KR20240040467A - Mosapride sustained-release formulation - Google Patents

Abstract

The present invention relates to a sustained-release formulation in which the drug effect appears quickly upon oral administration and the drug effect lasts for 24 hours. The present invention includes an immediate-release portion containing the active ingredient and additives; and a sustained-release portion containing an active ingredient, an additive, and a cellulose derivative, wherein the active ingredient is Mosapride or a salt thereof, and the cellulose derivative satisfies the following conditions.
[condition]
The viscosity of an aqueous solution containing 2% by weight of a cellulose derivative satisfies 11,000 to 60,000 cps when measured at 20°C according to the rotational viscometer method in Article 2, Article 5 of the Korean Pharmacopoeia, General Test Method 57. Viscosity Measurement Method 2.

Description

Mosapride sustained-release formulation}

The present invention relates to Mosapride sustained-release formulations.

Mosapride (4-amino-5-chloro-2-ethoxy-N-{[4-(4-fluorobenzyl)-2-morpholinyl]methyl}benzamide) is a known compound having the structure of Formula 1 below. Mosapride and its physiologically acceptable salts (hereinafter referred to as ‘Mosapride’) are selective serotonin 5-hydroxytryptamine 4 (hereinafter referred to as ‘5-HT4’) receptor agonists that stimulate Knotweed root. By selectively promoting only the serotonin 5-HT4 receptors present in the nerve plexus, it promotes the release of acetylcholine from nerve endings, and acetylcholine contracts the smooth muscles of the digestive tract, thereby promoting digestive tract movement. Therefore, Mosapride is a drug that shows excellent efficacy in treating diabetic hypersecretory gastropathy, dyspepsia, gastritis, and gastroesphageal reflux disease. Mosapride does not have the risk of arrhythmia or sudden cardiogenic death due to QT interval prolongation that occurred with cisapride, a non-selective 5-HT4 receptor agonist, and does not have dopamine-2 (D-2) receptor antagonism, so it affects the Central Nervous System (CNS). It is a safe drug with no side effects such as CNS side effects (extrapyramidal symptoms) and hyperprolactinemia (galactorrhea, feminized breasts).

[Formula 1]

Mosapride has a digestive tract absorption rate of over 93% when administered orally, and is distributed to the liver, small intestine, stomach, kidneys, and adrenal glands at a concentration more than 10 times higher than the concentration in plasma, and to the lungs, parotid glands, pancreas, pituitary gland, thyroid gland, and lungs. It is distributed in high concentrations in the spleen, etc., and in the brain and eyes at a low concentration of about 1/2 of the blood concentration. When administered orally, Mosapride shows a rapid onset of drug effect, reaching the highest blood concentration in 0.5 to 1.4 hours.

Mosapride has a short half-life of 1.3 to 2 hours, so the drug disappears quickly after being absorbed into the body, resulting in a short duration of effect and having to be taken several times a day. Mosapride is currently developed and sold in tablet form, and one tablet containing 5 mg of Mosapride is to be taken three times a day. Therefore, it is necessary to increase the patient's medication compliance by reducing the number of doses and to continuously maintain the drug's efficacy by continuously maintaining the blood concentration of the drug.

In the case of general Mosapride sustained-release tablets, there is a problem that it takes a long time for the blood concentration of Mosapride to reach the effective blood concentration at which the therapeutic effect occurs after oral administration. On the other hand, in the case of preparations in which the blood concentration of Mosapride quickly reaches the effective blood concentration at which the therapeutic effect appears after oral administration, the blood concentration of Mosapride must not be maintained above the minimum blood concentration at which the therapeutic effect can be sustained for 24 hours. The problem is that you can't do it.

Accordingly, when administered orally, the Mosapride blood concentration quickly reaches the effective blood concentration showing the therapeutic effect, but the Mosapride sustained-release preparation maintains the Mosapride blood concentration above the minimum blood concentration for 24 hours to maintain the therapeutic effect. is needed.

Republic of Korea Patent Publication No. 10-2012-0094882 (2012.08.27.)

The purpose of the present invention is to solve the problems of the prior art as described above. The present invention provides a sustained-release formulation in which the blood concentration of Mosapride quickly reaches the effective blood concentration showing a therapeutic effect upon oral administration, and the blood concentration of Mosapride is maintained for 24 hours above the minimum blood concentration for the therapeutic effect to persist. to provide.

In order to achieve the above object, the sustained-release preparation according to the present invention includes an immediate-release portion containing the active ingredient and additives; and a sustained-release portion containing an active ingredient, an additive, and a cellulose derivative, wherein the active ingredient is Mosapride or a salt thereof, and the cellulose derivative satisfies the following conditions.

[condition]

The viscosity of an aqueous solution containing 2% by weight of a cellulose derivative satisfies 11,000 to 60,000 cps when measured at 20°C according to the rotational viscometer method in Article 2, Paragraph 5 of the Korean Pharmacopoeia, General Test Method 57. Viscosity Measurement Method 2.

The cellulose derivative may satisfy the following conditions.

[condition]

The viscosity of an aqueous solution containing 2% by weight of a cellulose derivative satisfies 32,000 to 42,000 cps when measured at 20°C according to the rotational viscometer method in Article 2, Paragraph 5 of the Korean Pharmacopoeia, General Test Method 57. Viscosity Measurement Method 2.

The sustained-release preparation according to the present invention may contain 5 to 20% by weight of the cellulose derivative based on the total weight of the preparation.

The sustained-release preparation according to the present invention may contain 15 to 30 mg of cellulose derivative.

The sustained-release preparation according to the present invention may contain 5 to 15% by weight of the active ingredient based on the total weight of the preparation.

The additives may include disintegrants, excipients, binders, or lubricants.

The sustained-release formulation according to the present invention may contain 10 to 30% by weight of a disintegrant based on the total weight of the formulation.

The sustained-release preparation according to the present invention may contain 30 to 50% by weight of excipients based on the total weight of the preparation.

The sustained-release preparation according to the present invention may contain 3 to 10% by weight of a binder based on the total weight of the preparation.

The sustained-release formulation according to the present invention may contain 0.5 to 5% by weight of a lubricant based on the total weight of the formulation.

The cellulose derivative contained in the sustained-release portion included in the sustained-release preparation according to the present invention may be hypromellose.

The sustained-release preparation according to the present invention is the active ingredient 1 hour after the start of the dissolution test when dissolution tested according to the test conditions of the Korean Pharmacopoeia General Test Method Dissolution Test Method 2, pH 4.0, 37 ± 0.5 ℃, and paddle 50 rpm. dissolution rate of 25 to 45%; The dissolution rate of the active ingredient at 8 hours from the start of the dissolution test is 60 to 80%; The dissolution rate of the active ingredient 10 hours after the start of the dissolution test is 70 to 80%; And the dissolution rate of the active ingredient 24 hours after the start of the dissolution test may be 85% or more.

When the sustained-release preparation according to the present invention is orally administered, the Mosapride blood concentration quickly reaches the effective blood concentration showing a therapeutic effect, and the drug effect appears quickly. In addition, when the sustained-release preparation according to the present invention is administered orally, the blood concentration of Mosapride is maintained above the minimum blood concentration for 24 hours to maintain the therapeutic effect, and the drug effect lasts for 24 hours.

The sustained-release formulation according to the present invention is sufficient for patients with gastrointestinal motility disorders to take oral administration once a day, so the patient's convenience and compliance are higher than conventional formulations that require oral administration three times a day.

Since the present invention can be subject to various changes and can have various forms, it will be described in detail in the text. However, this is not intended to limit the present invention to a specific disclosed form, and should be understood to include all changes, equivalents, and substitutes included in the spirit and technical scope of the present invention.

In this application, terms such as “comprise” or “have” are intended to designate the presence of features, numbers, steps, operations, components, parts, or combinations thereof described in the specification, but are not intended to indicate the presence of one or more other features. It should be understood that this does not exclude in advance the possibility of the existence or addition of elements, numbers, steps, operations, components, parts, or combinations thereof. Additionally, terms such as first, second, etc. may be used to describe various components, but the components should not be limited by the terms. The above terms are used only for the purpose of distinguishing one component from another. For example, a first component may be named a second component, and similarly, the second component may also be named a first component without departing from the scope of the present invention. Singular expressions include plural expressions unless the context clearly dictates otherwise.

Hereinafter, the present invention will be described in more detail.

In order for a formulation to quickly show efficacy when administered orally and to maintain the effect for 24 hours, when the formulation passes through the gastrointestinal tract, a certain amount of the active ingredient is rapidly dissolved and absorbed into the body, while the remaining active ingredient remains in the gastrointestinal tract for a long time and is slowly dissolved. It must be absorbed into the body.

In particular, the half-life of the blood concentration of Mosapride is short, about 1.3 to 2 hours, so in order for the Mosapride preparation to maintain its medicinal effect for 24 hours after oral administration, a certain amount of Mosapride must be allowed to remain in the gastrointestinal tract for a long period of time and be slowly dissolved. However, at this time, if too much Mosapride is slowly dissolved, the drug effect will not appear quickly after oral administration, so a certain amount of Mosapride must be allowed to be dissolved quickly.

The present inventor established dissolution test conditions and dissolution rate approval standards for each time period that can confirm that the dissolution of Mosapride is ideal as described above, as follows.

Dissolution test conditions

Dissolution test solution: pH 4.0 test solution

pH 4.0 Test solution: 0.05 mol/L sodium acetate buffer [0.05 mol/L acetic acid 0.05 mol/L

Use sodium acetate mixture (82:18).

Test temperature: 37 ± 0.5 ℃

Dissolution method: Korean Pharmacopoeia dissolution test method 2 (paddle method), 50 revolutions per minute

The present inventor set the dissolution rate approval standards as follows when performing a dissolution test according to the above dissolution test conditions, at 1 hour, 8 hours, 10 hours, and 24 hours after the start of the dissolution test. At this time, 1 hour represents the initial time of the dissolution test, 8 hours and 10 hours represent the middle time of the dissolution test, and 24 hours represent the end time of the dissolution test.

Dissolution rate approval standards by time period

1 hour after starting dissolution test: 25~45%

8 hours after starting dissolution test: 60~80%

10 hours after starting dissolution test: 70~80%

24 hours after starting dissolution test: 85% or more

At this time, the reason for setting the dissolution rate approval standards for each time zone as above is as follows.

If the dissolution rate at 1 hour from the start of the dissolution test is less than 25%, the formulation cannot be considered to exhibit rapid efficacy. If the dissolution rate at 1 hour from the start of the dissolution test exceeds 45%, excessive dissolution of the active ingredient at the initial time may cause side effects due to excessive drug efficacy or the drug effect may not be maintained continuously for 24 hours.

If the dissolution rate at 8 hours from the start of the dissolution test is less than 60%, it can be considered to have an excessive sustained-release effect due to the low dissolution rate of the active ingredient at the mid-point. This will result in insufficient drug release, resulting in a deviation from the effective concentration in the blood, thereby affecting the appropriate drug effect. You can prevent it from appearing. If the dissolution rate exceeds 80% after 8 hours from the start of the dissolution test, the active ingredient has been excessively dissolved at the intermediate point, and the duration of the drug effect may be shorter than 24 hours.

The dissolution rate at 10 hours after the start of the dissolution test has a similar meaning to the dissolution rate at 8 hours after the start of the dissolution test. If the dissolution rate at 10 hours after the start of the dissolution test is less than 70%, the dissolution rate of the active ingredient at the intermediate time point is considered low. It can be considered to have an excessive sustained-release effect, and if the dissolution rate exceeds 80% 10 hours after the start of the dissolution test, the duration of the drug effect may be shortened due to excessive dissolution of the active ingredient at the intermediate time point.

If the dissolution rate at 24 hours from the start of the dissolution test is less than 85%, it can be considered that the active ingredient was not properly dissolved at the end. In this case, the drug's efficacy in the body may be insufficient.

In general, the dissolution pattern of the active ingredient of a preparation can be adjusted through the type and/or content ratio of additives in the preparation.

In order to ensure that the sustained-release formulation satisfies the dissolution rate approval criteria for each time period described above under the above-described test conditions, the present inventor included an immediate-release portion and a sustained-release portion, the immediate-release portion contained Mosapride and additives, and the sustained-release formulation was The part contained active ingredients, additives, and cellulose derivatives. In particular, the present inventor used a cellulose derivative as a release control mechanism and found that when the viscosity of the cellulose derivative was 11,000 to 60,000 cps, the sustained-release formulation satisfied the dissolution rate approval criteria for each time period described above under the above-described test conditions.

At this time, a single cellulose derivative having a viscosity of 11,000 to 60,000 cps can be used as the cellulose derivative contained in the sustained release portion of the present invention. Additionally, if two types of cellulose derivatives with different viscosities are mixed and the mixed cellulose derivative has a viscosity of 11,000 to 60,000 cps, the mixed cellulose derivative can be used as the cellulose derivative contained in the sustained-release part of the present invention. Likewise, if three or more types of cellulose derivatives with different viscosities are mixed and the mixed cellulose derivative has a viscosity of 11,000 to 60,000 cps, the mixed cellulose derivative can be used as the cellulose derivative contained in the sustained-release portion of the present invention.

In the present invention, the cellulose derivative may preferably be contained in an amount of 5 to 20% by weight, and more preferably in an amount of 8 to 16% by weight, based on the total weight of the formulation. If the cellulose derivative is included in less than 5% by weight of the total weight of the formulation, the sustained-release effect is weak and the drug release rate appears excessively fast, and the blood concentration of the active ingredient in the body may become too high due to excessive drug release 2 hours after oral administration. If the cellulose derivative is included in more than 20% by weight of the total weight of the preparation, the release rate of the drug may be excessively slow due to excessive sustained-release effect, and the blood concentration of the active ingredient in the body may be too low even after 8 hours of oral administration.

The viscosity of the aqueous solution containing 2% by weight of the cellulose derivative of the present invention is preferably 11,000 to 60,000 when measured at 20°C according to the rotational viscometer method in Article 2, No. 5 of the Korean Pharmacopoeia, General Test Method 57. Viscosity Measurement Method 2. cps, more preferably 22,000 to 52,000 cps, and most preferably 32,000 to 42,000 cps.

Formulations that use a cellulose derivative with a viscosity of less than 11,000 cps or more than 60,000 cps as a release control mechanism do not meet the approval standards for dissolution rate by time period because the dissolution rate of Mosapride appears too fast or slow. This means that the drug does not take effect quickly when administered orally or that the drug effect is not maintained for 24 hours.

Therefore, it is preferable that the cellulose derivative of the present invention satisfies the following conditions.

[condition]

The viscosity of an aqueous solution containing 2% by weight of a cellulose derivative satisfies 11,000 to 60,000 cps when measured at 20°C according to the rotational viscometer method in Article 2, Article 5 of the Korean Pharmacopoeia, General Test Method 57. Viscosity Measurement Method 2.

Meanwhile, in the case of formulations using cellulose derivatives with a viscosity of less than 32,000 cps as a release control mechanism, more cellulose derivatives must be used in order to meet the dissolution rate approval standards for each time period, and the proportion of other additives in the overall formulation may be reduced, which may reduce tableting properties. In the case of formulations using cellulose derivatives with a viscosity exceeding 42,000 cps as the release control mechanism, the proportion of the release control mechanism in the entire formulation is reduced, so even if the uniformity of the mixture is slightly reduced, the dissolution rate may change relatively significantly.

Therefore, it is most preferable that the cellulose derivative of the present invention satisfies the following conditions.

[condition]

The viscosity of an aqueous solution containing 2% by weight of a cellulose derivative satisfies 32,000 to 42,000 cps when measured at 20°C according to the rotational viscometer method in Article 2, Article 5 of the Korean Pharmacopoeia, General Test Method 57. Viscosity Measurement Method 2.

To describe the viscosity measurement method for the cellulose derivative of the present invention in more detail, Brookfield DV-II and Pro viscometer were used as measuring equipment, and the rotation speed was 0.3 to 200 rpm. The rotation speed is measured by visually determining the approximate viscosity of the cellulose derivative and then setting the rotation speed of the viscometer appropriately. At this time, the appropriate rotation speed is set to be faster as the visual viscosity is lower, and slower as the viscosity is higher. This is because the range of viscosity that can be measured varies depending on the rotation speed.

Cellulose derivatives contained in the sustained-release part of the sustained-release preparation according to the present invention include hypromellose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, It may be one or more selected from the group consisting of carboxymethyl ethyl cellulose, hydroxypropyl methyl cellulose acetylsuccinate, and sodium carboxymethyl cellulose.

The cellulose derivative contained in the sustained-release portion of the sustained-release preparation according to the present invention is preferably hypromellose.

active ingredient

Mosapride, the active ingredient of the present invention, selectively acts on serotonin (5-HT) receptors on the cholinergic nerves of the digestive tract to promote the release of acetylcholine from the nerve endings, and the acetylcholine promotes smooth muscle movement of the digestive tract, thereby creating a strong digestive tract. Mosapride citrate is a serotonin receptor agonist that promotes exercise and gastric emptying. Mosapride citrate is a salt-bound form of Mosapride. The two substances are pharmacologically identical, and Mosapride citrate has improved water solubility compared to Mosapride. , It is a form that facilitates drug absorption.

Mosapride or its salt, which is the active ingredient of the present invention, is preferably contained in an amount of 5 to 15% by weight, more preferably in an amount of 8 to 12% by weight, based on the total formulation weight, assuming the total formulation weight is 155 mg. If Mosapride or its salt is included in less than 5% by weight, the pharmacological effect is reduced, and if it is included in more than 15% by weight, side effects such as loose stool, diarrhea, dry mouth, etc. may occur. In other words, when manufactured as an extended-release tablet with a total weight of 155 mg, the weight of the active ingredient per tablet when taken once a day is preferably about 8 to 23 mg, and more preferably about 12 to 19 mg. .

additive

The additives contained in the immediate-release portion and sustained-release portion of the sustained-release preparation according to the present invention may be additives commonly used in the pharmaceutical field and may include at least one of a disintegrant, an excipient, a binder, and a lubricant.

The disintegrant absorbs moisture and causes tablet disintegration through an increase in volume or dispersion power. This is used to promote disintegration of the formulation and improve dissolution of Mosapride. Disintegrants include Croscamellose sodium, Sodium starch glycolate, microcrystalline cellulose, Crospovidone (cross-linked povidone), and commercially available Povidone (Polyvinylpyrrolidone, PVP, Povidone). ), low substituted hydroxypropylcellulose, alginic acid, powdered cellulose, starch, sodium alginate, and mixtures thereof can be used, but are not limited thereto. . The disintegrant is added to the oral solid preparation, and can be added additionally in a pharmaceutically acceptable manner. A secondary disintegrant can be additionally used for the purpose of more rapid release of the preparation. The disintegrant may preferably be included in an amount of 10 to 30% by weight, and most preferably in an amount of 20 to 30% by weight, based on the total weight of the formulation.

Excipients may include, but are not limited to, lactose, mannitol, glucose, maltose, sorbitol, dextrin, sucrose, microcrystalline cellulose, and mixtures thereof. Excipients may preferably be included in an amount of 30 to 50% by weight, more preferably in an amount of 35 to 45% by weight, based on the total weight of the formulation. Among excipients, lactose improves the ease of tableting, facilitates the formation of water-soluble channels when coexisting with hypromellose (HPMC) in the eluate, and plays a role in maintaining the shape of the tablet. Lactose may preferably be included in 10 to 30% by weight of the total weight of the formulation, and more preferably in 15 to 25% by weight. If lactose is included in less than 10% by weight of the total weight of the preparation, the mixture may stick to the punch of the tablet press during tablet manufacturing, causing sticking, and if it is included in more than 30% by weight, it may affect the total weight of the preparation. This is a growing problem. Instead of lactose, mannitol is used at 10 to 30% by weight of the total weight of the preparation, sorbitol is used at 10 to 30% by weight of the total weight of the preparation, glucose is used at 20 to 40% by weight of the total weight of the preparation, and dextrin is used at 20 to 30% by weight of the total weight of the preparation. % or maltose may be included in 20 to 40% by weight of the total weight of the formulation.

The binder is a water-soluble polymer that can be dissolved in organic solvents and serves to increase the binding force of the agent. Polyvinylpyrrolidone (common name is povidone) may be used as a binder, but is not limited thereto. The binder may preferably be included in an amount of 3 to 10% by weight, and more preferably in an amount of 5 to 7% by weight, based on the total weight of the formulation. If the binder is included in less than 3% by weight, the binding force is weak, which reduces the flowability and compressibility of the granules. If the binder is included in more than 10% by weight, the dissolution rate of the immediate-release part is relatively slow, which has a significant effect on controlling the dissolution rate of the drug. It goes crazy.

As a lubricant, light anhydrous silicic acid, silicon dioxide, talc, stearic acid, magnesium stearate, or mixtures thereof may be used, but are not limited thereto. The lubricant improves the fluidity of the powder and granular material, increasing the filling ability into the die, which is the lower part of the tablet press, and the friction between the powder and granular particles and between the powder and the punch*?*die, which is the upper part of the tablet press. This reduces the compression and release of tablets. The lubricant may preferably be included in an amount of 0.5 to 5% by weight, and more preferably in an amount of 0.5 to 2% by weight, based on the total weight of the formulation. If the lubricant is included in less than 0.5% by weight, the lubricant power is insufficient and the risk of tableting failure increases, making it difficult to tablet tablets. If the lubricant is included in excess of 5% by weight, the dissolution pattern of the tablet is affected due to the coating phenomenon of the lubricant granules. .

The sustained-release formulation according to the present invention contains 5 to 15% by weight of the active ingredient Mosapride or a salt thereof, 5 to 20% by weight of a cellulose derivative, 10 to 30% by weight of a disintegrant, 30 to 50% by weight of an excipient, and a binder, based on the total weight of the formulation. It may contain 3 to 10% by weight and 0.5 to 5% by weight of lubricant.

The sustained-release preparation according to the present invention may be a two-layer tablet in which each layer consists of an immediate-release portion and a sustained-release portion.

The sustained-release preparation according to the present invention may have a total weight of 200 mg or less, preferably 150 mg to 160 mg. If the total weight of the sustained-release preparation is 150 mg to 160 mg, the small size of the preparation makes it easy to swallow as it passes down the throat smoothly, increases patient compliance, and is economical.

Manufacturing method

The sustained-release preparation according to the present invention can be manufactured by manufacturing the sustained-release part and the immediate-release part through mixing, kneading, and granulation processes, respectively, and then compressing them into tablets.

The immediate release part mixes Mosapride citrate, excipients, and disintegrants, then adds a binder dissolved in ethanol, goes through a kneading and granulation process, and dries in a fluidized bed dryer at a temperature of 50-60°C to a loss on drying (LOD) of less than 2%. It is prepared by sizing and mixing an appropriate amount of lubricant.

The western part mixes Mosapride citrate, excipients, disintegrants, and cellulose derivatives, then adds a binder dissolved in ethanol, goes through a kneading and granulation process, and loses on drying (LOD) 2% in a fluidized bed dryer at a temperature of 50~60℃. It is prepared by drying and sizing as follows and mixing an appropriate amount of lubricant.

A multi-layer tablet can be manufactured by first compressing the sustained-release portion, filling the immediate-release portion thereon, and performing secondary compression. At this time, it is not necessary that the immediate-release portion is compressed after the western-release portion has been compressed, and the immediate-release portion is compressed first, and it is also possible to fill the western-release portion and compress it into tablets. In addition, it is also possible to fill the immediate-release portion and the sustained-release portion sequentially or in reverse order and perform single tableting.

The Mosapride oral administration formulation according to the present invention may be a pellet-type tablet, double-layer tablet, or multi-layer tablet prepared by mixing an immediate-release portion and a sustained-release portion.

Example

Example 1

After mixing Mosapride citrate, excipients, and disintegrant, a binder previously dissolved in ethanol was added for kneading and granulation, and dried in a fluidized bed dryer at a temperature of 50-60°C for 30-40 minutes (LOD 2% or less). After sizing, a lubricant was mixed to prepare an immediate-release layer.

After mixing Mosapride citrate, excipients, disintegrant, and hypromellose, a binder previously dissolved in ethanol was added, kneaded and granulated, and dried in a fluidized bed dryer at a temperature of 50-60°C for 30-40 minutes (LOD less than 2%). ). After sizing, the remaining lubricant was mixed to prepare a sustained-release layer. At this time, the viscosity of hypromellose used as the release control agent was 51350 cps, and the viscosity was measured as described above.

A two-layer tablet was compressed using the mixture of the immediate-release layer and the sustained-release layer prepared above, and film-coated in a conventional manner with Opadry-OY-C-7000A (Colorcon's product name) coating base, so that each tablet contains about 15 mg of Mosapride citrate. The formulation of Example 1 was prepared.

Examples 2 to 10

The preparations of Examples 2 to 10 were prepared in the same manner as Example 1, except that the viscosity of hypromellose was changed as shown in Table 1 below.

Hypromellose viscosity (cps) Example 1 51350 Example 2 36683 Example 3 34592 Example 4 30419 Example 5 25834 Example 6 24914 Example 7 22637 Example 8 18567 Example 9 18125 Example 10 13131

Comparative Examples 1 to 11

The preparations of Comparative Examples 1 to 11 were prepared in the same manner as in the Examples, except that the viscosity of hypromellose was changed as shown in Table 2 below.

Hypromellose viscosity (cps) Comparative Example 1 96629 Comparative Example 2 68787 Comparative Example 3 60520 Comparative Example 4 10587 Comparative Example 5 8282 Comparative Example 6 7750 Comparative Example 7 6057 Comparative Example 8 4016 Comparative Example 9 2783 Comparative Example 10 607 Comparative Example 11 44

Experiment example

The dissolution rates of Examples 1 to 10 and Comparative Examples 1 to 11 over time were measured under the following dissolution test conditions. The measurement results are shown in Table 3 below.

Dissolution test conditions

Dissolution test solution: pH 4.0 test solution

pH 4.0 Test solution: 0.05 mol/L sodium acetate buffer [0.05 mol/L acetic acid 0.05 mol/L

Use sodium acetate mixture (82:18).

Test temperature: 37 ± 0.5 ℃

Dissolution method: Korean Pharmacopoeia dissolution test method 2 (paddle method), 50 revolutions per minute

Dissolution rate (%) 1 hour after start of dissolution test 8 hours after starting the dissolution test 10 hours after the start of the dissolution test 24 hours after start of dissolution test Comparative Example 1 31.6 58.8 63.6 85.7 Comparative Example 2 31.9 62.5 67.4 89.4 Comparative Example 3 34.5 63.2 67.9 91.6 Example 1 34.2 63.0 71.1 93.9 Example 2 36.6 69.6 73.2 95.6 Example 3 35.3 68.3 74.6 96.9 Example 4 35.8 69.8 75.4 98.0 Example 5 36.2 70.1 76.2 98.0 Example 6 35.0 67.5 74.1 96.7 Example 7 35.3 68.2 75.2 97.1 Example 8 38.5 68.3 74.1 97.5 Example 9 39.3 67.8 74.0 97.2 Example 10 40.0 72.3 78.4 94.9 Comparative Example 4 44.2 77.9 82.8 98.9 Comparative Example 5 45.8 75.5 81.6 98.6 Comparative Example 6 46.5 80.8 85.9 95.3 Comparative Example 7 48.3 81.7 86.6 95.3 Comparative Example 8 47.4 85.5 89.2 98.6 Comparative Example 9 46.2 89.7 92.1 99.7 Comparative Example 10 73.6 98.7 100.1 100.2 Comparative Example 11 80.8 99.9 99.8 99.9

Looking at the above measurement results, the formulations of Examples 1 to 10 satisfy the dissolution rate approval criteria for each time slot, while Comparative Examples 1 to 11 do not satisfy the dissolution rate approval criteria for each time slot. This means that when the cellulose derivative satisfies the following conditions as in Examples 1 to 10, upon oral administration of the preparation, the Mosapride blood concentration quickly reaches the effective blood concentration showing the therapeutic effect, and the drug effect appears quickly, but the Mosapride blood concentration does not reach the therapeutic effect. It remains above the minimum blood concentration for the effect to last for 24 hours, showing that the drug effect can last for 24 hours.

[condition]

The viscosity of an aqueous solution containing 2% by weight of a cellulose derivative satisfies 11,000 to 60,000 cps when measured at 20°C according to the rotational viscometer method in Article 2, Paragraph 5 of the Korean Pharmacopoeia, General Test Method 57. Viscosity Measurement Method 2.

Claims (11)

Immediate release part containing active ingredients and additives; and
Contains a sustained-release portion containing active ingredients, additives, and cellulose derivatives,
The active ingredient is Mosapride or a salt thereof,
A sustained-release preparation wherein the cellulose derivative satisfies the following conditions.
[condition]
The viscosity of an aqueous solution containing 2% by weight of a cellulose derivative satisfies 11,000 to 60,000 cps when measured at 20°C according to the rotational viscometer method in Article 2, Paragraph 5 of the Korean Pharmacopoeia, General Test Method 57. Viscosity Measurement Method 2.
According to paragraph 1,
A sustained-release preparation wherein the cellulose derivative satisfies the following conditions.
[condition]
The viscosity of an aqueous solution containing 2% by weight of a cellulose derivative satisfies 32,000 to 42,000 cps when measured at 20°C according to the rotational viscometer method in Article 2, Paragraph 5 of the Korean Pharmacopoeia, General Test Method 57. Viscosity Measurement Method 2.
According to paragraph 1,
A sustained-release preparation containing 5 to 20% by weight of the cellulose derivative based on the total weight of the preparation.
According to paragraph 1,
A sustained-release preparation containing 15 to 30 mg of the cellulose derivative.
According to paragraph 1,
A sustained-release preparation containing the active ingredient in an amount of 5 to 15% by weight based on the total weight of the preparation.
According to paragraph 1,
The additive includes a disintegrant,
A sustained-release formulation containing 10 to 30% by weight of the disintegrant based on the total weight of the formulation.
According to paragraph 1,
The additive includes an excipient,
A sustained-release formulation containing 30 to 50% by weight of the excipients relative to the total weight of the formulation.
According to paragraph 1,
The additive includes a binder,
A sustained-release formulation containing 3 to 10% by weight of the binder based on the total weight of the formulation.
According to paragraph 1,
The additive includes a lubricant,
A sustained-release formulation containing 0.5 to 5% by weight of the lubricant based on the total weight of the formulation.
According to paragraph 1,
A sustained-release preparation wherein the cellulose derivative is hypromellose.
Immediate release part containing active ingredients and additives; and
Contains a sustained-release portion containing active ingredients, additives, and cellulose derivatives,
In the sustained-release formulation, the active ingredient is Mosapride or a salt thereof,
The sustained-release preparation was tested for dissolution according to the test conditions of the Korean Pharmacopoeia General Test Method Dissolution Test Method 2, pH 4.0, 37 ± 0.5 ℃, and paddle 50 rpm,
The dissolution rate of the active ingredient 1 hour after the start of the dissolution test is 25 to 45%;
The dissolution rate of the active ingredient at 8 hours from the start of the dissolution test is 60 to 80%;
The dissolution rate of the active ingredient 10 hours after the start of the dissolution test is 70 to 80%; and
A sustained-release preparation with a dissolution rate of the active ingredient of 85% or more 24 hours after the start of the dissolution test.