KR101156054B1 - A stable and control-released pharmaceutical composition comprising eperisone - Google Patents

Abstract

PURPOSE: A sustained release medicinal composition containing eperisone is provided to improve stability and to suppress decomposition of a main ingredient without release change under a severe condition. CONSTITUTION: A sustained release medicinal composition containing stable eperisone contains acid pH adjusting agent or acidifier which indicates under pH 5.0 condition in case of mixing, suspending, or dissolving in water. The acidity of the composition is pH 0.5-5.6 in case of 05%(W/V) of an aqueous solution. The acidic pH adjusting agent includes 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, citric acid, oxalic acid, and succinic acid.

Description

Stable and Control-Released Pharmaceutical Composition comprising Eperisone

The present invention is a long-term storage stability of the formulation, as well as the long-term retention in the intestinal tract due to the nature of the drug in the extreme properties of the gastrointestinal tract and improved efficacy in the extreme environment of the drug that requires fast release and sustained release eferison containing a double-release property A sustained release pharmaceutical composition.

In general, Eperisone (Eperisone) is a drug that has been used for the treatment of stiff paralysis due to long-term musculoskeletal disorders, including painful muscle spasms and nervous system diseases, the chemical structure is as follows.

Eperisone

Although the drugs were easily decomposed into piperidine rings in an alkaline environment and had very unstable properties, studies to improve their stability have been very insufficient until now. As a result, even in the case of commercially available products, the content of impurities is very unstable, such as an increase in impurities content of 1 to 2% or more within 1 or 2 months immediately after manufacture, during long-term storage, or even after storage. There was a problem such as being halved.

In addition, when the drug is developed as a once-release sustained release formulation that keeps the drug in the gastrointestinal tract for a long time and releases the drug slowly, the drug has a short half-life and a short time in blood loss, and the absorption portion of the drug is in the upper intestinal tract. As described above, there is a problem of very unstable characteristics in the alkaline environment of the intestine, and therefore, efforts to improve the stability of the formulation itself for long-term storage as well as to improve the stability in the intestinal extreme environment during long-term intestine are required. .

In addition, the drug has a short half-life and a short loss time in blood, making it difficult to formulate into sustained release. Up to now, the drug is mainly used three times a day. As a result, patients have been difficult to comply with the dosage regimen, and as a result, their compliance has been reduced, and the treatment effects of patients have been halved. Also, recently, NSAIDs-based drugs usually taken together with these drugs are daily 1 Despite the increasing number of cases developed by the use of the above-mentioned problems, these drugs still have only three formulations per day, there has been a problem due to mutual unevenness in the dosage method.

Therefore, a lot of efforts have been made to improve the inconvenience caused by the above-mentioned three times daily use method, such as a method of manufacturing a wax matrix [US Patent No. 5,700,410], a method using a sustained-release capsule [US Patent No. 5,498,422], a method using a hydrogel [US Pat. No. 6,500,455], a method of placing a delayed-release coating layer between a nucleated tablet and a coating layer [Korean Patent No. 574213], and a method of coating with an expandable membrane [Korean Patent No. 1989- 0004685], a method of coating with a hydrophobic organic compound and a water-insoluble polymer film [WO 2000/24423], a method of using Eudragit as a sustained-release substrate [US Patent No. 2005/0196451], stomach-retention Methods of using drug systems [US Pat. No. 2010/0249423], and especially delayed release of hydrophilic polymers, hydrophobic polymers, cellulose derivatives, natural gums, water insoluble polymers, stearic acid and the like Use the There have been many efforts to develop sustained-release preparations [See: WO2010 / 103544].

However, all of these conventional methods have a problem that can not meet the dual release characteristics that the effect is to be continuously exerted while the initial drug expression rate required by the characteristics of the drug, such as the eferison of the present invention.

Therefore, it is necessary to improve the long-term storage stability of the formulation, as well as to improve the compliance with the medications by improving the stability during long-term stay in the extreme environment in the intestinal tract and the dual release characteristics of the product, and the convenience of taking it. Was also required.

The inventors of the present invention intensively tried to solve the above problems, as a result of formulating the entire formulation to a pH of 5.6 or less by including a specific type of acidifying agent, such as carbomer, citric acid, with a specific range of delayed release agent, In addition, due to the therapeutic properties of drugs requiring sustained release, as well as the stability of the preparations and the sustained release of the extended-dose preparations that must be retained for a long time in the intestinal tract, the main component degradation is suppressed and the dissolution properties do not change. The invention was completed.

The present invention relates to a stable ephericone-containing sustained-release pharmaceutical composition comprising an acidifying agent, wherein the acidifying agent is suspended, dissolved, swelled or miscible in an acidic pH adjusting agent or water. Preference is given to those selected from excipients which exhibit a pH of 5.0 or less. Here, the acidifying agent or an excipient exhibiting a pH of 5.0 or less is added to lower the environment in the formulation to pH 5.6 or less as described above, and the addition thereof can not only stabilize the main component eferison component itself, but also in the gastrointestinal tract. In addition to maintaining significant dissolution patterns in both acid and alkali environments during long-term stays, it also helps to maintain the main component stability during the absorption of the drug during intestinal retention by preventing degradation of the main component due to contact with alkali in the intestine.

Therefore, the content of the acidifying agent is different depending on the type, but the amount that can be adjusted so that the acidity of the 0.5% (W / V) aqueous solution of the composition is in the range of pH 0.5 ~ pH 5.6. More specifically, acidic pH regulators 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 One selected from ascorbic acid, erythorbic acid, citric acid, oxalic acid, oxalic acid, succinic acid, toluenesulfonic acid, methanesulfonic acid, nitric acid, hydrochloric acid, phosphoric acid, and sulfuric acid It is preferable to contain the above, and citric acid is especially preferable.

In addition, as an excipient having a pH of 5.0 or less, all excipients having a pH of 5.0 or less when suspended, dissolved, swelled or miscible in water are preferable. More specifically, a carbomer or a polycarbophil And at least one selected from Polydextrose is most preferred.

In the present invention, the acidity when the whole composition is prepared with 0.5% (W / V) aqueous solution is preferably in the range of pH 0.5 to 5.6, more preferably pH 4.5 or less. This is undesirable because a pH of less than 0.5 may adversely affect the oral and esophageal mucosa at the time of taking due to too strong acidic properties, whereas alkalizing above pH 5.6 will significantly reduce the stability of the composition, and the intestinal tract at the time of drug administration. This is because it is impossible to block decomposition of the main component due to contact with alkali caused by sudden change in the alkaline environment. At this time, the preferred eferison is eferison hydrochloride, and the content is 150 to 300 mg / day.

In addition, the present invention includes a sustained release formulation having a dual release property in terms of therapeutic properties of drugs requiring fast and sustained release. The term "sustained release" herein refers to a range in which more than 30% by weight of the total content in the initial 60 minutes of dissolution, less than 75% by weight in 6 hours, and 90% or more by weight in 24 hours. In general, this dual release pattern is applied to drugs that need to be activated early, such as painkillers, and then continue to be effective afterwards.

Therefore, in the present invention, unlike the general sustained-release preparations in which the release rate of the drug is straight from the beginning of the release, the preparation of the double release pattern is necessary to see the rapid muscle relaxation and analgesic effect at the beginning of the dose, and the content of each time zone is controlled. It is very important. That is, in the present invention, if the release rate of the initial drug is too lower than 30% by weight of the total content within 60 minutes, the patient cannot obtain the desired initial fast efficacy, and if it exceeds 50% by weight, problems such as initial dose dosing dumping As a result, the patient may be at risk, and if more than 75% by weight is eluted within 6 hours, there may be side effects due to the initial excessive dissolution, which may not be desirable and may not have a lasting effect. Controlling the release content is a very important factor in achieving the object of the present invention.

In addition, the present invention may include 0.05 to 3 parts by weight of the delayed release agent with respect to 1 part by weight of eferison hydrochloride as a main component in order to make a sustained release formulation of the double-release properties as described above, in particular 0.1 to 2.5 parts by weight of the delayed release agent It is preferable to include a part. Because, in the nature of the drug as in the present invention, it is very important for the patient to control the release content according to specific time periods to ensure the safety as well as the rapid muscle relaxation effect and analgesic effect, so that the content of the delayed release agent is too low. If the initial drug dissolution rate is too fast, dose dumping appears, which causes the patient to be in danger, which is not desirable. If the delayed release agent content is too high, the initial dissolution rate is too slow, and the initial drug expression rate is increased. This is because the patient's satisfaction, which must be fast, cannot be met.

At this time, the delayed-release agent is a cellulose derivative, methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose and the like; 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 (trade name: Eudragit), polyethylene, polyamides, polyvinylchloride, polyvinylacetate, polyvinyl alcohol, or mixtures thereof; At least one selected from among polyacrylic acid, acrylic resin, acrylic latex dispersion, cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropylmethylcellulose phthalate, or mixtures thereof is used as the water-insoluble polymer.

Among the delayed release agents, a mixture of a hydrophilic polymer and a hydrophobic polymer is preferable, and the ratio can be adjusted according to the initial release rate or the duration of effect expression. Particularly, in these mixtures, polyvinylpyrrolidone: polyvinylacetate is used. 2: 8 parts by weight of the mixture (trade name: 'collidone RS') is most preferred. In addition, the present invention includes a specific gravity of the composition as a whole range of 0.5 to 1.2 g / ml in an aqueous solution of pH 1, more preferably 0.6 to 1.2 g / ml, most preferably contains 0.8 to 1.2 g / ml do.

As described above, the sustained-release preparation of the present invention is required to have a sustained release from the gastrointestinal tract, because unlike the general three-day preparation, it should have the same effect as the general preparation only once a day. By the way, Eperisone is very unstable to alkali, which is an intestinal environment, and also the absorption part of the drug is mainly located in the upper gastrointestinal tract, so it is necessary to stay for a long time in an acidic environment if possible.

Therefore, it is possible to use a gastric retention system such as a conventional floating system, gastric adhesion system, swelling system, and in particular, it is preferable to adjust the specific gravity of these whole preparations to a range similar to or lower than that of gastric juice. As for the specific gravity range of the whole composition, 0.5-1.2 g / ml is preferable. Because, if the total composition specific gravity is too high exceeding 1.2 g / ml, the specific gravity is higher than the gastric juice to sink to the lower part of the stomach, and as a result, it is impossible to achieve the purpose of continuing to release the drug while staying on the stomach On the other hand, if the specific gravity of the composition is lower than 0.5 g / ml is located only in the upper portion of the gastric juice has a problem that the drug is released only on one side of the formulation is less release.

In addition, the present invention includes all known gas generators, including sodium bicarbonate, in the formulation as a conventional gastric retention system, wherein the gas generator is separate from the sustained phase to avoid contact with the main component for stability of the main component. It is preferable to locate in an external phase, and it is preferable to contact only one side of a tablet etc. especially in order not to inhibit elution of a slow release phase. At this time, the pH of the composition 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.

In addition, the present invention may further include nonsteroidal anti-inflammatory drugs (NSAID) -based drugs, specifically, aceclofenac, diclofenac, meloxycamp, naproxen, ibuprofen, dexibuprofen, roxofene, zaltoprofen , Felbinac, ketoprofen, etodolak, nabumetone, celecoxib, nimesulide and the like. In this way, if the nonsteroidal anti-inflammatory drugs are formulated together, the anti-inflammatory effect and the analgesic effect can be obtained through the synergistic effect between the two drugs, and the patient can increase the convenience of taking the drug and increase the drug compliance. .

Finally, the present invention includes granules, beads, pellets, tablets or capsules containing two or more phases, general formulations such as multilayers, coatings, nucleus, matrix, or all formulations controlled to be sustained in the stomach or gastrointestinal tract. do. As described above, the present invention can be formulated by including an acidifying agent and a delayed-release agent together with the eferison, it can be prepared through a conventional direct method, wet method, dry method and the like.

The present invention relates to a pharmaceutical composition containing eferisone, the present invention is formulated to a pH of 5.6 or less by including a specific type of acidifying agent such as carbomer, citric acid, so that the acidifying agent is not included immediately after the preparation of the preparation or during long-term storage In addition to being able to significantly improve stability over 20 times compared to formulations and commercially available formulations, the sustained release formulation has the effect of suppressing decomposition of the main component without changing the dissolution properties even in the extreme conditions of long-term residence in the intestine. In addition, the present invention has the effect of realizing a sustained release formulation of a double-release property that can make good use of the properties of the drug of the present invention that requires fast and sustained release by controlling a delayed release agent in a specific range.

1 is a graph showing the dissolution rate test results for the tablet prepared with the pharmaceutical composition according to the present invention.

Hereinafter, preferred embodiments of the present invention will be described in order to facilitate understanding of the present invention. However, the following examples are provided only for the purpose of easier understanding of the present invention, and the present invention is not limited by the examples.

75.0 g of eferisone hydrochloride, 40.0 g of microcrystalline cellulose, 72.5 g of collidone R (trade name), 5.0 g of carbomer, and 4.0 g of citric acid were weighed into a plastic bag and mixed for 10 minutes. In addition, 1.5 g of colloidal silicon dioxide and 2.0 g of magnesium stearate were weighed, filtered through a 50 mesh sieve, and mixed for 3 minutes to prepare a final mixture. The mixture was compressed into tablet presses to make tablets. The tablets were made up to 400 mg per tablet so as to contain 150 mg of eferisone hydrochloride.

75.0 g of eferisone hydrochloride, 55.0 g of microcrystalline cellulose, 50.0 g of collidone R (trade name) 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 added, filtered through a 50 mesh sieve, and then mixed for 3 minutes to obtain a final mixture. The mixture was compressed into tablet presses to make tablets. The tablets were made up to 400 mg per tablet to contain 150 mg of eferisone hydrochloride.

Add 300.0 g of Ephericone hydrochloride, 368.0 g of microcrystalline cellulose, 100.0 g of hydroxypropyl methylcellulose, 4.0 g of carbomer, and 16.0 g of citric acid, and place it in a speed mixer (KIS-5, KM-5). Mixed. Further water was added to rotate the agitator 100rpm, microwave 1500rpm to rotate for 3 minutes to form granules. The granules thus formed were dried in an oven at 50 ° C. for 2 hours, and then ground and granulated using 20 mesh (standard standard KSA5101-1) in an oscillator (Oscillator, AR-402, ERWEKA) to prepare granules. In addition, 4.0 g of colloidal silicon dioxide and 8.0 g of magnesium stearate were added, filtered through a 50 mesh sieve, and then mixed for 3 minutes in a plastic bag to obtain a final mixture. The mixture was compressed into tablet presses to make tablets. The tablets were made up to 400 mg per tablet to contain 150 mg of eferisone hydrochloride.

300.0 g of Ephericone hydrochloride, 399.0 g of microcrystalline cellulose, 30.0 g of citric acid, and 24.0 g of Eudragit (trade name) were added to a speed mixer (KM-5), and the mixture was spun at 100 rpm and mixed for 3 minutes. . In addition, ethanol was added to rotate the agitator 100rpm, microwave 1500rpm to rotate for 3 minutes to form a granule. The granules thus formed 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 added, filtered through a 50 mesh sieve, and mixed for 3 minutes in a plastic bag to obtain a final mixture. The mixture was compressed into tablet presses to make tablets. The tablet was 380 mg per tablet so that 150 mg of eferison hydrochloride was contained.

150.0 g of eferisone hydrochloride, 33.8 g of microcrystalline cellulose, 110.0 g of collidone RS (trade name), 12.0 g of carbomer, and 8.0 g of citric acid were weighed and mixed in a plastic bag for 10 minutes. In addition, 3.0 g of colloidal silicon oxide and 3.2 g of magnesium stearate were added, filtered through a 50 mesh sieve, and then mixed for 3 minutes to obtain a drug layer mixture. Separately, 22.8 g of microcrystalline cellulose, 80.0 g of collidone R, 6.0 g of capper, 5.0 g of citric acid, and 15.0 g of sodium bicarbonate were weighed and mixed in a plastic bag for 10 minutes. Then, the mixture was added and mixed for 3 minutes to prepare a floating layer mixture. The drug layer 320mg and the floating layer 130mg was compressed into a two-layer tablet press so that each layer was prepared as a tablet. The tablets were made up to 450 mg per tablet to contain 150 mg of eferisone hydrochloride.

Comparative Example 1

75.0 g of eferisone hydrochloride, 21.5 g of microcrystalline cellulose, and 100.0 g of collidone R (trade name) 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 added, filtered through a 50 mesh sieve, and then mixed for 3 minutes to obtain a final mixture. The mixture was compressed into tablet presses to make tablets. The tablets were made up to 400 mg per tablet to contain 150 mg of eferisone hydrochloride.

Comparative Example 2

300.0 g of eferisone hydrochloride, 429.0 g of microcrystalline cellulose, and 24.0 g of Eudragit (trade name) 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. In addition, ethanol was added to rotate the agitator 100rpm, microwave 1500rpm to rotate for 3 minutes to form a granule. The granules thus formed 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, 7.0 g of magnesium stearate was added, filtered through a 50 mesh sieve, and then mixed for 3 minutes in a plastic bag to obtain a final mixture. The mixture was compressed into tablet presses to make tablets. The tablet was 380 mg per tablet so that 150 mg of eferison hydrochloride was contained.

Experimental Example 1

The tablets prepared in Examples and Comparative Examples were ground in a mortar to make a fine powder, weighed in 1 tablet, and placed in 100 mL purified water for 10 minutes to be thoroughly mixed. The pH of each solution was measured using a pH meter (Denver, UB-5).

0.5% aqueous solution pH measurement result of each example and comparative example division Example Comparative example One 2 3 4 One 2 pH 4.35 5.12 4.46 4.21 6.15 6.08

As a result of the experiment, the pH of the case of adding an acidifying agent such as citric acid or carbomer was found to be 5.6 or less, and all of the comparative examples otherwise showed a pH of 6.0 or more. In the case of Example 5, the pH of the whole tablet was about 6.69, but this was probably due to sodium bicarbonate contained in the suspended layer, and the pH of the drug layer alone was measured to be low as 4.38 to exclude the effect. .

[Example 2]

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

Bottle packing-the amount of impurities generated at each time (%) Storage period
Example Comparative example One 2 3 4 5 One 2 Right after manufacturing ND ND ND 0.01 ND 0.02 0.08 2 weeks ND 0.03 0.05 0.04 0.08 0.44 0.61 4 weeks 0.02 0.04 0.09 0.08 0.15 0.82 1.28 8 Weeks 0.03 0.07 0.15 0.16 0.28 1.79 2.24 * ND: Not Detected

[Example 3]

Each tablet of Example 1 and Comparative Example 1 was put in 100 mL of pH6.8 buffer and left at 37 ° C. for 6 hours. Thereafter, 900 mL of 60% methanol containing 0.1% perchloric acid was further added, and then sufficiently dissolved by sonication, filtered through a 0.45 um membrane filter, and tested according to a liquid chromatograph method.

Percentage of impurities generated in tablets left for 6 hours in pH6.8 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

As described above, the conventional epherisone preparation is commercially prepared and released as an immediate release formulation three times daily, and since such disintegration is completed within 30 minutes to 1 hour, it disintegrates rapidly during the stay in the stomach, Absorption is achieved. However, the sustained-release preparation as in the present invention does not completely disintegrate during the time of staying in the stomach as well as the time of passing through the small intestine, so that the drug continues to contain the drug in the tablet.

In the present invention, while only about 30 to 40% of the main component of the erythrosine is released during the stomach, the remaining amount is gradually released while passing through the small intestine while remaining in the undisintegrated tablet. In this case, the eferisons remaining in the tablets begin to degrade rapidly by the high pH of the small intestine.

Therefore, it was necessary to keep the pH of the internal environment in the tablet low to maintain stability even at high pH of the small intestine in the case of the sustained-release agent containing eperisone. In the environment it was confirmed that the degradation products of eferison is produced significantly lower.

[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. 5mL was collected at each time point, filtered through a membrane filter, and the elution rate of the active ingredient was measured by liquid chromatography, and the results are shown in Table 4 and the accompanying FIG. 1.

Cumulative Dissolution Rate of Epherisone in Each Hour (%) Time (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 5 0 16.5 22.6 30.5 40.8 53.7 63.0 78.7 96.5

As shown in the above results, the release rate was 0.51 to 0.56% per minute until the first hour, and more than 30% of the drug was rapidly released for one hour. This amount is equivalent to one tablet of the existing commercial drug immediate release agent, which can be said to be necessary for rapid effect expression. After 6 hours, the release progressed at an average rate of 0.11 to 0.12% per minute, indicating that the drug release structure was stable over a long period of time. As a result, it was confirmed that the sustained release formulation according to the present invention exhibits a double release pattern, which may exhibit a continuous therapeutic effect while reducing the number of times of taking the drug with an initial rapid effect.

Claims (7)

An acidic pH adjusting agent or an acidifying agent selected from the group consisting of an excipient exhibiting a pH of 5.0 or less when suspended, dissolved, swelled, or mixed in water, and has an acidity of 0.5 to 5.6 when prepared in a 0.5% (W / V) aqueous solution. Stable ephericone-containing sustained-release pharmaceutical composition, characterized in that.
delete 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, A stable ephericone-containing sustained-release pharmaceutical composition, characterized in that at least one selected from the group consisting of erythorbic acid, citric acid, oxalic acid, succinic acid, toluenesulfonic acid, methanesulfonic acid, nitric acid, hydrochloric acid, phosphoric acid and sulfuric acid. According to claim 1, wherein the excipient exhibiting a pH of 5.0 or less, stable eferison containing sustained-release pharmaceutical composition, characterized in that at least one selected from the group consisting of carbomer, polycarbophil and polydextrose.
delete The pharmaceutical composition of claim 1, wherein the pharmaceutical composition additionally contains 0.05 to 3 parts by weight of a delayed release agent based on 1 part by weight of eferison hydrochloride, wherein the delayed release agent is methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, hydroxy. Propyl 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; A stable ephericone-containing sustained-release pharmaceutical composition, characterized in that it is at least one selected from the group consisting of polyacrylic acid, acrylic resin, acrylic latex dispersion, cellulose acetate phthalate, polyvinylacetate phthalate, and hydroxypropylmethylcellulose phthalate.
The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is aceclofenac, diclofenac, meloxycamp, naproxen, ibuprofen, dexibuprofen, loxoprofen, zaltoprofen, felbinac, ketoprofen, etodollac, nabumethone, sele A stable ephericone-containing sustained-release pharmaceutical composition further comprising at least one NSAID-based drug selected from the group consisting of coxib and nimesulide.

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