KR101320802B1 - Multilayer tablet containing release controlled dosage form of sarpogrelate hydrochloride - Google Patents

Abstract

The present invention (a) a rapid release containing safoglylate hydrochloride and fast-acting excipients; And (b) a controlled release tablet comprising a controlled release safoacrylate hydrochloride comprising a sustained release comprising safoacrylate hydrochloride, a hydrophilic polymer and an effervescent additive, or a controlled release sustained release comprising a safoacrylate hydrochloride, a hydrophilic polymer and a controlled release sustained release base. It is about. Multi-layered tablets containing controlled-release safoglylate hydrochloride according to the present invention are administered orally to give an immediate therapeutic effect, and the active ingredient maintains a constant concentration in plasma for a considerable time, so that the number of administrations is once a day. Not only can it be reduced, but as a result, drug compliance with patients can be increased, thereby increasing medication compliance.

Description

Multilayer tablet containing release controlled dosage form of sarpogrelate hydrochloride

The present invention relates to a multi-layered tablet containing controlled release safoglylate hydrochloride that can maintain an initial blood concentration as well as maintain an effective blood concentration continuously after drug administration.

When the vascular endothelium is damaged, platelets adhere to collagen in the vascular endothelium, and when von Willbrand factor stabilizes, they are not separated by the bloodstream but adhere to the vascular wall. When platelets are activated at the site, platelet aggregation is induced through the activation process of various platelet aggregation substances such as ADP, serotonin, and thromboxane in platelets. At this time, fibrinogen binds platelets to form platelet clumps. Therefore, the blood flow is blocked by platelet lumps inside the blood vessels by the process of adhesion, activation, and aggregation of platelets, and cerebral infarction and cardiovascular disease may occur.

Drugs that prevent the formation of platelet clumps are called antiplatelet drugs. Most drugs have mechanisms that inhibit the process of blood clots and platelet activation. Aspirin is a representative drug, and aspirin blocks antithrombotic action by blocking the action of cyclooxygenase and interfering with the action of thromboxane. Another drug is clopidogrel, which inhibits ADP activation and inhibits platelet function.

In another mechanism, the activation of platelets may be inhibited by inhibiting an increase in cellular calcium levels by inhibiting phosphodiesterase, an enzyme that promotes the breakdown of cAMP. Cilostazole and dipyridamole. Cilostazol has antiplatelet action through two mechanisms that inhibit the resorption of adenosine and inhibit phosphodiesterase to increase cAMP. It is mainly used to inhibit platelet aggregation, and thus has an anticoagulant effect, inhibits the proliferation of smooth muscle cells, and has a vasodilating effect, which may be used to prevent restenosis after a stent procedure.

Among the antiplatelet drugs, aspirin and clopidogrel are currently used a lot, but there are situations in which alternative drugs are needed due to side effects, resistance problems, and cost problems. In addition, when aspirin cannot be used due to gastrointestinal side effects, cilostazole may be used, but cilostazol has a disadvantage in that it is not convenient to take once a day.

On the other hand, sapogrelate is a representative antiplatelet drug that inhibits serotonin receptors, and has a short half-life, excellent effects, and fewer side effects, and thus may be a good alternative to such drugs. Seven subtypes of 5-HT (hydroxytryptamine), a serotonin receptor, show various physiological reactions by binding serotonin to each receptor. Type I 5-HT1 acts on the vascular endothelium and expands blood vessels, whereas type II 5-HT2 acts on smooth muscle, causing vasoconstriction and platelet activation. HT3 acts on the brain and acts as an antiemetic, 5-HT4 acts on the digestive tract. Among these receptors, 5-HT1 and 5HT2A act on blood vessels, of which 5-HT2A receptors are involved in platelet activation and proliferation of vascular smooth muscle cells and directly or indirectly affect vascular contraction by thromboxane.

Safoglylate having such a mechanism of action is the first serotonin receptor inhibitor effective for chronic arterial occlusion, and has the effect of inhibiting platelet aggregation and vasoconstriction. In addition, there are no side effects of headache or hot flashes, which are disadvantages of vasodilating action of other antiplatelet agents, and reversible platelet group is an inhibitory effect, which shortens the wash-out time during surgery and reduces side effects of bleeding.

 Anflag tablet containing safoglylate is the first drug to be developed as a selective 5-HT2 blocker. It is a model of chronic artery occlusion that inhibits platelet aggregation, which is enhanced by platelet aggregation, especially serotonin, and inhibits vasoconstriction. Effectiveness in various thrombus models. However, the commercialized safoglylate hydrochloride-containing tablets have the disadvantage that one tablet three times orally once. Accordingly, in view of the convenience of the patient and the optimal efficiency of the drug, it is necessary to develop a long-acting formulation of safoglylate that can rapidly reach a desired level and exhibit efficacy within a desired therapeutic range for a long time.

However, safoglylate has a fast absorption and rapid disappearance, and the action expression time is short, so that the time of action expression is the same as the existing drug, and the formulation is effective as a conventional technique to make a sustained formulation that can last until the desired time. Can't make it. Therefore, the conventional safoglylate hydrochloride-containing preparations are inconvenient in drug administration, in which the patient must take the drug frequently, and the patient forgets the drug taking time and the drug is not supplied at a predetermined time so that the effective blood concentration of the patient is maintained. There is a problem that the duration of treatment can be long because the symptoms are not improved and the half-life of safoglylate is very short (0.6 ~ 0.8 hours), so the blood concentration is not easily maintained after oral administration, and the drug cannot be continued. There is discomfort due to the difference.

In order to develop a sustained-release formulation of safoglylate hydrochloride, which has a rapid absorption and rapid loss, the present inventors have a rapid effect expression time as the immediate release formulation and at the same time maintain the drug duration time as the sustained release formulation. The formulation was studied. This includes both the immediate release portion and the sustained release portion, wherein the western portion is capable of controlling the release of the drug without being limited to the absorption portion of the human gastrointestinal tract, or the swelling of the matrix using a hydrophilic polymer and a controlled release sustained release base. In the case of using the sustained-release portion to control the dissolution rate, the above problems are solved, and the present invention was confirmed by confirming that once-daily administration is possible.

SUMMARY OF THE INVENTION An object of the present invention is to provide a multi-layered tablet containing controlled release safoglylate hydrochloride that can maintain the expression time of the safoglylate hydrochloride drug as it is and maintain the duration of the drug for a long time.

In order to solve the above problems, the present invention (a) a rapid release portion comprising a safoglylate hydrochloride and a fast-acting excipient; And (b) a controlled release tablet comprising a controlled release safoacrylate hydrochloride comprising a sustained release comprising safoacrylate hydrochloride, a hydrophilic polymer and an effervescent additive, or a controlled release sustained release comprising a safoacrylate hydrochloride, a hydrophilic polymer and a controlled release sustained release base. To provide.

As used herein, the term "release controlled safoglylate hydrochloride-containing multilayer tablet" is a formulation which can maintain a rapid effective expression time and a constant effective blood concentration for a long time, including immediate release and sustained release including safoglylate hydrochloride simultaneously. Means.

In general, safoglylate hydrochloride has fast absorption and fast disappearance, has a short half-life and a short time of onset of action. Due to this feature, the side effect is short and the drug is exerted quickly, and the short half-life gives the advantage that the drug can be taken before surgery because of the short wash-out time. It is required. However, safoglycerate hydrochloride is to be taken in combination with long-term use and other drugs, there is a problem that should be taken frequently because the half-life is short. On the other hand, in order to solve this problem, when the safoacrylate hydrochloride is made into a sustained release formulation, the sustained release of the drug can be maintained, but there is a problem that the expression time of the safoacrylate hydrochloride is delayed.

Therefore, the present invention includes both the immediate release portion and the sustained release portion including safoglylate hydrochloride simultaneously, while maintaining the drug expression time by the immediate release portion as it is, the sustained duration of the drug effect by the western portion, the conventional safoglylate hydrochloride drug It is possible to provide a formulation having an improved effect over the formulation.

Safoglylate hydrochloride, an antiplatelet drug formulation of the present invention, preferably contains 8 to 20% by weight in the immediate portion and 25 to 44% by weight in the western part, more preferably based on the total weight of the multilayer tablet. 12 to 18 weight percent in the immediate release and 30 to 39 weight percent in the sustained release based on the total weight of the multilayer tablet.

As used herein, the term "immediate part" refers to an agent that dissolves rapidly in the body after administration and rapidly elutes safoglylate hydrochloride. Unlike the "western part", which will be described below, the drug can be eluted quickly because there is no substance controlling the release of the drug.

Immediate release portion of the present invention is characterized in that it comprises a safoglylate hydrochloride and a fast-acting excipient. The immediate release may be prepared by pressing in tablet form, and the initial drug is released quickly to allow the active ingredient safoglylate hydrochloride to reach the effective therapeutic concentration quickly.

As used herein, the term “fast-acting excipient” refers to a substance that rapidly elutes the drug in the immediate release, facilitates granulation, and enhances binding force when compressed into tablets. The fast-acting excipient may be a sugar alcohol, a water-soluble polymer, an oil-based base or a mixture thereof, preferably a water-soluble polymer.

The fast-acting excipients usable in the present invention may be selected from the group consisting of lactose, dextrin, mannitol, sorbitol, starch, microcrystalline cellulose, calcium hydrogen phosphate, anhydrous calcium phosphate, calcium carbonate, sugars and mixtures thereof.

In the present invention, the immediate release portion may include 25 to 40% by weight fast-acting excipient. In addition, the fast-acting excipient included in the immediate release part is preferably included in the range of 45 to 70 parts by weight based on 100 parts by weight of safoglylate hydrochloride, and more preferably 50 to 65 parts by weight based on 100 parts by weight of safoglylate hydrochloride. It is included in the weight range.

As used herein, the term “western portion” refers to an agent that dissolves slowly in the body after administration and slowly elutes safoglylate hydrochloride. Unlike the "rapid part", the western part contains a substance that controls the dissolution of the safoglylate hydrochloride so that the safoglylate hydrochloride is eluted slowly.

The western part of the present invention is largely used in two types depending on the component, one is the western part (the first western part) containing safoglylate hydrochloride, a hydrophilic polymer and a foaming additive, and the other is safoglylate hydrochloride, hydrophilic A sustained release (second sustained release) comprising a polymer and a controlled release sustained release base.

First, the first sustained part has a feature of simultaneously including safoglylate hydrochloride, a hydrophilic polymer, and a foaming additive.

As used herein, the term "hydrophilic polymer" refers to a substance that forms a hydrogel in contact with moisture when administered and dissolves at a constant rate. Since the hydrophilic polymer is dissolved at a constant rate during administration, the safograte hydrochloride can also be eluted at a constant and constant rate. The hydrophilic polymer may be selected from the group consisting of hydroxypropyl methyl cellulose, ethyl cellulose, methyl cellulose, polyethylene oxide, sodium alginate, pectin, chitosan, carboxymethyl chitin, carrageenan, polyvinyl cellulose, polyvinyl alcohol, and mixtures thereof. Can be.

As used herein, the term "foamable additive" means a substance that generates bubbles (mainly carbon dioxide) in a formulation comprising a drug. The foamable additive may be an alkali metal carbonate or bicarbonate. Preferably, it may be selected from the group consisting of calcium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, sodium glycine carbonate and mixtures thereof.

The hydrophilic polymer is preferably hydroxypropylmethylcellulose, and the foamable additive is preferably at least one selected from the group consisting of calcium carbonate and sodium hydrogencarbonate.

In general, the effervescent additive may generate bubbles (mainly carbon dioxide) in the formulation during oral administration, thereby lowering the density of the formulation by bubbles, thereby allowing the formulation to float on the upper portion of the gastric juice inside the stomach. However, this purpose can be achieved only by maintaining the form of the formulation. In the case of a lot of bubbles, a large amount of water may be introduced into the voids generated, which may cause the formulation to collapse. It may not be suspended because the density is not lowered. In addition, when the formulation is designed to be too firm, there is a problem that the contact of gastric fluid and the foaming additive is blocked and bubbles are not generated smoothly.

Therefore, in the present invention, the above problems can be solved by using the foamable additive and the hydrophilic polymer together. That is, the present invention maintains the size of the formulation by preventing the collapse of the formulation by the hydrophilic polymer even if bubbles are generated by the foaming additive to form voids and moisture is introduced, and at the same time the gas generated by the foaming additive into the hydrophilic polymer It may be trapped to lower the specific gravity of the formulation, causing the formulation to float, causing slow release of safoglylate hydrochloride.

The first sustained-release portion, 20 to 45 parts by weight based on 100 parts by weight of the safoglylate hydrochloride, 100 parts by weight of safoglylate hydrochloride to the hydrophobic polymer to maintain the form of the formulation and to effectively remain in the stomach It is preferable to include in the range of 5 to 10 parts by weight relative to.

Next, the second sustained portion has a feature that simultaneously contains a safoglylate hydrochloride, a hydrophilic polymer, and a controlled release sustained release base. The hydrophilic polymer used in the second sustain portion is the same as the hydrophilic polymer used in the first sustain portion.

As used herein, the term "release controlled sustained release base" means a substance that is used to release a drug over a long period of time. Examples of the controlled release sustained release base include hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, polyvinylacetate-polyvinylpyrrolidone (collidone SR), and amoniomethacrylate copolymer (oil). Dragit RS series, Eudragit RL series), ethyl acrylate methyl methacrylate copolymer (Euradgit NE series), methacrylic acid copolymer (Euradgit L, Eudragit S), amino methacryl Latex (eudragit E), sodium alginate, propylene glycol ester alginate, xanthan gum, locust bean gum and mixtures thereof.

The hydrophilic polymer is preferably hydroxypropylmethylcellulose, and the release-controlled sustained release base is preferably an ammonio methacrylate copolymer.

The second sustain portion may form a matrix of the drug together with the hydrophilic polymer and the release-controlled sustained release base and adjust the swelling or dissolution rate by adjusting the hydrophilic polymer and the release-controlled sustained release base. Accordingly, it is possible to maintain the persistence of the effective blood concentration of the drug.

The second sustained-release part is 20 to 60 parts by weight based on 100 parts by weight of safoglylate hydrochloride, and 8 to 30 parts by weight of safoglylate hydrochloride by controlled release sustained-release base so as to effectively maintain the effective concentration of the drug. It is preferable to include in the range by weight.

In addition, the sustained, first or second sustained release portion of the present invention may further comprise a pharmaceutically acceptable excipient for maintaining the dosage form and hardness of the appropriate tablet.

Excipients can be used as long as they are commonly used in the pharmaceutical field. Typically, dextrin, mannitol, sorbitol, polyvinylpyrrolidone, copovidone, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl alkyl cellulose, cross carboxymethyl cellulose sodium, cross carboxy Methyl cellulose calcium, sodium croscarmellose, crospovidone, carboxymethyl starch, methacrylate-divinyl benzene 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, stearic acid, magnesium stearate, calcium stearate, glyceryl monostearate, sodium stearyl fumarate, talc and mixtures thereof Can be used.

In addition, the controlled release safoglylate hydrochloride-containing multilayer tablet including the immediate release portion and the sustained release portion may include the rapid release portion and the sustained release portion in a range of 1: 2 to 4 weight ratio (w / w).

In one embodiment of the present invention, the immediate release part including 63-64 parts by weight of D-mannitol based on 100 parts by weight of safoglylate hydrochloride; And 37 to 38 parts by weight of hydroxypropylmethylcellulose, 22 to 23 parts by weight of hypromellose, 1 to 2 parts by weight of hydroxypropyl cellulose and 20 parts by weight of eudragit RS PO, based on 100 parts by weight of safoglylate hydrochloride. After preparing a controlled release safoglylate hydrochloride-containing multilayer tablet comprising a second sustained-release portion in a range of 1: 2 to 4 weight ratio (w / w), dissolution test was performed using the same. As a result, the controlled release safoglylate hydrochloride-containing multilayer tablets were continuously eluted for 24 hours after a rapid increase in dissolution rate, 15-40% after 2 hours, 35-65% after 8 hours and 75% at 24 hours. The above dissolution criteria were satisfied (Experimental Example 5).

In addition, the immediate release portion containing 50 parts by weight of microcrystalline cellulose relative to 100 parts by weight of safoglylate hydrochloride; And 25 to 45 parts by weight of hydroxypropylmethylcellulose, 6 to 7 parts by weight of foaming additive, and a first sustained part containing 100 parts by weight of safoglylate hydrochloride, wherein the controlled release safoglylate hydrochloride-containing multilayer tablet is prepared. After the preparation, the dissolution test was conducted using this. As a result, it was confirmed that the drug was initially expressed quickly and the release of the drug was controlled for a long time, and it was confirmed that the time eluted over 85% could be adjusted (Experimental Example 6).

In addition, the immediate release portion containing 50 parts by weight of microcrystalline cellulose relative to 100 parts by weight of safoglylate hydrochloride; And a second sustained portion comprising 50 parts by weight of hydroxypropylmethylcellulose and 20 parts by weight of Eudragit RS PO, relative to 100 parts by weight of safoglylate hydrochloride, after the controlled release safoglylate hydrochloride-containing multilayer tablet is prepared. The dissolution test between the multilayer tablet and the western part was compared. As a result, the tablet consisting of the western portion was initially eluted slowly and continuously eluted for 12 hours, but the dual release controlled type of the present invention initially eluted rapidly and the drug was continuously eluted for 12 hours (Experimental Example 7 ).

Therefore, the multilayer tablet of the present invention has the advantage that the rapidly released active ingredient allows the plasma concentration to reach the minimum effective therapeutic concentration quickly, and the delayed released active ingredient maintains the effective blood concentration continuously for the planned time. In addition, the dosage and frequency of administration can be significantly reduced, which is very useful pharmacologically.

According to the present invention, a method for preparing a controlled release safoglylate hydrochloride-containing multilayer tablet comprises the steps of preparing an immediate release comprising safoglylate hydrochloride and a fast-acting excipient; Preparing a sustained portion comprising safoglylate hydrochloride, a hydrophilic polymer and a foaming additive, or a sustained portion comprising safoglylate hydrochloride, a hydrophilic polymer and a controlled release sustained release base; And double tableting the immediate part and the sustain part.

In the above production method, the step of preparing the immediate release portion or the sustained release portion may be performed by a method such as dry granules, wet granules, molten granules, fluidized bed granules, direct compression, molding and compression molding. Preferably it may be carried out by the method of dry granules, wet granules, melt granules.

As a representative example of the present invention, in the case of manufacturing a bilayer tablet consisting of a rapid release portion and a sustained release portion, the rapid release portion may be first tableted, followed by filling the sustained release layer on the secondary tablet to prepare a multilayer tablet. At this time, after tableting the immediate release layer, the tableting of the sustained release layer is not necessarily made, and the tableting of the sustained release layer is preferentially performed, and the granules of the immediate release layer may be filled and compressed. In addition, the immediate release layer and the sustained release layer may be filled in a sequential order or in reverse order, respectively.

In addition, the multilayer tablet of the present invention may be prepared as a single-layer tablet having both immediate release and sustained release properties, including a three-layer tablet consisting of an immediate release layer and a sustained release layer, and a mixed composition of the immediate release layer composition and a sustained release layer composition. In addition, after the sustained release layer is prepared as a nucleus, it may also be prepared as a multi-tablet containing a sustained release core (Core) surrounded by an immediate release layer.

According to the present invention, a multi-layer tablet consisting of a rapid release and a sustained release containing the same active ingredient is a paddle of 50 revolutions per minute using 900 ml of artificial intestinal fluid (the 9th Pharmacopoeia, the first disintegration test, pH 1.2) as an eluent. When the dissolution test is carried out by the law (the 9th amendment of the Korean Pharmacopoeia, the dissolution test method 2), the dissolution rate must be released after 15 hours to 45% after 2 hours, 35% to 65% after 8 hours, and 75% after 24 hours. Conforms to

Multi-layered tablets containing controlled-release safoglylate hydrochloride according to the present invention are administered orally to give an immediate therapeutic effect, and the active ingredient maintains a constant concentration in plasma for a considerable time, so that the number of administrations is once a day. Not only can it be reduced, but as a result it is very useful because it can increase the drug compliance to patients, thereby increasing the compliance with the medication.

Figure 1 shows the dissolution test results of the tablet including the immediate release prepared in Example 1 (1-1 to 1-3).
Figure 2 shows the dissolution test results of the tablet including the sustained portion prepared in Example 5 (5-1 to 5-5).
Figure 3 shows the dissolution test results of the double-release controlled tablet (formulation 1 and formulation 2) consisting of the immediate release prepared in Example 1-1 and the sustained release prepared in Example 5-2.
Figure 4 shows the dissolution test results of the controlled release safoglylate hydrochloride containing multilayer tablet (Formulation 3) comprising the immediate portion of Example 2-2 and the sustained portion of Example 4-5.
5 shows the dissolution test results of the controlled release safoglylate hydrochloride-containing multilayer tablet (Formulation 4) including the immediate release portion of Example 2-2 and the sustained portion of Example 6-2.
Figure 6 shows the results of the pharmacodynamic equivalence test of the release-controlled safoglylate hydrochloride-containing multi-layered tablet consisting of the immediate release prepared in Example 1-1 and the sustained release prepared in Example 5-2 and 100 mg of anflag tablets.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are provided to further understand the present invention, and the present invention is not limited by the examples.

Example 1 Preparation of Immediate Release Containing Safoglylate Hydrochloride and Mannitol

In order to prepare a controlled release safoacrylate hydrochloride-containing multilayer tablet according to the present invention, a rapid release portion containing safoacrylate hydrochloride and D-mannitol as a fast-acting excipient was prepared as follows.

1-1. Manufacture of immediate release (1)

First, a solution in which 3 mg of citric acid and 5 mg of hydroxypropyl cellulose was dissolved in 30 mg of ethanol was prepared. Next, after preparing a mixture of 63.7 mg of D-mannitol, 6 mg of carboxymethyl cellulose calcium, and 100 mg of safoglylate hydrochloride, the solution was granulated to prepare a wet mixture. The wet mixture was passed through # 4 to # 20 mesh screens and then dried in a dish drying oven. The dried granules were passed through a # 12 to # 30 mesh screen to prepare granule mixtures. 0.5 mg of hard silicic anhydride and 1.8 mg of calcium stearate were added to the prepared granule mixture, and the immediate part was prepared by continuously mixing for 1 to 3 minutes. The weight parts of the prepared immediate-release composition are shown in Table 1.

1-2. Manufacture of immediate release (2)

Example 1-1, using 57.7 mg of D-mannitol and 12 mg of carboxymethylcellulose calcium. The immediate release part was prepared by the same method as described above. The weight parts of the prepared immediate-release composition are shown in Table 1.

1-3. Manufacture of immediate release (3)

Example 1-1 using 51.7 mg of D-mannitol and 18 mg of carboxymethylcellulose calcium. The immediate release part was prepared by the same method as described above. The weight part of the prepared immediate-release composition is shown in Table 1 below.

ingredient Example 1-1 Examples 1-2 Example 1-3 Safoacrylate Hydrochloride 100 100 100 D-mannitol 63.7 57.7 51.7 Citric acid 3 3 3 Hydroxypropylcellulose 5 5 5 Carboxymethyl Cellulose Calcium 6 12 18 Light anhydrous silicic acid 0.5 0.5 0.5 Calcium stearate 1.8 1.8 1.8 ethanol 30 30 30 Gross weight 180 180 180

Example  2: Safograte  Containing hydrochloride and microcrystalline cellulose Immediate  Produce

In order to prepare a controlled release safoacrylate hydrochloride-containing multilayer tablet according to the present invention, a rapid release portion containing safoglylate hydrochloride and microcrystalline cellulose as a fast-acting excipient was prepared as follows.

First, a solution in which citric acid and hydroxypropyl cellulose were dissolved in ethanol was prepared. Next, after preparing a mixture of microcrystalline cellulose, crospovidone, safoglylate hydrochloride for 3 to 5 minutes, the solution was assembled to prepare a wet mixture. The wet mixture was passed through # 4 to # 20 mesh screens and then dried in a dish drying oven. The dried granules were passed through a # 12 to # 30 mesh screen to prepare granule mixtures. To the granules mixture, hard silicic anhydride and stearic acid were added, and continuous mixing was performed for 1 to 3 minutes to prepare immediate release. Three types of immediate release parts were prepared by varying the weight part of hydroxypropyl cellulose. The weight part of the composition of the immediate release part prepared is shown in Table 2 below.

ingredient Example 2-1 Example 2-2 Example 2-3 Safoacrylate Hydrochloride 100 100 100 Microcrystalline cellulose 50 50 50 Citric acid 3 3 3 Hydroxypropylcellulose 3 4 5 Crospovidone 7 7 7 Light anhydrous silicic acid One One One Stearic acid 3 3 3

Example  3: Safograte  First comprising hydrochloride, hydrophilic polymer and foaming additive Western  Manufacture (1)

In order to prepare a controlled release safoacrylate hydrochloride-containing multilayer tablet according to the present invention, a first sustained-release portion containing safoacrylate hydrochloride, a hydrophilic polymer and a foaming additive was prepared as follows. In order to compare the dissolution patterns of the drugs according to the type of hydrophilic polymer, the type of hydrophilic polymer (hypromellose 2208 4000 mPa.s, hypromellose 2208 4000 mPa.s SR, hypromellose 2910 4000 mPa.s SR) was used. Prepared otherwise.

First, a solution in which citric acid, hydroxypropyl cellulose, calcium carbonate and sodium hydrogen carbonate were dissolved in ethanol was prepared. Next, after preparing a mixture of hydroxypropylmethylcellulose and safoglylate hydrochloride for 3 to 5 minutes, the solution was granulated to prepare a wet mixture. The wet mixture was passed through # 4 to # 20 mesh screens and then dried in a dish drying oven. The dried granules were passed through a # 12 to # 30 mesh screen to prepare granule mixtures. Hard silicic anhydride, microcrystalline cellulose and magnesium stearate were added to the prepared granule mixture, and the mixture was continuously mixed for 1 to 5 minutes to prepare a first sustained portion. The weight part of the composition of the prepared first sustained part is shown in Table 3 below.

ingredient Example 3-1 Example 3-2 Example 3-3 Safoacrylate Hydrochloride 200.00 200.00 200.00 Hypromellose 2208 4000mPa.s 45.30 - - Hypromellose 2208 4000mPa.s SR - 45.30 - Hypromellose 2910 4000mPa.s SR - - 45.30 Calcium carbonate 10.20 10.20 10.20 Sodium hydrogencarbonate 3.50 3.50 3.50 Microcrystalline cellulose 22.00 22.00 22.00 Citric acid 5.00 5.00 5.00 Hydroxypropylcellulose 5.00 5.00 5.00 Light anhydrous silicic acid 3.00 3.00 3.00 Magnesium stearate 6.00 6.00 6.00

Example  4: Safograte  First comprising hydrochloride, hydrophilic polymer and foaming additive Western  Manufacturing (2)

In order to compare the degree of gastric retention and drug dissolution according to the type of hydrophilic polymer, the first sustained part including safoglylate hydrochloride, a hydrophilic polymer and a foaming additive was prepared as follows.

First, a solution in which citric acid, hydroxypropyl cellulose, calcium carbonate and sodium hydrogen carbonate were dissolved in ethanol was prepared. Next, after preparing a mixture of hydroxypropylmethylcellulose and safoglylate hydrochloride for 3 to 5 minutes, the solution was granulated to prepare a wet mixture. The wet mixture was passed through # 4 to # 20 mesh screens and then dried in a dish drying oven. The dried granules were passed through a # 12 to # 30 mesh screen to prepare granule mixtures. Hard silicic anhydride, microcrystalline cellulose and magnesium stearate were added to the prepared granule mixture, and the mixture was continuously mixed for 1 to 5 minutes to prepare a first sustained portion. The weight part of the composition of the prepared first sustained portion is shown in Table 4 below.

ingredient Example 4-1 Example 4-2 Example 4-3 Example 4-4 Example 4-5 Safoacrylate Hydrochloride 200.00 200.00 200.00 200.00 200.00 Hypromellose
2208 4000 mPa.s SR - - - - 20 Hypromellose
2208 100 mPa.s SR 50 50 50 50 50 Hypromellose
2910 4000mPa.s SR - 40 30 20 - Calcium carbonate 10.20 10.20 10.20 10.20 10.20 Sodium hydrogencarbonate 3.5 3.50 3.50 3.50 3.50 Microcrystalline cellulose 22.00 22.00 22.00 22.00 22.00 Citric acid 5.00 5.00 5.00 5.00 5.00 Hydroxypropylcellulose 8.00 8.00 8.00 8.00 8.00 Light anhydrous silicic acid 3.00 3.00 3.00 3.00 3.00 Magnesium stearate 6.00 6.00 6.00 6.00 6.00

Example  5: Safograte  Hydrochloride, hydrophilic polymer and controlled release Sue castle  A second containing base Western  Manufacture (1)

In order to prepare a release-controlled safoacrylate hydrochloride-containing multilayer tablet according to the present invention, a second sustained-release portion comprising a safoacrylate hydrochloride, a hydrophilic polymer and a controlled release sustained release base was prepared as follows. In the second western portion, hydrophilic polymer was used as hypromellose 2208 4000 mPa.s and hypromellose 2208 100 mPa.s, and hydroxypropyl cellulose or Eudragit RS PO was used as a controlled release sustained-release base. .

5-1. Production of the second western part (1)

First, a solution in which 6 mg of citric acid, 3 mg of povidone K90 and 40 mg of Eudragit RS PO was dissolved in 145 mg of ethanol was prepared. Next, a mixture of hydroxypropyl methyl cellulose 2208 4000 mPa.s 75 mg, hydroxypropyl methyl cellulose 2208 100 mPa.s 25 mg, safoacrylate hydrochloride 300 mg, and calcium hydrogen phosphate hydrate 26 mg was prepared, and then the solution was granulated. Wet mixtures were prepared. The wet mixture was passed through a screen and then dried in a dish drying oven. The granulated mixture was prepared by passing the dried granules through a screen, and 1 mg of hard silicic anhydride and 4 mg of magnesium stearate were added to the prepared granule mixture, and the mixing was continued for 1 to 5 minutes to prepare a sustained portion. The weight part of the composition of the prepared western part is shown in Table 5.

5-2. Production of the second western part (2)

By varying the weight parts of the constituents, a second sustained portion comprising safoglylate hydrochloride, a hydrophilic polymer and a controlled release sustained release base was prepared as follows.

First, a solution in which 6 mg of citric acid, 3 mg of hydroxypropyl cellulose, and 40 mg of Eudragit RS PO was dissolved in 145 mg of ethanol was prepared. Next, a mixture of hydroxypropylmethylcellulose 2208 4000 mPa.s 75 mg, hydroxypropylmethylcellulose 2208 100 mPa.s 25 mg, safoglylate hydrochloride 300 mg and microcrystalline cellulose 25 mg was prepared, and then the solution was granulated to give a wet mixture. Was prepared. The wet mixture was passed through a screen and then dried in a dish drying oven. The granulated mixture was prepared by passing the dried granules through a screen, and 2 mg of hard silicate anhydride and 4 mg of calcium stearate were added to the prepared granule mixture, and the mixing was continued for 1 to 5 minutes to prepare a sustained portion. The weight part of the composition of the prepared western part is shown in Table 5.

5-3. Production of the second western part (3)

By varying the weight parts of the constituents, a second sustained portion comprising safoglylate hydrochloride, a hydrophilic polymer and a controlled release sustained release base was prepared as follows.

First, a solution in which 6 mg of citric acid and 3 mg of povidone K90 was dissolved in 145 mg of ethanol was prepared. Next, a mixture of hydroxypropylmethylcellulose 2208 4000mPa.s 75mg, hydroxypropylmethylcellulose 2208 100mPa.s 25mg, safoglylate hydrochloride 300mg, and microcrystalline cellulose 66mg was prepared, and then the solution was granulated to give a wet mixture. Was prepared. The wet mixture was passed through a screen and then dried in a dish drying oven. The granulated mixture was prepared by passing the dried granules through a screen, and 1 mg of hard silicic anhydride and 4 mg of magnesium stearate were added to the prepared granule mixture, and the mixing was continued for 1 to 5 minutes to prepare a sustained portion. The weight part of the composition of the prepared western part is shown in Table 5.

5-4. Production of the second western part (4)

By varying the weight parts of the constituents, a second sustained portion comprising safoglylate hydrochloride, a hydrophilic polymer and a controlled release sustained release base was prepared as follows.

First, a solution in which 6 mg of citric acid, 3 mg of povidone K90 and 40 mg of Eudragit RS PO was dissolved in 145 mg of ethanol was prepared. Next, a mixture of hydroxypropylmethylcellulose 2208 4000 mPa.s 75 mg, hydroxypropylmethylcellulose 2208 100 mPa.s 25 mg, safoglylate hydrochloride 300 mg, and microcrystalline cellulose 22 mg was prepared, and then the solution was granulated to give a wet mixture. Was prepared. The wet mixture was passed through a screen and then dried in a dish drying oven. The granulated mixture was prepared by passing the dried granules through a screen, and 2 mg of hard silicate anhydride and 6 mg of magnesium stearate were added to the prepared granule mixture, and the mixing was continued for 1 to 5 minutes to prepare a sustained portion. The weight part of the composition of the prepared western part is shown in Table 5.

5-5. Production of the second western part (5)

By varying the weight parts of the constituents, a second sustained portion comprising safoglylate hydrochloride, a hydrophilic polymer and a controlled release sustained release base was prepared as follows.

First, a solution in which 6 mg of citric acid, 3 mg of povidone K90 and 40 mg of Eudragit RS PO was dissolved in 145 mg of ethanol was prepared. Next, a mixture of 100 mg of hydroxypropylmethylcellulose 2208 4000 mPa.s, 300 mg of safoglylate hydrochloride, and 22 mg of microcrystalline cellulose was prepared, and then the solution was assembled to prepare a wet mixture. The wet mixture was passed through a screen and then dried in a dish drying oven. The granulated mixture was prepared by passing the dried granules through a screen, and 2 mg of hard silicate anhydride and 6 mg of magnesium stearate were added to the prepared granule mixture, and the mixing was continued for 1 to 5 minutes to prepare a sustained portion. The weight part of the composition of the prepared western part is shown in Table 5.

ingredient Example 5-1 Example 5-2 Example 5-3 Examples 5-4 Example 5-5 Safoacrylate Hydrochloride 200 200 200 200 200 Hypromellose 2208 4000mPa.s SR 75 75 75 75 100 Hypromellose 2208 100mPa.s SR 25 25 25 25 Microcrystalline cellulose 25 66 22 22 Calcium hydrogen phosphate 26 - Citric acid 6 6 6 6 6 Povidone K90 3 - 3 3 3 Hydroxypropylcellulose 3 Eudragit RS PO 40 40 40 40 Light anhydrous silicic acid One 2 One 2 2 Calcium stearate 4 4 Magnesium stearate 4 6 6 ethanol 145 145 145 145 145 Gross weight 380 380 380 380 380

Example  6: Safograte  Hydrochloride, hydrophilic polymer and controlled release Sue castle  A second containing base Western  Manufacturing (2)

In order to prepare a release-controlled safoacrylate hydrochloride-containing multilayer tablet according to the present invention, a second sustained-release portion comprising a safoacrylate hydrochloride, a hydrophilic polymer and a controlled release sustained release base was prepared as follows. As the hydrophilic polymer in the second western part, hypromellose 2208 4000 mPa.s SR or hypromellose 2208 100 mPa.s SR was used, and Eudragit RS PO was used as the controlled release sustained-release base. In addition, the content of the hydrophilic polymer was changed in order to compare the dissolution of the drug according to the proportion of the hydrophilic polymer.

First, a solution in which citric acid and povidone K-90 were dissolved in ethanol was prepared. Next, after preparing a mixture of hydroxypropyl methyl cellulose, safoglylate hydrochloride and microcrystalline cellulose for 3 to 5 minutes, the solution was assembled to prepare a wet mixture. The wet mixture was passed through # 4 to # 20 mesh screens and then dried in a dish drying oven. The dried granules were passed through a # 12 to # 30 mesh screen to prepare granule mixtures. Eudragit RS PO, hard silicic anhydride, and magnesium stearate were added to the granule mixture prepared, and mixing continued for 1 to 5 minutes to prepare a second sustained portion. The weight part of the composition of the prepared second sustained portion is shown in Table 6 below.

Raw material name Example 6-1 Example 6-2 Example 6-3 Safoacrylate Hydrochloride 200 200 200 Hypromellose 2208 4000mPa.s SR 25 75 100 Hypromellose 2208 100mPa.s SR 75 25 - Microcrystalline cellulose 22 22 22 Eudragit RS PO 40 40 40 Citric acid 5 5 5 Povidone K-90 3 3 3 Light anhydrous silicic acid 2 2 2 Magnesium stearate 3 3 3

Example  7: Immediate release  And Westward  Preparation of bilayer tablets

First tableting the granules of the immediate release prepared in Examples 1 and 2 with a hardness of about 2 to 3kp, and then filling the granules of the sustained release layer prepared in Examples 3 to 5 on the secondary tablets with a hardness of about 10 to 16kp. The bilayer tablet was prepared and coated.

Experimental Example 1: Dissolution test of the immediate release tablet of Example 1

Anflag tablet, a commercially available tablet under the following conditions, based on the method for setting a rapid-release drug in the Korean Food and Drug Administration's `` Guidelines for Establishing Elution Standards for Oral Medicines '' using the fast-release tablet prepared in Example 1 The comparative dissolution test was performed, and the results are shown in Table 7 and FIG. 1.

<Test Conditions>

Specimen: Immediate layer purification of Example 1 (1-1 to 1-3)

Elution test solution: KEPCO Disintegration Test Method 1 (pH 1.2), 900 ml, 37 ± 0.5 ° C

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

Dissolution rate (%) Elution time (min) Example 1-1 Examples 1-2 Example 1-3 Anflag tablet
(Great treaty) 5 23.04 45.41 68.62 27.01 10 59.41 88.80 95.34 68.68 15 86.01 93.38 98.74 86.07

As shown in Table 7 and Figure 1, all the immediate release tablets prepared in Example 1 showed a rapid dissolution rate of more than 85% within 1 hour after the start of dissolution. Therefore, the immediate release tablets prepared in the present invention are suitable for expressing fast drug efficacy.

Experimental Example 2: Dissolution test of the immediate release tablet of Example 2

Using the immediate release tablets prepared in Example 2 (2-1 to 2-3), they were marketed under the following conditions based on the method for setting rapid release drugs of the Korean Food and Drug Administration 『Guidelines for Setting Elution Standards for Oral Drugs』. A comparative dissolution test was carried out with a tablet of Anflag tablet (Yuhan Corporation), and the results are shown in Table 8 below.

<Test Conditions>

Specimen: Immediate layer tablet of Example 2 (2-1 to 2-3)

Elution test solution: KEPCO Disintegration Test Method 1 (pH 1.2), 900 ml, 37 ± 0.5 ° C

Dissolution method: Method 2, paddle method, KEPA, 50 revolutions per minute

Dissolution rate (%) Elution time (min) Example 2-1 Example 2-2 Example 2-3 Anflag tablet
(Great treaty) 5 65.6 30.5 18.9 39.3 10 78.9 62.6 45.9 63.1 15 78.9 78.8 67.1 82.6 30 84 83.7 76.4 93.5

As shown in the table, the immediate release part according to the present invention showed a fast drug expression time (fast dissolution rate) as in the reference drug.

Experimental Example  3: Example  1st of 3 Western  Dissolution test of tablets and Flotation  exam

The western part prepared in Example 3 was eluted with pH 1.2, 900 ml, 50 rpm, paddle method. The results are shown in Table 9 below.

Time (hr)
Dissolution rate (%) 0.25 0.5 One 1.5 2 3 5 6 8 10 12 16 Example 3-1 2.7 4.1 7.0 10.4 14.1 22.1 39.4 47.6 62.1 73.2 82.9 93.9 Example 3-2 3.1 4.4 7.4 10.9 14.5 22.6 40.3 48.7 63.2 75.5 85.0 97.8 Example 3-3 7.6 9.4 12.5 15.4 18.4 24.1 36.1 41.4 50.6 58.5 65.6 77.4

As shown in the above table, the western part of the present invention was able to confirm that the release of the drug is controlled for each time, it was also confirmed that the release amount is different depending on the type of hydrophilic polymer.

In addition, the suspension test of the western part was carried out at pH 1.2, 900ml. A 900 ml medium pH 1.2 solution was placed in a water-jacket beaker adjusted to 37 ± 0.5 ° C. to measure the time it takes for the tablet to float (float time) and the time for the suspended tablet to float on the surface of the medium (float duration). The results are shown in Table 10 below.

time Floating time Suspension duration Example 3-2 5sec 14hr Example 3-3 5sec 24hr

As shown in the table, since the initial suspension time is very short and the duration is more than 12 hours, it was confirmed that the western part can effectively stay in the stomach.

Experimental Example  4: Example  5, the second Western  Tablet dissolution test

Using the sustained-release tablet prepared in Example 5 (5-1 to 5-5) was carried out dissolution test under the following conditions, the results are shown in Table 11 and FIG.

<Test Conditions>

Specimen: sustained-release tablet of Example 5 (5-1 to 5-5)

Elution test solution: KEPCO Disintegration Test Method 1 (pH 1.2), 900 ml, 37 ± 0.5 ℃

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

Time (hr)
Dissolution rate (%) 0.5 One 2 3 5 6 8 10 12 16 20 24 Example 5-1 4.2 7 13 18.7 29.7 35.1 45.6 55.8 65.4 82.1 95.2 - Example 5-2 4.1 7.1 13.2 18.8 29.3 34.1 43.2 51.6 59.4 74.2 85.4 - Example 5-3 2.9 4.9 8.8 12.6 20.1 23.8 31.4 38.9 46 - - 105.3 Example 5-1 2.9 4.8 9.5 14.2 23.8 28.6 47.7 47.7 57.5 77.9 92.9 88.6 Example 5-5 2.4 3.9 7.5 11.3 18.7 22.3 29.7 36.9 44.6 61.4 75.6 103.7

As shown in Table 11 and Figure 2, the sustained-release tablet prepared in Example 5 slowly eluted the active ingredient of the western part for 24 hours.

Experimental Example  5: Example  1 of Immediate release  And Example  5 of Western  Including controlled release Safograte  Dissolution test of hydrochloride-containing multilayer tablets

After the first tableting the granules of the immediate release prepared in Example 1-1 with a hardness of about 2 to 3 kp and then filled the granules of the sustained release prepared in Example 5-2 on the secondary tablets with a hardness of about 10 to 16kp The controlled release formulation consisting of a multi-layer was prepared by the amount of the following Table 12 to be coated.

ingredient Formulation 1 Formulation 2 Immediate release Final mixture of Example 1-1 180 mg 135mg Western Final mixture of Example 5-2 380 mg 427.5 mg coating Opadry OYC-7000A 20 mg 20 mg Gross weight 580 mg 582.5 mg

Dissolution test was conducted under the following conditions using Formulation 1 and Formulation 2, and the results are shown in Table 13 and FIG. 3.

<Test Conditions>

Specimen: Formulation 1 and Formulation 2

Elution test solution: KEPCO Disintegration Test Method 1 (pH 1.2), 900 ml, 37 ± 0.5 ℃

Dissolution method: Method 2, paddle method, KEPA, 50 revolutions per minute

Time (hr)
Dissolution rate (%) 0.5 One 2 3 5 6 8 10 12 16 20 24 Formulation 1 12.4 19.6 28.7 34.6 42.7 46.2 52.6 58.5 63.9 72.9 83.4 89.6 Formulation 2 10.6 16.8 25.0 31.1 38.9 42.1 48.3 54.3 60.2 69.5 80.3 86.6

As shown in Table 13 and FIG. 3, the controlled release safoglylate hydrochloride-containing multilayer tablet of the present invention was continuously eluted for 24 hours after the dissolution rate was rapidly increased in the early stage, less than 30% at 30 minutes, and after 15 hours at 2 hours. Elution criteria of ~ 45%, 35-65% after 8 hours and 75% at 24 hours were met.

Experimental Example 6: Dissolution test of controlled release safoglylate hydrochloride-containing multilayer tablet comprising immediate release of Example 2 and extended release of Example 4

The granules of the sustained part prepared in Example 4 were compressed into tablets, and then, the granules of the immediate release prepared in Example 2-2 were added thereto, and the tablets were compressed in a double manner to control the release-controlled safoglylate hydrochloride-containing multilayer tablet (Formant 3). Was prepared.

The dissolution test was performed under the following conditions using a controlled release safoglylate hydrochloride-containing multilayer tablet (Preparation 3) prepared by the above method, and the results are shown in Table 14.

<Test Conditions>

Specimen: Multi-layered tablet containing controlled release safoglylate hydrochloride comprising immediate release of Example 2 and extended release of Example 4

Elution test solution: KEPCO Disintegration Test Method 1 (pH 1.2), 900 ml, 37 ± 0.5 ℃

Dissolution method: Method 2, paddle method, KEPA, 50 revolutions per minute

Time (hr)
Dissolution rate (%) 0.5 One 1.5 2 3 5 6 8 10 12 Example 2-2 + Example 4-1 26.0 34.6 40.8 46.8 58.9 76.2 81.5 89.0 91.3 91.7 Example 2-2 + Example 4-2 23.7 27.9 31.1 34.0 40.0 49.3 53.6 60.9 67.3 72.3 Example 2-2 + Example 4-3 26.0 30.5 34.6 38.5 45.9 59.4 65.3 75.5 84.4 90.7 Example 2-2 + Example 4-4 24.5 29.4 33.7 37.8 45.6 60.3 66.3 75.5 82.8 87.2 Example 2-2 + Example 4-5 23.7 28.4 32.6 36.8 44.8 59.9 65.8 76.4 83.8 88.4

As shown in the above table, the dissolution test result shows that each drug can be expressed early and drug release is controlled for a long time, and more than 85% of the dissolution time is 8 hours and 10 hours. , 12 hours can be adjusted. The graph of the dissolution test result of the dual release controlled formulation containing the immediate release part of Example 2-2 and the extended release part of Example 4-5 is shown in FIG.

Experimental Example  7: Example  2 of Immediate release  And Example  6 of Western  Including controlled release Safograte  Dissolution test of hydrochloride-containing multilayer tablets

The granules of the sustained part prepared in Example 6 were compressed into tablets, and then the granules of the immediate release prepared in Example 2-2 were added to compress the tablets twice, thereby controlling the release-controlled safoglylate hydrochloride-containing multilayer tablet (Formulation 4). Was prepared.

A dissolution test was performed under the following conditions using a controlled release safoglylate hydrochloride-containing multilayer tablet (Formulation 4) prepared by the above method, and the results are shown in Table 15. In addition, the graph of the dissolution test result of the dual release controlled formulation containing the immediate release part of Example 2-2 and the sustained release part of Example 6-2 is shown in FIG. 5.

<Test Conditions>

Specimens: Multi-layered tablet containing controlled release safoacrylate hydrochloride comprising immediate release of Example 2 and extended release of Example 6

Elution test solution: KEPCO Disintegration Test Method 1 (pH 1.2), 900 ml, 37 ± 0.5 ℃

Dissolution method: Method 2, paddle method, KEPA, 50 revolutions per minute

Time (hr)
Dissolution rate (%) 0.25 0.5 One 1.5 2 3 5 6 8 10 12 6-1 200mg 6.3 10.2 16.8 22.9 28.5 39.1 57.0 66.1 82.3 89.5 94.2 300 mg 5.6 8.5 14.0 18.5 23.1 31.3 45.8 53.2 65.2 75.6 86.2 Double tablet 28.6 36.8 43.3 47.9 51.8 59.4 70.1 77.8 89.2 94.0 97.6 6-2 200mg 5.4 8.6 13.4 17.8 21.9 29.5 41.4 47.1 57.5 67.0 74.7 300 mg 4.8 7.3 11.2 14.8 18.0 23.8 34.1 39.1 49.5 56.8 65.4 Double tablet 22.0 28.1 33.9 38.0 41.6 47.4 60.3 64.5 73.2 81.6 87.7 6-3 200mg 3.1 8.0 12.4 15.9 19.4 25.5 37.1 41.5 50.5 58.2 66.9 300 mg 4.1 6.8 10.3 13.3 16.1 21.5 30.8 35.2 43.6 51.4 58.9 Double tablet 28.4 34.3 39.8 43.3 45.9 51.9 59.6 63.7 72.7 78.4 82.8

As shown in the table, in the test using the sustained-release tablet of Example 6, the elution rate of the active ingredient safoglylate hydrochloride was low after the start of dissolution, and eluted slowly for 12 hours, but the dual release controlled type of the present invention ( In the trial with Formulation 3), the dissolution rate increased rapidly at the beginning and the drug was continuously eluted for 12 hours. That is, the dual release controlled type of the present invention satisfies both high initial blood concentration and sustained effective blood concentration maintenance.

Experimental Example 8: In vivo Kinetic Test

In order to check the in vivo kinetics of Anplag tablets (100 mg tablets as safoglylate hydrochloride), which were used in Preparation Example 1 and safoglylate hydrochloride tablets, used in Experimental Example 5, 12 beagle dogs were divided into two groups of 6 animals per group. , And administered under the same conditions, the results are shown in Table 16 and FIG.

<Test Conditions>

Specimen: Formulation 1 and Anflag Tablet 100mg

Individuals in each group: 6 animals per group, 12 in total

Dosing: In the first group, 100 mg of Anflag tablets of Yuhan Corporation, a safoglylate hydrochloride control drug, were administered twice at 6 hour intervals, and the second group was administered a bilayer tablet of Formulation 1, respectively. Each group consisted of randomly distributed beagle dogs.

AUC (ug.hr/ml) Cmax (ug / ml) Anflag tablet 100mg 28.21 17.47 Formulation 1 39.39 18.65

As shown in Table 16 and FIG. 6, the pharmacodynamic equivalence test of 100 mg of Anflag tablets commercially available as a bilayer tablet and safoglylate hydrochloride tablet of Formulation 1 showed that the maximum blood concentration (C _max ) was 100 mg of Anflag tablets and the formulation. At the dose of 1 the values were equivalent. In addition, the AUC value (42.32 ug.hr/ml) converted into three doses of 100 mg of Anflag tablets was equivalent to the area under the curve (AUC) of Formulation 1. As such, both agents have been shown to express equivalent body kinetics.

Claims (12)

(a) an immediate release comprising safoglylate hydrochloride and a fast-acting excipient; And
(b) a controlled release safoacrylate hydrochloride-containing multilayer tablet comprising a sustained-release portion comprising safoglylate hydrochloride, a hydrophilic polymer and an effervescent additive, or a sustained-release portion comprising a sapograte hydrochloride, a hydrophilic polymer and a controlled release sustained release base, ,
The fast-acting excipient is one or more excipients selected from the group consisting of mannitol and microcrystalline cellulose,
The hydrophilic polymer is hydroxypropylmethylcellulose,
The foamable additive is at least one additive selected from the group consisting of calcium carbonate and sodium hydrogen carbonate,
Wherein said controlled release sustained release base is one or more bases selected from the group consisting of hydroxypropylcellulose and amoniomethacrylate copolymers.
The controlled-release safoglylate of claim 1, wherein the safoglylate hydrochloride contains 8 to 20 wt% in the immediate portion and 25 to 44 wt% in the western portion based on the total weight of the multilayer tablet. Hydrochloride-containing multilayer tablets.
The multi-layer tablet of controlled release safoglylate hydrochloride according to claim 1, wherein the immediate release portion contains 25 to 40 wt% of the fast-acting excipient.
According to claim 1, wherein the fast-acting excipient included in the immediate release portion controlled release saponacrylate hydrochloride-containing multi-layer tablet, characterized in that included in the range of 45 to 70 parts by weight based on 100 parts by weight of safoglylate hydrochloride.
According to claim 1, wherein the sustained portion of the hydrophilic polymer 20 to 45 parts by weight relative to 100 parts by weight of the safoglylate hydrochloride; And a foamable additive in a range of 5 to 10 parts by weight based on 100 parts by weight of safoglylate hydrochloride.
delete According to claim 1, wherein the sustained portion is 20 to 60 parts by weight based on 100 parts by weight of the hydrophilic polymer safoglylate hydrochloride; And a controlled release sustained release base in the range of 8 to 30 parts by weight with respect to 100 parts by weight of safoglylate hydrochloride.
8. The multilayered tablet according to claim 7, wherein the hydrophilic polymer is hydroxypropylmethylcellulose, and the controlled release sustained release base is an ammonio methacrylate copolymer.
2. The controlled release saponacrylate hydrochloride-containing multilayer tablet according to claim 1, wherein the immediate release portion and the sustained release portion are contained in a range of 1: 2 to 4 weight ratio (w / w).
The multi-layer tablet of controlled release safoglylate hydrochloride according to claim 1, wherein the immediate or sustained portion further comprises an excipient.
The method of claim 10, wherein the excipient is dextrin, mannitol, sorbitol, polyvinylpyrrolidone, copovidone, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl alkyl cellulose, cross carboxy Sodium methyl cellulose, cross carboxymethyl cellulose calcium, croscarmellose sodium, crospovidone, carboxymethyl starch, methacrylate-divinyl benzene copolymer calcium, polyvinyl alcohol, lactose, microcrystalline cellulose, starch, cyclodextrin, pregela Controlled release, characterized in that it is selected from the group consisting of tinized starch, light silicic anhydride, stearic acid, magnesium stearate, calcium stearate, glyceryl monostearate, sodium stearyl fumarate, talc and mixtures thereof Multi-layered Tablets with Safoacrylate Hydrochloride .
The method according to any one of claims 1 to 5 and 7 to 11, after 2 hours under the test method of the method of dissolution of the Korean Pharmacopoeia 2, the first solution of the Korean Pharmacopoeia Disintegration Test and 50 revolutions per minute. 15-45%, 35-65% after 8 hours and 75% or more dissolution rate at 24 hours.

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