KR101265491B1 - Dissolution rate controlled multilayered tablet for oral administration containing sarpogrelate hydrochloride and manufacturing method thereof - Google Patents

Abstract

The present invention relates to a controlled-release sustained-release tablet containing a safoglylate hydrochloride and a method for preparing the same. Specifically, a pH-dependent release controlling agent, a pH-sensitive polymer, or a combination thereof is used together with safoglylate hydrochloride to form a sustained release layer, and a fast-release excipient and a safoglylate hydrochloride are used together to form an immediate release layer, and these are multi-layered. It is characterized by providing a multi-layered tablet in a form that can be administered once a day by tableting with tablets. The sustained-release tablet is administered not only to give an immediate therapeutic effect, but also to reduce the number of doses of the drug, as well as to maintain the constant concentration of the active ingredient in the plasma for a considerable time, as well as to adapt the drug to patients It is very useful because it can increase dosage compliance.

Description

Dissolution rate controlled multilayered tablet for oral administration containing sarpogrelate hydrochloride and manufacturing method

The present invention relates to an oral multilayer tablet containing a dissolution rate containing safoglylate hydrochloride and a method for preparing the same.

Sarpogrelate Hydrochloride has a specific antagonistic action against Serotonin receptors on platelets and vascular smooth muscle. As a result, it exhibits anti-platelet action and vasoconstriction effect, and is clinically used to improve ischemic symptoms such as ulcers, pain and cold feeling for chronic arterial occlusion, and has the following structural formula.

<Structure of Safoacrylate Hydrochloride>

Currently, sapoglylate hydrochloride is commercially available for immediate release (anplag tablet, sapoglychloride hydrochloride 100 mg / 1 tablet, 3 times / day, Yuhan Corporation), but no commercially released sustained release formulation is available. In the case of immediate-release preparations, 100 mg of safoglylate hydrochloride is contained in one tablet, and one tablet is administered three times a day to administer up to 300 mg per day.

Such conventional safoglylate hydrochloride formulations have a disadvantage of poor patient compliance with three-dose preparations per day, as well as a rapid change in blood drug concentrations during such repeated administrations, causing the patient to be quickly stimulated and Sensitivity is also lost, the treatment is not successful, there is a problem that the risk of side effects increases even more if repeated doses exceeding the effective blood concentration.

For this reason, it is desirable to obtain a long-acting formulation which releases the drug for a longer period of time with a dosage unit of safoglylate hydrochloride of 100 mg or more. In addition, monolayer sustained-release preparations alone cannot reach effective blood levels required for initial treatment, so controlled release with simultaneous release is necessary.

Known controlled release techniques in the art are as follows. Korean Laid-Open Publication No. 2010-0064015 describes a method for preparing double tablets containing aceclofenac, and Korean Laid-Open Publication No. 2009-0047310 discloses an immediate release layer containing dexibuprofen as an active ingredient and a desiccant and an excipient, respectively. Multilayer tablets comprising a sustained release layer comprising a desiccant and a release control agent are described.

However, these methods do not effectively control drug absorption due to changes in the pH environment in the body, and there is a disadvantage that the bioavailability may be changed according to the time difference in which the drug stays in the stomach. Therefore, it is necessary to develop a sustained-release sustained-release safoglylate hydrochloride multi-layer tablet that can continuously and controlled release of the drug in the stomach and intestine by minimizing the possibility of variation in drug release due to the difference in pH environment and gastric retention time in vivo.

Therefore, the present inventors have studied to overcome the problems of the prior art, and by implementing a multi-layered tablet consisting of an immediate release layer and a sustained release layer containing safoglylate hydrochloride as an active ingredient and controlling the drug release according to pH, In addition to the once-daily administration of safoglylate hydrochloride, it was possible to complete a multi-layered tablet containing safoglylate hydrochloride that can achieve rapid initial effective blood concentration and maintain a stable and stable effective blood concentration.

Therefore, the present invention has a first object to provide a multi-layered tablet containing safoglychloride hydrochloride with controlled drug release.

Another object of the present invention is to provide a method for preparing the safoglylate hydrochloride-containing multilayer tablet.

The present invention provides a rapid release layer comprising safoglylate hydrochloride and a fast-acting excipient; And a sustained release layer comprising a release regulator including a pH-independent polymer, a pH-sensitive polymer, or a combination thereof as a release regulator of the safoglylate hydrochloride and the safoglylate hydrochloride.

In addition, the present invention comprises the steps of (a) granulating a pH independent polymer, a pH sensitive polymer or a combination thereof with safoglylate hydrochloride to prepare a primary granule; (b) granulating the immediate release excipient and safoglylate hydrochloride together to prepare a secondary granule; And (c) tableting the primary granules and the secondary granules into multilayer tablets.

The multi-layer oral tablet consisting of a rapid release portion and a sustained release portion according to the present invention is not only administered orally to give an immediate therapeutic effect, but also to maintain a constant concentration in the plasma for a long time, In addition to reducing the number of times, the application of pH-sensitive polymers, in particular, improves the variability of drug absorption according to the difference in the patient's gastric emptying time and minimizes the problem of drug over-absorption in the upper gastrointestinal tract. This is very useful because it increases the adaptability and thus the medication compliance.

1 is a graph showing the results of dissolution test in a pH 1.2 eluate of tablets and Anflag tablets (Comparative Example 4) comprising the fast-release portion prepared in Examples 7 to 10.
2 is a graph showing the dissolution test results of the Anflag tablets described in Comparative Example 4.
3 is a graph showing the dissolution test results of the tablet including the sustained release portion prepared in Examples 17 to 20.
Figure 4 is a graph showing the dissolution test results in the pH 1.2 eluent of the tablet containing the sustained release portion prepared in Examples 17 to 18.
5 is a graph showing the dissolution test results in the pH 6.8 eluent of the tablet including the sustained release portion prepared in Examples 17 to 18.
6 is a graph showing the dissolution test results of the bilayer tablets prepared in Examples 21 to 24.
7 is a graph showing the dissolution test results of the coated tablet prepared in Example 25.
Figure 8 is a graph showing the dissolution test results of the monolayer tablets prepared in Comparative Examples 1 to 3.

The present invention relates to (±) -2- [2- (3-carboxypropionyloxy) -3-dimethylaminopropoxy] -3-methoxybibenzyl hydrochloride (hereinafter referred to as safoglylate hydrochloride), which is a bibenzyl derivative useful as an anticoagulant. ) As an active ingredient, and relates to a sustained release tablet and a method for producing the same, characterized in that the dissolution rate is controlled.

The safoglylate hydrochloride is currently commercialized as a rapid release formulation, but is rapidly absorbed upon administration to reach a maximum drug concentration within about 0.75 hours, and the dosage method is set to be administered three times a day due to the short half-life of about 0.7 hours. In addition, there is a disadvantage of poor patient compliance, and the drug concentration in the blood changes drastically with such repeated administrations, so that the patient is quickly stimulated by the drug and there is no sensitivity to the drug, so that the treatment is unsuccessful and exceeds the effective blood concentration. There is a problem that the greater the risk of side effects when repeated doses.

Therefore, the formulation of the present invention provides a sustained formulation which releases the safoglylate hydrochloride drug for a longer time, and also because the mono-release sustained release formulation alone does not reach the effective blood concentration required for the initial treatment, it is a rapid release. It is characterized by providing a controlled release sustained release multi-layer tablet that can have simultaneously.

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

The present invention provides a rapid release layer comprising safoglylate hydrochloride and a fast-acting excipient; And it provides a sustained-release tablet comprising a sustained release layer comprising a release control agent of pH-independent polymer, pH-sensitive polymer or a combination thereof as the release regulator of the safoglylate hydrochloride and the sapograte hydrochloride.

The safoglycerate hydrochloride has a high absorption rate over the upper and lower gastrointestinal tract, and has a short half-life. An object of the present invention is to provide a dosage form that can be administered once a day by controlling the release to maintain the initial effective therapeutic concentration and the effective concentration for the next 24 hours. In the present invention, in order to make the immediate release layer and the sustained release layer of the matrix type into one formulation in order to obtain two release profiles of the initial effective therapeutic concentration and the maintenance concentration, it is compressed into a multilayer tablet form.

In many oral drug delivery systems, the drug administered can be affected by absorption in a variety of in vivo environmental factors, among which the difference in gastric emptying time depending on the individual affects the retention time of the formulation. In fasting conditions, even if the maximum amplitude of the MMC cycle (migration motor complex (MMC) stage 3) empties all of the above contents every 90 minutes, the range of gastric emptying after meals is up to 10-fold, depending on the individual and diet. It can make a difference. Gastrointestinal food grinding, which aids digestion in dietary mode, provides hydrodynamic erosion to tablets, resulting in faster drug delivery in vivo, and up to 20-fold hydrodynamics in the human body in fasting and dietary conditions. This corresponds to an eluting stirring speed of 10 to 150 rpm.

Therefore, considering the hydrodynamic difference and gastric emptying time in the stomach during oral administration of a matrix tablet consisting of an immediate release layer and a sustained release layer, it is recommended that the drug in the immediate release layer is rapidly released to obtain an initial effective drug concentration in the stomach. It is important to control the drug release of the western layer as much as possible in the stomach where the hydrodynamic difference between individuals is large, so as to prevent excessive drug release. In order to develop a once-daily formulation of safoglycerate hydrochloride for this, the multilayer tablet according to the present invention is composed of the immediate release layer and the sustained release layer.

In the present invention, the active ingredient includes all pharmaceutically acceptable salts as sarpogrelate hydrochloride.

The safoglylate hydrochloride is used in both the immediate release layer and the sustained release layer, wherein the total sum of the safoglylate hydrochloride used in the immediate release layer and the sustained release layer is preferably 260 to 340 mg, more preferably in one tablet. 280 to 320 mg to be used, most preferably to use 300 mg. If the total amount of safogrelate hydrochloride is used less than 260 mg, there is a problem that does not obtain sufficient bioavailability, and when used in excess of 340 mg, the maximum blood concentration (C _max ) increases and is overexposed to the drug to maintain an appropriate maintenance concentration. There is a problem that does not get.

The safoglylate hydrochloride is preferably used in the immediate release layer and the sustained release layer in a weight ratio of 1: 1.5 to 1: 4, and more preferably in a weight ratio of 1: 2 to 1: 3.3. For example, it is preferable to use 60-120 mg in the immediate release layer of the tablet and 180-240 mg of safoglylate hydrochloride in the sustained release layer, more preferably 70-100 mg in the immediate release layer, the sustained release layer. It is recommended to use between 200 and 230 mg of safoacrylate hydrochloride. When the immediate release layer and the sustained release layer of safoglylate hydrochloride are used in the above weight ratio range, there is an advantage in that the rapid initial effective drug concentration is obtained by the immediate release layer and the maintenance drug concentration is controlled by the sustained release layer.

In addition, the immediate release layer and the sustained release layer may be used in a weight ratio of 1: 1 to 1: 5, so that the composition of the active ingredient and excipients suitable for maintaining the release profile may be obtained while at the same time obtaining a convenient tablet size. Do.

The immediate release layer of the present invention comprises the safoglylate hydrochloride and the fast-acting excipient. The immediate release layer may be prepared by compressing the safoglylate hydrochloride and the fast-acting excipient in tablet form. The immediate release layer acts to rapidly disintegrate the safoglylate hydrochloride so that the elution takes place quickly to reach a therapeutically effective amount of blood in the early stage.

The fast-acting excipient may be used in granulation into dry granules, wet granules or fluidized beds and then mixed with disintegrants and lubricants that are acceptable in the art. In this case, the total amount of the fast-acting excipient used is preferably used in the range of 50 to 300 parts by weight, more preferably in the range of 100 to 200 parts by weight based on 100 parts by weight of the safoglycerate hydrochloride used in the immediate release layer. good. When the amount of the fast-acting excipient is less than 50 parts by weight, there is a problem in tableting in the form of a multilayer tablet due to insufficient tableting weight, and when the amount exceeds 300 parts by weight, the size of the tablet is too large.

The fast-acting excipient according to the present invention is a sugar alcohol, polyethylene glycol, sodium starch glycolate, crospovidone, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose calcium, gelatinized starch composed of xylitol, sorbitol, mannitol and mixtures thereof. , Croscarmellose sodium, ion exchange resin, corn starch, microcrystalline cellulose and lactose one or a mixture of two or more selected may be used, but is not limited thereto and within the scope does not impair the object of the present invention Anything allowed can be used.

The sustained release layer of the present invention uses a pH independent polymer, a pH sensitive polymer, or a combination thereof as a release regulator of the safograte hydrochloride together with safoglylate hydrochloride, and may further include a pharmaceutically acceptable excipient. . The sustained release layer can be prepared by compressing the composition as a matrix in the form of a tablet. The sustained dissolution is gradually performed due to the delayed release effect and the release control effect of the contained safoglylate hydrochloride, which serves to maintain a therapeutically effective amount for a long time. Do it.

The sustained release layer of the present invention uses a pH-independent polymer, which is a pH-dependent polymer, as a release control agent, and the pH-independent polymer has a role of delaying and controlling the release of the drug constantly without being affected by the pH environment in the gastrointestinal tract. Do it. The pH-independent polymer is preferably used in the range of 1 to 150 parts by weight, and more preferably in the range of 40 to 100 parts by weight, based on 100 parts by weight of the safoglycerate hydrochloride used in the sustained release layer. When the pH-independent polymer is used in less than 1 part by weight, there is a disadvantage in that sustained release is not secured, and when used in excess of 150 parts by weight, the drug is excessively delayed release or, thereby, impedes the role of the pH-sensitive polymer. There is this. The pH-independent polymer may be one or a mixture of two or more selected from cellulose derivatives, gums, hydrophilic (meth) acrylate copolymers, hydrophilic polyvinyl derivatives, polyethylene derivatives, carboxyvinyl compounds, and polysaccharides, but is not limited thereto. Without limitation, any pharmaceutically acceptable compound can be used within the scope of not impairing the object of the present invention. Preferably, low-viscosity hydroxypropylmethylcellulose and high-viscosity hydroxypropylmethylcellulose are used alone or in a mixture thereof in the cellulose derivative.

As the pH-sensitive polymer used in the present invention, a polymer exhibiting a swelling insoluble below the pH 5 but dissolving therein may be used. However, the present invention is not limited thereto and does not impair the object of the present invention. Any pharmaceutically acceptable one may be used to the extent that it does not. In the present invention, by using the pH-sensitive polymer, the insoluble membrane is added to the outside of the tablet to delay the drug release of the sustained release layer in the gastric fluid variability of the stomach, which is delayed in patients with long stomach emptying time Inhibition of drug release may have the effect of improving the problem of over-absorption of the drug. The pH-sensitive polymer preferably comprises a range of 10 to 50 parts by weight based on 100 parts by weight of safogrelate hydrochloride of the sustained release layer. When the pH sensitive polymer is used in less than 10 parts by weight, there is a problem in that it does not inhibit the drug release in an acidic pH environment such as the stomach at a low pH sensitive polymer containing concentration, when used in excess of 50 parts by weight of the alkaline environment pH Due to the fast dissolving property in the present invention there is a problem that it is difficult to maintain the proper release rate delayed by promoting the release of the drug. As the pH sensitive polymer, for example, one or a mixture of two or more selected from eudragit, phthalate hydroxypropylmethylcellulose and shellac may be used.

The present invention may further comprise a pharmaceutically acceptable excipient for maintaining the dosage form and hardness of the appropriate tablet. The excipient is preferably used in an amount of 1 to 50 parts by weight based on 100 parts by weight of safoglylate hydrochloride used in the sustained release layer. Such excipients which may be used include, for example, crosslinked polyvinylpyrrolidone, crosslinked carboxymethylcellulose sodium, carboxymethylstarch, methacrylate-divinylbenzene copolymer calcium, polyvinyl alcohol, lactose, microcrystalline Cellulose and cellulose derivatives, starch and derivatives thereof, cyclodextrins and dextrin derivatives, pregelatinized starch and derivatives thereof, light silicic anhydride, magnesium stearate, glyceryl monostearate, sodium stearyl fumarate, talc and hydrogenated One or two or more selected from among the castor oils may be used, but the present invention is not limited thereto, and any pharmaceutically acceptable compound may be used within the scope of not impairing the object of the present invention.

In the case of preparation of the sustained-release tablet of the present invention can be prepared using a method known in the art, there is no limitation in the production method. Specifically, in the part for designing sustained release, granules of pH-independent polymers, pH-sensitive polymers, or a combination thereof with safoglylate hydrochloride are prepared to produce primary granules, and in the part for designing sustained release, After forming the granules by granulating the square excipient and safoglylate hydrochloride together, and tableting them in a multilayer tablet, a sustained-release tablet containing safoglylate hydrochloride can be prepared.

When preparing a bilayer tablet consisting of the immediate release layer and the sustained release layer as described above, the tablet may be prepared by first tableting the sustained release layer and then filling the rapid release layer thereon to perform secondary tableting. At this time, the tableting of the immediate release layer is not necessarily made after the tableting of the sustained release layer, and the tableting of the immediate release layer is performed first, and it is also possible to fill the tablets by filling the granules of the sustained release layer. In addition, it is also possible to tablet the immediate release layer and the sustained release layer sequentially or in reverse order, and single tableting.Multilayer tablets are composed of a bilayer, trilayer tablet or sustained release matrix composed of an immediate release layer and a sustained release layer as inner cores, and an immediate release matrix is used. It can also be manufactured in the form of a nuclear tablet made as an external phase, and there is no limitation in terms of its form. In addition, the sustained-release tablet of the present invention may include a suitable film coating layer, the additive and coating method for forming the coating layer may be carried out by conventional methods in the art.

The sustained-release multilayer tablet of the present invention can rapidly reach the minimum effective therapeutic concentration in the plasma concentration of the rapidly released active ingredient, the delayed-release active ingredient has the advantage of maintaining the effective blood concentration continuously for a certain time In addition, the number of doses and side effects can be significantly reduced, which is very useful pharmacologically.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are only for illustrating the present invention, and the scope of the present invention is not limited to the examples.

< Example  1 to 10 Immediate  Produce

According to the composition of Table 1, after the primary mixing of the main component safoglylate hydrochloride (product of KPX Life Science Co., Ltd.) and fast-acting excipient, the binder and stabilizer was dissolved in 30 mg of purified water (pharmaceutical) per tablet wet granulation Thereafter, after drying and sizing, after mixing with a lubricant and tableting, tablets were prepared immediately.

division Ingredients Unit (mg) Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Example 8 Example 9 Example 10 chief ingredient Safograte
Hydrochloride 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 100.0 Fast-acting excipients D-mannitol 50.0 25.0 50.0 25.0 100.0 100.0 100.0 100.0 100.0 100.0 Corn starch 50.0 75.0 12.5 12.5 12.5 12.5 15.0 19.8 Lactose baggage 50.0 75.0 - - - - - - Binder Polyvinylpyrrolidone 3.0 3.0 3.0 3.0 - - 3.7 7.4 7.4 7.4 Hydroxypropylmethylcellulose
2910 (6 cps) - - - - 3.7 7.4 - - - - Stabilizer Anhydrous citric acid 3.0 3.0 3.0 3.0 2.5 2.5 2.5 2.5 2.5 2.5 Lubricant Colloidal
Silicon dioxide 2.0 2.0 2.0 2.0 3.0 3.0 2.0 2.0 3.0 3.0 Stearic acid
magnesium 2.0 2.0 2.0 2.0 4.0 4.0 3.0 3.0 4.0 4.0 Talc 2.0 2.0 2.0 2.0 4.0 4.0 3.0 3.0 4.0 4.0 Immediate layer total weight 212.0 212.0 212.0 212.0 229.7 233.4 226.7 230.4 235.9 240.7

< Example  11-20> Western  Produce

According to the composition of Table 2, after primary mixing of the main component, excipient, pH independent polymer and pH sensitive polymer, the stabilizer was dissolved in 80 mg of ethanol (pharmaceutical) per tablet, wet granulated, dried and formulated After post-mixing with a tablet, tablets were prepared by sustained release tablets.

division Ingredients Unit (mg) Example 11 Example 12 Example 13 Example 14 Example 15 Example 16 Example 17 Example 18 Example 19 Example 20 chief ingredient Safoglylate Hydrochloride 200.0 200.0 200.0 200.0 200 200 200 200 200 200.0 Excipient Lactose baggage 36.0 36.0 36.0 36.0 36.0 36.0 36.0 36.6 46.6 24.0 pH independent polymer Hydroxypropylmethylcellulose
(6cps) - - - 66.6 66.6 - - - - - Hydroxypropylmethylcellulose
(50 cps) 99.9 - - - - 66.6 66.6 66.6 66.6 66.6 Hydroxypropylmethylcellulose
(4,000 cps) 99.9 - - 33.3 - 33.3 33.3 23.3 45.3 Hydroxypropylmethylcellulose
(15,000 cps) - - 99.9 33.3 - 33.3 - - - - pH sensitive polymer Eudragit L100-55 36.1 36.1 36.1 36.1 36.1 36.1 - 36.1 36.1 36.1 Stabilizer Anhydrous citric acid 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 Lubricant Colloidal silicon dioxide 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 6.0 6.0 Magnesium stearate 6.0 6.0 6.0 6.0 6.0 6.0 6.0 6.0 8.0 8.0 Talc 6.0 6.0 6.0 6.0 6.0 6.0 6.0 6.0 8.0 8.0 Western layer total weight 392.0 392.0 392.0 392.0 392.0 392.0 355.9 392.6 398.6 398.0

< Example  21 ~ 24> Immediate layer  And To the west  Preparation of bilayer tablets

The second-layer tablets were prepared by first tableting the immediate-release layer components of the examples shown in the composition of Table 3 below with the hardness of about 3 to 5 kp, followed by secondary tableting with the hardness of about 12 to 18 kp. .

ingredient Example  21 Example  22 Example  23 Example  24 Immediate layer Example 7 Example 8 Example 9 Example 10 Western layer Example 18 Example 19 Example 20 Example 20 Total weight of bilayer tablets (mg) 618.3 629.0 633.9 638.7

< Example  25> Two-story  coating

After preparing a bilayer tablet according to Example 24, a coated tablet was prepared using a SEPI Film LP-770 coating base. 75% ethanol was used as the solvent and the coating amount was 20 mg.

< Comparative example  1-3> Preparation of Monolayer Tablets

According to the composition shown in Table 4 below, the primary component and excipients were first mixed, and the binder and the stabilizer were dissolved in 80 mg ethanol (pharmacopoeia) per tablet, and then wet granulated, dried, and granulated to form a pH independent polymer and a lubricant. After post-mixing, it was compressed to prepare a monolayer tablet.

division Ingredients Unit (mg) Comparative Example
One Comparative Example
2 Comparative Example
3 chief ingredient Safoglylate Hydrochloride 300 300 300 Excipient Lactose baggage 100 100 100 Colloidal silicon dioxide 4 4 4 Binder Polyvinylpyrrolidone 2 2 2 pH
Independence
Polymer Hydroxypropylmethylcellulose
(4000 cps) 153 - - Hydroxypropylmethylcellulose
(15000 cps) - 153 - Hydroxypropylmethylcellulose
(100000cps) - - 153 Stabilizer Anhydrous citric acid 20 20 20 Lubricant Colloidal silicon dioxide 9 9 9 Talc 12 12 12 Western layer total weight 600 600 600

< Comparative example  4> Anflag  refine

As a comparative example, a commercially available anflag (100 mg as safoglylate hydrochloride, Yuhan Corporation, serial number: 0004, expiration date: 2013.01.14) was used as a safoglylate hydrochloride tablet.

< Test Example  1> Immediate layer  Tablet Dissolution Test

The dissolution test was carried out under the following conditions based on the method for setting the rapid release drug of the dissolution standard setting guidelines of the Korea Food and Drug Administration using the immediate release layer tablets prepared in Examples 7 to 10, and the results It is shown in Table 5 and FIG.

Exam conditions

Specimen: Immediate layer tablets of Examples 7 to 10

Dissolution test solution: pH 1.2 (artificial gas solution), 900 mL,

37 ± 0.5 ℃

Dissolution Method: Method 2 of the KEPCO dissolution test (paddle method), 50 revolutions per minute

Elution time Dissolution rate (%) Example 7 Example 8 Example 9 Example 10 15 min 39.7 25.0 11.8 19.1 30 min 79.8 69.3 24.9 35.8 45 min 96.5 93.8 51.0 72.7 60 min 105.2 102.7 76.1 100.0

As shown in Table 5 and FIG. 1, the immediate release layer tablets prepared in Examples 7 to 10 exhibited a rapid dissolution rate of 90% or more within 1 hour after the start of dissolution except Example 9, thereby activating the safoglylate hydrochloride. Immediate release tablets used as ingredients are suitable for exerting rapid efficacy.

< Test Example  2> Western layer  Tablet Dissolution Test

The dissolution test was carried out under the following conditions using the sustained release layer tablets prepared in Examples 17 to 20, and the results are shown in Table 6 and FIG. 3.

Exam conditions

Specimen: Sustained-Release Tablets of Examples 17-20

Dissolution test solution: pH 6.8 (in-plant solution), 900 mL,

37 ± 0.5 ℃

Dissolution Method: Method 2 of the KEPCO dissolution test (paddle method), 50 revolutions per minute

Elution time Dissolution rate (%) Example 17 Example 18 Example 19 Example 20 1hr 19.0 11.3 15.0 12.0 2 hr 35.1 19.3 24.8 21.2 4hr 57.3 32.1 42.9 36.7 8hr 88.3 51.4 74.4 61.4 12hr 102.0 70.9 93.7 84.8 18hr 102.1 90.1 99.6 99.2 24hr 102.3 98.2 100.2 101.6

As shown in Table 6 and Figure 3, the sustained-release tablet prepared in Examples 17 to 20 it was confirmed that the active ingredient in the sustained release layer slowly eluted for 24 hours.

< Test Example  3> Western layer  Tablet Dissolution Test- pH  Sensitive Polymer Evaluation

The dissolution test was conducted under the following conditions using the sustained-release tablets prepared in Examples 17 to 18, and the results are shown in Table 7 and FIGS. 4 to 5.

Exam conditions

Specimen: Sustained-Release Tablets of Examples 17-18

Dissolution test solution: pH 1.2 (artificial gastric fluid) and pH 6.8

Phosphorus solution, 900 mL, 37 ± 0.5 ° C

Dissolution Method: Method 2 of the Pharmacopoeia dissolution test (paddle method), 50 revolutions per minute

Elution time Dissolution rate (%) pH 1.2 pH 6.8 Example 18 Example 17 Example 18 Example 17 1 hr 10.8 12.3 19.6 24.7 2 hr 17.4 19.2 31.9 35.1 4 hr 27.1 37.6 50.3 57.3 6 hr 34.7 53.4 68.2 75.3 8 hr 41.2 74.4 83.9 88.3 12 hr 51.4 91.1 102.5 102.0

As shown in Table 7 and FIGS. 4 to 5, the dissolution rate of Example 18 to which pH-sensitive polymer Eudragit L100-55 was added at pH 1.2 (artificial gastric juice) was not added to Eudragit L100-55. The result was lower than 17, but the same level of elution resulted in pH 6.8 (in-house solution).

The results show the dissolution behavior of maintaining a constant release pattern in the intestinal fluid while suppressing drug release from the upper gastrointestinal tract by using a pH sensitive polymer. Through this, the release of the pH-sensitive polymer is suppressed in the acidic pH environment of the virtual gastric juice, but it can be seen that there is an advantage in maintaining a similar release profile in the alkaline pH environment.

< Test Example  4> Immediate layer  And To the west  Dissolution test of bilayer tablets

The dissolution test was performed under the following conditions using the bilayer tablets prepared in Examples 21 to 24, and the results are shown in Table 8 and FIG. 6.

Exam conditions

Specimen: Bilayer Tablet of Examples 21-24

Dissolution test solution: pH 1.2 (artificial gastric fluid) and pH 6.8

Phosphorus solution, 900 mL, 37 ± 0.5 ° C

Dissolution Method: Method 2 of the Pharmacopoeia Dissolution Test (paddle method), 100 revolutions per minute

Elution time Dissolution rate (%) Example 21 Example 22 Example 23 Example 24 pH 1.2 pH 6.8 pH 1.2 pH 6.8 pH 1.2 pH 6.8 pH 1.2 pH 6.8 15 min 13.2 20.4 8.3 19.7 4.2 28.1 6.4 30.1 30min 26.6 32.5 23.1 34.7 9.8 36.3 11.9 38.5 45min 32.2 37.9 31.3 40.3 21.3 39.0 24.2 41.2 1hr 35.1 41.3 34.2 42.6 31.6 40.8 33.3 43.3 2 hr 39.7 47.4 40.3 48.4 39.2 46.2 41.7 49.8 4hr 46.1 57.7 48.2 58.3 46.2 54.7 49.7 61.8 8hr 55.0 74.2 59.7 74.5 54.7 67.5 59.6 82.8 12hr 62.8 88.3 67.7 89.8 62.9 80.5 70.2 95.7 18hr 71.4 98.5 76.9 99.3 71.9 93.3 80.6 99.6 24hr 78.6 101.4 84.1 101.0 79.2 98.7 90.4 100.1

As shown in Table 8 and Figure 6, the bilayer tablet of the present invention can express a rapid medicinal effect by rapid dissolution during the initial 1 hour, and then slowly elution is continuously made a stable release pattern suitable for showing a continuous medicinal effect Could be confirmed.

< Test Example  5> Coating  Dissolution test

The dissolution test was performed under the following conditions using the coated tablets prepared in Example 25, and the results are shown in Table 9 and FIG. 7.

Exam conditions

Specimen: Specimen of Example 25

Dissolution test solution: pH 1.2, 6.8, water, 900 mL, 37 ± 0.5 ℃

Dissolution Method: Method 2 of the KEPCO dissolution test (paddle method), 50 revolutions per minute

Elution time Example 25 Dissolution Rate (%) pH1.2 pH6.8 water 15 min 4.3 25.2 17.7 30min 11.4 31.9 31.4 45min 24.2 39.8 37.0 1hr 34.0 42.3 39.8 2 hr 40.7 49.0 45.8 4hr 47.8 59.9 57.2 8hr 56.7 76.4 72.2 10hr 63.1 84.7 80.9 12hr 67.1 89.8 86.2 15hr 72.3 94.0 91.8 18hr 77.1 96.2 96.2 24hr 84.2 96.4 98.8

As shown in Table 9 and Figure 7, the coating tablet of the present invention shows a rapid dissolution pattern during the initial 1 hour, and also shows that the release control effect does not occur excessive drug release even under strong acid conditions (pH 1.2) Able to know. In addition, elution proceeded slowly from 1 hour, showing a release pattern suitable for maintaining a sustained effective blood concentration.

< Test Example  6> Dissolution test of monolayer tablets

The dissolution test was performed under the following conditions using the monolayer tablets prepared in Comparative Examples 1 to 3, and the results are shown in Table 10 and FIG. 8.

Exam conditions

Specimens: Sustained release tablets of Comparative Examples 1 to 3

Dissolution test solution: pH 6.8 (in-plant solution), 900 mL,

37 ± 0.5 ℃

Dissolution Method: Method 2 of the KEPCO dissolution test (paddle method), 50 revolutions per minute

Elution time Dissolution rate (%) Comparative Example 1 Comparative Example 2 Comparative Example 3 1hr 8.7 8.9 7.6 2 hr 16.2 16.6 14.8 3hr 23.0 23.3 20.9 4hr 29.4 29.6 26.2 6hr 40.2 39.9 34.9 8hr 50.7 50.0 43.4 10hr 60.6 59.4 50.7 12hr 69.3 68.2 57.4

As shown in Table 10 and Figure 8, the monolayer tablets prepared in Comparative Examples 1 to 3 can be confirmed that the active ingredient is slowly and continuously eluted, due to the initial delayed dissolution pattern to reach the effective blood concentration required for treatment An inappropriate elution pattern was shown.

< Test Example  7> Anflag  Tablet Dissolution Test

The dissolution test of the Anflag (100 mg as safoglychloride hydrochloride, Yuhan Corporation, Manufacturing No.: 0004, Expiry date: 2013.01.14) tablet which is the safoglylate hydrochloride tablet of Comparative Example 4 was carried out, and the results are shown in the following table. 11 and FIG. 2.

Exam conditions

Specimen: Anflag tablet (Manufacturing number: 0004, Expiration date: 2013.01.14)

Dissolution test solution: pH1.2, 4.0, 6.8, water, 900mL

37 ± 0.5 ℃

Dissolution Method: Method 2 of the Pharmacopoeia dissolution test (paddle method), 50 revolutions per minute

Anflag  Definition Elution Result Elution time pH 1.2 (%) pH 4.0 (%) pH 6.8 (%) water (%) 15 min 25.2 80.9 84.9 82.6 30 min 63.6 93.7 98.1 96.6 45 min 91.8 94.5 98.6 98.4 60 min 97.2 94.6 98.6 98.4

As shown in Table 11 and Figures 1 and 2, in the case of Anflag tablets, the result shows that 90% or more of all the pH ranges are eluted after the initial 1 hour elapsed, and thus, the effect of maintaining the effective blood concentration in the present invention can be shown. I could confirm that there is no.

Claims (12)

Safoglylate hydrochloride, and xylitol, sorbitol, mannitol and mixtures thereof, polyethylene glycol, sodium starch glycolate, crospovidone, low-substituted hydroxypropyl cellulose, carboxymethylcellulose calcium, gelatinized starch, croscarmellose sodium, A rapid release layer comprising one or two or more fast-acting excipients selected from the group consisting of corn starch, microcrystalline cellulose and lactose; And
A sustained-release tablet comprising a sustained release layer comprising a release regulator which is a pH-independent polymer, a pH-sensitive polymer, or a combination thereof as a release regulator of safoglylate hydrochloride and the safoglylate hydrochloride.
The sustained-release tablet according to claim 1, wherein the total sum of sapoglylate hydrochloride contents of the immediate release layer and the sustained release layer is 260 to 340 mg.
The sustained-release tablet according to claim 1, wherein the safoglylate hydrochloride is used in the immediate release layer and the sustained release layer by dividing in a weight ratio of 1: 1.5 to 1: 4.
The sustained-release tablet according to claim 1, wherein the immediate release layer and the sustained release layer have a weight ratio of 1: 1 to 1: 5.
The sustained-release tablet according to claim 1, wherein the fast-acting excipient is in the range of 50 to 300 parts by weight based on 100 parts by weight of safoglylate hydrochloride used in the immediate release layer.
The sustained-release tablet according to claim 1, wherein the pH-independent polymer is in the range of 1 to 150 parts by weight relative to 100 parts by weight of safoglylate hydrochloride used in the sustained release layer.
The sustained-release tablet according to claim 1, wherein the pH sensitive polymer is in the range of 10 to 50 parts by weight based on 100 parts by weight of safoglylate hydrochloride used in the sustained release layer.
delete The method of claim 1, wherein the pH independent polymer is one or a mixture of two or more selected from cellulose derivatives, gums, hydrophilic (meth) acrylate copolymers, hydrophilic polyvinyl derivatives, polyethylene derivatives, carboxyvinyl compounds, and polysaccharides. Sustained release tablet characterized in.
The sustained-release tablet according to claim 1, wherein the pH sensitive polymer is one or a mixture of two or more selected from Eudragit, phthalate hydroxypropylmethylcellulose and shellac.
The polyvinylpyrrolidone crosslinked with excipients in the sustained release layer, sodium crosslinked carboxymethylcellulose, carboxymethyl starch, methacrylate-divinylbenzene copolymer calcium, polyvinyl alcohol, lactose , Microcrystalline cellulose and cellulose derivatives, starch and derivatives thereof, cyclodextrins and dextrin derivatives, pregelatinized starch and derivatives thereof, hard silicic anhydride, magnesium stearate, glyceryl monostearate, sodium stearyl fumarate, talc and Sustained release tablet, characterized in that one or a mixture of two or more selected from hydrogenated castor oil.
(a) granulating a pH independent polymer, a pH sensitive polymer, or a combination thereof with safoglylate hydrochloride to prepare a primary granule;
(b) granulating the fast-acting excipient and safoglylate hydrochloride together to produce secondary granules; And
(c) compressing the primary granules and the secondary granules into a multilayer tablet, respectively, in a single layer;
Method for producing a sustained release tablet comprising a.

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