JP5948648B2 - Sustained release formulation containing stabilized eperisone - Google Patents

Description

  The present invention relates to a stabilized eperisone pharmaceutical composition and a sustained-release preparation containing the same, and more specifically, it is composed of an active ingredient eperisone salt and an acidifying agent. Of course, the drug contains a stabilized eperisone pharmaceutical composition that maintains the chemical stability of the active ingredient even while the drug stays in the patient's body, and in addition to the eperisone and acidifying agent, a delayed release agent is additionally included to provide a rapid action. The present invention relates to a sustained-release preparation containing stabilized eperisone that exhibits a dual-release characteristic of long-lasting and sustained release.

  Eperisone is a drug that has been used for the treatment of tonic paralysis due to neurological diseases including painful muscle spasms associated with musculoskeletal diseases, and its chemical structure is as shown in Formula 1 below. .

[Chemical Formula 1]

  The drug is characterized by being extremely unstable chemically, such as being easily decomposed into a piperidine ring in an alkaline environment. Therefore, in the case of a commercially available eperisone formulation, there is a problem that the active ingredient starts to decompose immediately after production and the content of impurities increases to 1 to 2% within 1 to 2 months from the start of product storage.

  In addition, the drug has a short half-life and disappearance time in the blood, and the dosage method is mainly three times a day. However, recently developed non-steroidal anti-inflammatory analgesics (NSAIDs) family drugs that are often prescribed with eperisone preparations are mainly developed once a day or twice a day to increase patient compliance. Therefore, development of an eperisone sustained-release preparation that can be taken once a day or twice a day is required.

  Various attempts have been made in the past to improve the inconvenience of using eperisone three times a day. For example, a method for producing a wax matrix (Patent Document 1), a method using a sustained-release capsule (Patent Document 2), a method using a hydrogel (Patent Document 3), a dry-coated tablet and a clothing layer A delayed release coating layer (Patent Document 4), a method of coating with an expandable film (Patent Document 5), a method of coating with a hydrophobic organic compound and a water-insoluble polymer film (Patent Document 6), Eudra A method of using Jud (Eudragit) as a sustained release substrate (Patent Document 7), a method of using a gastrointestinal retention drug system (Patent Document 8), and the like are known.

  However, all of the conventional sustained-release preparations produced by the above-described method have the purpose of delaying the release of the active ingredient eperisone, and are intended to improve the chemical stability of eperisone. The intention to do is not seen. Even if the release of the active ingredient can be delayed, it is naturally difficult to expect an effective treatment if the stability of the active ingredient is not ensured in the human body during storage of the product or after taking the drug.

  In particular, since eperisone is mainly absorbed in the upper part of the intestinal tract, in order to develop a sustained-release preparation that gradually releases the drug while staying in such an absorption site for a long time, the alkaline environment in the intestinal tract must first be developed. It is necessary to improve the stability at

  Therefore, the problem to be solved by the present invention is stabilized to keep the active ingredient chemically stable even in the alkaline environment in the intestinal tract of the human body after the patient takes the drug as well as during the storage of the finished product. It is to provide an eperisone pharmaceutical composition.

  In addition, another problem to be solved by the present invention is a sustained release containing eperisone having a dual release characteristic so as to exhibit a useful solubility effect even when taken once a day or twice a day. Providing a pharmaceutical preparation.

  A stable eperisone pharmaceutical composition according to the present invention is formed comprising an eperisone salt and an acidifying agent, but the acidity of a 0.5% (W / V) aqueous solution is pH 0.5 to pH 5.6, The acidifying agent is selected from an acidic pH adjusting agent or an excipient exhibiting a pH of 5.0 or less when suspended, dissolved, swollen or mixed in water.

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

  The acidifying agent functions to adjust the acidity to be 0.5 to 5.6 when the pharmaceutical composition of the present invention is produced into a 0.5% (W / V) aqueous solution, In such an acidic environment, eperisone, which is an active ingredient, has chemical stability not only during storage of the finished product but also in an alkaline environment in the intestinal tract after taking it. Therefore, the content of the acidifying agent includes an amount in which a 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 eperisone pharmaceutical composition according to the present invention is less than pH 0.5, the acid characteristics are too strong, and the patient's oral cavity and esophageal mucosa may be damaged when taken This is not preferable. In addition, if the acidity exceeds pH 5.6 and is alkalized, the stability of the active ingredient is remarkably lowered, and it is not possible to block the decomposition of the active ingredient particularly in the alkaline environment inside the intestinal tract after taking the drug. A problem occurs.

In the present invention, as the acidifying agent, an acidic pH adjusting agent or an excipient exhibiting a pH of 5.0 or less when suspended, dissolved, swollen or miscible in water is used. Here, as the acidic pH regulator, alginic acid, acetic acid, formic acid, adipic acid, edetic acid, fumaric acid, lactate (lactic acid), malic acid (malic acid), maleic acid (maleic acid), palmitic acid (palmitic acid), propionic acid (propionic acid), sorbic acid (sorbic acid), stearic acid (stearic acid), tartaric acid (Taric acid), ascorbic acid (Ascorbic acid), erythorbic acid (Erthorbic acid), citric acid (Citric acid) Any one or more selected from oxalic acid, succinic acid, toluenesulfonic acid, methanesulfonic acid, nitric acid, hydrochloric acid, phosphoric acid and sulfuric acid may be used. Acid is most preferred.

  In addition, as the excipient, all excipients exhibiting a pH of 5.0 or less when suspended, dissolved, swollen or mixed in water may be used, but more specifically, carbomer, It is preferable to use one or more selected from polycarbophil and polydextrose.

  In general, if the release rate of the active ingredient is too low at the initial elution rate after taking the drug, the patient will not be able to obtain a fast drug effect.On the other hand, if the target elution rate is exceeded, problems such as dose dumping at the initial dose may occur. The blood levels in the body may rise excessively, creating problems that can make the patient dangerous. And if the release rate at the intermediate or final time point is too fast compared to the target dissolution rate, the effective blood concentration of the drug until the next dose cannot be maintained, so an effective therapeutic effect cannot be expected. If the rate of dissolution is too slow compared to the target elution rate, not only the sustained blood concentration cannot be maintained, but the next dose may cause an increase in the drug concentration in the body and cause side effects. Therefore, adjusting the release content according to the time period after taking the drug is a very important factor to achieve the desired therapeutic purpose.

  The sustained-release preparation containing eperisone according to the present invention is a double-release that simultaneously exhibits rapid efficacy for obtaining rapid muscle relaxation and analgesic effect at the initial stage of administration, and sustained efficacy that can be taken once or twice a day. Has characteristics. In order to have such a double release characteristic, the sustained-release preparation of the present invention is 0.05 to 3 in addition to 1 part by weight of the eperisone salt in addition to the active ingredient eperisone salt and acidifying agent. Part by weight, preferably 0.1 to 2.5 parts by weight of delayed release agent is included.

  In this case, as the delayed release agent, methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose as cellulose derivatives, and polysacaride, polyacrylate, hydrogel, polyvinyl alcohol, polyvinyl as hydrophilic polymers Pyrrolidone, Carbopol, Polyethylene oxide, Magnesium aluminum silicate, Starch derivatives or mixtures of these and copolymers of acrylic acid and methacrylic acid ester as hydrophobic polymers, polyethylene, polyamide, polyvinyl chloride, polyvinyl acetate, polyvinyl Alcohol or a mixture of these and water-insoluble polymers such as polyacrylic acid, acrylic resin, acrylic Tex dispersions, cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, may be used any one or more selected from among.

  The amount of the delayed release agent may be adjusted according to the initial release rate, the degree of sustained effect, and the like. In addition, the delayed release agent may be used alone or in combination, and hydroxypropylmethylcellulose is preferred when referred to alone, and when used as a mixture, as a hydrophilic polymer and a hydrophobic polymer. What mixed polyvinyl pyrrolidone and polyvinyl acetate in 2: 8 weight part is preferable.

  The sustained-release preparation containing eperisone 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 characteristics of 30 to 50% by weight of the active ingredient content within 60 minutes of elution, 55 to 75% by weight within 6 hours, and 85% by weight or more within 24 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 delayed release agent as necessary.

  In order for the sustained-release preparation containing eperisone of the present invention to have the same pharmacological effect as taken once a day or twice a day and taken three times a day, the active ingredient must be continuously released in the gastrointestinal tract. I must. However, eperisone has very unstable characteristics in the alkali that is the intestinal environment, and the absorption site of the drug is mainly located in the upper part of the gastrointestinal tract, so it is necessary to stay in the stomach that is an acidic environment as long as possible. is there. Therefore, it is preferable to use an ordinary gastric retention system such as a floating system, a gastric adhesion system, and a swelling system, and it is particularly preferable to adjust the specific gravity of the entire preparation to be similar to or lower than the specific gravity of the gastric juice. .

  Specifically, using a low-density excipient such as polypropylene foam powder (Accurel) or porous calcium silicate (Fluorite), the sustained-release preparation has an aqueous solution with a specific gravity of pH 1 of 0.5 to 1.2 g / ml. It is preferable to have the range. This is because when the specific gravity of the sustained-release preparation exceeds 1.2 g / ml, the specific gravity is higher than that of the gastric juice and sinks to the lower part of the stomach, and in this case, the drug is continuously released while staying in the stomach. You will not be able to achieve your goal. In addition, when the specific gravity of the sustained-release preparation is lower than 0.5 g / ml, the shape as a solid agent cannot be maintained, and it is easily crushed into a powder or a granule, which causes a problem in handling during production and distribution. Arise. A preferred specific gravity range of the sustained-release preparation is 0.8 to 1.2 g / ml.

  Further, the sustained-release preparation containing eperisone of the present invention may contain all known gas generants such as sodium bicarbonate in the preparation as a normal gastric retention system. At this time, the gas generating agent is preferably positioned in a separate outer layer so as to avoid contact with the active ingredient so as not to adversely affect the stability of the active ingredient. It is preferable to contact only one surface such as a tablet so as not to impair the release characteristics. Moreover, it is necessary to adjust the pH inside the sustained-release preparation so that only the drug layer excluding the layer containing the gas generating agent has a pH of 0.5 to 5.6.

  On the other hand, the sustained-release preparation containing eperisone according to the present invention may additionally contain a non-steroidal anti-inflammatory analgesic (NSAID). Specifically, aceclofenac, diclofenac, meloxicam, naproxen, ibuprofen, dexibprofen , Loxoprofen, zaltoprofen, felbinac, ketoprofen, etodolac, nabumetone, celecoxib, nimesulide. As described above, when the sustained-release preparation contains a nonsteroidal anti-inflammatory analgesic, there is an advantage that an anti-inflammatory action as well as an analgesic action can be obtained through an ascending effect between the two drugs. Can improve the compliance with medication.

  Finally, the sustained-release preparation containing eperisone of the present invention is prepared by mixing the active ingredient eperisone salt together with an acidifying agent and a delayed-release agent together with a normal direct hit method, wet release, dry method, etc. It can be manufactured through granules, beads, pellets, tablets and capsules containing two or more layers, multilayers, coatings, nucleated, matrixed, etc. All controlled release formulations.

  In the stable formulation of Eperisone according to the present invention, the acidifying agent maintains the atmosphere around the active ingredient in the range of pH 5.6 or less, so that the patient after taking the drug as well as in the middle of storing the finished product. Furthermore, even in an alkaline environment in the human intestinal tract, it has the effect of improving the chemical stability of the active ingredient by 20 times or more as compared with conventional commercial preparations.

  The stable eperisone-containing sustained-release preparation of the present invention comprises an active ingredient, an acidifying agent, and a delayed-release agent, so that it has a quick-release and sustained-release double-release characteristic, and further has a 1 day Since it can be taken once or twice a day, there is an effect that the patient's compliance with medication can be improved.

The graph which showed the elution rate according to time with respect to the 1st sustained release formulation (taken once a day) by this invention.

The graph which showed the elution rate according to time with respect to the 2nd sustained release formulation (taken twice a day) by this invention

The graph which showed the elution rate according to time measured by the rotation sample cylinder method with respect to the 2nd sustained release formulation (taken twice a day) by this invention.

A graph comparing blood concentrations of sustained-release preparations according to the present invention and conventional commercial preparations

  Hereinafter, preferred embodiments will be presented in order to facilitate understanding of the present invention. However, the following examples are provided only for easier understanding of the invention and do not limit the scope of the invention.

  [Example 1]

  75.0 g of eperisone 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 vinyl bag and mixed for 10 minutes. The Kollidon SR is a trade name of BASF, and is a delayed release agent in which polyvinyl pyrrolidone and polyvinyl acetate are mixed at a ratio of 2: 8 parts by weight.

  Then, 1.5 g of colloidal silicon dioxide and 2.0 g of magnesium stearate were weighed and sifted onto a 50 mesh sieve, and then charged and mixed for 3 minutes. This mixture was compressed with a tableting machine to produce 400 mg tablets containing 150 mg of eperisone hydrochloride per tablet.

  [Example 2]

  75.0 g of eperisone hydrochloride, 55.0 g of microcrystalline cellulose, 50.0 g of Kollidon SR, and 15.0 g of carbomer were weighed into a vinyl bag and mixed for 10 minutes. In addition, 3.0 g of colloidal silicon dioxide and 2.0 g of magnesium stearate were weighed and sifted into a 50 mesh screen, then charged and mixed for 3 minutes. This mixture was compressed with a tableting machine to produce 400 mg tablets containing 150 mg of eperisone hydrochloride per tablet.

  [Example 3]

  300.0 g of eperisone hydrochloride, 368.0 g of microcrystalline cellulose, 100.0 g of hydroxylpropyl methylcellulose, 4.0 g of carbomer and 16.0 g of citric acid were weighed and put into a speed mixer (Xan Machinery, KM-5). And rotated at 100 rpm for 3 minutes. Water was added thereto, and the mixture was rotated at 100 rpm and chopper 1500 rpm for 3 minutes to form granules.

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

  Then, 4.0 g of colloidal silicon dioxide and 8.0 g of magnesium citrate were weighed and selected with a 50 mesh sieve, and then charged and mixed for 3 minutes in a vinyl bag. This mixture was compressed with a tableting machine to produce 400 mg tablets containing 150 mg of eperisone hydrochloride per tablet.

  [Example 4]

  Tablets were produced 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 above.

  [Example 5]

  Tablets were produced 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 above.

  [Example 6]

  300.0 g of eperisone hydrochloride, 399.0 g of microcrystalline cellulose, 30.0 g of citric acid and 24.0 g of Eudragit RS PO are weighed in a speed mixer (Xan Machinery, KM-5) and rotated at 100 rpm with an agitator And mixed for 3 minutes. The Eudragit is a trade name of EVONIK Industries and is a copolymer of acrylic acid and methacrylic acid ester.

  Ethanol was added thereto and rotated at an agitator of 100 rpm and a chopper of 1500 rpm for 3 minutes to form granules. The above granules are dried in an oven at 50 ° C. for 1 hour, and then pulverized and blended with 20 mesh (standard KSA5101-1) in an oscillator (Oscillator, ERWEKA AR-402) to produce granules. did.

  Then, 7.0 g of magnesium stearate was weighed and screened with a 50 mesh sieve, then charged and mixed in a plastic pack for 3 minutes, and this mixture was compressed with a tableting machine to contain 150 mg of eperisone hydrochloride per tablet. 380 mg tablets were produced.

  [Example 7]

  Eperisone hydrochloride 150.0 g, microcrystalline cellulose 33.8 g, Kollidon SR 110.0 g, carbomer 12.0 g and citric acid 8.0 were weighed and placed in a vinyl bag and mixed for 10 minutes. Then, 3.0 g of colloidal silicon dioxide and 3.2 g of magnesium stearate were weighed and screened with a 50 mesh sieve, and then charged and mixed for 3 minutes to prepare a drug layer mixture.

  Separately, 22.8 g of microcrystalline cellulose, 80.0 g of Kollidon SR, 6.0 g of carbomer, 5.0 g of citric acid and 15.0 g of sodium bicarbonate were weighed into a vinyl bag and mixed for 10 minutes. After weighing 1.2 g of magnesium oxide and selecting with 50 mesh sieve, it was charged and mixed for 3 minutes to produce a floating layer mixture.

  Tableting was performed with a tableting machine for a double-layer tablet so that 320 mg of the drug layer mixture and 130 mg of the floating layer mixture were contained in each layer to produce 450 mg of a bilayer tablet containing 150 mg of eperisone hydrochloride per tablet.

  [Example 8]

  37.5 g of eperisone hydrochloride, 48.7 g of microcrystalline cellulose, 6.5 g of hydroxylpropyl methylcellulose, 4.0 g of citric acid and 2.0 g of sodium chollate sodium tens were placed in a vinyl bag and mixed with 5. Then, 0.4 g of colloidal silicon dioxide and 0.9 g of magnesium stearate were weighed and selected with a 50 mesh sieve, and then charged and mixed for 1 minute.

  The mixture was compressed with a tableting machine to produce 200 mg tablets containing 75 mg of eperisone hydrochloride per tablet.

  [Comparative Example 1]

  75.0 g of eperisone hydrochloride, 21.5 g of microcrystalline cellulose and 100.0 g of Kollidon SR were weighed into a vinyl bag and mixed for 10 minutes. Then, 1.5 g of colloidal silicon dioxide and 2.0 g of magnesium stearate were weighed and selected with a 50 mesh sieve, and then charged and mixed for 3 minutes. The mixture was compressed with a tableting machine to produce 400 mg tablets containing 150 mg of eperisone hydrochloride per tablet.

  [Comparative Example 2]

  300.0 g of eperisone hydrochloride, 429.0 g of microcrystalline cellulose, and 24.0 g of Eudragit RS PO were weighed and placed in a speed mixer (Xan Machinery, KM-5) and rotated at 100 rpm with an agitator and mixed for 3 minutes. Ethanol is added thereto and rotated at an agitator of 100 rpm and a chopper of 1500 rpm for 3 minutes to form granules.

  The above granules are dried in an oven at 50 ° C. for 1 hour, and then pulverized and blended with 20 mesh (standard KSA5101-1) in an oscillator (Oscillator, ERWEKA AR-402) to produce granules. did. Then, 7.0 g of magnesium stearate was weighed and selected with a 50 mesh sieve, and then charged and mixed in a vinyl pack for 3 minutes. This mixture was compressed with a tableting machine to produce 380 mg tablets containing 150 mg of eperisone hydrochloride per tablet.

  [Experiment 1]

  The tablets produced in each of the examples and comparative examples were pulverized into fine powders in a mortar, and the amount of one tablet was weighed, placed in 100 ml purified water, stirred for 10 minutes and thoroughly mixed. The pH of each solution was measured using Denver, UB-5).

  As can be seen from Table 1 above, in the examples to which an acidifying agent such as citric acid or carbomer was added according to the present invention, except for Example 7, the pH of the 0.5% aqueous solution was 5.6. It is as follows. However, all the comparative examples to which no acidifying agent is added have a pH of 6.0 or higher.

  However, in the case of Example 7, the pH of the whole tablet appeared to be high at about 6.69, which was caused by sodium bicarbonate contained in the floating layer, and excluded the floating layer. When the pH of only the drug layer was measured, it was confirmed that the pH was 4.38.

  [Experiment 2]

  After the tablets produced in each of the examples and comparative examples are put into bottles made of HDPE material and capped, they are stored in a thermo-hygrostat with a temperature of 40 ° C. and a relative humidity of 75%, and the degree of impurity generation is maintained for 8 weeks. Compared. At this time, the impurities were measured by putting each tablet in a 60% methanol solution containing 0.1% and chloric acid and dissolving it sufficiently through ultrasonic treatment, followed by filtration through a 0.45 / dish membrane filter. Tested by chromatographic method.

  [Experiment 3]

  One tablet of each of Example 1 and Comparative Example 1 was placed in 100 ml of pH 6.8 buffer solution and allowed to stand at 37 ° C. for 6 hours. Thereafter, 900 ml of a 60% methanol solution containing 0.15 perchloric acid was added and dissolved sufficiently through sonication, then filtered through a 0.45 / dish membrane filter and tested by liquid chromatography.

  The sustained-release preparation according to the present invention does not completely disintegrate during not only the time for staying in the stomach but also the time for passing through the small intestine, and moves in a state in which the drug is contained in the tablet. That is, while staying in the stomach, only a part of the active ingredient, eperisone, is released, and the remaining amount remains in the undisintegrated tablet and gradually releases while passing through the small intestine.

  Therefore, it is necessary to keep the pH environment inside the tablet low so that Eperisone is chemically stable even in the high pH environment inside the small intestine. In accordance with such technical requirements, in the present invention, since an acidifying agent is added, it can be confirmed that the degradation product of eperisone is remarkably reduced in a pH 6.8 buffer solution.

  [Experimental Example 4]

  One tablet of each of the above examples was placed in a ph1.2 buffer solution at 37 ° C., and an elution experiment was performed by the paddle method at 50 rpm. At each time point, 5 ml was collected and filtered through a membrane filter, and then tested by liquid chromatography, and the results were recorded in FIGS.

  As can be seen from the results of Table 4 and FIG. 1, in the case of the first sustained-release preparation (containing 150 ml of eperisone hydrochloride per tablet) developed by the once-daily method in the present invention, until the first hour, It represents an average release rate of 0.77 to 0.84 mg per minute and rapidly releases about 50 mg of eperisone hydrochloride over 1 hour. Such a release amount corresponds to the release amount of one tablet taken three times a day, which is an existing commercial preparation, and can be said to be an amount necessary for rapid effect expression.

  Further, the first sustained-release preparation may be released at an average rate of 0.17 to 0.18 mg per minute for 6 hours thereafter, and represents a drug release pattern that is stable over a long period of time. I can confirm. As a result, it can be confirmed that the sustained-release preparation containing the eperisone of the present invention has double-release characteristics that have both rapid and sustained effects.

  As can be seen from the results shown in Table 5 and FIG. 2, in the case of the second sustained-release preparation (contains 75 mg of eperisone hydrochloride per tablet) developed by the twice-daily method, the total content of 34.7 is obtained in the initial 15 minutes. %, And an elution rate of 69% in 60 minutes and 99.7% in 240 minutes can be expressed, indicating a pattern suitable for the target elution rate. Such an elution pattern releases 0.86 mg of active ingredient per minute up to 60 minutes after taking and releases 50 mg of eperisone hydrochloride which is baked at 1 hour. The release amount is almost the same as that of the first sustained-release preparation (taken once a day).

  It can also be seen that the second sustained-release preparation gradually releases 0.13 mg of eperisone hydrochloride on average per minute from 60 minutes to 240 minutes. Therefore, it can be confirmed that the second sustained-release preparation in the previous period also has the same double-release characteristics as the first sustained-release preparation.

  [Experimental Example 5]

  One tablet of each of Example 8 was placed in a ph1.2 buffer solution at 37 ° C., and an elution experiment was performed under the condition of 100 rpm by the rotating specimen cylinder method. At each time point, 5 ml was collected and filtered through a membrane filter, and then tested by a liquid chromatograph, and the result was recorded in a graph in FIG.

  [Experimental example 6]

  A blood concentration analysis experiment was conducted on the beagle dog using the tablet of Example 8. The beagle dogs used in the test were fasted from 10 o'clock on the day of administration until 4 hours after dosing, and each of the 6 beagle dogs was given 150 mg (75 mg / tablet, 2 tablets) and 100 mg (50 mg / tablet, 2 tablets) of a commercially available drug, myonal tab, were orally administered. Each drug was orally cross-dosed in a one week gap, which is a sufficient elimination period considering the half-life of the drug, and a cross-over study was performed. Blood was collected from the brachial vein of a beagle dog immediately before dosing, 1.5 hours after dosing, and 4 hours after dosing, placed in a heparin-containing culture tube, and centrifuged (3000 rpm, 10 minutes) for plasma. And the concentration of eperisone in blood was analyzed using LC-MASS, and the results were recorded in FIG.

  As can be seen from the results of FIG. 4 attached, when the blood concentration was analyzed after taking the sustained-release preparation of the present invention and the commercially available drug Myonal Tablet, the maximum blood concentration in the initial 1.5 hours was A similar degree was shown at 1.205 ng / ml and 0.353 ng / ml respectively, but after 4 hours, 0.939 ng / ml, 0.497 ng / ml, and 6 hours, respectively, 0.539 ng / ml It was observed that the blood concentration was maintained about twice as high as 0.271 ng / ml as compared with the commercially available drug. That is, it was confirmed that when the sustained-release preparation of the present invention was taken, the blood concentration could be maintained longer than that of a general quick-release preparation.

Claims (6)

An eperisone salt, an acidifying agent and a delayed release agent are formed, but the acidity of a 0.5% (W / V) aqueous solution is pH 0.5 to pH 5.6, and the acidifying agent has an acidic pH. It is selected from among excipients exhibiting a pH of 5.0 or less when suspended, dissolved, swollen or mixed in a regulator or water, and the content of the delayed release agent is 0. 1 part by weight of the eperisone salt. Containing stabilized eperisone, characterized in that it is from 05 to 3 parts by weight ,
The sustained-release preparation containing stabilized eperisone, wherein the excipient is any one or more selected from carbomer, polycarbophil, and polydextrose .   Examples of the delayed release agent include methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, carboxymethylcellulose, polysaccharide, polyacrylate, hydrogel, polyvinyl alcohol, polyvinylpyrrolidone, carbopol, polyethylene oxide, magnesium aluminum silicate , Starch derivatives, acrylic acid and methacrylic acid ester copolymers, polyethylene, polyamide, polyvinyl chloride, polyvinyl acetate, polyvinyl alcohol, polyacrylic acid, acrylic resin, acrylic latex dispersion, cellulose acetate phthalate, poly Vinyl acetate phthalate, hydroxypropyl methylcellulose lid Sustained-release preparation containing a eperisone stabilized according to claim 1, wherein the chromatography bets and is any one or more selected from among.   The sustained-release preparation is eluted at 30-50% by weight of the total content within 60 minutes of initial dissolution, less than 55-75% by weight within 6 hours, and more than 85% by weight within 24 hours. A sustained-release preparation comprising the stabilized eperisone according to claim 1 or 2. Claim 1 wherein the sustained-release formulation, wherein 15 to 55 wt% of the total content within early eluting 15 minutes, 55 to 75 wt% within 1 hour, to be eluted 85% by weight or more within 3 hours Alternatively, a sustained-release preparation containing the stabilized eperisone according to claim 2 . In addition to the eperisone salt, the acidifying agent and the delayed release agent, a non-steroidal anti-inflammatory analgesic (NSAID) is additionally included. As the non-steroidal anti-inflammatory analgesic, 3. Stabilized according to claim 1 or 2 , characterized in that it is one or more selected from dexibprofen, loxoprofen, zaltoprofen, felbinac, ketoprofen, etodolac, nabumetone, celecoxib, nimesulide Sustained release preparation containing eperisone. The acidic pH adjuster 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, erythorbic acid, The stabilized product according to claim 1 or 2, which is at least one selected from citric acid, succinic acid, succinic acid, toluenesulfonic acid, methanesulfonic acid, nitric acid, hydrochloric acid, phosphoric acid and sulfuric acid. Sustained-release preparation containing eperisone.

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