day and can be taken both before and after meals because it is absorbed stably regardless of meals. After taking the drug, the drug is expressed quickly and has a high improvement effect of digestive dysfunction by administration for about 2 weeks. In addition, mosapride has a short biological half-life of 1.4-2.0 hours, and C _max (maximum blood concentration after drug administration) and AUC (area under blood drug concentration-time curve) increase in proportion to dose up to 5-40 mg. do.

Mosapride is absorbed by about 93% in the gastrointestinal tract, but several times a day (e.g., 5 mg × 3 times) due to its low solubility, low bioavailability and short half life in aqueous solutions. There is a problem to be administered. Since mosapride is metabolized and lost at a very high rate when absorbed into the body due to its physicochemical properties, the immediate or immediate release formulations on the market have a problem in that the duration of the drug is short because the blood duration is very short.

In order to improve this, WO 03/11256 A1 proposes a sustained-release tablet in which mosafrid is prepared as a sustained-release matrix tablet using a water-soluble hydrogel, but is a single layer matrix using the water-soluble hydrogel. The formulation has the disadvantage that it is difficult to quickly achieve an effective blood concentration of mosaprid.

Given that the sustained release pattern of a simple drug is difficult to satisfy rapid and constant drug properties, it would be desirable to design a drug with a specific release rate and pattern to allow rapid release while sustained release after administration. .

Accordingly, the present inventors prepared a mosaprid-containing sustained-release pharmaceutical composition having two phases (biphase) satisfying a unique dissolution profile, and through the dissolution profile, the initial effective blood concentration of mosafrid and the maintenance of the late effective blood concentration It was confirmed that the possible and completed the present invention.

It is an object of the present invention to provide a pharmaceutical composition comprising mosaprid or a salt thereof which exhibits a unique biphasic elution profile.

In accordance with the above object, the present invention provides a pharmaceutical composition having the immediate and sustained-release portion of the mosaprid including mosapride or a salt thereof and a pharmaceutically acceptable carrier,

The pharmaceutical composition is characterized by satisfying the following elution profile as measured in an aqueous buffer solution at 37 ° C. according to the Elution 2 method (paddle method) according to the Korean Pharmacopoeia:

1) within 30 minutes from 10% to 50% of the total weight of the mosafride or salt thereof is released,

2) A release of 50% to 95% of the total weight of the mosaprid or salt thereof is achieved between 6 and 16 hours.

The pharmaceutical composition according to the present invention can quickly reach the effective blood concentration of mosapride early by satisfying the unique two-phase dissolution profile (immediate release phase and delayed release phase), and later maintains the effective blood concentration continuously Dosing once a day as a dosage form not only increases the efficacy of mosapride, but also improves medication compliance.

1 and 2 are graphs showing the respective dissolution rates in water and pH 1.2 of bilayer tablets prepared by varying the ratio of mosaprid in the immediate and sustained release portions in Examples 1 to 3 of the present invention.
3 and 4 are graphs showing the respective dissolution rates in water and pH 1.2 of bilayer tablets prepared by varying the ratio of mosaprid in the immediate and sustained release portions in Comparative Examples 1 and 2 of the present invention.
5 and 6 are graphs showing the dissolution rates of water and pH 1.2 of the bilayer tablets prepared by different types of release-controlling polymers in Examples 4 to 6 of the present invention.
7 and 8 are graphs showing the dissolution rates of water and pH 1.2 of the capsule containing the delayed-release pellet prepared in Example 7 of the present invention.
9 and 10 are graphs showing the dissolution rates of the bilayer tablets prepared in Example 8 of the present invention in water and pH 1.2, respectively.
11 and 12 are graphs showing the dissolution rate of each of the tablets in water and pH 1.2 of the tablet including the immediate-release drug coating layer prepared in Example 9 of the present invention.
13 and 14 are graphs showing the respective dissolution rates in water and pH 1.2 of tablets prepared with a nuclear tablet including a delayed-release nuclear layer in Example 10 of the present invention.
15 and 16 are graphs showing the dissolution rates of water and pH 1.2, respectively, of capsules containing the immediate release sub-tablet and the sustained release sub-tablet prepared in Example 11 of the present invention.
17 is a graph showing the change in blood concentration with time upon administration of the bilayer tablet prepared in Examples 1 to 3 of the present invention.
18 is a graph showing the change in blood concentration with time upon administration of the bilayer tablet prepared in Comparative Examples 1 to 2 of the present invention.
19 is a graph showing the change in blood concentration with time upon administration of the bilayer tablet prepared in Example 2 of the present invention and a commercial control drug (Gasmotin ^® tablet).

The present invention is a pharmaceutical composition having the immediate and sustained-release portion of the mosaprid including mosapride or a salt thereof and a pharmaceutically acceptable carrier,

The pharmaceutical composition is characterized by satisfying the following elution profile as measured in an aqueous buffer solution at 37 ° C. according to the Elution 2 method (paddle method) according to the Korean Pharmacopoeia:

1) within 30 minutes from 10% to 50% of the total weight of the mosafride or salt thereof is released,

2) A release of 50% to 95% of the total weight of the mosaprid or salt thereof is achieved between 6 and 16 hours.

In one preferred embodiment of the present invention, the pharmaceutical composition of the present invention may satisfy the following dissolution profiles:

1) within 30 minutes 20% to 40% of the total weight of the mosafride or salt thereof is released;

2) Release of 60% to 90% of the total weight of mosaprid or salts thereof is achieved within 8 to 14 hours.

The composition of the present invention elutes the mosaprid or salt thereof according to the biphasic profile, wherein the first phase is an immediate release (or immediate release, immediate release) phase with immediate release, and the second phase is sustained release. Controlled release by the sustained release portion as a (or delayed release) phase. The mosaprid-containing composition according to the present invention enables the separation of the immediate and sustained release phases by the immediate and sustained release portions in one formulation, and thus the different release aspects without affecting the release of each other. Controlled release of the formulation should be possible.

In addition, the sustained-release pharmaceutical composition according to the present invention can quickly reach the initial effective blood concentration of the therapeutically effective mosaprid due to rapid dissolution by including the immediate release portion and the sustained release portion in an appropriate ratio, after which the mosafried gradually As it is released, effective blood levels can be maintained continuously. The two-phase emission pattern according to the present invention does not mean increasing the general emission pattern, but it means that the homeostasis of the drug appears only when a specific range of emission is performed at a specific time interval. In addition, it is necessary to specifically set the release period so that the drug lasts until the night time except the active time of the day so that the gastrointestinal movement is not activated even during the sleep time.

In the composition according to the present invention, the first phase or the immediate phase is the dissolution profile portion obtained at 0 to 30 minutes in a suitable in vitro dissolution test, and the suitable dissolution test is the Korean Pharmacopoeia (or US Pharmacopoeia) in 37 ° C. aqueous buffer. According to the second eluting method (paddle method) according to the method performed by a general apparatus, or a method for making some changes to the extent that is well known to those skilled in the art. In one embodiment of the composition according to the invention, 10 to 50%, preferably 20 to 40% of the total weight of the mosafride or salt thereof is released within 30 minutes in the first phase.

In the composition according to the invention, said second phase or sustained release phase is the portion of the dissolution profile after 30 minutes measured in a suitable in vitro dissolution test. In one embodiment of the preparations according to the invention, the time taken for the release of 50% to 95% of the total weight of the mosaprid or salt thereof in the second phase is 6 to 16 hours, preferably 60% to 90% of the release. The time required is between 8 and 14 hours. Exemplary compositions according to the present invention, as shown in Figure 1, wherein about 30% of the total weight of the mosaprid or salt thereof is released in the instantaneous phase and the second phase is about 90% of the total weight of the mosaprid or salt thereof It elutes around 12 hours in sustained release phase.

The rapid release of the first phase allows the dissolution of the mosapride to proceed quickly to achieve a therapeutically effective amount of the mosapride concentration early, while the continued release of the second phase allows to maintain its effective amount for a long time.

The reason why the dissolution profile is the key is to show rapid drug expression without exceeding the maximum blood concentration when ingesting the amount generally taken in a day due to the drug efficacy of mosaprid itself. As a result of verifying through various clinical trials by the researchers, if the release is slower than the immediate dissolution of the instantaneous dissolution proposed by the present invention, the rapid effect is not expressed and the improvement of gastrointestinal motility does not appear quickly after eating. Excessive blood levels can cause side effects. Therefore, the optimal ratio of the instantaneous and sustained release portions proposed in the present invention can solve the above problems. Also, the presenting means that the release taking place inventors set up discharge to reach the C _max on the graph of log transformation as then there generally views difficult complete primary emission in the PK profile of the sustained release formulations aspect be seen half-life of the following drugs (medicine 3 hours) is characterized by maintaining almost linearity (r ² > 0.85). This means that the rate of disappearance of the commercially available generic immediate release type was completely changed, and it was confirmed that constant gastrointestinal motility could be induced by controlling the intrinsic body dissipation rate as a dosage form. The present invention is characterized by being able to induce constant and regular gastrointestinal motility due to a constant release, rather than simply sustaining the effect of stopping the drug repeatedly appearing in the day due to the excessively short half-life of mosaprid. In addition, it is very important to limit the release time of the drug so that the release is completed before the sleep time and the gastrointestinal motility is not activated continuously through the drug expression from the sleep time. This prevents the discomfort of patients who may have a sleep disorder.

The composition according to the invention may comprise an active ingredient of mosaprid or a salt thereof in an effective amount of 0.1 to 500 mg, preferably 0.5 to 100 mg per unit dose.

Furthermore, in the compositions according to the invention, it is preferred to comprise 20 to 40% of the total weight of the immediate release addition mosaprid or salts thereof, and to comprise 60 to 80% of the total weight of the sustained release addition mosapride or salts thereof. .

The immediate and sustained-release portions each include mosapride or a salt thereof and a pharmaceutically acceptable carrier, wherein the carriers used in each portion are suitably selected from those conventionally used at a level that achieves the desired dissolution profile. And may be used in an appropriate amount conventionally used for formulation.

Specifically, the sustained-release portion is a pharmaceutically acceptable diluent selected from the group consisting of lactose, dextrin, mannitol, sorbitol, starch, microcrystalline cellulose, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, calcium carbonate, sugars and mixtures thereof. As the binder, polyvinylpyrrolidone, copovidone, gelatin, starch, sucrose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl alkyl cellulose and mixtures thereof May be used. Lubricants include stearic acid, stearate, talc, corn starch, carnauba wax, hard silicic anhydride, magnesium silicate, synthetic aluminum silicate, hardened oil, white lead, titanium oxide, microcrystalline cellulose, macrogol 4000 and 6000, isopropyl acid myristic acid, Any one selected from the group consisting of calcium hydrogen phosphate, talc and mixtures thereof may be used, and as a release controlling agent (sustained release base), a cellulose derivative, a gum, a hydrophilic or hydrophobic (meth) acrylate copolymer, a hydrophilic or hydrophobic polyvinyl derivative , Polyethylene derivatives, carboxyvinyl compounds and polysaccharides can be selected from the group consisting of. Specific emission control agents include hydroxypropyl cellulose, hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, methyl cellulose, ethyl cellulose, carboxymethyl cellulose sodium, cellulose acetate, cellulose acetate phthalate, methyl hydroxyethyl cellulose, Guar gum, locust bean gum, tragacanth gum, carrageenan, acacia gum, xanthan gum, arabian gum, gellan gum, karaya gum, tara gum, tamarind gum, gati gum, polyvinyl alcohol, polyvinylpyrrolidone, polyvinyl Acetyldiethylaminoacetate, polyethylene derivative, polyethylene glycol, polyethylene oxide, carbomer, dextrin, polydextrin, dextran, pectin, pectin derivative, alginate, polygalacturonic acid, xylan, arabinoxylan, arabinogalactan, Starch, hydroxypropylstarch, amylose, amy Milopectin, Flurane, Met, Purseleran, Colorinane, Glucosamine, Chitosan, Chitin, Gelatin, Collagen, Casein, Agar, Albumin, Poly (Methacrylic Acid, Methyl Methacrylate) Copolymer, Poly (Methacrylic Acid , Ethyl methacrylate) copolymer, polyvinylacetate, poly (ethyl acrylate, methyl methacrylate) copolymer and poly (ethyl acrylate, methyl methacrylate, trimethylaminoethyl methacrylate) copolymer . At this time, the release controlling agent is preferably used in an amount of 5 to 80% by weight, more preferably 10 to 30% by weight based on the total weight of the sustained release portion.

The pharmaceutical compositions according to the invention may be prepared in dosage forms of powders, pellets, capsules, tablets, coated tablets or combinations thereof. Preferably, it may be made in the form of a bilayer tablet consisting of a layer of immediate release portions and a layer of sustained release portions, or may be composed of tablets comprising delayed release coating pellets contained in a matrix.

The immediate release portion in the pharmaceutical composition according to the present invention is in the present invention a single pharmaceutical immediate release unit such as, for example, an immediate release tablet or pellet, as several such units formulated to be immediate release in the form of capsules or tablets; As an immediate release layer that can be incorporated into a multilayer tablet; Or as an immediate release coating layer in one or more coated tablets or pellets.

Sustained release portions in the pharmaceutical compositions according to the invention are used herein as pharmaceutical delayed release units such as, for example, delayed release tablets or pellets; As several delayed release units formulated in capsules or tablets; As a delayed release layer that can be incorporated into a multilayer tablet; As a delayed release core or delayed release coating layer in one or more coated tablets; Or as delayed release pellets in a disintegrating tablet.

Also included in the present invention are formulations that comprise the immediate release portion and the sustained release portion at the same time, but which exhibit a specific release aspect by dividing the release in the body.

The composition of the present invention may be formulated by conventional mixing methods such as granulation, mixing, filling and compression.

For example, tablets can be made by a wet granulation process, in which the immediate and sustained release portions are produced separately. Suitably, the active ingredient and the pharmaceutically acceptable carrier are screened and mixed in a high shear mixing granulator or fluid bed dryer for either the immediate or sustained release portions. The mixture is granulated by adding a granulation solution (typically a disintegrant dissolved / dispersed in purified water, purified water, or a drug dissolved / dispersed in purified water or a suitable solvent) sprayed into a high shear mixing granulator or fluid bed dryer. do. If necessary, wetting agents, for example surfactants, can be added. The resulting (optionally pelletized) granules are dried by tray, fluidized bed or microwave drying techniques, usually to 1-5% residual moisture. The dried granules are ground to make the particle size constant, and the granules are mixed with extragranular excipients, generally lubricants and glidants (eg magnesium stearate, silicon dioxide) as needed. The separately prepared immediate and sustained release granules can then be tableted together typically in the range of 100 to 600 mg using a rotary tablet compressor (such as a bilayer tablet compressor). The resulting tablets can be coated in a pan coater so that typically an aqueous film coat of 1-5% is obtained and then polished with wax.

Alternatively, tablets can be prepared by a direct tableting process. Suitably, the active ingredient and the pharmaceutically acceptable carrier are screened separately for the immediate and sustained release portions and then mixed in a suitable mixer, for example a cone, cube or V-shaped mixer. If necessary, other pharmaceutically acceptable carriers are added and further mixed. The separately prepared immediate and sustained release portions can be combined and compressed together using a rotary tablet compressor as described above. The resulting tablet can be coated with a pan coater.

It is also possible to prepare tablets using both a wet granulation process and a direct tableting process. For example, sustained-release portions can be prepared by wet granulation as described above, while immediate release portions can be prepared by directly mixing tableting excipients. In addition, a commercially available mixture of immediate release mosaprid can also be used for tableting directly. The two phases can then be combined and tableted together as described above.

Suitably, the capsules can be prepared by screening the active ingredient and pharmaceutically acceptable salts and mixing in a suitable mixer, such as a conical, cubic or V-shaped mixer, to separately prepare the immediate and sustained release portions. .

If desired, other pharmaceutically acceptable carriers, such as lubricants and glidants, are typically added, then the mixture is mixed. The separately prepared immediate and sustained release portions can then be mixed and filled in an appropriate amount into the capsule using a standard capsule filling machine.

The composition according to the present invention can provide a superior therapeutic effect of mosaprid even by taking a single dosage form in a single dosage form, unlike the conventional method of administering three times a day, thereby greatly improving medication compliance.

Hereinafter, the present invention will be described with reference to specific examples, but the scope of the present invention is not limited to these examples.

Example  1 to 3: Immediate  Department and Sustained Release Mosafried  Preparation of Two-Layered Tablets According to Content Ratio

Two-layer tablets were prepared by varying the mosaprid content in the immediate and sustained release portions, as shown in Table 1 below. In the case of Example 1, the mosaprid content in the immediate part was 20% based on the total weight of the mosafrid, and in Example 2, 30% and Example 3 were 40%. Specific manufacturing process is as follows.

<Step 1> Immediate  Preparation of minor granules

After dissolving hydroxypropyl cellulose in purified water to prepare a binding solution, citric acid mosapride, lactose monohydrate and corn starch were sieved through a mesh of 24 mesh. Subsequently, wet granules were prepared using a high speed mixer (MIC Developer-5, COMASA), dried and sieved, and then substituted with low-substituted hydroxypropyl cellulose, magnesium stearate, and hard anhydrous with 35 mesh. Silicate and the like were mixed to prepare an immediate part.

Step 2 Preparation of Sustained Release Sub-Granules

Hydroxypropyl cellulose (low viscosity) was dissolved in purified water to prepare a binding solution, and citric acid mosapride, lactose monohydrate, microcrystalline cellulose, and hydroxypropyl methyl cellulose (high viscosity) were sieved and mixed with 24 mesh as a release controlling polymer. . Then, wet granules were prepared using a high speed mixer (MIC Developer-5, COMASA), dried and sieved, and then a slow-release portion was prepared by mixing hard silicic anhydride and magnesium stearate, which were sieved with 35 mesh. It was.

Step 3 Preparation of Bilayer Tablet

Each of the prepared immediate-release and sustained-release portions was compressed using a bilayer tablet press (BB-11, RIVA) to prepare a bilayer tablet composed of respective layers. The prepared bilayer tablet was placed in a pan coater (LDCS, VECTOR) and then coated with Opadry.

division Example 1 Example 2 Example 3 Instantaneous parts
(mg / tablet) chief ingredient Citric acid mosfried 3.174 4.761 6.348 Excipient Lactose baggage 63.776 62.189 60.602 Excipient Corn starch 32.5 32.5 32.5 Binder Hydroxypropylcellulose 2.6 2.6 2.6 Disintegrant Low Substituted Propyl Cellulose 26 26 26 Lubricant Magnesium stearate 1.3 1.3 1.3 Lubricant Light anhydrous silicic acid 0.65 0.65 0.65 Total (mg / tablet) 130.0 130.0 130.0 Sustained release
(mg / tablet) chief ingredient Citric acid mosfried 12.696 11.109 9.522 Excipient Lactose baggage 102.554 120.141 93.728 Excipient Microcrystalline cellulose 40.0 40.0 40.0 Binder Hydroxypropylcellulose 5.0 5.0 5.0 Excipient Hydroxypropylmethylcellulose
4000cps 27 15 35 Excipient Hydroxypropylmethylcellulose
(High viscosity) 9 5 13 Lubricant Light anhydrous silicic acid 1.25 1.25 1.25 Lubricant Magnesium stearate 2.5 2.5 2.5 Coating agent Opadry 12.0 12.0 12.0 Total (mg / tablet) 342.0 342.0 342.0

Comparative example  1 to 2: Immediate  Department and Sustained Release Mosafried  Preparation of Two-Layered Tablets According to Content Ratio

In order to compare the effect according to the mosapride content in the immediate release portion and the sustained release portion, two-layered tablets were prepared in the same manner as in the above example with the composition shown in Table 2 below. In Comparative Example 1, the content of mosaprid in the immediate portion was 10% based on the total weight of the mosaprid, and in Comparative Example 2, 50%.

division Comparative Example 1 Comparative Example 2 Instantaneous parts
(mg / tablet) chief ingredient Citric acid mosfried 1.588 7.94 Excipient Lactose baggage 65.362 59.01 Excipient Corn starch 32.5 32.5 Binder Hydroxypropylcellulose 2.6 2.6 Disintegrant Low Substituted Propyl Cellulose 26 26 Lubricant Magnesium stearate 1.3 1.3 Lubricant Light anhydrous silicic acid 0.65 0.65 Total (mg / tablet) 130.0 130.0 Sustained release
(mg / tablet) chief ingredient Citric acid mosfried 14.292 7.94 Excipient Lactose baggage 121.958 83.31 Excipient Microcrystalline cellulose 40.0 40.0 Binder Hydroxypropylcellulose 5.0 5.0 Excipient Hydroxypropylmethylcellulose
4000cps 10 45 Excipient Hydroxypropylmethylcellulose
(High viscosity) 5 15 Lubricant Light anhydrous silicic acid 1.25 1.25 Lubricant Magnesium stearate 2.5 2.5 Coating agent Opadry 12.0 12.0 Total (mg / tablet) 342.0 342.0

Example  4 to 8: according to the polymer for controlling release Mosafried  Preparation of Containing Two-Layered Tablets

As shown in Table 3 components and contents, mosapride-containing bilayer tablets were prepared by varying the polymer for controlling release.

<Step 1> Immediate  Preparation of minor granules

After dissolving hydroxypropyl cellulose in purified water to prepare a binding solution, citric acid mosapride, lactose monohydrate and corn starch were sieved through a mesh of 24 mesh. Subsequently, wet granules were prepared using a high speed mixer (MIC Developer-5, COMASA), dried and sieved, and then substituted with low-substituted hydroxypropyl cellulose, magnesium stearate and hard anhydride, which were sieved through 24 mesh. Silicate and the like were mixed to prepare an immediate part.

Step 2 Preparation of Sustained Release Sub-Granules

After dissolving hydroxypropyl cellulose (low viscosity) in purified water to prepare a binding solution, citric acid mosapride, lactose hydrate, microcrystalline cellulose and polyethylene oxide (Example 4), hydroxypropyl cellulose (high viscosity, implementation) Example 5), crosslinked sodium carboxymethylcellulose (Example 6), crosslinked polyvinylpyrrolidone (Example 7) or xanthan gum (Example 8) were sieved through a 24 mesh and mixed. Then, wet granules were prepared using a high speed mixer (MIC Developer-5, COMASA), dried and sieved, and then a slow-release portion was prepared by mixing hard silicic anhydride and magnesium stearate, which were sieved with 35 mesh. It was.

Step 3 Preparation of Bilayer Tablet

Each of the prepared immediate-release and sustained-release portions was compressed using a bilayer tablet press (BB-11, RIVA) to prepare a bilayer tablet composed of respective layers. The prepared bilayer tablets were placed in a pan coater (LDCS, VECTOR) and then coated with Opadry.

division Example
4 Example
5 Example
6 Example
7 Example
8 Instantaneous parts
(mg / tablet) chief ingredient Citric acid mosfried 4.232 4.232 4.232 4.232 4.232 Excipient Lactose baggage 62.718 62.718 62.718 62.718 62.718 Excipient Corn starch 32.5 32.5 32.5 32.5 32.5 Binder Hydroxypropylcellulose 2.6 2.6 2.6 2.6 2.6 Disintegrant Low Substituted Propyl Cellulose 26 26 26 26 26 Lubricant Magnesium stearate 1.3 1.3 1.3 1.3 1.3 Lubricant Light anhydrous silicic acid 0.65 0.65 0.65 0.65 0.65 Total (mg / tablet) 130.0 130.0 130.0 130.0 130.0 Sustained release
(mg / tablet) chief ingredient Citric acid mosfried 11.639 11.639 11.639 11.639 11.639 Excipient Lactose baggage 103.611 103.611 103.611 103.611 103.611 Excipient Microcrystalline cellulose 40.0 40.0 40.0 40.0 40.0 Binder Hydroxypropylcellulose 5.0 5.0 5.0 5.0 5.0 Excipient Hydroxypropylmethylcellulose 2208 27 27 27 27 27 Excipient Polyethylene oxide 15 - - - - Excipient Hydroxypropyl cellulose (high viscosity) - 10 - - - Excipient Crosslinked sodium
Carboxymethyl Cellulose - - 20 - - Excipient Crosslinked polyvinylpyrrolidone - - - 10 - Excipient Xanthan gum - - - - 15 Lubricant Light anhydrous silicic acid 1.25 1.25 1.25 1.25 1.25 Lubricant Magnesium stearate 2.5 2.5 2.5 2.5 2.5 Coating agent Opadry 12.0 12.0 12.0 12.0 12.0 Total (mg / tablet) 348.0 343.0 353.0 343 348

Example  9: delayed release Pellets  Containing Mosafried  Preparation of Containing Capsules

According to the ingredients and contents of Table 4, mosapride containing capsules containing the delayed release pellets were prepared as follows.

<Step 1> Immediate  Preparation of minor granules

After dissolving hydroxypropyl cellulose in purified water to prepare a binding solution, citric acid mosapride, lactose monohydrate and corn starch were sieved through a mesh of 24 mesh. Subsequently, wet granules were prepared using a high speed mixer (MIC Developer-5, COMASA), dried and sieved, and then substituted with low-substituted hydroxypropyl cellulose, magnesium stearate, and hard anhydrous with 35 mesh. Silicate and the like were mixed to prepare an immediate part.

<Step 2> forming a sustained release secondary drug coating layer

Non-pareil beads of 25-30 mesh size were placed in a fluidized bed coater, and mosaprid, hydroxypropylmethylcellulose (low viscosity) and hydroxypropylmethylcellulose 4000 cps were mixed with water and methanol (1 (2, weight ratio) to coat with a coating solution prepared to form a drug coating layer. Coating conditions were spray air 2.7 bar, outlet air temperature 24 degreeC, inlet air temperature 34 degreeC, flow 4-7, and outlet air plate 28%.

<Step 3> Sustained release Control layer  formation

In the fluidized bed coater, the pellet formed with the drug coating layer obtained in step 2 was coated with a coating solution prepared by dissolving ethyl cellulose and hydroxypropyl methyl cellulose in a mixed solution of water and methanol (1: 41.5, weight ratio) to release the control film layer. Formed. Coating conditions were spray air 2.8 bar, outlet air temperature 24 degreeC, inlet air temperature 34 degreeC, flow 5-18, and outlet air plate 28%.

<Step 4> Capsule Filling

The prepared immediate-release granules and sustained-release pellets were filled in No. 1 capsules using a capsule filling machine (DMF1500, Daesan Pharmatech).

division Example 9 Instantaneous parts
(mg / tablet) chief ingredient Citric acid mosfried 4.232 Excipient Lactose baggage 64.489 Excipient Corn starch 32.5 Binder Hydroxypropylcellulose 2.6 Disintegrant Low Substituted Propyl Cellulose 26 Lubricant Magnesium stearate 1.3 Lubricant Light anhydrous silicic acid 0.65 Total (mg / tablet) 130.0 Sustained release
(mg / tablet) chief ingredient Citric acid mosafried 11.639 Excipient Celphere 120 Binder Hydroxypropylmethylcellulose 8.69 Excipient Hydroxypropylmethylcellulose 4000cps 2.0 Excipient Ethyl cellulose 8.7 Solvent Methanol 158 Coating agent Opadry 9.2 Total (mg / tablet) 292.0

Example  10: delayed release Pellets  Containing Mosafried  Preparation of Containing Two-Layered Tablets

A mosapride containing bilayer tablet was prepared comprising delayed release pellets according to the ingredients and contents in Table 5 below.

<Step 1> Immediate  Preparation of minor granules

After dissolving hydroxypropyl cellulose in purified water to prepare a binding solution, citric acid mosapride, lactose monohydrate and corn starch were sieved through a mesh of 24 mesh. Subsequently, wet granules were prepared using a high speed mixer (MIC Developer-5, COMASA), dried and sieved, and then substituted with low-substituted hydroxypropyl cellulose, magnesium stearate, and hard anhydrous with 35 mesh. Silicate and the like were mixed to prepare an immediate part.

<Step 2> forming a sustained release secondary drug coating layer

A non-pareil bead of 25-30 mesh size was placed in a fluidized bed coater, and a coating solution prepared by dissolving mosaprid and hydroxypropylmethylcellulose in a mixed solution of water and methanol (1: 2, weight ratio). Coating to form a drug coating layer. Coating conditions were spray air 2.7 bar, outlet air temperature 24 degreeC, inlet air temperature 34 degreeC, flow 4-7, and outlet air plate 28%.

<Step 3> Sustained release part Control layer  formation

In the fluidized bed coater, the pellet formed with the drug coating layer obtained in step 2 was coated with a coating solution prepared by dissolving ethyl cellulose and hydroxypropylmethyl cellulose in a mixed solution of water and methanol (1: 41.5, weight ratio) to release the control film layer. Formed. Coating conditions were spray air 2.8 bar, outlet air temperature 24 degreeC, inlet air temperature 34 degreeC, flow 5-18, and outlet air plate 28%.

Then, hydroxypropylmethylcellulose (high viscosity), microcrystalline cellulose, hard silicic anhydride, and magnesium stearate, which were sieved through 35 mesh, were mixed to prepare a sustained release portion.

Step 4 Preparation of Bilayer Tablet

Each of the prepared immediate-release and sustained-release portions was compressed using a bilayer tablet press (BB-11, RIVA) to prepare a bilayer tablet composed of respective layers. The prepared bilayer tablets were placed in a pan coater (LDCS, VECTOR) and then coated with Opadry.

division Example 10 Instantaneous parts
(mg / tablet) chief ingredient Citric acid mosfried 4.232 Excipient Lactose baggage 56.989 Excipient Corn starch 32.5 Binder Hydroxypropylcellulose 2.6 Disintegrant Low Substituted Propyl Cellulose 26 Lubricant Magnesium stearate 1.3 Lubricant Light anhydrous silicic acid 0.65 Total (mg / tablet) 130.0 Sustained release
(mg / tablet) chief ingredient Citric acid mosafried 11.639 Excipient Celphere 120 Binder Hydroxypropylmethylcellulose 2.89 Excipient Microcrystalline cellulose 48.1 Lubricant Light anhydrous silicic acid 1.2 Lubricant Magnesium stearate 1.2 Excipient Hydroxypropylmethylcellulose (high viscosity) 10.0 Excipient Ethyl cellulose 8.7 Solvent Methanol 158 Coating agent Opadry 12 Total (mg / tablet) 340.0

Example  11: containing a drug coating layer Mosafried  Preparation of Containing Tablets

According to the ingredients and contents of Table 6, mosaprid-containing coated tablets were prepared.

<Step 1> Western  Tablet manufacturing

After dissolving hydroxypropyl cellulose in purified water to prepare a binding solution, citric acid mosafride, lactose monohydrate, microcrystalline cellulose and hydroxypropyl cellulose were sieved through a mesh of 24 mesh. Then, the wet granules were prepared using a high speed mixer, dried and sieved, and then mixed with hard silicic anhydride and magnesium stearate, which was sieved through 24 mesh, to prepare a sustained-release portion. Tablets were prepared by tableting the sustained-release portion with a continuous tablet press (Picola D-8, RIVA).

<Step 2> Drug Coating Process

Mosaprid, hydroxypropylmethylcellulose, propylene glycol 6000 and Eudragit E100 were dissolved in a mixed solution of ethanol (fermented alcohol) and water (65:35, weight ratio) to prepare a coating solution (immediate part), step 1 Sustained release secondary tablets were put in a pan coater (LDCS, VECTOR) and then coated with the coating solution.

division Example 11 Instantaneous parts
(mg / tablet) chief ingredient Citric acid mosfried 4.232 Coating agent Hydroxypropylmethylcellulose 3.125 Coating agent Propylene Glycol 6000 0.3215 Coating agent Eudragit E100 0.0015 Solvent ethanol 84.5 Total (mg / tablet) 130.0 Sustained release
(mg / tablet) chief ingredient Citric acid mosfried 11.639 Excipient Lactose baggage 99.431 Excipient Microcrystalline cellulose 40.0 Binder Hydroxypropylcellulose 5.0 Excipient Hydroxypropylmethylcellulose 4000cps 27 Excipient Hydroxypropyl cellulose (high viscosity) 9 Lubricant Light anhydrous silicic acid 1.25 Lubricant Magnesium stearate 2.5 Coating agent Opadry 12.0 Total (mg / tablet) 300.0

Example  12 delayed release The nuclear layer  Containing Mosafried  Preparation of Containing Tablets

To prepare a mosapride containing tablet comprising a delayed-release nuclear layer in the ingredients and contents of Table 7.

<Step 1> Sustained release part Nuclear layer  Tablet manufacturing

After dissolving hydroxypropyl cellulose in purified water to prepare a binding solution, citric acid mosafride, lactose monohydrate, microcrystalline cellulose and hydroxypropyl cellulose were sieved through a mesh of 24 mesh. Then, wet granules were prepared using a high speed mixer (MIC Developer-5, COMASA), dried and sieved, and then a slow-release portion was prepared by mixing hard silicic anhydride and magnesium stearate, which were sieved with 35 mesh. It was. Tablets were prepared by tableting the sustained-release portion with a continuous tablet press (Picola D-8, RIVA). The prepared sustained release sub-tablet was placed in a pan coater (LDCS, VECTOR) and then film-coated with Opadry.

<Step 2> Immediate  Secondary outer layer tablet manufacturing

After dissolving hydroxypropyl cellulose in purified water to prepare a binding solution, citric acid mosapride, lactose monohydrate and corn starch were sieved through a mesh of 24 mesh. Subsequently, wet granules were prepared using a high speed mixer (MIC Developer-5, COMASA), dried and sieved, and then substituted with low-substituted hydroxypropyl cellulose, magnesium stearate, and hard anhydrous with 35 mesh. Silicate or the like was mixed to prepare a mixture of immediate parts.

<Step 3> Nuclear layer  Tablets manufacturing

The tablets containing the nuclear layer were prepared by tableting the granules of the sustained-release portion and the granules of the immediate release portion using a single tablet press (EKO, Korsch). The prepared core tablet was placed in a pan coater (LDCS, VECTOR) and then coated with Opadry.

division Example 12 Sustained release
Nuclear layer
(mg / tablet) chief ingredient Citric acid mosfried 11.639 Excipient Lactose baggage 25.611 Excipient Microcrystalline cellulose 20.0 Binder Hydroxypropylcellulose 5.0 Excipient Hydroxypropylmethylcellulose 4000cps 27.0 Excipient Hydroxypropylmethylcellulose (high viscosity) 12.0 Lubricant Light anhydrous silicic acid 1.25 Lubricant Magnesium stearate 2.5 Coating agent Opadry 5.0 Total (mg / tablet) 110.0 Instantaneous Outer Layer
(mg / tablet) chief ingredient Citric acid mosfried 4.232 Excipient Lactose baggage 158.568 Excipient Corn starch 80 Excipient Microcrystalline cellulose 175.0 Binder Hydroxypropylcellulose 5.5 Disintegrant Low Substituted Propyl Cellulose 48 Lubricant Magnesium stearate 2.5 Lubricant Light anhydrous silicic acid 1.2 Coating agent Opadry 15 Total (mg / tablet) 600.0

Example  13: Immediate  Departmental and sustained-release minor mini-tablets containing Mosafried  Preparation of Containing Capsules

<Step 1> Immediate  Production of minor mini-tablets

The immediate release minor mini-tablets were prepared according to the ingredients and contents in Table 8 below.

After dissolving hydroxypropyl cellulose in purified water to form a binding solution, citric acid mosapride and microcrystalline cellulose were sieved through 35 mesh, and wet granules were prepared by using a high speed mixer (MIC Developer-5, COMASA), and dried and sieved. After carrying out the process, the hard parts were prepared by mixing hard silicic anhydride and magnesium stearate, which were sieved to 35 mesh. The instantaneous portion was compressed using a single tablet press (EKO, Korsch). The prepared mini tablets were put in a pan coater (LDCS, VECTOR) and then coated with Opadry. The diameter of the mini-tablets is in the range of 2-4 mm.

Step 2 Preparation of Sustained Release Mini-Tablets

Slow release minor mini-tablets were prepared according to the ingredients and contents in Table 8 below. After dissolving hydroxypropyl cellulose in purified water to prepare a binding solution, citric acid mosapride, microcrystalline cellulose and hydroxypropyl methyl cellulose (high viscosity) were sieved through 35 mesh, and a high speed mixer (MIC Developer-5, COMASA) was used. The wet granules were prepared, dried and subjected to a sieving process, and then a slow-release portion was prepared by mixing hard silicic anhydride and magnesium stearate, which were sieved to 35 mesh. The sustained release portion was compressed using a single tablet press (EKO, Korsch). The diameter of the mini-tablets ranges from 4-6 mm.

Step 3 Release of the Sustained-Release Mini Tablet Control layer  formation

The western mini-tablet obtained in step 2 was placed in a pan coater (LDCS, VECTOR), and then ethyl cellulose and hydroxypropyl methyl cellulose were dissolved in a mixed solution of water and methanol (1: 41.5, weight ratio). Coating to form a release controlling membrane layer. Coating conditions were spray air 1.7 bar, outlet air temperature 24 degreeC, inlet air temperature 34 degreeC, flow 5-7, fan speed 10-15 rpm. The mini-tablet with the emission control layer formed thereon was film coated with Opadry. The immediate release mini tablets and sustained release mini tablets were filled into hard capsules.

division Example 13 Instantaneous parts
(mg / tablet) chief ingredient Citric acid mosfried 4.232 Excipient Microcrystalline cellulose 16.668 Binder Hydroxypropylcellulose 1.1 Lubricant Talc 0.25 Lubricant Magnesium stearate 0.50 Lubricant Light anhydrous silicic acid 0.25 Coating agent Opadry 1.0 Total (mg / tablet) 24.0 Sustained release
(mg / tablet) chief ingredient Citric acid mosfried 11.639 Excipient Microcrystalline cellulose 43.986 Binder Hydroxypropylcellulose 3.025 Excipient Hydroxypropylmethylcellulose (high viscosity) 14.0 Coating agent Hydroxypropylmethylcellulose 0.55 Coating agent Ethyl Cellulose 8.4 Lubricant Light anhydrous silicic acid 0.70 Lubricant Magnesium stearate 0.70 Solvent Methanol 154.0 Coating agent Opadry 3.0 Total (mg / tablet) 110.0

Test Example  1: dissolution test

The mosapride-containing formulations prepared in Examples 1 to 13 and Comparative Examples 1 and 2 were subjected to dissolution test under the following conditions using an eluting device (Vankel VK7025 Vk8000, USA), and the results are shown in FIGS. 1 to 16. Shown in

[Dissolution test condition]

Eluent: water and pH 1.2, 900 mL

Temperature: 37 ± 0.5 ℃

Test method: Method 2 (paddle method) of the Korean Pharmacopoeia Dissolution Test, Sinker for capsule

Paddle rotation speed: 50 rpm

For Examples 1 to 13, the rapid disintegration of the immediate release layer completes the release of the immediate release portion of citric acid mosapride within 30 minutes, as shown in FIGS. 1, 2 and 5 to 16, after which the role of the release controlling polymer It can be seen that the release of the western region occurs by. In addition, the results of Examples 1 to 3 shown in Figures 1 and 2, it can be seen that it is possible to easily control the immediate release and delayed release by adjusting the ratio of the drug of the immediate release portion and the sustained release portion.

On the other hand, in the case of Comparative Examples 1 and 2, as soon as the rapid disintegration of the immediate release layer, the release of citric acid mosapride is completed within 30 minutes, and then the release of the western part occurs as a release control polymer. However, unlike Examples 1 to 3, the elution rate for 30 minutes was very low at about 10% or very high at 50%. This is because in Examples 1 to 3, the ratio of mosaprid in the immediate release layer is about 20 to 40%, whereas Comparative Example 1 is about 10% and Comparative Example 2 is about 50%.

In Figures 5 and 6 (Examples 4 to 8) it can be seen that the release of the sustained-release portion can exhibit a variety of patterns depending on the type of the controlled release polymer, through which a variety of controlled release polymer alone or in combination It is believed that the elution phase can be obtained. In Figures 7 to 10 (Examples 9 to 10) it can be seen that the pellets prepared by coating the controlled release polymer are delayed release so that immediate release and delayed release can be controlled through capsules or bilayer tablets. 11 and 12 (Example 11) it can be seen that by coating the immediate release drug layer on the sustained release tablet, the immediate release drug coating layer is eluted immediately, and then the sustained release portion is delayed release. It can be seen from FIGS. 13 and 14 (Example 12) that the immediate release portion of the outer layer is eluted immediately and the delayed release portion of the inner layer is delayed and exhibits a two-phase dissolution profile. 15 and 16 (Example 13), it can be seen that after the capsule disintegrates within 5 minutes, the immediate release minor tablets are eluted at the same time and the release of the sustained release secondary tablets takes place.

Experimental Example  2: Immediate  Department and Sustained Release Mosafried  Evaluation of Blood Concentration Changes through Clinical Trials of Two-Layered Tablets with Different Contents

In order to examine the absorption pattern of the bilayer tablet according to the mosapride content in the immediate release portion and the sustained release portion, the bilayer tablets of Examples 1 to 3 were compared with the bilayer tablets of Comparative Examples 1 and 2. Specifically, the change in blood concentration was measured in 20 healthy adult males by administering the mosaprid-containing bilayer tablets (containing 15 mg of mosaprid) of Examples 1 to 3 and Comparative Examples 1 and 2.

Twenty males were randomly divided into five groups, and the bilayer tablets prepared in Examples 1 to 3 and Comparative Examples 1 to 2 were dosed with the start of the test, followed by 0, 0.25, 0.5, 0.75, 1, Blood samples were collected at 1.25, 1.5, 2, 4, 6, 8, 10, 12, 14, 16 and 18 hours, and the concentration of mosaprid in plasma was measured from samples pretreated with blood using LC-MS. The measurement results are shown in Table 9 and FIGS. 17 and 18.

AUC, hr.ng/mL C _max , ng / mL Example 1 302.22 ± 152.88 39.61 ± 25.58 Example 2 297.28 ± 182.45 51.59 ± 38.45 Example 3 305.91 ± 208.33 61.89 ± 42.58 Comparative Example 1 253.55 ± 130.58 28.16 ± 19.53 Comparative Example 2 329.22 ± 258.28 81.25 ± 69.26

As shown in Table 9, the bilayer tablets of Examples 1 to 3 did not show a significant difference in the case of AUC (area curved area), 39.61 ng / mL, 51,59 ng / mL in the C _max category, respectively; 61.89 ng / mL, which shows that the maximum blood concentration of mosapride in vivo can be adjusted according to the proportion of immediate release portions released immediately after dosing. Therefore, after appropriately adjusting the ratio of the immediate release portion to achieve the effective blood concentration range by immediate release, it is possible to maintain the blood concentration of the drug to the desired time by controlling the delayed release of the sustained release portion.

However, in the absorption pattern of the bilayer tablets of Comparative Examples 1 and 2, the average AUC was 253.55 hr.ng/mL and 329.22 hr.ng/mL, respectively. In Comparative Example 2, the level was 110%. In addition, in the case of C _max , Comparative Example 1 was 28.16 ng / mL, and Comparative Example 2 was 81.25 ng / mL, which means that the C _max of 5 mg (Daewoong Pharmaceuticals) of the currently available control drug gasmotin tablet was 50-60 ng. Considering that / mL Comparative Example 1 is about 40% to 50% lower level, Comparative Example 2 is about 30 to 60% higher level. As described above, when the AUC and C _max values are lower or higher than those of the reference drug, the drug may not exhibit sufficient efficacy or cause side effects. Therefore, in consideration of drug efficacy equality with the reference drug, it can be seen that the ratio between the immediate release portion and the sustained release portion is 20-40%: 60-80%.

Experimental Example  3: Evaluation of blood concentration change through clinical trial

The absorption pattern of the mosaprid-containing bilayer tablet prepared in Example 2 was evaluated. A; (Daewoong gaseumotin ^® tablet 5 mg content), specifically, to target a healthy adult male and female 16 persons, Example 2 Mosapride containing Second purification (Mosapride 15 mg-containing) and citric acid Mosapride in bangjeong commercially available as a control Dosage was measured to change the blood concentration.

As a dosing method, one group of the first dose group doses the double-layer tablet of Example 2 with the start of the test, and the second group doses one gasmotin ^® tablet with the start of the test and the second dose after 6 hours, and again after 6 hours. The third dose was administered. After a period of drug suspension, the second dose group was administered in the same manner as the first dose, except that the first and second dose samples were crossed.

After taking 0, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 4, 6, 6.25, 6.5, 6.75, 7, 7.5, 8, 10, 12, 12.25, 12.5, 12.75, 13, 13.5, 14 Blood samples were taken at 16 and 18 hours and the concentration of mosaprid in plasma was measured from samples pretreated with blood using LC-MS. The measurement results are shown in Table 10 and FIG. 19.

AUC, hr.ng/mL C _max , ng / mL Comparator X 3 times 290.99 ± 192.33 53.63 ± 31.60 Test drug X 1 time 303.27 ± 205.17 55.06 ± 35.70

* 90% confidence interval of the logarithmic difference of AUC mean is 0.8744≤δ≤1.1480

* 90% confidence interval of the logarithmic difference of C _max mean is 0.8194≤δ≤1.1629

As a result of comparing the pharmacokinetics of the reference drug, Gasmotin ^® 3 times / day, and the test drug once / day, 104.2% of the drug compared to the reference in the AUC and C _max items, respectively, were compared. , 102.6%. This is very similar to the reference drug that has been well proven for a long time and can be expected to have an effect of improving the patient's medication compliance while securing the equality of the drug with the reference drug when taking the test drug.

Claims (9)

A pharmaceutical composition in the form of a bilayer tablet consisting of a layer of immediate release portions and a layer of sustained release portions, including mosapride or a salt thereof and a pharmaceutically acceptable carrier,
20 to 40% of the total weight of the immediate release addition mosapride or salt thereof, 60 to 80% of the total weight of the sustained release addition mosapride or salt thereof and cellulose derivative, gum, hydrophilic or hydrophobic (meth) acrylate A release modifier selected from the group consisting of copolymers, hydrophilic or hydrophobic polyvinyl derivatives, polyethylene derivatives, carboxyvinyl compounds and polysaccharides,
A pharmaceutical composition characterized by satisfying the following dissolution profile as measured in an aqueous buffer solution at 37 ° C. according to Elution 2 method (paddle method) according to the Korean Pharmacopoeia:
1) within 30 minutes from 10% to 50% of the total weight of the mosafride or salt thereof is released,
2) A release of 50% to 95% of the total weight of the mosaprid or salt thereof is achieved between 6 and 16 hours.
The pharmaceutical composition of claim 1, wherein the pharmaceutical composition meets the following dissolution profile:
1) within 30 minutes 20% to 40% of the total weight of the mosafride or salt thereof is released;
2) Release of 60% to 90% of the total weight of mosaprid or salts thereof is achieved between 8 and 14 hours.
delete delete The pharmaceutical composition according to claim 1, wherein the release controlling agent is included in an amount of 5 to 80% by weight based on the total weight of the sustained release portion.
delete delete delete The pharmaceutical composition according to claim 1, which is for administration once daily.

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