KR102497608B1 - Fixed Dose Combination Comprising Mosapride and Proton Pump Inhibitor - Google Patents

Abstract

The present invention relates to a combination preparation containing a proton pump inhibitor and Mosapride, which includes enteric-coated proton pump inhibitor particles and has excellent acid resistance, while increasing the effect of the two active ingredients by administering one tablet once a day. Provides the pharmaceutical composition shown. In addition, the pharmaceutical composition of the present invention is a two-layer tablet or a press-coated tablet formulation that can be directly compressed into tablets, and is suitable for mass production because it can be rapidly and stably manufactured.

Description

Combination preparation containing Mosapride and Proton Pump Inhibitor {Fixed Dose Combination Comprising Mosapride and Proton Pump Inhibitor}

The present invention relates to a combination preparation containing Mosapride and a proton pump inhibitor.

Mosapride is a selective serotonin 5-hydroxytryptamine 4 (hereinafter referred to as '5-HT4') receptor agonist. It promotes the release of acetylcholine from the nerve terminals, and this acetylcholine contracts the smooth muscle of the digestive tract and promotes the movement of the digestive tract, leading to diabetic gastropathy, dyspepsia, and gastritis. , It is a drug that shows excellent efficacy in the treatment of gastroesphageal reflux disease. Mosapride does not have the concerns of arrhythmia and sudden cardiac death due to QT interval prolongation, which was seen in Cisapride, a non-selective 5-HT4 receptor agonist, and does not have dopamine-2 (D-2) receptor antagonism. It is a safe drug with no side effects such as CNS) side effects (extrapyramidal symptoms) and hyperprolactinemia (lactation, feminized breast).

On the other hand, a proton pump inhibitor (PPI) is one of the types of drugs that inhibit gastric acid secretion. When administered orally, it is absorbed from the intestine and reaches the parietal cells of the gastric mucosa through the bloodstream It inhibits gastric acid secretion by inhibiting H+/K+ATPase, a proton pump activated by the action of gastric acid in the glandular tubules. The combination of PPI and proton pump is irreversible, and recovery of the acid secretion function is very effective as it does not occur until a new proton pump is created. In addition, PPI induces basal acid secretion and inhibition of acid secretion by stimulation, and is attracting attention as a treatment for gastric and duodenal ulcers.

When the two ingredients having different mechanisms are administered orally as a combined preparation, it can replace the combined administration of each single agent, and the patient's convenience of taking the medicine is improved, so that the treatment effect can be expected to be improved. In addition, there is an advantage in terms of economy than taking each single agent in combination. However, if you try to manufacture a complex by simply mixing the two ingredients, content variation due to non-uniform mixing of the ingredients or related substances may occur due to drug interactions, especially for drugs with low stability such as PPI drugs. In this case, the corresponding method is not suitable because it requires formulation of a composition to minimize the formation of related substances. In addition, when a combination drug is prepared in the form of a simple mixture between the two active ingredients, the elution of the PPI drug occurs under acidic conditions, and all drugs are denatured by acid without securing acid resistance, resulting in insufficient pharmacological activity. Side effects such as toxicity may occur in the body due to a decrease in bioavailability or a rapid increase in related substances. In order to prevent direct exposure to an acidic environment, the form of particles in which enteric coating is applied to the PPI drug may also be considered, but enteric-coated PPI particles are generally weak in buffering power and are very vulnerable to impact, so they can easily disintegrate during the manufacturing process, Simply enteric coating of PPI cannot completely solve the problem of loss of PPI components in an acidic environment. In fact, when the PPI particles are enterically coated and then mixed with other active ingredients or excipients or compressed into tablets, the coating layer on the surface of most PPI particles collapses, resulting in a greatly reduced acid resistance.

In this regard, Korean Patent Publication No. 10-2017-0001664 (Patent Document 1) contains Mosapride, which shows a double dissolution pattern by immediate release and sustained release, and rabeprazole, one of the PPI-type drugs, as active ingredients. Various formulations for combination preparations are suggested. In addition, in Korea Patent Publication No. 10-2019-0071424 (Patent Document 2), Mosapride is contained in the outer layer divided into an immediate-release layer and a sustained-release layer, and rabeprazole is added to the inner core of a tablet form surrounded by the outer layer. A press-coated tablet combination formulation containing However, it is a combination formulation of PPI other than rabeprazole and Mosapride, and the specific and detailed composition and formulation form to achieve the same level of therapeutic effect as the single drug combination administration of the two drugs with only one tablet once a day is not presented. is not In addition, studies on a single-formulation combination formulation capable of selectively applying various types of PPI and concurrently administering Mosapride have not yet been sufficiently conducted.

Depending on the type of PPI preparation, the daily dosage is different, and the physical properties such as flowability and chemical stability of the preparation are also different. Therefore, in conventional formulations optimized for rabeprazole and Mosapride, when rabeprazole is simply substituted with another type of PPI formulation, the size of the core increases and the size of the outer core accordingly increases, resulting in an increase in tablet size. Depending on the difference in physical properties, if an excipient of the same composition is used during tableting of the core tablet, problems such as formulation uniformity and quality stability of the core tablet may be greatly reduced.

In particular, in the case of the cored tablet structure presented in Korean Patent Publication No. 10-2019-0071424 (Patent Document 2), the position of the cored tablet and the tableting pressure are the main process factors, and these process factors are defined according to the type of PPI. Different sizes and outer layers require different designs each time. If the factor does not fall within the appropriate range of process parameters, the dissolution and drug stability of the PPI-based drug may not be secured within the appropriate range. In addition, when the diameter and thickness of the inner core tablet increases, the structure of the core tablet press requires that the specifications of the transfer device and input device for inserting the core tablet must be adjusted to the size, that is, the structure of the tablet press must be changed. When selecting a formulation, it is difficult to flexibly cope with changes in the type and content of PPI because the factors to be additionally changed according to the change in the core specification are quite difficult.

Korean Patent Publication No. 10-2017-0001664 Korean Patent Publication No. 10-2019-0071424

The present invention provides a novel single-formulation combination preparation to which various types of PPI can be flexibly applied in a combination preparation containing PPI and Mosapride as active ingredients. Therefore, unlike the prior art, in addition to rabeprazole, different types of PPI such as dexlansoprazole and esomeprazole can be applied in various ways without any particular limitation, and sufficient pharmacological effects can be achieved by administering one tablet once a day. Its object is to provide pharmaceutical preparations that can be used.

In addition, it overcomes the low acid resistance of the PPI formulation, minimizes the interaction between different drugs, and the manufacturing method is simple, but it is not greatly affected by the tableting speed and tableting pressure, so it can be manufactured stably and quickly, making it suitable for mass production. Accordingly, it is an object of the present invention to provide pharmaceutical formulations with excellent versatility that can be easily produced by substituting the PPI drug type of the production line to further enhance the marketability and productivity of the formulation.

A pharmaceutical composition according to the present invention comprising: a first composition comprising enteric coated particles containing a proton pump inhibitor, Mosapride or a pharmaceutically acceptable salt thereof, pre-mixed granules, and post-mixed material; and a second composition comprising Mosapride or a pharmaceutically acceptable salt thereof and a sustained-release agent, wherein the premixed granules include a filler, a disintegrant, and a binder, and the postmixed material includes a lubricant. It is characterized by doing.

In this case, the proton pump inhibitor may be one or two or more selected from the group consisting of rabeprazole, dexlansoprazole, and esomeprazole.

The pharmaceutical composition of the present invention may further include a buffer excipient to protect the coating layer of enteric coated particles containing a proton pump inhibitor, wherein the buffer excipient is polyethylene glycol, low-substituted hydroxypropyl cellulose and hydroxypropyl It may be one or two or more selected from the group consisting of methyl cellulose.

The filler is in the group consisting of lactose hydrate, anhydrous lactose, microcrystalline cellulose, D-mannitol, pregelatinized starch, corn starch, low-substituted hydroxypropyl cellulose, magnesium aluminate silicate, calcium silicate, dibasic calcium phosphate, and tricalcium phosphate. It may be one or two or more selected species.

The binder may be one or two or more selected from the group consisting of hydroxypropyl cellulose, copovidone, and povidone K 30.

The disintegrant may be one or two or more selected from the group consisting of crospovidone, croscarmellose sodium, and sodium starch glycolate.

In order to further improve tableting properties, the post-mixed material may further include a direct compression excipient, wherein the direct compression excipient is selected from the group consisting of microcrystalline cellulose 102, rudipress, dicalcium phosphate, tricalcium phosphate, and pregelatinized starch. It may be 1 type or 2 or more types.

The lubricant may be one or two or more selected from the group consisting of magnesium stearate, light anhydrous silicic acid, colloidal silicon dioxide, and talc.

The second composition further includes a sustained-release agent for delayed release of the active ingredient of Mosapride. In this case, the sustained-release agent may be one or two or more selected from the group consisting of hydroxypropylmethylcellulose, ethylcellulose, polyethylene glycol, carbomer, collidone SR, polyvinyl alcohol, polyvinyl acetate, and xanthan gum.

More specifically, the sustained-release agent may be hydroxypropylmethyl cellulose having a viscosity of 75,000 to 140,000 mPa s and hydroxypropyl methyl cellulose having a viscosity of 3,000 to 5,600 mPa s, and these are 1: 4 to 4: 1 It can be used by mixing in proportion. This is to ensure that Mosapride, which had a short half-life and was administered three times a day, exhibits a sufficient pharmacological effect with only once-a-day administration. The pharmacological effect may not appear properly due to excessive delay in the release of the component.

The pre-mixed granules and proton pump inhibitor enteric coated particles may be included in a weight ratio of 1.5 to 2.5: 1.

The pre-mixed granules and the post-mixed material may be included in a weight ratio of 2.5 to 5:1.

The premixed granules and the buffering excipient may be included in a weight ratio of 4 to 7:1.

The pharmaceutical composition of the present invention is characterized in that it is produced by mixing enteric-coated PPI particles with active ingredients of Mosapride, excipients and additives, and then directly compressing them into tablets. However, since the enteric coating layer formed on the surface of the PPI particle is generally very vulnerable to impact, the coating layer collapses during manufacturing in a conventional method, resulting in very low acid resistance. Therefore, the present invention is a pharmacology in which the enteric coating layer of PPI is maintained even when tablets are manufactured by preparing pre-mixed granules including a filler, disintegrant, and binder, and then adjusting the ratio of the proton pump inhibitor, the post-mixed granules, and buffer excipients composition is provided. Therefore, if it is out of the above range, standard deviation, dissolution rate, friability, etc. may be negatively affected, and the enteric coating layer may be damaged or a failure may occur during tableting.

On the other hand, the enteric coated particles may preferably be in the form of granules or pellets, more preferably in the form of pellets in order to easily perform the enteric coating process.

The pharmaceutical composition according to the present invention may be a two-layer tablet formulation consisting of a first layer containing the first composition and a second layer containing the second composition.

In addition, the pharmaceutical composition according to the present invention is a tablet form of the inner core containing the second composition; and a press-coated tablet formulation comprising an outer layer portion surrounding all outer circumferential surfaces of the inner core and containing the first composition.

The pharmaceutical composition of the present invention is prepared by a direct tableting method, and the compression pressure at this time is 7 to 10 kN, and it can be produced quickly and stably, so it is suitable for mass production.

The combination preparation according to the present invention has the same effect as the administration of a single PPI tablet and Mosapride immediate-release single tablet three times with only oral administration of one tablet once a day, and is easily applicable to various types of PPI. It is possible, and it is characterized by excellent production and quality stability while manufacturing is simple.

1 is a schematic diagram of a pre-coated tablet or double-layer tablet formulation, which is divided into a first layer for immediate release in which PPI and Mosapride are mixed and a second layer for sustained release including Mosapride.
Figure 2 shows a graph of Mosapride dissolution at pH 4.0 for Examples 1 to 5.
Figure 3 shows a graph of Mosapride dissolution at pH 4.0 for Examples 6 to 10.
Figure 4 shows a continuous dissolution graph of esomeprazole under acidic conditions and basic conditions for Examples 2 and 8.
Figure 5 shows a continuous rabeprazole dissolution graph under acidic conditions and basic conditions for Examples 11 and 13.
Figure 6 shows a continuous dissolution graph of dexlansoprazole under acidic conditions and basic conditions for Examples 12 and 14.

The present invention relates to a combination preparation of a press-coated tablet or a double-layer tablet formulation, which is divided into an immediate-release first layer containing PPI and Mosapride as active ingredients and a sustained-release second layer containing Mosapride as an active ingredient. , The purpose of the present invention is to provide a formulation having the same effect as oral administration of 1 single tablet of PPI and 3 tablets of immediate-release Mosapride, which are the existing daily doses required for oral administration of 1 tablet once a day. In particular, a mixture containing Mosapride and a proton pump inhibitor is provided in a form that solves the stability problem that may occur due to drug-drug interaction and the possibility of PPI's unsecured acid resistance problem.

In addition, problems in the tableting process of PPI and Mosapride press-coated tablets that may appear in the prior art are improved, and the existing three-part combination preparation is reduced to a two-part tablet or single tablet, making it more difficult to manufacture. An object of the present invention is to provide a method for producing a combination preparation of PPI and Mosapride press-coated tablets having an easy and excellent quality.

The present invention may be a press-coated tablet or a double-layer tablet formulation, which is divided into a first immediate-release composition containing enteric-coated PPI particles and Mosapride as active ingredients, and a sustained-release second composition containing Mosapride as an active ingredient. there is. The PPI particles may be preferably in the form of granules or pellets for stable enteric coating, more preferably in the form of pellets. In the case of a press-coated tablet or a double-layer tablet formulation, the first composition and the second composition may contain Mosapride, more specifically, Mosapride citrate dihydrate (MOCD) as an active ingredient. In addition, the first composition may contain PPI as an active ingredient. In the case of PPI, in one embodiment of the present invention, esomeprazole magnesium trihydrate (ESMT), rabeprazole sodium, and dexlansoprazole are used, but the types of PPI are not limited thereto.

The manufacturing method is divided into four steps as follows, but is not necessarily limited thereto.

Step 1: Manufacturing the PPI part as enteric coated particles into granules or pellets.

Step 2: Preparing a first composition by mixing the enteric coated granules or pellets of Step 1 with MOCD, a filler, a disintegrant, a binder, and a lubricant, and optionally additionally mixing a buffer excipient or direct excipient if necessary

Step 3: preparing a second composition containing MOCD and a sustained-release agent.

Step 4: Tableting into a double-layer tablet or press-coated tablet using the mixture prepared in Steps 2 to 3.

The structure of the press-coated tablet or double-layer tablet composite preparation prepared through the above preparation method is schematically shown in FIG.

Hereinafter, the present invention will be described in more detail through comparative examples and examples. The following examples are intended to explain the present invention in more detail, and the scope of the present invention is not limited by these examples.

<Preparation Examples 1 to 3: Preparation of enteric coated pellets containing PPI>

Tablets were prepared according to the composition shown in Table 1 below by adding excipients and lubricants after preparing PPI enteric coated pellets according to the components and contents listed in Table 1 below.

classification ingredient
(Unit: mg) Preparation Example 1 Preparation Example 2 Preparation Example 3 spherical pellets active ingredient Rabeprazole Sodium 20.00 - - active ingredient Dexlansoprazole - 30.00 - active ingredient ESMT - - 22.30 excipient spherical white sugar 33.00 49.50 30.70 binder Hydroxypropyl Cellulose 7.50 11.25 7.50 plasticizer Tween 80 1.50 2.25 1.50 1st coating coating agent Opadry 03K19229 Clear 7.50 11.25 7.50 2nd coating Enteric coating agent Acrylicize 93A18597 White 20.00 30.00 20.00 plasticizer propylene glycol 3.00 4.50 3.00 anti-adhesion agent Sorbitan Monooleate 0.15 0.23 0.15 3rd coating coating agent Opadry 03K19229 Clear 7.50 11.25 7.50 Total (mg) 100.15 150.23 100.15

<Preparation Examples 4 to 12: Preparation of Immediate-Release Granule Mixtures Containing Mosapride>

According to the ingredients and contents shown in Table 2 below, as in Preparation Examples 4 to 12, immediate-release granule mixtures containing MOCD and containing different disintegrants and binders were prepared. The granulation process was prepared by mixing active ingredients with all excipients except direct excipients and lubricants, using purified water as a solvent, and after drying, using a No. 16 sieve (1000μm). Thereafter, the direct compression excipient and the lubricant were mixed together to finally prepare a granule mixture.

classification ingredient
(Unit: mg) Production Example 4 Preparation Example 5 Preparation Example 6 Preparation Example 7 Preparation Example 8 Preparation Example 9 Preparation Example 10 Preparation Example 11 Preparation Example 12 available
ingredient MOCD 5.29 5.29 5.29 5.29 5.29 5.29 5.29 5.29 5.29 filler lactose hydrate 89.71 89.71 89.71 89.71 89.71 89.71 89.71 89.71 89.71 disintegrant crospovidone 30.00 30.00 30.00 - - - - - - disintegrant Croscarmellose
salt - - - 30.00 30.00 30.00 - - - disintegrant starch glycolic acid
salt - - - - - - 30.00 30.00 30.00 binder Hydroxypropyl
cellulose 15.00 - - 15.00 - - 15.00 - - binder copovidone - 15.00 - - 15.00 - - 15.00 - binder Povidone K30 - - 15.00 - - 15.00 - - 15.00 direct hit
excipient undecided
Cellulose 102 100.00 100.00 100.00 100.00 100.00 100.00 100.00 100.00 100.00 glidant stearic acid
magnesium 10.00 10.00 10.00 10.00 10.00 10.00 10.00 10.00 10.00 Total (mg) 250.00 250.00 250.00 250.00 250.00 250.00 250.00 250.00 250.00

The granule mixture prepared in each Preparation Example was mixed with the ESMT enteric pellets prepared in Preparation Example 3, and then subjected to a tableting process, resulting in effective buffering action and mixing uniformity in the mixing and tableting processes, suitable for manufacturing pellet tablets. A test was conducted to select the type of granule. Tableting was performed by applying a strong tableting pressure of 15 kN or more to discriminately check whether the enteric pellets were damaged. As the test items, the content in the tablet, the uniformity of the formulation, the dissolution rate after 2 hours under acidic conditions, and the degree of friability were selected, and additionally, the occurrence of failure during tableting was checked. The dissolution rate after 2 hours in acidic conditions could not be measured directly due to the degradation of PPI in acidic conditions, and the dissolution rate in basic conditions was then measured and calculated as an estimated value (dissolution rate in acidic conditions (%) = 100 - Dissolution rate under basic conditions). The test results are shown in Table 3 below.

classification comparative example
One comparative example
2 comparative example
3 comparative example
4 comparative example
5 comparative example
6 comparative example
7 comparative example
8 comparative example
9 MOCD immediate-release granules
(250.0mg) manufacturing example
4 manufacturing example
5 manufacturing example
6 manufacturing example
7 manufacturing example
8 manufacturing example
9 manufacturing example
10 manufacturing example
11 manufacturing example
12 ESMT
enteric pellets
(100.15 mg) manufacturing example
3 manufacturing example
3 manufacturing example
3 manufacturing example
3 manufacturing example
3 manufacturing example
3 manufacturing example
3 manufacturing example
3 manufacturing example
3 content 96.17% 108.08% 113.24% 109.14% 118.61% 89.04% 98.41% 105.40% 93.29% Standard Deviation
(content) 7.72% 9.78% 16.92% 16.84% 17.52% 14.41% 8.67% 13.18% 15.20% Dissolution rate in acidic conditions 8.3% 13.4% 12.7% 10.2% 15.6% 21.4% 9.2% 13.2% 14.9% Masondo 0.26% 0.55% 0.42% 0.39% 0.20% 0.23% 0.18% 0.39% 0.45% sleep disorder
Occurrence X X X X O
(laminating) X X O
(laminating) X

According to the test results, it can be confirmed that some of the ESMT enteric pellets are damaged as elution occurs in acidic conditions in all comparative examples. Among them, it was found that the acid resistance of enteric pellets was best preserved when hydroxypropyl cellulose was used as a binder, and when crospovidone was used as a disintegrant, the standard deviation of content between formulations was the lowest. In addition, it was confirmed that when copovidone was used as a binder, a lamination phenomenon occurred during tableting, and thus proper quality was not obtained. As a result of the test, the standard deviation of all contents was high, but among them, Comparative Examples 1 and 7 showed the best results, and among them, Comparative Example 1, which had a lower content standard deviation, was judged to be the most suitable form did

<Preparation Examples 13 to 20: ESMT enteric pellets in which microcrystalline cellulose of different specifications and buffering excipients are mixed and preparation of immediate-release granule mixture containing Mosapride>

Although the formulation shown in Comparative Example 1 showed results that satisfied the appropriate range in the test items, it was determined that the standard deviation of the content and the dissolution rate in acidic conditions did not show very satisfactory results in relation to the quality of the formulation. As a method for lowering the content standard deviation and the dissolution rate in acidic conditions, Preparation Examples 13 to 17 were prepared as shown in Table 4 by using different methods during the manufacturing process of microcrystalline cellulose based on the formulation of Comparative Example 1. In addition, by adding a buffering excipient capable of additionally imparting a buffering effect and adjusting the particle size of the granules, it was confirmed through Preparation Examples 18 to 20 whether or not quality improvement, such as an improvement in the buffering effect, appears. A buffering excipient is a polymeric material having buffering properties, which prevents damage to an active ingredient or a coating layer due to impact when mixing materials, and can improve tableting properties during tableting. In the formulation of the present invention, buffering excipients having such an effect include polyethylene glycol, low-substituted hydroxypropyl cellulose, and hydroxypropyl methyl cellulose, among which one or two or more may be further included together with a binder. In this case, an excellent buffering effect was shown.

First, granules were prepared by mixing Mosapride active ingredients with pre-mixed granulation components consisting of fillers, disintegrants, and binders, and buffer excipients, and then granulating with purified water. A final mixture was prepared by post-mixing the semi-finished product of Preparation Example 3 with the components of the post-mix material consisting of a direct compression excipient and a lubricant in the prepared granules. Thereafter, the tableting process was performed by applying a strong tableting pressure of 15 kN or more using a rotary tableting machine to the mixture. For the manufactured tablets, the content in the tablet, the uniformity of the formulation, the dissolution rate after 2 hours under acidic conditions, and the degree of friability were selected, and additionally, the occurrence of failure during tableting was checked. The dissolution rate after 2 hours under acidic conditions is difficult to directly measure the amount of PPI because PPI is immediately degraded when exposed to an acidic environment. (%) = 100 - dissolution rate in basic conditions). The test results are shown in Table 4.

classification Ingredients (unit: mg) Preparation Example 13 Preparation Example 14 Preparation Example 15 Preparation Example 16 Preparation Example 17 Preparation Example 18 Preparation Example 19 Production Example 20 Semi-manufactures Preparation Example 3 100.15 100.15 100.15 100.15 100.15 100.15 100.15 100.15 available
ingredient MOCD 5.29 5.29 5.29 5.29 5.29 5.29 5.29 5.29 filler lactose hydrate 89.71 89.71 89.71 89.71 89.71 89.71 89.71 89.71 disintegrant crospovidone 30.00 30.00 30.00 30.00 30.00 30.00 30.00 30.00 binder Hydroxypropyl
cellulose 15.00 15.00 15.00 15.00 15.00 15.00 15.00 15.00 filler Microcrystalline Cellulose 101 20.00 40.00 60.00 80.00 100.00 30.00 30.00 30.00 buffer excipient low degree of substitution
Hydroxypropyl
cellulose - - - - - 30.00 - - buffer excipient Hypromellose 2910 - - - - - - 30.00 - buffer excipient Polyethylene glycol 6000 - - - - - - - 30.00 direct hit
excipient Microcrystalline Cellulose 102 80.00 60.00 40.00 20.00 - 40.00 40.00 40.00 glidant stearic acid
magnesium 10.00 10.00 10.00 10.00 10.00 10.00 10.00 10.00 Total (mg) 350.15 350.15 350.15 350.15 350.15 350.15 350.15 350.15 content 103.10% 98.94% 105.31% 94.03% 102.39% 100.84% 101.85% 98.75% standard deviation (content) 9.12% 8.13% 6.62% 8.47% 10.23% 2.92% 7.54% 3.68% Dissolution rate in acidic conditions 8.33% 7.06% 7.74% 9.43% 8.53% 9.24% 10.32% 8.52% Masondo 0.68% 0.56% 0.70% 0.44% 0.76% 0.54% 0.28% 0.16% Occurrence of tableting disorder X X X X X X X X

As a result of the test, when comparing Preparation Examples 13 to 17, it was found that Preparation Example 15 had the lowest content standard deviation between formulations. According to the result, when the weight ratio of ESMT enteric pellets, pre-mixed granules and post-mixed material is about 2: 4: 1 as in Preparation Example 15, it can be determined that the mixing appears most uniformly. Based on this, as a result of repeating the experiments of Preparation Examples 18 to 20 in which a buffering excipient was added, the following optimal composition ratio could be derived.

Weight ratio of pre-mixed granules and PPI enteric coated pellets: 1.5 to 2.5: 1

Weight ratio of premixed granules and postmixed material = 2.5 to 5:1

Weight ratio of premixed granules and buffering excipients = 4 to 7:1

The formulation of the present invention is a method of enteric coating on pellets containing PPI, then mixing with active ingredients and excipients of Mosapride and directly tableting. To prevent collapse of the enteric coating layer during material mixing and tableting, a polymer having a buffering effect It is preferred to include a buffering excipient as a substance. In addition, if the relative ratio of pre-mixed granules including fillers, disintegrants and binders, post-mixed materials including direct hitting excipients and lubricants, and PPI enteric coated pellets is out of the above range, the standard deviation, dissolution rate, and friability are negatively affected. It is undesirable because damage to the enteric coating layer or difficulty in tableting may occur.

In other test items, it was determined that there was no significant difference between Preparation Examples 13 to 17.

In addition, when comparing the content standard deviation values of Preparation Example 15 and Preparation Examples 18 to 20, it was confirmed that a significant level of improvement was shown in the standard deviation of the content between formulations when a specific buffering excipient was added. In particular, in Preparation Example 18 and Preparation Example 20, it was confirmed that the standard deviation of the content between formulations was greatly reduced. In addition, the buffering excipient is converted into a form with a certain level of viscosity when in contact with the granulation solvent. In this process, it has a buffering effect and an effect of making the particle size of the granule larger, and is often used as a binder during the granulation process. . That is, according to this principle, the size of the particles increased in Preparation Examples 18 and 20, and accordingly, the size of the individual particles of the ESMT enteric coating pellets and granules became more similar, and it could be determined that more uniform mixing was achieved. there is.

In order to determine the tableting pressure range in which the ESMT enteric pellets do not break and the tablets are appropriately tableted for Preparation Examples 18 and 20, the change in dissolution rate and friability in acidic conditions according to tableting pressure was additionally tested. The test results are shown in Table 5 below.

Test Items Hardness Preparation Example 18 Production Example 20 Dissolution rate in acidic conditions 5 to 7kN 6.48% 4.80% 7 to 10 kN 7.04% 5.52% 10~13kN 7.54% 6.48% 13~15kN 10.48% 8.48% Masondo 5 to 7kN 1.51% 1.64% 7 to 10 kN 0.88% 0.77% 10~13kN 0.58% 0.37% 13~15kN 0.39% 0.51% Hardness 5 to 7kN 6~8kPa 4 to 6 kPa 7 to 10 kN 10 to 12 kPa 6 to 9 kPa 10~13kN 15 to 18 kPa 10 to 12 kPa 13~15kN 23~27kPa 12~15kPa

As a result of the test, the dissolution rate, friability, and hardness in acidic conditions according to the tableting pressure showed significant changes. Overall, the higher the tableting pressure, the higher the dissolution rate and hardness in acidic conditions. In the case of wear and tear, it was confirmed that there was no significant difference when a certain level of tableting pressure was applied. Compared to Preparation Example 18, it was confirmed by comparing the dissolution rate in acidic conditions that the breakage of the enteric coating was less even when the same tableting pressure was applied in Preparation Example 20. If the tableting pressure is too low, there may be problems with tablet quality, such as an increase in the wear value. However, if the tableting pressure is about 7 kN or more, the hardness is more than 6 kpa and the wear value is less than 1%. However, it was determined that there would be no particular problem in terms of the quality of the tablets. It seems that the lower the tableting pressure, the less breakage of the enteric coating, so considering the tablet quality comprehensively, the suitable hardness during tableting can be determined to be about 7 to 10 kN, and the buffering effect in Preparation Example 20 is more pronounced than in Preparation Example 18. can be expected

<Examples 1 to 5: Preparation of two-layer tablet formulation containing esomeprazole and Mosapride immediate-release and sustained-release parts>

According to the ingredients and contents shown in Table 6 below, as in Preparation Examples 1 to 5, a two-layer tablet consisting of an immediate-release layer and a sustained-release layer containing ESMT and MOCD and a sustained-release agent in a different ratio in the second layer was prepared. Some of the excipients in the mixture of each layer were prepared in the form of post-mixing the remaining excipients after the granulation process. and the rest are included in the granulation process. During the two-layer tableting process, the preload and main pressure were adjusted to 1~2 kN and 7~10kN, respectively. process was carried out.

classification ingredient
(Unit: mg) Example 1 Example 2 Example 3 Example 4 Example 5 note 1st layer Semi-manufactures Preparation Example 3 100.15 100.15 100.15 100.15 100.15 20 mg as esomeprazole available
ingredient MOCD 5.29 5.29 5.29 5.29 5.29 5 mg as Mosapride filler lactose hydrate 89.71 89.71 89.71 89.71 89.71 disintegrant crospovidone 30.00 30.00 30.00 30.00 30.00 binder Hydroxypropyl
cellulose 15.00 15.00 15.00 15.00 15.00 filler Microcrystalline Cellulose 101 30.00 30.00 30.00 30.00 30.00 buffer
excipient Polyethylene glycol 6000 30.00 30.00 30.00 30.00 30.00 direct hit
excipient Microcrystalline Cellulose 102 40.00 40.00 40.00 40.00 40.00 glidant Magnesium Stearate 10.00 10.00 10.00 10.00 10.00 2nd layer available
ingredient MOCD 10.58 10.58 10.58 10.58 10.58 10 mg as Mosapride filler Microcrystalline Cellulose 101 10.00 10.00 10.00 10.00 10.00 filler lactose hydrate 16.42 16.42 16.42 16.42 16.42 sustained release agent Hypromellose 2910 20.00 17.00 14.00 11.00 8.00 Viscosity: 4000 mPa.s sustained release agent hypromellose 2208 19.00 22.00 25.00 28.00 31.00 Viscosity: 100,000 mPa.s binder Povidone K30 5.60 5.60 5.60 5.60 5.60 disintegrant low substituted hydroxyl
propyl cellulose 19.60 19.60 19.60 19.60 19.60 glidant light anhydrous silicic acid 2.80 2.80 2.80 2.80 2.80 glidant Magnesium Stearate 1.00 1.00 1.00 1.00 1.00 Total (mg) 455.15 455.15 455.15 455.15 455.15

A test was conducted to confirm the dissolution pattern of Mosapride between the two-layer tablet combination preparations prepared in Examples 1 to 5. 900 mL of 0.05 mol/L sodium acetate buffer solution (pH 4.0) was used as the eluent condition, and one tablet prepared in each example was added according to the above conditions, and a paddle method of 50 revolutions per minute (Korean Pharmacopoeia 11th revision, Dissolution Test Method Article) Method 2) was applied to confirm the dissolution pattern for 24 hours. The test results are shown in FIG. 2 .

As a result of the test, it was confirmed that the ideal dissolution pattern of Mosapride appeared in Examples 1 and 2. In the case of Examples 3 to 5, the dissolution was slower, and it was found that the dissolution of the drug was not achieved even after 24 hours. Due to the nature of sustained-release preparations, when taking a drug, most of the drug is released from the small intestine and large intestine for a long time. At this time, the pH conditions in the small intestine and large intestine may be basic, but the solubility of MOCD in basic conditions is low, and drug release may be slower than the current dissolution pattern. In other words, sustained release of the active ingredient is achieved, but the rate of release should appear slightly faster at the beginning rather than being constant. Considering this, among Examples 1 and 2, Example 2, which shows a relatively fast release rate at the beginning, is expected to be ideal as a sustained drug release formulation composition. Accordingly, the most preferred formulation composition was determined as Example 2.

<Examples 6 to 10: Preparation of press-coated tablet formulations containing esomeprazole and Mosapride immediate-release and sustained-release parts>

According to the ingredients and contents shown in Table 7 below, press-coated tablets containing ESMT and MOCD were prepared as in Preparation Examples 1 to 5. The press-coated tablet is composed of an outer layer and an inner core tablet, and the inner core tablet contains two types of sustained-release agents having different viscosities in a constant ratio.

First, all components except for the lubricant were mixed to form granules, and the lubricant was then mixed to prepare an inner core tablet mixture. The mixture of the prepared inner core tablet was compressed into a tablet form, and then a coating process was performed.

Pre-mixed granulation components consisting of the semi-finished product, direct compression excipient, and lubricant of Preparation Example 3, that is, filler, disintegrant, and binder, buffer excipient, and active ingredient of Mosapride are first mixed to prepare granules, An outer layer mixture was prepared by post-mixing the semi-finished product of Preparation Example 3 and the post-mix material consisting of direct compression excipient and lubricant.

Using the mixture of the inner core tablet and the outer layer, it was compressed into a press-cored tablet. After filling 1/2 of the filling amount of the outer layer mixture and the inner core tablet in order, the rest of the outer layer mixture was filled and pressure was applied to prepare tablets. The tableting pressure was adjusted to 7~10kN, and the preload was not applied.

classification Ingredients (unit: mg) Example 6 Example 7 Example 8 Example 9 Example 10 note outer layer Semi-manufactures Preparation Example 3 100.15 100.15 100.15 100.15 100.15 20 mg as esomeprazole available
ingredient MOCD 5.29 5.29 5.29 5.29 5.29 5 mg as Mosapride filler lactose hydrate 89.71 89.71 89.71 89.71 89.71 disintegrant crospovidone 30.00 30.00 30.00 30.00 30.00 binder Hydroxypropyl
cellulose 15.00 15.00 15.00 15.00 15.00 filler Microcrystalline Cellulose 101 30.00 30.00 30.00 30.00 30.00 buffer excipient Polyethylene glycol 6000 30.00 30.00 30.00 30.00 30.00 direct hit
excipient Microcrystalline Cellulose 102 40.00 40.00 40.00 40.00 40.00 glidant Magnesium Stearate 10.00 10.00 10.00 10.00 10.00 inner core tablet available
ingredient MOCD 10.58 10.58 10.58 10.58 10.58 10 mg as Mosapride filler Microcrystalline Cellulose 101 5.50 5.50 5.50 5.50 5.50 filler lactose hydrate 9.42 9.42 9.42 9.42 9.42 sustained release agent Hypromellose 2910 9.50 8.00 6.50 5.00 3.50 Viscosity: 4000 mPa.s sustained release agent hypromellose 2208 10.00 11.50 13.00 14.50 16.00 Viscosity: 100,000 mPa.s binder Povidone K30 3.00 3.00 3.00 3.00 3.00 disintegrant low substituted hydroxyl
propyl cellulose 10.00 10.00 10.00 10.00 10.00 glidant light anhydrous silicic acid 1.40 1.40 1.40 1.40 1.40 glidant Magnesium Stearate 0.60 0.60 0.60 0.60 0.60 coating agent OPADRY 03K19229 clear 5.00 5.00 5.00 5.00 5.00 Total (mg) 415.15 415.15 415.15 415.15 415.15

A test was conducted to confirm the dissolution pattern of Mosapride between the press-coated tablets prepared in Examples 6 to 10. The test was conducted by the dissolution test method, and 900mL of 0.05 mol/L sodium acetate buffer (pH 4.0) was used as the eluent condition. According to the above conditions, one tablet prepared in each example was put in, and the dissolution pattern was confirmed for 24 hours by applying a paddle method of 50 rotations per minute (Korean Pharmacopoeia 11th revision, dissolution test method 2). The test results are shown in FIG. 3 .

As a result of the test, it was confirmed that all of Examples 6 to 10 exhibited similar dissolution patterns. The elution pattern between each example proceeded in a similar form until 480 minutes after the elution, and then the elution was completed in a slightly different form. When comparing the final dissolution rate, it was confirmed that Examples 7 to 9 showed a dissolution rate of 95% or more, and the remaining Examples 6 and 10 showed a slightly lower dissolution rate. For the same reasons as described above in Examples 7 to 9, a preparation having a relatively fast dissolution pattern in the beginning can be judged to be ideal. Accordingly, Example 8 was selected as a formulation having the most suitable composition.

<Examples 11 to 14: Preparation of two-layer tablets and press-coated tablets containing Mosapride sustained-release and immediate-release parts and PPI other than esomeprazole>

According to the ingredients and contents shown in Tables 8 to 9 below, as in Examples 11 to 14, two-layer tablets and press-coated tablets containing MOCD and rabeprazole sodium and dexlansoprazole, which are different types of PPI, were prepared.

Double-decker - Classification Ingredients (unit: mg) Example 11 Example 12 note 1st layer Semi-manufactures Preparation Example 1 100.15 - 20 mg as rabeprazole sodium Semi-manufactures Preparation Example 2 - 150.23 30 mg as dexlansoprazole active ingredient MOCD 5.29 5.29 5 mg as Mosapride filler lactose hydrate 89.71 134.57 disintegrant crospovidone 30.00 45.00 binder Hydroxypropyl Cellulose 15.00 22.50 filler Microcrystalline Cellulose 101 30.00 45.00 buffer excipient Polyethylene glycol 6000 30.00 45.00 direct excipient Microcrystalline Cellulose 102 40.00 60.00 glidant Magnesium Stearate 10.00 15.00 2nd layer active ingredient MOCD 10.58 10.58 10 mg as Mosapride filler Microcrystalline Cellulose 101 10.00 10.00 filler lactose hydrate 16.42 16.42 sustained release agent Hypromellose 2910 17.00 17.00 Viscosity: 4000 mPa.s sustained release agent hypromellose 2208 22.00 22.00 Viscosity: 100,000 mPa.s binder Povidone K30 5.60 5.60 disintegrant Low-substituted hydroxypropyl cellulose 19.60 19.60 glidant light anhydrous silicic acid 2.80 2.80 glidant Magnesium Stearate 1.00 1.00 Total (mg) 455.15 627.59

Pre-coated tablets - Classification Ingredients (unit: mg) Example 13 Example 14 note outer layer Semi-manufactures Preparation Example 1 100.15 - 20mg as rabeprazole sodium Semi-manufactures Preparation Example 2 - 150.23 30 mg as dexlansoprazole active ingredient MOCD 5.29 5.29 5 mg as Mosapride filler lactose hydrate 89.71 134.57 disintegrant crospovidone 30.00 45.00 binder Hydroxypropyl Cellulose 15.00 22.50 filler Microcrystalline Cellulose 101 30.00 45.00 buffer excipient Polyethylene glycol 6000 30.00 45.00 direct excipient Microcrystalline Cellulose 102 40.00 60.00 glidant Magnesium Stearate 10.00 15.00 inner core tablet active ingredient MOCD 10.58 10.58 10 mg as Mosapride filler Microcrystalline Cellulose 101 5.50 5.50 filler lactose hydrate 9.42 9.42 sustained release agent Hypromellose 2910 6.50 6.50 Viscosity: 4000 mPa.s sustained release agent Hypromellose 2208 13.00 13.00 Viscosity: 100,000 mPa.s binder Povidone K30 3.00 3.00 disintegrant Low-substituted hydroxypropyl cellulose 10.00 10.00 glidant light anhydrous silicic acid 1.40 1.40 glidant Magnesium Stearate 0.60 0.60 coating agent OPADRY 03K19229 clear 5.00 5.00 Total (mg) 415.15 587.59

<Test Example 1: PPI dissolution test for combined formulations containing MOCD sustained-release part, immediate-release part and PPI>

A dissolution test for each PPI was conducted on Examples 2, 8 and Examples 11 to 14. The test was conducted continuously in acidic and basic conditions, and after conducting a dissolution test for 2 hours in 750mL of an acidic condition solution, 250mL of buffer was added and a dissolution test was conducted in 1000mL of a basic condition solution for 1 hour. proceeded. The solutions used in each condition are as follows.

- Acid condition eluate: 0.1 mol/L hydrochloric acid solution

- Buffer solution: A solution obtained by mixing 0.56 g of anhydrous sodium carbonate and 4.76 g of anhydrous sodium bicarbonate in 1 L of a 0.3 mol/L sodium hydroxide solution.

The test results are shown in Figures 4 to 6. As a result of the test, it was confirmed that all of them had a low dissolution rate in acidic conditions, and through this, it was determined that sufficient acid resistance was secured in the formulation. That is, regardless of the type of PPI, it can be determined that there is no damage to the enteric coating of the pellets and acid resistance is secured when the ratio of each component according to the amount of pellets is properly adjusted. In addition, dissolution in basic conditions was confirmed to occur rapidly in all examples, so that pharmacological activity can be expected to occur appropriately regardless of the type of PPI when designing a double-layer tablet or press-coated tablet according to each composition.

<Test Example 2: Stability test for combined formulations containing MOCD sustained-release part, immediate-release part and PPI>

Examples 2, 8 and Examples 11 to 14 were stored under accelerated conditions (40 ℃, 75% RH), and then content tests were conducted according to the lapse of 0, 1, 2, and 3 months to determine the active ingredient and It was confirmed whether an interaction between the excipients occurred. In addition, the state of simple mixing of the excipients and main components used in Examples 2, 11, and 12 was used as control groups 1 to 3, and after storage in the same conditions, changes in the contents were compared and observed. The corresponding test results for each main component are shown in Tables 10 and 11 below.

Content test - PPI 0 months 1 month 2 months 3 months Control 1 101.2 96.4 93.7 91.2 Control 2 102.4 94.2 90.1 87.4 Control 3 98.9 95.5 93.4 91.1 Example 2 99.7 99.6 99.6 99.8 Example 8 100.2 100.4 100.2 100.4 Example 11 98.9 99.3 99.2 98.8 Example 12 99.5 99.5 99.1 99.2 Example 13 102.4 102.2 102.3 102.0 Example 14 100.7 100.8 100.4 100.5

Content test - Mosapride 0 months 1 month 2 months 3 months Control 1 98.8 98.3 98.5 98.6 Control 2 100.4 100.4 100.1 100.2 Control 3 101.1 100.8 100.9 101.3 Example 2 100.7 100.4 100.5. 101.2 Example 8 102.4 102.6 102.1 101.9 Example 11 97.5 97.5 97.8 97.6 Example 12 100.4 100.1 100.2 99.9 Example 13 99.8 99.7 99.9 99.5 Example 14 101.2 101.2 101.4 101.1

Test Results It was confirmed that the Mosapride content test results were maintained at a constant value over time. In all controls and examples, the content values over time are within the error range, and it is confirmed that there is no degradation of the active ingredient due to the interaction as there is no particularly significant change in the content.

However, in the case of PPI, it can be seen that the content of all of the control groups 1 to 3 decreases significantly over time. This is due to the unstable nature of PPI, and it is assumed that this is because PPI is rapidly decomposed when it comes into contact with specific excipients and active ingredients. On the other hand, in all embodiments of the present invention, the PPI content reduction phenomenon does not occur. The excipients used to prepare the PPI spherical pellets did not interact with PPI, and the pellets were first coated with Opadry 03K19229 Clear to block contact with other excipients including an enteric coating base. In other words, by going through the process, the pathway in which PPI can be decomposed due to the interaction is properly blocked. That is, it can be determined that Examples 2, 8 and Examples 11 to 14 are formulations capable of maintaining a constant quality over time by securing stability against interaction and decomposition of active ingredients.

Claims (18)

A first composition comprising enteric coated particles containing a proton pump inhibitor, Mosapride or a pharmaceutically acceptable salt thereof, pre-mixed granules, buffering excipients, and post-mixed materials; and
A pharmaceutical composition comprising a second composition comprising Mosapride or a pharmaceutically acceptable salt thereof and a sustained-release agent,
The proton pump inhibitor is one or two or more selected from the group consisting of rabeprazole, dexlansoprazole and esomeprazole,
The pre-mixed granules include a filler, a disintegrant and a binder,
The buffering excipient includes one or two or more selected from the group consisting of polyethylene glycol, low-substituted hydroxypropyl cellulose, and hydroxypropyl methyl cellulose,
The post-mixed material includes a lubricant,
The pre-mixed granules and proton pump inhibitor enteric coated particles are included in a weight ratio of 1.5 to 2.5: 1,
The pre-mixed granules and the post-mixed material are included in a weight ratio of 2.5 to 5: 1,
The pre-mixed granules and the buffering excipients are 4 to 7: a pharmaceutical composition that is included in a weight ratio of 1.
delete delete According to claim 1,
The filler is in the group consisting of lactose hydrate, anhydrous lactose, microcrystalline cellulose, D-mannitol, pregelatinized starch, corn starch, low-substituted hydroxypropyl cellulose, magnesium aluminate silicate, calcium silicate, dibasic calcium phosphate, and tricalcium phosphate. A pharmaceutical composition that is one or two or more selected species.
According to claim 1,
Wherein the binder is one or two or more selected from the group consisting of hydroxypropyl cellulose, copovidone and povidone K 30, the pharmaceutical composition.
According to claim 1,
The disintegrant is a pharmaceutical composition that is one or two or more selected from the group consisting of crospovidone, croscarmellose sodium and sodium starch glycolate.
According to claim 1,
The post-mix material further comprises one or two or more direct excipients selected from the group consisting of microcrystalline cellulose 102, ludipress, dicalcium phosphate, tricalcium phosphate, and pregelatinized starch.
According to claim 1,
The lubricant is a pharmaceutical composition that is one or two or more selected from the group consisting of magnesium stearate, light anhydrous silicic acid, colloidal silicon dioxide and talc.
According to claim 1,
The sustained-release agent is a pharmaceutical composition that is one or two or more selected from the group consisting of hydroxypropylmethylcellulose, ethylcellulose, polyethylene glycol, carbomer, collidone SR, polyvinyl alcohol, polyvinyl acetate, and xanthan gum.
According to claim 9,
The sustained-release agent is a pharmaceutical composition comprising hydroxypropylmethylcellulose having a viscosity of 75,000 to 140,000mPa·s and hydroxypropylmethylcellulose having a viscosity of 3,000 to 5,600mPa·s in a ratio of 1: 4 to 4: 1 .
delete delete delete According to claim 1,
The enteric coated particles are a pharmaceutical composition in the form of granules or pellets.
According to claim 1,
The pharmaceutical composition is a pharmaceutical composition that is a two-layer tablet formulation consisting of a first layer containing the first composition and a second layer containing the second composition.
According to claim 1,
The pharmaceutical composition may include an inner core of a tablet form comprising the second composition; and
A pharmaceutical composition that surrounds all outer circumferential surfaces of the inner core and is a press-coated tablet formulation comprising an outer layer containing the first composition.
According to claim 1,
The pharmaceutical composition is a pharmaceutical composition that is prepared by direct compression method.
According to claim 17,
A pharmaceutical composition wherein the compression pressure during direct compression is 7 to 10 kN.

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