KR20130083675A - Pharmaceutical composition with an improved stability comprising eperisone or a pharmaceutically acceptable salt thereof and specific acidifying agent - Google Patents

Abstract

PURPOSE: A pharmaceutical composition containing eperisone with improved stability or a pharmaceutically acceptable salt thereof, and a predetermined acidifier is provided to effectively suppress the generation of related materials by adding the predetermined acidifier and to enable long-term maintenance of drug efficacy, thereby being applied to a pharmaceutical industry. CONSTITUTION: A pharmaceutical composition contains eperisone or a pharmaceutically acceptable salt thereof, an acidifier, and a pharmaceutically acceptable excipient. Eperisone or the pharmaceutically acceptable salt is eperisone hydrochloride. The pH concentration of the pharmaceutical composition is pH 1-5 when the pharmaceutical composition is dissolved or dispersed in 10-20 mL of water. The acidifier is selected among organic acids and a mixture thereof. The organic acids are selected among alginic acid, phosphoric acid, sulfuric acid, hydrochloric acid, boric acid, hydrobromic acid, and a mixture thereof. The pharmaceutically acceptable excipient is selected among a dispersing agent, a disintegrant, a binder, a lubricant, and a mixture thereof. [Reference numerals] (AA) Acceleration condition; (BB) Related material; (C1) Example 1; (C2) Example 2; (DD) Comparative example 1

Description

PHARMACEUTICAL COMPOSITION WITH AN IMPROVED STABILITY COMPRISING EPERISONE OR A PHARMACEUTICALLY ACCEPTABLE SALT THEREOF AND SPECIFIC ACIDIFYING AGENT}

The present invention relates to a pharmaceutical composition comprising eferison or a pharmaceutically acceptable salt thereof and a specific acidifying agent having improved stability, a pharmaceutical preparation prepared using the same, and a method of preparing the pharmaceutical preparation.

Eperisone is a skeletal muscle relaxant widely used in the treatment of spastic paralysis caused by neuromuscular diseases such as painful muscular spasm and cerebrovascular disorder, spastic spinal palsy and cervical spondylosis accompanied by musculoskeletal disorders such as brachial syndrome, shoulder joint and low back pain. Eperisone acts on the r-motor nerve of the spinal cord to exert muscle relaxation effects, as well as to antagonize the central neurotransmitting peptide, substrate P, produced during pain expression and to inhibit spinal reflex. Blocks reflections and produces analgesic effects. In addition, calcium antagonism and sympathetic nervous system suppression of vascular smooth muscle contraction by reducing the blood circulation smoothly, and directly affects the motor nerves because the frequency of side effects is low.

Eperisone was developed in Japan as an eperison hydrochloride having a structure of formula (1) and is commercially available throughout Japan, India and East Asia. At present, many products, including MULEX Tab (secondary medicine), are approved and sold as muscle relaxants. However, the drug containing the eferison is deteriorated in stability due to temperature, light, humidity and oxygen when stored for a long time, the active ingredient is decomposed to lead substances (starting materials, intermediates, by-products and decomposition products present as impurities) ) May cause an increase. If lead substances are increased by long-term storage, problems with product quality, such as poor efficacy, can not be expected the same treatment effect.

Meanwhile, Li Ding, et al. , Journal of Pharmaceutical and Biomedical Analysis ., 46 (2008) 282-287, disclose that certain degradants of the active ingredient, ephrisonone hydrochloride (formula 2), in solid oral pharmaceutical compositions containing eferison hydrochloride, are It was shown that the production increased greatly in basic conditions.

In addition, the present inventors have found that products containing epherizone hydrochloride produce and increase soft substances under severe (temperature 60 ° C.) and acceleration (temperature 40 ° C. and relative humidity (RH) 75%) conditions. When exposed to solvents such as water and ethanol used in this wet granulation process, it was confirmed that a soft substance is produced, which lowers the content of the active ingredient and thus affects stability.

Accordingly, the present inventors have made diligent efforts to improve the stability of the pharmaceutical composition containing eferison hydrochloride, and found that the use of a specific acidifying agent as a stabilizer can effectively improve the stability of the product containing eferison hydrochloride. Furthermore, by designing the types and ratios of acidifying agents that meet the criteria of the International Conference on Harmonization (ICH) and minimize the formation of flexible substances, the sticking phenomenon is improved. The present invention has been completed by developing the composition.

[Non-Patent Document 1] Li Ding, et al. , Journal of Pharmaceutical and Biomedical Analysis ., 46 (2008) 282-287

It is an object of the present invention to provide a pharmaceutical composition with improved stability containing as an active ingredient eferison hydrochloride or a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a pharmaceutical formulation prepared using the pharmaceutical composition.

Still another object of the present invention is to provide a method for preparing the pharmaceutical formulation.

In order to achieve the above object, the present invention provides a pharmaceutical composition comprising eferisone or a pharmaceutically acceptable salt thereof, an acidifying agent and a pharmaceutically acceptable excipient as an active ingredient.

In order to achieve the above another object, the present invention provides a pharmaceutical formulation prepared using the pharmaceutical composition.

According to another object of the present invention

(i) preparing a granule comprising epherisone or a pharmaceutically acceptable salt thereof, an acidulant and a pharmaceutically acceptable excipient; And

(ii) mixing the granules with pharmaceutically acceptable excipients.

The pharmaceutical composition of the present invention can suppress the formation of a flexible substance derived from epheris hydrochloride by using a specific acidifying agent, thereby reducing unexpected side effects, and the content of the active ingredient can be preserved so that the drug can be preserved. It can be used stably in the treatment of diseases such as low back pain and cerebrovascular disorder. In addition, since the problems in the production process, such as sticking due to the addition of the acidifier is improved, it can be usefully applied to the pharmaceutical industry.

Figure 1 shows the increase or decrease of the flexible material according to the forced decomposition test conditions of the eferison hydrochloride.
2 is a graph showing the results of the severe stability test of Examples 1 to 5 and Comparative Example 1 according to the present invention.
3 is a graph showing the results of the severe stability test of Example 6 and Comparative Example 2 according to the present invention.
4 is a graph showing the results of the severe stability test of Examples 1, 7 to 9 and Comparative Example 1 according to the present invention.
5 is a graph showing the results of the severe stability test of Examples 2, 10 to 12 and Comparative Example 1 according to the present invention.
Figure 6 is a graph showing the results of the acceleration stability test of Examples 1 and 2, and Comparative Example 1 according to the present invention.

The present invention provides a pharmaceutical composition comprising, as a pharmacologically active ingredient, epherisone or a pharmaceutically acceptable salt thereof, certain acidifying agents and pharmaceutically acceptable excipients.

(1) Active Ingredient

In the pharmaceutical composition of the present invention, the active ingredient is epherizone or a pharmaceutically acceptable salt thereof widely used as a skeletal musculoskeletal relaxant, and the pharmaceutically acceptable salt may be a pharmaceutically acceptable salt that may be commonly used in the art. Can be. Preferably, it may be eferison hydrochloride, but is not limited thereto.

The active ingredient may be included in a conventionally available dose to exhibit pharmacological activity, but may preferably be contained in the range of 25 mg to 150 mg. According to one preferred embodiment according to the present invention, the eperisone or a pharmaceutically acceptable salt thereof may be contained in an amount of 10 to 60% by weight, preferably 20 to 60% by weight, based on the total weight of the pharmaceutical composition. However, it is not limited thereto.

(2) acidifying agent

The pharmaceutical composition of the present invention includes certain acidifying agents. Not all acidifying agents help to improve stability, and certain acidifying agents serve as stabilizers in the present invention, and can effectively suppress the formation of a flexible substance derived from the active ingredient eferison hydrochloride, thus contributing to improving the stability of the pharmaceutical composition. Can be.

The acidifying agent refers to an excipient that lowers the pH of the substance or solution by increasing acidity since the acidifying agent has a property of having a hydrogen ion concentration greater than that of a hydroxyl ion when ionized in an aqueous solution. . Specifically, in the present invention, the acidifying agent is an excipient having an acidifying effect or enhancing acidity, and means an excipient capable of imparting a pH not exceeding 7 to an aqueous solution or dispersion.

Acidifying agents according to the present invention are those which are dissolved in water or have a pH of less than 7 at the time of dispersion, such as organic acids such as alginic acid; Mineral acids selected from the group consisting of phosphoric acid, sulfuric acid, hydrochloride, boric acid, hydrogen bromide and mixtures thereof; And mixtures thereof. Preferably, it may be selected from the group consisting of phosphoric acid, alginic acid and mixtures thereof, and more preferably phosphoric acid, but is not limited thereto.

The pharmaceutical composition of the present invention may include an acidulant within a range of a daily allowable amount in consideration of stability, and 0.01 to 1 part by weight (ie, total weight of the total composition) based on 1 part by weight of eferison or a pharmaceutically acceptable salt thereof. 0.1 to 60% by weight), preferably 0.02 to 0.4 parts by weight, more preferably 0.04 to 0.2 parts by weight.

In the case of tablets containing acidifying agents, sticking phenomenon (stickiness of the composition on the machine) may occur in the production process. In order to be able to inhibit the production, it is even more preferable that the pharmaceutical composition of the present invention contains the acidifying agent in an amount of 0.05 to 0.1 parts by weight based on 1 part by weight of eferison or a pharmaceutically acceptable salt thereof.

(3) pharmaceutically acceptable excipients

The pharmaceutical composition according to the invention comprises a pharmaceutically acceptable excipient. The pharmaceutically acceptable excipient may be a component selected from the group consisting of a dispersant, a disintegrant, a lubricant, a binder, other acidifiers and mixtures thereof, and generally any excipient used in the pharmaceutical field may be used. .

In the present invention, the dispersant may use a component selected from the group consisting of lactose, microcrystalline cellulose, mannitol, and mixtures thereof, but is not limited thereto. The dispensing agent may be contained in an amount of 15 to 70% by weight, preferably 25 to 50% by weight, based on the total weight of the composition.

In the present invention, a disintegrant may use a component selected from the group consisting of corn starch, crospovidone, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropyl cellulose, and mixtures thereof, but is not limited thereto. The disintegrant may be contained in an amount of 3 to 20% by weight, preferably 5 to 10% by weight, based on the total weight of the composition.

In the present invention, the binder may be a component selected from the group consisting of povidone, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and mixtures thereof, but is not limited thereto. The binder may be contained in an amount of 1 to 10% by weight, preferably 3 to 7% by weight, based on the total weight of the composition.

In the present invention, the lubricant may be a component selected from the group consisting of talc, stearic acid, magnesium stearate, and mixtures thereof, but is not limited thereto. Glidants may be contained in an amount of 0.5 to 5% by weight, preferably 2 to 4% by weight, based on the total weight of the composition.

The pharmaceutical composition of the present invention is characterized in that, when dissolved or dispersed in 10-20 mL of water, for example, the pH of the solution or dispersion is 1-5.

The present invention also provides a pharmaceutical formulation prepared using the pharmaceutical composition. The pharmaceutical preparations of the present invention may be in the form of solid oral preparations selected from the group consisting of powders, granules, pellets, tablets and capsules, preferably in tablet form.

The present invention also provides a method for preparing a granule comprising (i) preparing granules comprising epherisone or a pharmaceutically acceptable salt thereof, an acidifying agent and a pharmaceutically acceptable excipient; And (ii) mixing the granules with a pharmaceutically acceptable excipient.

In step (i), the granules may be prepared by mixing eperison or a pharmaceutically acceptable salt thereof, an acidifying agent and a pharmaceutically acceptable excipient. At this time, in order to evenly mix the components with the main component, it is preferable to sift through a sieve of 30 to 80 mesh (mesh) and then mix.

The granulation step may be performed by a dry granulation process or a wet granulation process.

The dry granulation process in the present invention comprises the steps of: a) mixing the epherisone or pharmaceutically acceptable salts, acidifying agents and pharmaceutically acceptable excipients (eg, dispersants, disintegrants and binders); b) compression molding the mixture to produce granules; And c) crushing the compacted granules to obtain dry granules.

In the dry granulation process, the compression molding of the mixture is a roller compactor, and the crushing of the compacted granulation is a device commonly used in granulation processes such as a crushing granulator (Oscillator and Fitz mill). Can be performed using

The wet granulation process in the present invention comprises the steps of: a) dissolving and dispersing the acidifying agent and the pharmaceutically acceptable excipient in the binder solution to prepare a mixed binder solution; b) admixing the epherisone or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, then associating the prepared combined binder solution; And c) drying and crushing the association to obtain wet granules.

In the wet granulation process, the association of the mixed binder solution is performed using a high speed mixer or a fluid bed granulator, and the crushing of the union is a granulation process such as a crushing granulator (oscillator or pits mill). This can be done using devices commonly used in the city.

The acidifying agent in step (i) can be used in the granulation process as follows to increase the contact specific surface area with epherisone or a pharmaceutically acceptable salt thereof.

For example, the acidifying agent can be mixed with the active ingredient and a pharmaceutically acceptable excipient and sieved through a sieve of 30 to 80 mesh and the resulting mixture can be subjected to a dry or wet granulation process.

Alternatively, the acidifying agent may be dissolved or dispersed in the binder solution to prepare a mixed binder solution, which is then combined with the active ingredient and a pharmaceutically acceptable excipient and applied to the wet granulation process.

In step (ii), the pharmaceutically acceptable excipient is further mixed with the granules prepared in step (i). In this case, the pharmaceutically acceptable excipient is as described above, and for example, a dispersant, a disintegrant and a lubricant may be used.

The preparation method of the present invention may further comprise formulating the final mixture prepared in step (ii) in the form of an oral solid preparation selected from the group consisting of powders, granules, pellets, tablets and capsules.

Specifically, the final mixture prepared in step (ii) may be prepared in the form of an oral solid preparation according to a conventional pharmaceutical preparation method, and according to one embodiment of the present invention, in step (ii) The final mixture prepared can be tableted by tableting with a tablet machine.

The inventors have surprisingly found that certain acidifying agents, such as phosphoric acid, alginic acid, and the like, can effectively inhibit the decomposition of eferison hydrochloride by external environments such as temperature, humidity, oxygen, light, etc., compared to other conventional stabilizers, thereby reducing drug efficacy or It has been confirmed that it has an effect of preventing side effects due to the flexible material. It was confirmed that certain acidifying agents such as phosphoric acid and alginic acid effectively inhibit the formation of the analogues of eferison hydrochloride. In addition, it showed below the criteria of the Guidelines for the International Cooperation of Medicines on Eperisone Hydrochloride, and confirmed that it can suppress the formation of lead substances.

Hereinafter, the present invention will be described in detail based on the following examples. However, the following examples are only for illustrating the present invention, and the scope of the present invention is not limited thereto.

Example 1: Preparation of Tablets

Eperisone containing tablets were prepared using the ingredients and contents listed in Table 1 below. Specifically, epherisone hydrochloride (Dong Bang Ftiel, Korea) was mixed with lactose, microcrystalline cellulose and corn starch. At this time, the main component was mixed after passing through a 30 mesh circular body so as to be evenly mixed. Separately, povidone was added to purified water and stirred to dissolve. Then, phosphoric acid was added to form a binding solution, which was then added to the mixture containing epherizone hydrochloride and coalesced to prepare an association. The association was dried at 60 ° C. to remove moisture and to establish a 30 mesh prototype. After the microcrystalline cellulose and corn starch were mixed again in the sieved material, talc and magnesium stearate were added and finally mixed. The final mixture was compressed into tablets using a tablet press (GRC-18, Sejong Pharmatech) to prepare a tablet.

Examples 2 to 5: Preparation of Tablets

Eperisone containing tablets were prepared using the ingredients and contents listed in Table 1 below. The tablets were prepared in the same manner as in Example 1, except that alginic acid, fumaric acid, ascorbic acid, and ersorbic acid were used instead of phosphoric acid used in the preparation of the binder solution in Example 1, respectively.

Comparative Example 1: Preparation of Tablet

Eperisone containing tablets were prepared using the ingredients and contents listed in Table 1 below. In this case, except that phosphoric acid was not used in Example 1, tablets were prepared in the same manner as in Example 1.

Raw material name Amount (mg) Example 1 Example 2 Example 3 Example 4 Example 5 Comparative Example 1 inside
Granules  Eperisone Hydrochloride 50 50 50 50 50 50  Lactose 15 15 15 15 15 15 Microcrystalline cellulose 7 7 7 7 7 7  Corn starch 5 5 5 5 5 5  Povidone 4 4 4 4 4 4  Phosphoric Acid 5 - - - - -  Alginic acid - 5 - - - -  Fumaric acid - - 5 - - -  Ascorbic acid - - - 5 - -  Ersorbic acid - - - - 5 -  Purified water 30 30 30 30 30 30 Add
Granules  Microcrystalline cellulose 5 5 5 5 5 5  Corn starch 5 5 5 5 5 5  Talc One One One One One One  Magnesium stearate One One One One One One Total 98 mg 98 mg 98 mg 98 mg 98 mg 93 mg

Example  6: manufacture of tablets

Eperisone containing tablets were prepared using the ingredients and contents listed in Table 2 below. Specifically, epherisone hydrochloride (Dong Bang Ftiel, Korea) was mixed with alginic acid, lactose, microcrystalline cellulose and corn starch. At this time, the main component was mixed after passing through a 30 mesh circular body so as to be evenly mixed. After the compressed powder is made into a uniform size and shape of a ribbon shape using a roller compactor (FREUND), the compressed granule is crushed or divided using an oscillator (FREUND) to irregular shape. Dry granules were prepared.

Microcrystalline cellulose and corn starch were added to the dry granules and mixed again, and talc and magnesium stearate were added and finally mixed. The final mixture was compressed into tablets using a tablet press (GRC-18, Sejong Pharmatech) to prepare a tablet.

Comparative example  2: Preparation of tablets

Eperisone containing tablets were prepared using the ingredients and contents listed in Table 2 below. In this case, except that the alginic acid was not used to prepare the internal granules in Example 6, tablets were prepared in the same manner as in Example 6.

 Raw material name Amount (mg) Example 6 Comparative Example 2 inside
Granules  Eperisone Hydrochloride 50 50  Alginic acid 5 -  Lactose 15 15  Microcrystalline cellulose 7 7  Corn starch 5 5  Povidone 4 4 Add
Granules  Microcrystalline cellulose 5 5  Corn starch 5 5  Talc One One  Magnesium stearate One One Sum 98 mg 93 mg

Example  7: Preparation of tablet

Eperisone containing tablets were prepared using the ingredients and contents listed in Table 3 below. Specifically, epherisone hydrochloride (Dong Bang Ftiel, Korea) was mixed with lactose, microcrystalline cellulose and corn starch. At this time, the main component was mixed after passing through a 30 mesh circular body so as to be evenly mixed. Separately, povidone was added to purified water and stirred to dissolve. Then, phosphoric acid was added to form a binding solution, which was then added to the mixture containing epherizone hydrochloride and coalesced to prepare an association. The union was dried at 60 ° C. to remove moisture and sintered into 30 mesh prototypes to produce wet granules. After further mixing microcrystalline cellulose and corn starch in the wet granules, talc and magnesium stearate were added and finally mixed. The final mixture was compressed into tablets using a tablet press (GRC-18, Sejong Pharmatech) to prepare a tablet.

Examples 8 and 9: Preparation of Tablets

Eperisone containing tablets were prepared using the ingredients and contents listed in Table 3 below. In this case, except that the amount of phosphoric acid added to the binding liquid in Example 7 was used in the same manner as in Example 7 to prepare a tablet.

 Raw material name Amount (mg) Example 1 Example 7 Example 8 Example 9 inside
Granules  Eperisone Hydrochloride 50 50 50 50  Lactose 15 15 15 15 Microcrystalline cellulose 7 7 7 7  Corn starch 5 5 5 5  Povidone 4 4 4 4  Phosphoric Acid 5 1.25 2.5 10  Purified water 30 30 30 30 Add
Granules  Microcrystalline cellulose 5 5 5 5  Corn starch 5 5 5 5  Talc One One One One  Magnesium stearate One One One One Sum 98 mg 94.25 mg 95.5 mg 103 mg

Example  10: Preparation of Tablet

Eperisone containing tablets were prepared using the ingredients and contents listed in Table 4 below. Specifically, epherisone hydrochloride (Dong Bang Ftiel, Korea) was mixed with lactose, microcrystalline cellulose and corn starch. At this time, the main component was mixed after passing through a 30 mesh circular body so as to be evenly mixed. Separately, povidone was added to purified water, followed by stirring to dissolve. Alginic acid was added to the mixture to form a binding solution. The union was dried at 60 ° C. to remove moisture and sintered into 30 mesh prototypes to produce wet granules. After further mixing microcrystalline cellulose and corn starch in the wet granules, talc and magnesium stearate were added and finally mixed. The final mixture was compressed into tablets using a tablet press (GRC-18, Sejong Pharmatech) to prepare a tablet.

Examples 11 and 12 Preparation of Tablets

Eperisone containing tablets were prepared using the ingredients and contents listed in Table 4 below. In this case, except that the amount of the alginic acid added to the binding solution in Example 10 was used in the same manner as in Example 10 to prepare a tablet.

 Raw material name Amount (mg) Example 2 Example 10 Example 11 Example 12 inside
Granules  Eperisone Hydrochloride 50 50 50 50  Lactose 15 15 15 15  Microcrystalline cellulose 7 7 7 7  Corn starch 5 5 5 5  Povidone 4 4 4 4  Alginic acid 5 2.5 10 20  Purified water 30 30 30 30 Add
Granules  Microcrystalline cellulose 5 5 5 5  Corn starch 5 5 5 5  Talc One One One One  Magnesium stearate One One One One Sum 98 mg 95.5 mg 103 mg 113 mg

Experimental Example  One: Eperison  Forced decomposition test of hydrochloride

In order to confirm the effect of the acidifying agent on the suppression of the formation of analogues of eferison hydrochloride, the forced decomposition test of the active ingredient eferison hydrochloride was carried out as follows. Test conditions are as follows.

-Forced decomposition test condition-

(1) Decomposition conditions: Strong acid (0.1N hydrochloric acid), strong base (0.1N sodium hydroxide), oxidation (10% hydrogen peroxide), heat (90 ° C)

(2) Test sample: Eperison hydrochloride

Specifically, in order to confirm under which conditions eferison hydrochloride accelerates decomposition, the solution of eferison hydrochloride dissolved in acetonitrile was left for 2 hours under the above four conditions. Subsequently, liquid chromatography was performed under the following analytical conditions using a solution prepared so that the final concentration of eferisone hydrochloride was 1000 μg / mL, and the result of analyzing the formation of the flexible substance was shown in FIG. 1. .

<Analysis condition>

(1) Column: A column packed with a octadecylsilylated silica gel for chromatography having a particle diameter of 5 μm in a stainless tube having an inner diameter of about 4.6 mm and a length of 15 cm.

(2) Mobile phase: Methanol: 0.0375 mol / L 1-decanesulfonic acid sodium: phosphoric acid

             = 600: 400: 1 (v / v)

(3) Detector: ultraviolet absorption photometer (wavelength 254 nm)

(4) Flow rate: Adjusted so that the holding time of eferison is about 17 minutes

(5) Analysis temperature: 30 ℃

(6) Injection amount: 20 μL

(7) Analysis time: twice as long as holding eferison

(8) Extract: Mobile Phase

As shown in FIG. 1, it was confirmed that the formation of the flexible material rapidly increased at 0.1 N sodium hydroxide and 90 ° C. conditions, and the formation of the flexible material was not observed at 0.1 N hydrochloric acid. Therefore, it was confirmed that the eferison hydrochloride is stable in the acidic condition without the formation of a flexible substance, and the acidifying agent is an excellent stabilizer for improving the stability of the eferison hydrochloride.

Experimental Example 2: Severity Storage Stability Test

In order to confirm that the acidifying agent affects the stability of the eferison hydrochloride, the tablets prepared in Examples 1 to 12 and Comparative Examples 1 and 2 were stored for 4 weeks under the following severe storage conditions.

Severity Storage Stability Test Conditions

(1) Temperature and humidity: Severe storage conditions (60 ℃ ± 2 ℃)

(2) Sample packaging form: HDPE bottle

(3) Test time: From the date of manufacture until the time of 4 weeks

After 4 weeks, the test samples were taken at least about 20 tablets and pulverized into fine powder. Then, the solution was adjusted to a concentration of 1000 μg / mL in the extract (mobile phase) as a sample solution. Liquid chromatography was performed in the same manner as in the analysis of the degree of formation of the flexible material. The results are shown in FIGS. 2-5 and Tables 5-8.

As shown in Table 5 and FIG. 2, after 4 weeks of severe stability, the degree of formation of the flexible substance was significantly higher than those of Examples 3 to 5, which include the acidifying agents, phosphoric acid and alginic acid, as stabilizing agents. Low. Therefore, it can be seen that certain acidifying agents such as phosphoric acid and alginic acid effectively inhibited the formation of analogues derived from eferison hydrochloride.

Time (Note) Example 1 Example 2 Example 3 Example 4 Example 5 Comparative Example 1 0 0.005 0.008 0.773 1.893 1.491 0.035 2 0.014 0.021 0.874 2.731 2.073 0.11 4 0.019 0.035 1.021 3.157 4.303 0.241

In addition, the results of the formation of a flexible material according to the presence or absence of the addition of the acidifying agent of the preparation containing eferison hydrochloride prepared by the dry granulation process are shown in Table 6 and FIG. As shown in FIG. 3, the results of analysis of the soft material of Example 6 including alginic acid and Comparative Example 2 including no acidifying agent after 4 weeks of severity stability showed that Example 6 was more stable than Comparative Example 2. Can be. Therefore, it can be seen that certain acidifying agents effectively inhibit the generation of the flexible substance even in preparations containing epherisone hydrochloride prepared as dry granules.

Time (week) Example 6 Comparative Example 2 0 0.005 0.025 2 0.012 0.035 4 0.024 0.063

Table 7 and 8, and Figures 4 and 5 show the results of the formation of a flexible material of the preparation containing the eferison hydrochloride according to the addition amount of the acidifying agent.

As shown in Table 7 and Figure 4 it was confirmed that the formation of the flexible material is suppressed when phosphoric acid, a kind of inorganic acid is added. As the amount of phosphoric acid added increases, the amount of formation of the flexible substance decreases, but when the amount is more than a certain amount, it is confirmed that the effect of suppressing the flexible substance is similar.

Example 1 Example 7 Example 8 Example 9 Comparative Example 1 0 0.005 0.002 0.003 0.002 0.035 2 0.014 0.028 0.021 0.013 0.11 4 0.019 0.057 0.04 0.02 0.241

Example 2 Example 10 Example 11 Example 12 Comparative Example 1 0 0.008 0.008 0.012 0.011 0.035 2 0.021 0.052 0.021 0.022 0.11 4 0.035 0.11 0.031 0.032 0.241

As shown in Table 8 and Figure 5, it was confirmed that the addition of the flexible material is suppressed when the alginic acid which is a kind of organic acid is added. As the amount of alginic acid added increases, the amount of generation of the flexible substance decreases, but when the amount is greater than or equal to a certain amount, the effect of suppressing the flexible substance is similar.

As mentioned above, it can be seen that, under severe stability conditions, addition of an acidifying agent to the preparation containing eferison hydrochloride can effectively suppress the formation of the flexible substance.

Experimental Example 3: Accelerated Storage Stability Test

In order to confirm the effect of the acidifier on the stability of the eferison hydrochloride, the tablets prepared in Examples 1 and 2 and Comparative Example 1 were stored for 6 months under the following accelerated storage conditions.

-Accelerated storage stability test conditions-

(1) Temperature and humidity: Accelerated storage conditions (60 ℃ ± 2 ℃, 75% relative humidity)

(2) Sample package type: HDPE bottle

(3) Time of test: From the date of manufacture until the end of 6 months

 After 6 months, the test samples were taken at least about 20 tablets and pulverized into fine powder. Then, the solution was adjusted to a concentration of 1000 μg / mL in the extract (mobile phase) as a sample solution. Liquid chromatography was performed in the same manner as described above, and the results of analysis of the degree of formation of the flexible material are shown in Table 9 and FIG. 6.

Example 1 Example 2 Comparative Example 1 0 0.005 0.008 0.035 2 0.012 0.018 0.072 4 0.026 0.037 0.162 6 0.043 0.072 0.335

As shown in Table 9 and Figure 6 it can be seen that after 6 months of accelerated stability, the degree of formation of the flexible material is significantly lower than in Example 1 and the comparative example 1 containing the acidifying agent without the acidifying agent.

Therefore, it can be seen that the acidifying agents phosphoric acid and alginic acid effectively inhibited the formation of a flexible substance due to the eferison hydrochloride under accelerated storage conditions.

Claims (22)

A pharmaceutical composition comprising eferison or a pharmaceutically acceptable salt, acidifying agent and pharmaceutically acceptable excipient thereof. The method of claim 1,
The pharmaceutical composition, characterized in that the eferison or a pharmaceutically acceptable salt thereof is eperison hydrochloride. The method of claim 1,
The pharmaceutical composition is characterized in that the pH is 1 to 5 when the pharmaceutical composition is dissolved or dispersed in 10 to 20 mL of water. The method of claim 1,
The acidifier is alginic acid; Inorganic acids selected from the group consisting of phosphoric acid, sulfuric acid, hydrochloride, boric acid, hydrogen bromide and mixtures thereof; And mixtures thereof. The method of claim 1,
Pharmaceutical composition, characterized in that the acidifier is selected from the group consisting of phosphoric acid, alginic acid and mixtures thereof. The method of claim 1,
Pharmaceutical composition, characterized in that the acidifying agent is phosphoric acid. The method of claim 1,
The acidifying agent is a pharmaceutical composition, characterized in that it comprises 0.01 to 1 part by weight based on 1 part by weight of eferison or a pharmaceutically acceptable salt thereof. The method of claim 1,
The acidifying agent is characterized in that it comprises 0.05 to 0.1 parts by weight based on 1 part by weight of eferison or a pharmaceutically acceptable salt thereof. The method of claim 1,
Pharmaceutical composition, characterized in that the pharmaceutically acceptable excipients are selected from the group consisting of dispersants, disintegrants, binders, glidants, and mixtures thereof. The method of claim 9,
The pharmaceutical composition, characterized in that the distribution agent is selected from the group consisting of lactose, microcrystalline cellulose, mannitol and mixtures thereof. The method of claim 9,
The disintegrant is characterized in that selected from the group consisting of corn starch, crospovidone, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropyl cellulose, and mixtures thereof. The method of claim 9,
Pharmaceutical composition, characterized in that the binder is selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methyl cellulose and mixtures thereof. The method of claim 9,
The lubricant composition is characterized in that selected from the group consisting of talc, stearic acid, magnesium stearate and mixtures thereof. The method of claim 9,
The dispersant is 15 to 70% by weight based on the total weight of the composition, the disintegrant is 3 to 20% by weight based on the total weight of the composition, the binder is 1 to 10% by weight based on the total weight of the composition, the lubricant is the total weight of the composition A pharmaceutical composition, characterized in that included in an amount of 0.5 to 5% by weight. A pharmaceutical formulation prepared using the pharmaceutical composition of any one of claims 1 to 9. The method of claim 15,
Pharmaceutical formulation, characterized in that the pharmaceutical formulation is in the form of solid oral formulations selected from the group consisting of powders, granules, pellets, tablets, and capsules. 17. The method of claim 16,
Pharmaceutical formulation, characterized in that the pharmaceutical formulation is in tablet form. (i) preparing a granule comprising epherisone or a pharmaceutically acceptable salt thereof, an acidulant and a pharmaceutically acceptable excipient; And
(ii) mixing the granules with a pharmaceutically acceptable excipient
A method for producing a pharmaceutical formulation according to claim 15 comprising a. The method of claim 18,
In the step (i), each component is sieved through a sieve of 30 to 80 mesh (mesh), followed by mixing to produce granules. The method of claim 18,
Step (i) comprises the steps of: a) mixing the epherisone or a pharmaceutically acceptable salt, acidifying agent and pharmaceutically acceptable excipient thereof; b) compression molding the mixture to produce granules; And c) crushing the compacted granules. The method of claim 18,
Step (i) comprises the steps of: a) dissolving and dispersing the acidifying agent and the pharmaceutically acceptable excipient in the binder to prepare a mixed binder; b) admixing the epherisone or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, then associating the prepared combined binder solution; And c) drying and crushing the coalescence to obtain a wet granule. The method of claim 18,
The preparation method is characterized in that it further comprises the step of formulating the mixture obtained in step (ii) into an oral solid preparation selected from the group consisting of powders, granules, pellets, tablets, and capsules.

Images