WO2013058450A1 - Stabilized eperisone medical composition, and sustained-release preparation containing same - Google Patents

Abstract

The present invention relates to a stabilized eperisone medical composition, and a sustained-release preparation containing same. More particularly, the present invention relates to a stabilized eperisone medical composition which consists of an eperisone salt and an oxidant as effective ingredients, to thus maintain the chemical stability of the active ingredients during the residence time of drugs in a body as well as the storage of finished products, and also relates to a sustained-release preparation containing the stabilized eperisone which exhibits dual release characteristics of fast- and slow-release because the preparation further includes a release retardant in addition to the eperisone and the oxidant.

Description

Stabilized Epherisone Pharmaceutical Compositions and Sustained-release Formulations Containing the Same

The present invention relates to a stabilized epherizone pharmaceutical composition and a sustained release formulation containing the same, and more specifically, it is composed of the active ingredient eferison salt and an acidifying agent, which is active during storage of the finished product as well as while the drug stays in the patient's body. A stabilized ephericone pharmaceutical composition for maintaining the chemical stability of the component, and a stabilized ephericone-containing sustained-release preparation containing a release delaying agent in addition to the eferison and the acidifying agent, which exhibits a fast release and sustained release dual release properties will be.

Eperisone (Eperisone) is a drug used for the treatment of stiff paralysis caused by neurological diseases including painful muscle spasms associated with musculoskeletal diseases for a long time, the chemical structure is represented by the following formula (1).

Formula 1

The drug has chemically very unstable properties such as easy decomposition into piperidine ring in alkaline environment. Thus, in the case of commercially available epherisone formulations, decomposition of the active ingredient starts immediately after preparation, and there is a problem in that the impurity content increases by 1 to 2% within 1 and 2 months after the start of product storage.

In addition, the drug has a short half-life and a short time in the blood, so the method of administration is mainly three times a day. Recently, nonsteroidal anti-inflammatory drugs (NSAIDs), which are frequently prescribed together with eferison, have been developed once daily or twice daily to improve patient compliance. There is a need for the development of a drug for sustained release eperisone that can be taken twice daily.

In the past, various efforts have been made to improve the inconvenience caused by the use of eferison three times a day. For example, a method of preparing a wax matrix (USP 5,700,410), a method using a sustained release capsule (USP 5,498,422), a method using a hydrogel (USP 6,500,455), a method of placing a delayed-release coating layer between the nucleated tablet and the coating layer (Korean Patent Registration No. 574213), Method of Coating with Expandable Membrane (Korea Patent Publication No. 1989-0004685), Method of Coating with Hydrophobic Organic Compound and Water Insoluble Polymer Film (WO 2000/24423), Eudragit ) As a sustained release substrate (US 2005/0196451), a method using a gastric-retention drug system (US 2010/0249423) and the like are known.

However, all of the conventional sustained release preparations prepared by the above method have only the purpose of delaying the release of the active ingredient eferison, and there is no intention to improve the chemical stability of the eferison. Even if the release of the active ingredient can be delayed, it is difficult to expect effective treatment unless the stability of the active ingredient is secured in the human body during product storage or after taking the drug.

In particular, since eperisone is mainly absorbed in the upper part of the intestine, it is necessary to improve stability in the intestinal alkali environment in order to develop a sustained release formulation which stays in this absorption site for a long time and slowly releases the drug.

The problem to be solved by the present invention is to provide a stabilized eferison pharmaceutical composition that keeps the active ingredient chemically stable during storage of the finished product, as well as in the alkaline environment of the human intestinal tract after the patient takes the drug.

In addition, another problem to be solved by the present invention is to provide a sustained release formulation containing eferisone having a dual release property to express a useful therapeutic effect even when taken once or twice daily.

The stabilized eferison pharmaceutical composition according to the present invention comprises an eferison salt and an acidifying agent, wherein the acidity of the 0.5% (W / V) aqueous solution is pH 0.5 to pH 5.6, and the acidifying agent is an acidic pH adjusting agent, Or an excipient which exhibits a pH of 5.0 or lower when suspended, dissolved, swelled or miscible in water.

First, the active ingredient eferison includes all pharmaceutically acceptable salt forms, but the preferred salt is hydrochloride, and the effective amount of eferison hydrochloride is 150-300 mg / day.

And when the acidifying agent is prepared in 0.5% (W / V) aqueous solution of the pharmaceutical composition of the present invention functions to adjust the pH so that the pH 0.5 ~ 5.6, the active ingredient eferison under such an acidic environment It has chemical stability during storage of the finished product and in the intestinal alkaline environment after taking it. Therefore, the content of the acidifying agent includes an amount in which the 0.5% (W / V) aqueous solution of the pharmaceutical composition has an acidity of pH 0.5 to 5.6.

If the acidity of the 0.5% (W / V) aqueous solution of the eferrizone pharmaceutical composition according to the present invention is less than pH 0.5, it is not preferable because the acid property of the efferison can damage the oral cavity and esophageal mucosa of the patient when taken. In addition, when the acidity is alkalinized above pH 5.6, the stability of the active ingredient is remarkably degraded, and in particular, the problem of preventing the decomposition of the active ingredient in the alkaline environment inside the intestine after taking the drug occurs.

In the present invention, the acidifying agent may be an acidic pH adjusting agent or an excipient exhibiting a pH of 5.0 or less when suspended, dissolved, swelled or miscible in water. The acidic pH adjusting agent may include alginic acid, acetic acid, formic acid, adipic acid, edetic acid, fumaric acid, and lactic acid. ), Malic acid, maleic acid, maleic acid, palmitic acid, propionic acid, sorbic acid, stearic acid, tartaric acid, ascorbic acid Any one selected from ascorbic acid, erythorbic acid, citric acid, oxalic acid, succinic acid, toluene sulfonic acid, methane sulfonic acid, nitric acid, hydrochloric acid, phosphoric acid, sulfuric acid The above can be used and citric acid is the most preferable.

In addition, the excipient may be any excipient having a pH of 5.0 or less when suspended, dissolved, swelled, or miscible in water, and more specifically, carbomer, polycarbophil, polydextrose. It is preferable to use one or more selected from (Polydextrose).

In general, if the release rate of the active ingredient is too low than the target dissolution rate at the initial time after taking the drug, the patient cannot obtain the fast drug. On the contrary, if the target dissolution rate is exceeded, the blood concentration in the body is excessively increased due to problems such as initial dose dosing. This may cause problems for the patient. If the release rate at the intermediate or final time point is too fast for the target dissolution rate, the effective blood concentration of the drug cannot be maintained until the next dose, so that an effective therapeutic effect cannot be expected. If the release rate is too late for the target dissolution rate, the continuous blood concentration is maintained. In addition, there is a concern that the next dose may further increase the body's concentration of the drug, causing side effects. Therefore, controlling the release content over time after taking the drug is a very important factor in achieving the desired therapeutic purpose.

Eperisone-containing sustained-release preparation according to the present invention has a dual release property that exhibits both fast-acting for obtaining rapid muscle relaxation and analgesic effect at the beginning of the administration, and sustained release that can be taken once or twice a day. In order to have such a double-release property, the sustained-release preparation of the present invention is 0.05 to 3 parts by weight, preferably 0.1 to 2.5 parts by weight, with respect to 1 part by weight of the eferison salt in addition to the active ingredient eferison salt and an acidifying agent. Includes the first.

At this time, the delayed release agent is a cellulose derivative, methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose; Hydrophilic polymers include polysaccharides, polyacrylates, hydrogels, polyvinyl alcohols, polyvinylpyrrolidones, carbopol, polyethylene oxides, magnesium aluminum silicates, starch derivatives, or mixtures thereof; Hydrophobic polymers include copolymers of acrylic acid and methacrylic acid esters, polyethylene, polyamides, polyvinylchloride, polyvinylacetate, polyvinyl alcohol, or mixtures thereof; As the water-insoluble polymer, any one or more selected from polyacrylic acid, acrylic resin, acrylic latex dispersion, cellulose acetate phthalate, polyvinylacetate phthalate, and hydroxypropylmethylcellulose phthalate can be used.

The delayed release agent may adjust the amount used according to the initial release rate or the duration of effect expression. In addition, the delayed-release agent may be used alone or mixed, hydroxypropyl methyl cellulose is preferred when used alone, polyvinylpyrrolidone and polyvinylacetate as a mixture of hydrophilic polymer and hydrophobic polymer when used alone It is preferable that 2: 8 weight part mixed.

The ephericone-containing sustained-release preparation includes a first sustained-release preparation that can be taken once a day and a second sustained-release preparation that can be taken twice a day. The first sustained-release preparation has the property of eluting 30 to 50% by weight of the active ingredient content within 60 minutes of initial dissolution, 55 to 75% by weight within 6 hours, and 85% by weight or more within 24 hours. In addition, the second sustained-release preparation has a characteristic of eluting 15 to 55% by weight of the active ingredient content within 15 minutes of the initial dissolution, 55 to 75% by weight within 1 hour, and 85% by weight or more within 3 hours. The first sustained-release preparation and the second sustained-release preparation can be prepared by appropriately adjusting the contents of the active ingredient and the release delaying agent as necessary.

In order to achieve the same pharmacological effect as the three doses of eferison containing sustained-release preparation of the present invention only once or twice daily, the active ingredient must be continuously released in the gastrointestinal tract. By the way, Eperisone is very unstable to alkali, which is an intestinal environment, and since the absorption site of the drug is mainly located in the upper gastrointestinal tract, it is necessary to stay for a long time in an acidic environment if possible. Therefore, it is preferable to use a conventional intragastric retention system such as a floating system, a gastric adhesion system, a swelling system, and in particular, it is preferable to adjust the specific gravity of the entire formulation to a range similar to or lower than that of the gastric juice.

Specifically, it is preferable that the specific gravity of the sustained release formulation is in the range of 0.5 to 1.2 g / ml in an aqueous solution of pH 1 using an excipient exhibiting a low density such as polypropylene form powder (Accurel) or porous calcium silicate (Florite). Because if the specific gravity of the sustained-release preparation exceeds 1.2 g / ml, the specific gravity is higher than the gastric juice to sink to the lower part of the stomach, which will not achieve the purpose of continuing to release the drug while staying in the stomach . In addition, when the specific gravity of the sustained-release preparation is lower than 0.5 g / ml, there is a problem in handling during manufacture and distribution because it does not maintain its shape as a solid and easily breaks into a powder or granular form. The specific specific gravity range of the sustained release formulation is 0.8 to 1.2 g / ml.

In addition, the eferison containing sustained release formulations of the present invention may include all known gas generants, including sodium bicarbonate, in the formulation as a conventional intragastric retention system. At this time, the gas generating agent is preferably placed in a separate outer layer to avoid contact with the active ingredient in order not to adversely affect the stability of the active ingredient, in particular, such as tablets so as not to inhibit the double release characteristics It is preferable to contact only one side. In addition, the pH of the sustained-release preparation needs to be adjusted so that the pH of only the drug layer except for the layer containing the gas generator is 0.5 to 5.6.

Meanwhile, the eferisone-containing sustained-release preparation according to the present invention may additionally include nonsteroidal anti-inflammatory drugs (NSAIDs), specifically, aceclofenac, diclofenac, meloxycamp, naproxen, ibuprofen, dexibuprofen, and roxofol. It may include any one or more selected from lofen, zaltoprofen, felbinac, ketoprofen, etodolak, nabumetone, celecoxib, nimesulide. As such, when the sustained-release preparation contains a nonsteroidal anti-inflammatory drug, the anti-inflammatory effect and the analgesic effect can be obtained together through the synergistic effect between the two drugs, thus enhancing the convenience of taking patients to improve medication compliance. It can be increased.

Finally, the ephericone-containing sustained-release preparation of the present invention may be prepared by mixing the active ingredient, the eferison salt, the acidifying agent and the delayed-release agent together, and then using a conventional direct method, a wet method, a dry method, granules, It includes all types of controlled release preparations, such as beads, pellets, tablets or capsules containing two or more phases, capsules, multilayers, coatings, nucleus, matrix, etc., as well as sustained release from the stomach or upper gastrointestinal tract.

The stabilized eferrizone pharmaceutical composition according to the present invention has an acidifying agent that maintains the atmosphere around the active ingredient in a pH range of 5.6 or less, so that even during storage of the finished product, even in the alkaline environment of the intestinal tract after the patient has taken the drug. Compared with conventional commercial formulations, there is an effect of improving the chemical stability of the active ingredient 20 times or more.

In addition, the stabilized sustained-release preparation containing eferisone of the present invention contains an active ingredient, an acidifying agent and a release delaying agent, which has dual release properties of fast-acting and sustained release, and can be taken once or twice a day. Because it is effective to improve patient compliance.

1 is a graph showing the hourly dissolution rate for the first sustained release formulation of the present invention (taken once daily),

Figure 2 is a graph showing the dissolution rate over time for the second sustained release formulation of the present invention (taken twice daily),

3 is a graph showing the dissolution rate according to time measured according to the rotational sample method for the second sustained-release preparation of the present invention (taken twice a day);

Figure 4 is a graph comparing the blood concentration of the sustained release formulation of the present invention and the conventional commercial formulation.

Hereinafter, preferred examples are provided to aid in understanding the present invention. However, the following examples are merely provided to more easily understand the present invention and do not limit the scope of the present invention.

Example 1

75.0 g of eferisone hydrochloride, 40.0 g of microcrystalline cellulose, 72.5 g of Kollidon SR, 5.0 g of carbomer, and 4.0 g of citric acid were weighed into a plastic bag and mixed for 10 minutes. The collidone SL is a trade name of BASF, which is a release retardant in which polyvinyl pyrrolidone and polyvinyl acetate are mixed in an amount of 2: 8 parts by weight.

In addition, 1.5 g of colloidal silicon dioxide and 2.0 g of magnesium stearate were weighed and appled into a 50 mesh sieve, and then mixed and mixed for 3 minutes. The mixture was compressed in a tablet press to prepare 400 mg tablets containing 150 mg of eferisone hydrochloride per tablet.

Example 2

75.0 g of eferisone hydrochloride, 55.0 g of microcrystalline cellulose, 50.0 g of collidone AL and 15.0 g of carbomer were weighed and mixed in a plastic bag for 10 minutes. In addition, 3.0 g of colloidal silicon dioxide and 2.0 g of magnesium stearate were weighed and appled into 50 mesh sieves, and then mixed for 3 minutes. The mixture was compressed in a tablet press to prepare 400 mg tablets containing 150 mg of eferisone hydrochloride per tablet.

Example 3

300.0 g of Ephericone hydrochloride, 368.0 g of microcrystalline cellulose, 100.0 g of hydroxypropyl methyl cellulose, 4.0 g of carbomer, and 16.0 g of citric acid were added to a speed mixer (KM-5) and rotated at 100 rpm using an agitator. Mix for 3 minutes. Further water was added to rotate the agitator 100rpm, microwave 1500rpm to rotate for 3 minutes to form granules.

The granules were dried in an oven at 50 ° C. for 2 hours, and then ground and granulated using an oscillator (Oscillator, ERWEKA AR-402) using 20 mesh (standard standard KSA5101-1) to prepare granules.

Further, 4.0 g of colloidal silicon dioxide and 8.0 g of magnesium stearate were weighed and appled in a 50 mesh sieve, and then added and mixed in a plastic bag for 3 minutes. The mixture was compressed in a tablet press to prepare 400 mg tablets containing 150 mg of eferisone hydrochloride per tablet.

Example 4

Tablets were prepared in the same manner as in Example 3, except that 16.0 g of alginic acid was used instead of 16.0 g of citric acid in Example 3.

Example 5

Tablets were prepared in the same manner as in Example 3, except that 16.0 g of tartaric acid was used instead of 16.0 g of citric acid in Example 3.

Example 6

300.0 g of Ephericone hydrochloride, 399.0 g of microcrystalline cellulose, 30.0 g of citric acid and 24.0 g of Eudragit RS PO were added to a speed mixer (KM-5), and the mixture was spun at 100 rpm and mixed for 3 minutes. . Eudragit is a copolymer of acrylic acid and methacrylic acid ester under EVONIK Industries.

In addition, ethanol was added to rotate the agitator 100rpm, microwave 1500rpm to rotate for 3 minutes to form a granule. The granules were dried in an oven at 50 ° C. for 1 hour, and then ground and granulated using an oscillator (Oscillator, ERWEKA AR-402) using 20 mesh (standard standard KSA5101-1) to prepare granules.

Further, 7.0 g of magnesium stearate was weighed and appled into a 50 mesh sieve, and then mixed and mixed in a plastic bag for 3 minutes, and the mixture was compressed in a tableting machine to prepare 380 mg tablets containing 150 mg of eferisone hydrochloride per tablet.

Example 7

150.0 g of eferison hydrochloride, 33.8 g of microcrystalline cellulose, 110.0 g of collidone AL, 12.0 g of carbomer, and 8.0 g of citric acid were weighed into a plastic bag and mixed for 10 minutes. Further, 3.0 g of colloidal silicon oxide and 3.2 g of magnesium stearate were weighed and appled in a 50 mesh sieve, and then mixed for 3 minutes to prepare a drug layer mixture.

Separately, 22.8 g of microcrystalline cellulose, 80.0 g of collidone SL, 6.0 g of capper, 5.0 g of citric acid, and 15.0 g of sodium bicarbonate were added to a plastic bag, mixed for 10 minutes, and 1.2 g of magnesium stearate was weighed and appled in a 50 mesh sieve. After the addition and mixing for 3 minutes to prepare a floating layer mixture.

The drug layer mixture 320 mg and the floating layer mixture 130 mg were tableted with a bilayer tablet press so as to be included in each layer, thereby preparing a 450 mg bilayer tablet containing 150 mg of eferison hydrochloride per tablet.

Example 8

37.5 g of eferisone hydrochloride, 48.7 g of microcrystalline cellulose, 6.5 g of hydroxypropyl methylcellulose, 4.0 g of citric acid, and 2.0 g of sodium starch glycolate were weighed and mixed in a plastic bag for 5 minutes. In addition, 0.4g of colloidal silicon dioxide and 0.9g of magnesium stearate were weighed and appled into a 50 mesh sieve, and then mixed for 1 minute.

The mixture was compressed in a tablet press to prepare 200 mg tablets containing 75 mg of eferison hydrochloride per tablet.

Comparative Example 1

75.0 g of eferisone hydrochloride, 21.5 g of microcrystalline cellulose, and 100.0 g of collidone AL were weighed and mixed in a plastic bag for 10 minutes. In addition, 1.5 g of colloidal silicon dioxide and 2.0 g of magnesium stearate were weighed and appled into a 50 mesh sieve, and then mixed for 3 minutes. The mixture was compressed in a tablet press to prepare 400 mg tablets containing 150 mg of eferison hydrochloride per tablet.

Comparative Example 2

300.0 g of eferison hydrochloride, 429.0 g of microcrystalline cellulose, and 24.0 g of Eudragit RS PO were added to a speed mixer (KM-5, KM-5), and the mixture was spun at 100 rpm and mixed for 3 minutes. Further ethanol was added to rotate the agitator at 100rpm, microwave 1500rpm to rotate for 3 minutes to prepare a granule.

The granules were dried in an oven at 50 ° C. for 1 hour, and then ground and granulated using an oscillator (Oscillator, ERWEKA AR-402) using 20 mesh (standard standard KSA5101-1) to prepare granules. In addition, 7.0g of magnesium stearate was weighed, appled into a 50 mesh sieve, and then mixed and mixed in a plastic bag for 3 minutes. The mixture was compressed in a tablet press to prepare 380 mg tablets containing 150 mg of eferison hydrochloride per tablet.

Experimental Example 1

The tablets prepared in each of Examples and Comparative Examples were ground into fine powder in Judo, weighed in one tablet, poured into 100 mL of purified water, stirred for 10 minutes, and thoroughly mixed, followed by a pH meter (Denver, UB-5). Was used to measure the pH of each solution.

Table 1 PH measurement result of 0.5% aqueous solution

division	Example								Comparative example
	One	2	3	4	5	6	7	8	One	2
pH	4.35	5.12	4.46	4.61	4.32	4.21	6.69	4.27	6.15	6.28

As shown in Table 1, in the case of adding an acidifying agent such as citric acid or carbomer according to the present invention, the pH of the 0.5% aqueous solution was all 5.6 or less except Example 7. However, all of the comparative examples without addition of the acidifying agent showed pH 6.0 or higher.

However, in the case of Example 7, the pH of the whole tablet was found to be about 6.69 high, but this was due to the sodium bicarbonate contained in the floating layer. When the pH of the drug layer was measured without the floating layer, the pH was determined to be 4.38.

Experimental Example 2

The tablets prepared in each Example and Comparative Example were put in a bottle made of HDPE, and capped, and then the degree of generation of impurities was compared for 8 weeks while being kept in a constant temperature and humidity chamber at a temperature of 40 ° C. and a relative humidity of 75%. At this time, the impurity measurement was put in a 60% methanol solution containing 0.1% perchloric acid, dissolved sufficiently by sonication and then filtered through a 0.45㎛ membrane filter was tested according to the liquid chromatograph method.

TABLE 2 Comparison of the amount of impurities generated in the bottle packaging storage

Storage period	Example								Comparative example
	One	2	3	4	5	6	7	8	One	2
Right after manufacturing	ND	ND	ND	ND	ND	0.01	ND	ND	0.02	0.08
2 weeks	ND	0.03	0.05	0.03	0.02	0.04	0.08	ND	0.44	0.61
4 Weeks	0.02	0.04	0.09	0.04	0.03	0.08	0.15	0.01	0.82	1.28
8 Weeks	0.03	0.07	0.15	0.08	0.06	0.16	0.28	0.03	1.79	2.24
* ND: Not Detected

Experimental Example 3

Each tablet of Example 1 and Comparative Example 1 was put in 100 mL of pH 6.8 solution buffer and left at 37 ° C. for 6 hours. Subsequently, 900 mL of 60% methanol solution containing 0.1% perchloric acid was added, and dissolved sufficiently by sonication, filtered through a 0.45 μm membrane filter, and tested according to a liquid chromatograph method.

TABLE 3 Percentage of impurities generated from purification left for 6 hours in pH 6.8 buffer

division	Example 1	Comparative Example 1
Starting point	ND	0.02
6 hours later	0.04	0.26
Increase	0.04	0.24
* ND: Not Detected

The sustained-release preparation according to the present invention is not completely disintegrated during the time of staying in the stomach as well as the time of passing through the small intestine, and moves to the state of continuously containing the drug in the tablet. In other words, only a part of the active ingredient, epherisone, is released while staying in the stomach, and the remaining amount remains in the non-disintegrated tablet and passes slowly through the small intestine.

Therefore, it is necessary to keep the pH environment inside the tablet low so that eferison maintains chemical stability even in the high pH environment inside the small intestine. In accordance with the technical requirements in the present invention it can be seen that the addition of the acidifying agent produced a significantly lower decomposition product of the eferison in the buffer of pH6.8.

Experimental Example 4

Each tablet of the tablet of Example 1 was put in a buffer of pH 1.2 at 37 ℃, the dissolution test was carried out at 50rpm conditions by the paddle method. 5 mL was collected at each time point, filtered through a membrane filter, tested by liquid chromatography, and the results are shown in FIGS. 1 and 2.

Table 4 Cumulative dissolution rate (%) of eferison hydrochloride over time of the first sustained-release preparation (daily dose)

Minutes	0	15	30	60	120	240	360	720	1440
Example 1	0	18.1	24.9	33.8	45.3	59.7	70.2	86.1	99.6
Example 2	0	17.4	24.0	32.7	44.1	58.0	68.0	84.7	98.8
Example 7	0	16.5	22.6	30.5	40.8	53.7	63.0	78.7	96.5

As can be seen from the results of Table 4 and FIG. 1, in the case of the first sustained-release preparation (containing 150 mg of eferisone hydrochloride per tablet) developed by the daily use in the present invention, the average per minute up to the first hour was used. The release rate is 0.77-0.84 mg, and about 50 mg of eferison hydrochloride is rapidly released in one hour. The amount of release corresponds to the amount of release of one tablet three times daily, which is a conventional commercial preparation, and can be said to be an amount required for rapid effect expression.

In addition, the first sustained-release preparation can be confirmed that the release proceeds at an average rate of 0.17 to 0.18 mg per minute for 6 hours thereafter, indicating a stable drug release pattern for a long time. As a result, it can be confirmed that the eferisone-containing sustained-release preparation according to the present invention has a dual release property with both fast and sustained release.

Table 5 Cumulative dissolution rate of eferisone hydrochloride over time of the second sustained-release preparation (2 times a day usage) (%)

Minutes	0	15	30	60	120	180	240
Example 8	0	29.9	48.2	68.9	87.4	96.3	99.9

As can be seen from the results of Table 5 and FIG. 2, in the case of the second sustained-release preparation (containing 75 mg of eferisone hydrochloride per tablet) developed by the twice daily dosage, 34.7% of the total content in the first 15 minutes The dissolution rate was 69% at 60 minutes and 99.7% at 240 minutes, indicating a pattern suitable for the target dissolution rate. This dissolution pattern releases 0.86 mg of active ingredient per minute up to 60 minutes after administration and releases about 50 mg of epherisone hydrochloride at 1 hour time point, so that the conventional dosage form or the first sustained release formulation (1 Release almost equivalent to one dose).

In addition, the second sustained release formulation gradually released an average of 0.13 mg of eferison hydrochloride per minute from 60 minutes to 240 minutes. Therefore, it can be seen that the second sustained release formulation also has a double release property in the same manner as the first sustained release formulation.

Experimental Example 5

One tablet of the sustained-release preparation of Example 8 was put in a buffer of pH 1.2 at 37 ° C., and the dissolution test was performed under a rotational sample method at 100 rpm. 5 mL was collected at each time point, filtered through a membrane filter, tested by liquid chromatography, and the results are shown graphically in FIG. 3.

Table 6 Cumulative dissolution rate (%) of the second sustained release formulation (twice a day) by the rotational sample method

Minutes	0	15	30	60	120	180	240
Example 8	0	20.9	37.9	59.7	83.5	94.8	100.1

Experimental Example 6

The blood concentration analysis experiment in the beagle dog was carried out with the tablet of Example 8. The beagle dog used for the test was fasted for 4 hours after dosing from 10 o'clock on the day before dosing, and 150 mg (75 mg / tablet, 2 tablets) of the sustained-release tablet of Example 8 was added to each of 6 beagle dogs as 30 ml of water. 100 mg (50 mg / tablet, 2 tablets) of a commercial drug, MYONAL tab. Considering the half-life of the drug, the crossover test was performed by oral cross-dosing of each drug at 1 week interval, which is a sufficient discharge period. Blood was collected immediately before dosing, 1.5 hours and 4 hours after dosing in the beagle dog's brachial vein, and placed in a heparinized culture tube, followed by centrifugation (3000 rpm, 10 minutes) to separate plasma and LC-MASS. Esperison concentration in blood was analyzed using the result and the results are shown in FIG.

As can be seen from the results of FIG. 4, when the blood concentrations were analyzed by taking the sustained release formulation of the present invention and a commercial drug, myonal tablet, the initial blood concentrations of the initial 1.5 hours were 1.205 ng / mL and 1.353 ng, respectively. / mL similar to that, but at 4 hours, 0.973 ng / mL, 0.497 ng / mL, and at 6 hours, 0.539 ng / mL and 0.271 ng / mL, respectively, about twice the blood concentration of the commercial drug. Observation could be observed. That is, when the sustained-release tablet of the present invention is taken, it can be seen that blood concentration is maintained for a longer time than the general rapid-release preparation.

Claims (8)

1. The acidity of the 0.5% (W / V) aqueous solution is pH 0.5 to pH 5.6, and the acidifying agent may be suspended, dissolved, swelled or miscible in an acidic pH adjuster or water. Stabilized eferison pharmaceutical composition, characterized in that it is selected from excipients exhibiting when pH 5.0 or less.
2.  According to claim 1, wherein the acidic pH adjusting agent is alginic acid, acetic acid, formic acid, adipic acid, edetic acid, fumaric acid, lactic acid, malic acid, maleic acid, palmitic acid, propionic acid, sorbic acid, stearic acid, tartaric acid, ascorbic acid, Stabilized epherison pharmaceutical composition, characterized in that any one or more selected from erythorbic acid, citric acid, oxalic acid, succinic acid, toluenesulfonic acid, methanesulfonic acid, nitric acid, hydrochloric acid, phosphoric acid and sulfuric acid.
3. The stabilized eferison pharmaceutical composition according to claim 1 or 2, wherein the excipient is any one or more selected from carbomer, polycarbophil and polydextrose.
4. It comprises an eferison salt, an acidifying agent and a release delaying agent, wherein the acidity of the 0.5% (W / V) aqueous solution is pH 0.5 to 5.6, and the content of the release delaying agent is 0.05 to 1 part by weight of the eferison salt. It is-3 weight part, The stabilized eferison containing slow-release formulation.
5. The method of claim 4, wherein the delayed release agent is methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose; Polysaccharides, polyacrylates, hydrogels, polyvinyl alcohols, polyvinylpyrrolidones, carbopol, polyethylene oxides, magnesium aluminum silicates, starch derivatives; Copolymers of acrylic acid and methacrylic acid esters, polyethylene, polyamides, polyvinylchlorides, polyvinylacetates, polyvinyl alcohols; Stabilized ephericone-containing sustained-release preparation, characterized in that any one or more selected from polyacrylic acid, acrylic resin, acrylic latex dispersion, cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropyl methylcellulose phthalate.
6. The method of claim 4 or 5, wherein the sustained-release preparation is eluted at 30 to 50% by weight of the total content within 60 minutes of dissolution, less than 55 to 75% by weight within 6 hours, and 85% or more by weight within 24 hours. A stabilized sustained release formulation containing esperison.
7. The sustained-release preparation according to claim 4 or 5, wherein the sustained-release preparation has a double release which elutes 15 to 55% by weight of the total content within the initial 15 minutes of dissolution, 55 to 75% by weight within 1 hour, and 85% by weight or more within 3 hours. A stabilized sustained release formulation comprising a stabilized eferison.
8. The non-steroidal anti-inflammatory analgesic agent (NSAID) of claim 4 or 5, in addition to the eferison salt, the acidifying agent and the release delaying agent, the non-steroidal anti-inflammatory analgesic agent (NSAID) comprises aceclofenac, diclofenac, melamine. Stabilization characterized by at least one selected from oxycam, naproxen, ibuprofen, dexibuprofen, roxofene, zaltoprofen, felbinac, ketoprofen, etodolak, nabumethone, celecoxib, nimesulide Sustained-release preparations containing eferison.

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