‘ (12) INTERNATIONAL APPLICATION PUBL (19) World Intellectual Property Organ Z 2 International Bureau (43) International Publication Date 18 July 2013 (18.07.2013) SHED UNDER TH p PATE! ‘T COOPERATION TREATY (PCT) ANOKA 0 (10) International Publication Number WO 2013/105819 Al WIPO|PCT 61) ay @ es) 26) 60) om m International Patent Classification AGIK 31/445 (2006.01) A6IK 920200601) ABIK 31/435 (2006.01) 461K 948 (200601) International Application Number PCT/KR2013/000253 11 January 2013 (11.01.2013) age: English anguage: English Priority Data: 10-2012-0004432 13 January 2012(13.01.2012) KR Applicant; HANMI PHARM. CO., LTD. [K&/KR}} #893-5, Hajeorri, Paltan-myeon, Hwascong-si, Gyeong: indo 445-910 (KR), Inventors: KIM, Yong Ul; Jinheung Apt, 147-2201, Hiwasco-dong, Paldal-gn, Suwon-si, Gyeonggi-do 442-718 (KR). KWON, Yeong’ Jin; Sinchang Apt, 112-1004, Suyoung-ri, Bongdam-eup, Hwaseong-si, Gyeonggi-do 445-896 (KR). SEO, Dong Woo; 102-ho, #443-106, ‘Yuljeon-dong, Jangan-pu, Susvon-si, Gyeongsi-do 440-828 (KR). PARK, Hyung Min; Neunggok I-cha Hyundai Ho- 4) wn (84) rmetown Apt, 107-1603, #352, Todang-dong, Deoky- ang-pu, Goyang-si, Gyeonggi-do 412-761 (KR). PARK, Jue Hyun; Cheongmyeongmnaeal Dongsin Apt. 311-404, Yeongiong-dong, Yeongiong-gu, Suwon-si, Gyeongai-do 443-737 (KR). WOO, Jong So9; Cheoncheon Prugio Apt. 120-2303, Cheoncheon-dong, Jengan-gu, Suwon-si, Gyeonggi-do 440-330 (KR). FIRSTLAW P.C; Trust Tower, 275-7 Yang: eoul 137-739 (KR), Agent: jne-Dong, Seocho-Ku, Designated States (unless otherwise indicated, for every Kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA; CH, CL, CN, CO, CR, CU, CZ, DE, DK,'DM, DO, DZ, EC, FE, FG, PS, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP. KZ, LA, LC, LK, 1, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, (OM, PA, PE, PG, Pil, PL, PT, QA, RO, RS, RU, RW, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TH, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, G GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, UG, 2M, ZW), Burasian (AM, AZ, BY, KG, KZ, RU, TI, {Continued on next page) = EN % & g a S a 9 S (64) Tite: STABLE PHARMACEUTICAL COMPOSITION COMPRISING EPERISONE OR A PHARMACEUTICALLY AC- CEPTABLE SALT THEREOF AND AN ACIDIFYING AGENT Accelerated conditions Related substances oo 020 020 ono og ol ° (87) Abstract: Provided are @ pharmaceutical composition having an improved. stability comprising eperisone or a pharmaceutically acceptable salt thereof, an acidifying agent and 2 pharmaceutically acceptable excipient, 8 pharmaceutical. formulation prepared using such composition snd a method for preparing the pharmaceutical formulation. The pharm: ceutical composition of the present invention can effectively inhibit the production of re lated substances derived ftom the active in- aredient by employing a parieular acidifying ‘agent and, thus, is useful for a Tong-term sto. age. ‘ample 1 ‘ample 2 ‘acemp. 643TM), Buropean (AL, AT, BE, ES, Fl, FR, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, Si, SK, oM, GA, GN, GQ, SM, TR), OA GW, ML. MR, NE, SN, T (BE, BI, CR, CG, TG) hed: with international search report (Art. 21(3))20 28 30 WO 2013/105819 PCT/KR2013/000253 DESCRIPTION STABLE PHARMACEUTICAL COMPOSITION COMPRISING EPERISONE OR A PHARMACEUTICALLY ACCEPTABLE SALT THEREOF AND AN ACIDIFYING AGENT FIELD OF THE INVENTION ‘The present invention relates to a pharmaceutical composition showing an improved stability comprising eperisone or a pharmaceutically acceptable salt thereof and a particular acidifying agent, a pharmaceutical formulation prepared from the composition and a method for preparing the formulation. BACKGROUND OF THE INVENTION Eperisone is a skeletal muscle relaxant widely used for the treatment of spastic paralysis induced by neurological disorders such as dolorifie spasm, cerebrovascular disorders, spastic spinal paralysis, cervical spondylosis, etc. which are often accompanied by musculoskeletal disorders such as cervico-omo-brachial syndrome, adhesive capsulitis, lumbodynia and the like. Eperisone not only acts on r-motor nerve in the spinal cord to result in muscle relaxation effects but also acts as an analgesic by suppressing the pain reflex via inhibition of the spinal reflex and antagonizing the effect of substance P, a central peptide neurotransmitter which is released in response to nociceptive stimuli, In addition, eperisone functions as a calcium antagonist and an anti-sympathomimetic agent by reducing vascular smooth muscle contraction, thereby helping blood circulation with low adverse side effects, because it acts directly on motor neurons. Eperisone was developed in Japan in the form of eperisone hydrochloride having the structure of formula (1) below, and is commercially available in Japan, India and across East Asia, Currently, many products including Mulex Tab. (Chodang Pharm.) have been approved as skeletal muscle relaxants and are sold in Korea. However, the stability of products containing eperisone is affected by temperature, light, humidity, oxygen and the like during a long-term storage, and suchWO 2013/105819 factors may break down the active ingredient and increase related substances (i.e., impurities such as starting materials, intermediates, byproducts and decomposition products). When the amount of such related substances increases during a long-term storage, the therapeutic effect deteriorates due to quality problems including decrease sin drug potency, Meanwhile, Li Ding, ef al, reported that a significant amount of a decomposed material of formula (If) was produced from an oral pharmaceutical composition containing eperisone hydrochloride in the form of a solid formulation under high temperature and basic conditions (see Li Ding, et al., Journal of Pharmaceutical and 10 Biomedical Analysis, 46, 2008, 282-287), ° | oe “ee Ny Hee I “f HCI cH * ® Hee oy a 1s The inventors of the present invention discovered that products containing eperisone hydrochloride produced related substances and the amount thereof increased under severe conditions (60°C) and accelerated conditions (40°C, 75% relative humidity). It was also confirmed that related substances were produced and the amount of the active ingredient reduced when eperisone hydrochloride was exposed to 20 solvents such as water and ethanol used in a wet granulation process, thereby adversely affecting the stability of the product.10 20 28 30 WO 2013/105819 The inventors of the present invention have found that the stability of a product containing eperisone hydrochloride is significantly improved when a particular acidifying agent is employed as a stabilizer. Further, the types and ratios of the acidifying agent are chosen to satisfy the stability criteria required under the International Conference on Harmonization (ICH) guideline by minimizing the production of related substances. Thus, a pharmaceutical composition with an improved stability having reduced sticking property has been obtained. sul RY OF THE IN TI It is an object of the present invention to provide a pharmaceutical composition with an improved stability containing an eperisone hydrochloride or a pharmaceutically acceptable salt thereof as an active ingredient, It is another object of the present invention to provide a pharmaceutical formulation prepared from such a composition It is a further object of the present invention to provide a method for preparing such a formulation, Accordingly, a pharmaceutical composition of the present invention contains eperisone or a pharmaceutically acceptable salt thereof as an active ingredient, an acidifying agent and a pharmaceutically acceptable exci Also, a pharmaceutical formulation of the present invention is prepared by using the above pharmaceutical composition. Further, thete is provided a method for preparing a pharmaceutical formulation comprising the steps of: (i) preparing granules containing eperisone or a pharmaceutically acceptable salt thereof, an acidifying agent and a pharmaceutically acceptable excipient; and Gi) mixing the granules obtained from step (i) with a pharmaceutically acceptable excipient. A. pharmaceutical composition in accordance with the present invention employs a particular acidifying agent, inhibiting the production of related substances derived from eperisone hydrochloride, thereby preventing undesirable side effects. Such pharmaceutical composition can be safely used for the treatment of cervico-omo-1s 20 25 30 WO 2013/108 PCT/KR2013/000253 brachial syndrome, lumbodynia and the like because the content of the active ingredient can be maintained and its therapeutic effect is preserved. Also, problems associated with the addition of the acidifying agent during the manufacturing process, eg,, sticking, have been improved, and hence, it can be useful in the pharmaceutical industry, BRIEF DESCRIPTIO! OF THE DRAWINGS Fig. 1 is a graph showing production rates of related substances as a result of a forced degradation testing. Fig. 2 is a result of stability test of Examples 1 to 5 and Comparative Example 1 under severe conditions. Fig, 3 is a result of stability test of Example 6 and Comparative Example 2 under severe conditions. Fig. 4 is a result of stability test of Examples 1, 7 and 9 and Comparative Example 1 under severe conditions. Fig. 5 is a result of stability test of Examples 2 and 10 to 12 and Comparative Example | under severe conditions. Fig. 6 is a result of stability test of Examples 1 and 2 and Comparative Example 1 under accelerated conditions. DETAILED DESCRIP” OF THE INVENTY The present invention provides a pharmaceutical composition comprising eperisone or a pharmaceutically acceptable salt thereof as a pharmaceutically active ingredient, an acidifying agent and a pharmaceutically acceptable excipient. 1) Active ingredient ‘An active ingredient employed in the pharmaceutical composition of the present invention is eperisone, which is widely used as a skeletal muscle relaxant, or a pharmaceutically acceptable salt thereof, ‘The pharmaceutically acceptable salt is any pharmaceutically acceptable salt conventionally available, preferably eperisone hydrochloride, but not limited thereto10 1s 20 25 30 WO 2013/105819 The active ingredient may be employed in an amount conventionally acceptable to give pharmacological activity, preferably in an amount ranging from 25 mg to 150 mg, In a preferred aspect of the present invention, eperisone or a pharmaceutically acceptable salt thereof may be employed in an amount ranging from 10 to 60% by weight, preferably 20 to 60% by weight, based on the total weight of the pharmaceutical composition, but not limited thereto. 2) Acidifying ager The pharmaceutical composition of the present invention comprises a particular acidifying agent. Only certain acidifying agents can act as a stabilizing agent in the present invention, which effectively inhibits the production of related substances derived from eperisone hydrochloride, to improve stability of the pharmaceutical composition. The acidifying agent has a property of increasing the concentration of hydrogen ion more than hydroxide ion when in aqueous solution, and thus, represents an excipient that lowers pH of a substance or a solution by increasing acidity thereof. Specifically, an acidifying agent in the present invention may be an excipient which has acidifying effect or increases its acidity, resulting in a pH value of 7 or lower in an aqueous solution or dispersion. ‘The acidifying agent in accordance with the present invention may have a pH value less than 7 when dissolved in water or dispersed, which may be selected from the group consisting of an organic acid such as alginic acid; a mineral acid such as phosphoric acid, sulfuric acid, hydrochloric acid, boric acid, hydrobromic acid and a mixture thereof; and a mixture thereof, preferably phosphoric acid, alginic acid or a mixture thereof, more preferably phosphoric acid, but not limited thereto, A. pharmaceutical composition of the present invention may contain an acidifying agent in an amount within the range of acceptable daily intake for humans, 0.01 to I parts by weight, based on 1 part by weight of eperisone or a pharmaceutically acceptable salt thereof (i.e., 0.1 to 60% by weight based on the total weight of the pharmaceutical composition), preferably 0.02 to 0.4 parts by weight, more preferably 0.04 0 0.2 parts by weight. A sticking phenomenon may occur (a condition where a composition sticks 310 20 25 30 WO 2013/105819 with a tablet machine) during the manufacturing process of tablets containing an acidifying agent. In order to prevent such problem and to satisfy the requirement set forth in the ICH guideline by inhibiting the production of related substances, a pharmaceutical composition in accordance with the present invention preferably contains an acidifying agent in an amount ranging from 0.05 to 0.1 parts by weight, based on 1 part by weight of eperisone or a pharmaceutically acceptable salt thereof. (3) Pharmaceutically acceptable excipient A pharmaceutical composition in accordance with the present invention may contain a pharmaceutically acceptable excipient. The pharmaceutically acceptable excipient may be any conventional excipient commonly used in the pharmaceutical industry, which may be selected from the group consisting of a dispersing agent, a disimegrating agent, a lubricating agent, a binding agent, other acidifying agent(s) and a mixture thereof. Examples of the dispersing agent in the present invention may be selected from the group consisting of lactose, microcrystalline cellulose, mannitol and a mixture thereof, but not limited thereto. The amount of dispersing agent employed may be, based on the total weight of composition, 15 to 70% by weight, preferably 25 to 50% by weight. Examples of the disintegrating agent in the present invention may be selected from the group consisting of corn starch, crospovidone, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropyl cellulose and a mixture thereof, but not limited thereto. The amount of disintegrating agent employed may be, based on the total weight of composition, 3 to 20% by weight, preferably 5 to 10% by weight. Examples of the binding agent in the present invention may be selected from the group consisting of povidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose and a mixture thereof, but not limited thereto. The amount of binding agent employed may be, based on the total weight of composition, 1 to 10% by weight, preferably 3 to 7% by weight. Examples of the lubricating agent in the present invention may be selected from the group consisting of talc, stearic acid, magnesium stearate and a mixture thereof, but not limited thereto. The amount of lubricating agent employed may be, 610 20 28 30 WO 2013/105819 based on the total weight of the composition, 0.5 to 5% by weight, preferably 2 to 4% by weight. The pharmaceutical composition of the present invention has a pH value of | to 5, €g., when dissolved or dispersed in 10 to 20 mL. of water, The present invention provides a pharmaceutical formulation prepared by using the above pharmaceutical composition, The pharmaceutical formulation in accordance with the present invention is in the form of an oral solid pharmaceutical formulation selected from the group consisting of a powder, a granule, a pellet, a tablet and a capsule, preferably in the form of a tablet. Also, the present invention provides a method for manufacturing a pharmaceutical formulation comprising the steps of: (j) preparing granules containing eperisone or a pharmaceutically acceptable salt thereof, an acidifying agent and a pharmaceutical acceptable excipient; and (ii) mixing the granules obtained from step (i) with a pharmaceutically acceptable excipient. In the step (i) above, granules may be prepared by mixing eperisone or a pharmaceutically acceptable salt thereof, an acidifying agent, and a pharmaceutically acceptable excipient. The ingredients were sifted through a 30 to 80 mesh sieve to allow a homogeneous mixture. The process for the preparation of granules may be accomplished by a dry granulation process or a wet granulation process. The dry granulation process in accordance with the present invention comprises the steps of: a) mixing eperisone or a pharmaceutically acceptable salt thereof with an acidifying agent and a pharmaceutically acceptable excipient (e.g., a dispersing agent, a disintegrating agent and a binding agent); b) compressing the mixture into agglomerates; and ¢) pulverizing the compressed agglomerates into dry granules, In the dry granulation process, the compression of the mixture may be 720 28 30 WO 2013/105819 accomplished by using a roller compactor, and the pulverization of the compressed agglomerates may be done by using an oscillator and a Fitz mill, or any conventional device used for a granulation process in the pharmaceutical industry, ‘The wet granulation process in accordance with the present invention comprises the steps of: a) dissolving and dispersing an acidifying agent and a pharmaceutically acceptable excipient in a binding solution to prepare a mixed binding solution; b) combining eperisone or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient with the mixed binding solution prepared; and ©) drying and pulverizing the combined material to obtain wet granules. In the wet granulation process, the combining of the mixed binding solution may be accomplished by using a high speed mixer or a fluid bed granulator, and the pulverizing of the combined material may be accomplished by using an oscillator and a Fitz mill, or any conventional device used for a granulation process in the pharmaceutical industry. The acidifying agent may be used in the step (i) of the granulation process so as to increase the specific surface area in contact with eperisone or a pharmaceutically acceptable salt thereof, For example, the acidifying agent may be mixed with an active ingredient and a pharmaceutically acceptable excipient, sifted through a 30 to 80 mesh sieve, and the resulting mixture may be used for a dry or wet granulation process. Alternatively, the acidifying agent may be dissolved or dispersed in a binding solution to obtain a mixed binding solution, followed by combining with an active ingredient and a pharmaceutically acceptable excipient, The resulting combined material may be used for a wet granulation process. ent may be added to the In step (ii), a pharmaceutically acceptable exci granules prepared in step (i), wherein the pharmaceutically acceptable excipient is as defined above (e.g., a dispersing agent, a disintegrating agent and a lubricating agent). The method may further comprise an additional step of formulating the mixture obtained in step (ii) into an oral solid pharmaceutical formulation in the form selected from the group consisting of a powder, a granule, a pellet, a tablet and a capsule.25 30 WO 2013/105819 Specifically, the final mixture obtained in step (ii) may be prepared into an oral solid pharmaceutical formulation using any conventional method commonly used in the pharmaceutical industry. In an aspect of the present invention, the final mixture obtained in step (ii) may be compressed into a tablet using a tableting machine. Surprisingly, the inventors of the present invention have discovered that a number of acidifying agents (e.g., phosphoric acid and alginic acid) can effectively inhibit the degradation of eperisone hydrochloride induced by an external environment such as temperature, moisture, oxygen, light and the like as compared to other conventional stabilizing agents, thereby preventing reduction in drug efficacy as well as lowering adverse side effects associated with related substances. It was observed that particular acidifying agents such as phosphoric acid and alginic acid have inhibitory activity on the production of related substances derived from eperisone hydrochloride, In addition, the pharmaceutical composition satisfied the requirement set forth in the ICH guideline for eperisone hydrochloride, and hence the inhibitory activity on the production of related substances was confirmed. The following Examples are provided to illustrate preferred embodiments of the present invention, and are not intended to limit the scope of the present invention. Example 1: Preparation of Tablet In accordance with the ingredients listed in Table 1, a tablet containing eperisone was prepared. Specifically, eperisone hydrochloride (Dongbang FTL, Korea) was mixed with lactose, microcrystalline cellulose and com starch. To allow a homogeneous mixture, the ingredients were sifted through a 30 mesh sieve before the mixing, Povidone was added to distilled water in a separate container, and stirred to yield a solution, Phosphoric acid was added thereto, followed by stirring to yield a binding solution. ‘The mixture prepared comprising eperisone hydrochloride was added to the binding solution, followed by combining to obtain combined material. The combined material obtained was dried at 60°C to eliminate moisture, and then pulverized through a 30 mesh sieve. Microcrystalline cellulose and com starch was added to the pulverized material, followed by adding tale and magnesium stearate for10 Is 20 WO 2013/105819 final mixing. The final mixture was compressed into a tablet using a tableting machine (GRC-18, Sejong Pharmatech). Examples 2 to 5: Preparation of Tablet In accordance with the ingredients listed in Table 1, tablets containing eperisone were prepared. The procedure of Example 1 was repeated except for using alginic acid, fumaric acid, ascorbic acid and erythorbic acid, instead of phosphoric acid, to prepare a tablet. Comparative Example 1: Preparation of Tablet In accordance with the ingredients listed in Table 1, a tablet containing eperisone was prepared. The procedure of Example 1 was repeated to prepare a tablet except that no phosphoric acid was employed. Tabk Componest OCT fet [ees [ee Ped [eS Cor Tare Epemone 30 30 0 30 30 P30 sranvles_| hydrochloride Lactose is i Micron saline cellulose Com sarc 5 Fovidone a 5 Phosphor acid alge Foran a Ascorbic ald Enthoble aid Disilled water [3 Micwaysallie | 3] Additional |_ “cellulose aranules [Com starch Ts Magnesium sere 1 7 Tot Bmg_| mg HW mg [V8 mg |W mg | me] Example 6: Preparation of Tablet In accordance with the ingredients listed in Table 2, a tablet containing eperisone was prepared, Specifically, eperisone hydrochloride (Dongbang FTL, Korea) was mixed with alginic acid, lactose, microcrystalline cellulose and corn starch. The ingredients were sifted through a 30 mesh sieve to allow a homogeneous mixture.Is 25 WO 2013/105819 ‘The mixture was formed into a compressed material having a ribbon shape in uniform size by using a roller compactor (Freund), followed by pulverizing or dividing the prepared compressed materials to obtain dry granules with irregular shape by using oscillator (Freund). ‘The dry granules obtained were mixed with microcrystalline cellulose and com starch, followed by adding talc and magnesium stearate for final mixing. The final mixture was compressed into a tablet using a tableting machine (GRC-18, Sejong Pharmatech). Comparative Example 2: Preparation of Tablet In accordance with the ingredients listed in Table 2, a tablet containing eperisone was prepared, The procedure of Example 6 was repeated to prepare a tablet except that no alginic acid was employed. Table 2 - ~ Component ‘Amount Gray Example 6 ‘Comparative Example? ‘Core granules | Eperisone hydrochioride = 30 7 Alginic acid 3 5 Tctose is i “Mierosrstallne Talons 7 = | Corn starch 5 5 = Povidone -——— 1 ‘aaional | — Meroe stalline exToose 5 s sganules Com sarc 3 3 Tale i i ‘Magaesium searate os = Total mg 35 mg Example 7: Preparation of Tablet In accordance with the ingredients listed in Table 3, a tablet containing eperisone was prepared. Specifically, eperisone hydrochloride (Dongbang FT Korea) was mixed with lactose, microcrystalline cellulose and com starch. These ingredients were sifted through a 30 mesh sieve to allow a homogenous mixture. Povidone was added to distilled water in a separate container, and stirred to yield a solution. Phosphoric acid was added thereto, followed by stirring to yield a binding solution, The mixture prepared containing eperisone hydrochloride was added to the binding solution, followed by combining to obtain a combined material. The20 WO 2013/105819 ture, and then combined material obtained was dried at 60°C to eliminate m: pulverized through a 30 mesh sieve to prepare wet granules. Microcrystalline cellulose and corn starch were additionally mixed, followed by adding tale and magnesium stearate for final mixing. The final mixture was compressed into a tablet using a tableting machine (GRC-18, Sejong Pharmatech). Examples 8 and 9: Preparation of Tablet In accordance with the ingredients listed in Table 3, tablets containing eperisone were prepared, The procedure of Example 7 was repeated to prepare a tablet except that different amounts of phosphoric acid added to the binding solution were used. Copan asa a angie [Bamps amend com game} Epos 3 o 2 3 | Iyceare aoe a Wierecysaline 7 7 7 7 caluise as 5 3 3 3 ono i i i a Phosphor sad $ is 35 in Sse 30 30 30 3 ‘aliional } Mirorstatine 3 $ 3 $ Traies__ | ettioe _ : dansk 3 3 5 Tae i t | ee i T i t ee eae ee Example 10: Preparation of Tablet In accordance with the ingredients listed in Table 4, tablets containing eperisone were prepared. Specifically, eperisone hydrochloride (Dongbang FTL, Korea) was mixed with lactose, microcrystalline cellulose and com starch, The said ingredients were sifted through a 30 mesh sieve to allow a homogeneous mixture Povidone was added to distilled water in a separate container, and stirred to yield a solution. Alginic acid was added thereto, followed by stirring to yield a binding solution, ‘The mixture prepared containing eperisone hydrochloride was added to the binding solution, followed by combining to obtain a combined material. TheWO 2013/105819 combined material obtained was dried at 60°C to eliminate moisture, and then pulverized through a 30 mesh sieve to prepare wet granules. Microcrystalline cellulose and com starch were additionally mixed, followed by adding talc and magnesium stearate for final mixing, The final mixture was compressed into a tablet 5 using a tableting machine (GRC-18, Sejong Pharmatech). Examples 11 and 12: Preparation of Tablet In accordance with the ingredients listed in Table 4, tablets containing eperisone were prepared. The procedure of Example 10 was repeated to prepare a 10 tablet except that different amounts of alginic acid added to the binding solution were used. Table 4 E Component ‘Amount (ng) ample Example 10] Example 11 [Example 12 Core granules | Eperisone hydrochloride | so ___s0 50 Lactose 15 15 1s ‘Microcrystalline 7 7 7 cellulose _ Com starch z z 3 5 | Povidone [~~ 4 4 4 Alpinie acid —s 35 10 20 Distilled water 30 30 30 30 Raditional | Microcrystalline 3 5 5 3 granules cellulose Com starch 5 3 3 3 — Tale 0 H i 1 a Magnesium T T T T ~ Tora | 98mg 1 TO mg Td mg 15. Experimental Example 1: Forced Degradation Test of Eperisone Hydrochloride A forced degradation test of eperisone hydrochloride was performed to compare the production rate of related substances according to acidifying agents of the pharmaceutical composition, The test conditions are described hereinafter. 20 Test Conditions for Forced Degradation - Degradation conditions: strong acid (0.1 N hydrochloric acid), strong base (0.1 N sodium hydroxide), oxidation (10% hydrogen peroxide), heat (90°C) - Test sample: eperisone hydrochloride B1s 20 25 30 WO 2013/105819 Specifically, eperisone hydrochloride was dissolved in acetonitrile and the solution was stored under four different degradation conditions mentioned above for 2 hours each so as to determine under which condition degradation of eperisone hydrochloride is accelerated. Thereafter, an eperisone hydrochloride solution was prepared to have a final concentration of 1000 jig/mL, and the resulting solution was analyzed for related substances under the following conditions using a liquid chromatography. ‘The results are shown in Fig. | - Column: stainless column (internal diameter of about 4.6 mm and length of 15 cm) packaged with octasilyl silica gel (5 um diameter) for liquid chromatography luent: Methanol : 0.0375 mol/L. sodium 1-decanesulfonate : phosphoric acid = 600 : 400 : 1 (w/v) - Detector: UV-absorption detector (absorbance at 254 nm) - Flow rate: retention time of eperisone was controlled to approximately 17 minutes = Column temperature: 30°C = Injection volume: 20 pL. ~ Analysis time: 2-fold period of retention time of eperisone - Extraction solution: mobile phase ‘As shown in Fig. 1, a rapid increase of the production of related substances was observed under the storage conditions of 0.1 N sodium hydroxide and 90°C. Under the strong acid condition (0.1 N hydrochloric acid), related substances were not produced, Therefore, eperisone hydrochloride was most stable under acid conditions, without producing any substantial related substances, confirming that an acidifying agent can be useful to enhance the stability of eperisone hydrochloride. Experimental Example 2: Test under Severe Conditions The formulations prepared in Examples 1 to 12, and Comparative Examples 1 and 2 were stored under severe conditions for 4 weeks to compare the stability of eperisone hydrochloride depending on acidifying agents, 420 30 WO 2013/105819 = Storage conditions: severe storage condition (60°C + 2°C) - Sample container: HDPE bottle - Test duration: initial, 2 and 4 weeks after the initial test About 20 or more tablets were obtained after 4 weeks under severe storage conditions, and pulverized to obtain fine powders, Next, the resulting powders were dissolved in an extraction solution (mobile phase) to yield a final concentration of 1000 g/mL. The procedure of Experimental Example 1 for liquid chromatography was repeated to analyze the production of related substances. The results are shown in Figs. 2 to 5 and Tables 5 to 8 As shown in Table 5 and Fig. 2, after being stored under severe conditions, Examples 1 and 2 containing phosphoric acid or alginic acid, as a stabilizer, yielded a significantly less amount of related substances as compared to Examples 3 to 5. Therefore, it was confirmed that some particular acidifying agents can inhibit the production of related substances derived from eperisone hydrochloride more effectively than other acidifying agents. Table Time (weeks) [Example 1 [Example 2 [Example 3 [Example 4 | “Example 3] Comp. Ex. 1 0 0.005 0.008, 0.773 1.893 LO 0.035 2 0.014 0.021 0.874 2731 2.073 On sf 0019 0.035 Loi [3.137 | 4303 0247 Additionally, the results of the production of related substances for formulations containing eperisone hydrochloride prepared by dry granulation process depending on the presence of an acidifying agent are shown in Table 6 and Fig. 3. As shown in Fig. 3, Example 6 containing alginic acid resulted in less related substances than Comparative Example 2 which does not contain alginic acid when stored under severe conditions for 4 weeks. Therefore, it was confirmed that a particular acidifying agent can effectively inhibit the production of related substances in a formulation containing eperisone hydrochloride prepared by a dry granulation process as well. 1520 2s WO 2013/105819 Table 6 Time (weeks) Example 6 Comp Ex? a - 05 11025 —3 “o012 0.035 a 024 0.063 The results of the production of related substances for formulations containing eperisone hydrochloride depending on the amount employed are shown in Tables 7 and 8, and Figs, 4 and 5. As shown in Table 7 and Fig. 4, the production of related substances reduced as the amount of phosphoric acid, a type of inorganic acid, increased. However, it was observed that when the amount of phosphoric acid reaches a certain level, its inhibitory activity on the production of the related substances did not change much. Table 7 — Example 1 | — Example 7 Example ® Example [Comp ExT 7 0.003 0.002 ~ 0.003 0.002 0.035 z 0.014 0.028 0.021 0013 |. 4 0.019 0.057 0.04 0.02 O24 _ Example? [Example 10 [Example 11 [Example 12 [Comp Bx 1 on 0.008) — 0.008 0012 [011 0.038 z 0.021 (0.052 | boa. ~0.022 On 4 0.035 OL ‘0.03 (0.032 O2E As shown in Table 8 and Fig. 5, the production of related substances was reduced as the amount of alginic acid, a type of organic acid, increased. However, it was observed that when the amount of alginic acid reaches a certain level, its inhibitory activity on the production of the related substances did not change much. in the formulations ted As explained above, the production of related substance containing eperisone hydrochloride under severe conditions can be inhil effect ly by employing a particular acidifying agent. Experimental Example 3: Test under Accelerated Conditions The formulations prepared in Examples 1 and 2, and Comparative Example 1 were stored under accelerated conditions for 6 months to compare the stability of 1615 20 28 WO 2013/105819 eperisone hydrochloride depending on the use of acidifying agents. -Storage conditions: accelerated condition (60°C + 2°C, 75% relative humidity) - Sample container: HDPE bottle - Test duration: initial, 2, 4 and 6 months after the initial test ed after 6 months under accelerated About 20 or more tablets were obt storage conditions and pulverized to obtain fine powders, The resulting powders were dissolved in an extracted solution to yield a final concentration of 1000 pg/mL. The procedure of Experimental Example 1 for liquid chromatography was repeated to analyze the production of related substances. The results are shown in Table 9 and Fig. 6 Table 9 = — Baap |g = : anos O08 —> oat 1 aor 4 0.026 | 0.037 @ a3 oom In the result of the accelerated storage condition as shown in Table 9 and Fig. 6, a significant amount of related substances was reduced in Examples 1 and 2 containing an acidifying agent, as compared to Comparative Example 1, which contains no acidifying agent Therefore, it was confirmed that phosphoric acid and alginic acid as an acidifying agent, can inhibit the production of related substances derived from eperisone hydrochloride more effectively under accelerated conditions.10 20 25 30 WO 2013/105819 What is claimed is: 1. A pharmaceutical composition comprising eperisone or a pharmaceutically acceptable salt thereof, an acidifying agent and a pharmaceutically acceptable excipient. 2. The pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable salt of eperisone is eperisone hydrochloride. 3. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition results in a pH value of 1 to 5 when dissolved or dispersed in 10 to 20 mL, of water, 4, The pharmaceutical composition of claim 1, wherein the acidifying agent is selected from the group consisting of alginic acid; an inorganic acid selected from the group consisting of phosphoric acid, sulfuric acid, hydrochloric acid, boric acid, hydrobromic acid and a mixture thereof; and a mixture thereof, 5. The pharmaceutical composition of claim 1, wherein the acidifying agent is selected from the group consisting of phosphoric acid, alginic acid and a mixture thereof, 6. The pharmaceutical composition of claim 1, wherein the acidifying agent is phosphoric acid. 7. The pharmaceutical composition of claim 1, wherein the acidifying agent contained in an amount of 0.01 to 1 part by weight, based on 1 part by weight of eperisone or a pharmaceutically acceptable salt thereof 8. The pharmaceutical composition of claim 1, wherein the acidifying agent is contained in an amount of 0.05 to 0.1 part by weight, based on 1 part by weight of eperisone or a pharmaceutically acceptable salt thereof.20 2s 30 WO 2013/105819 9. ‘The pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable excipient is selected from the group consisting of a dispersing agent, a disintegrating agent, a binding agent, a lubricating agent and a mixture thereof. 10, The pharmaceutical composition of claim 9, wherein the dispersing agent is selected from the group consisting of lactose, microcrystalline cellulose, mannitol and a mixture thereof. 11, The pharmaceutical composition of claim 9, wherein the disintegrating agent is selected from the group consisting of corn starch, crospovidone, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropyl cellulose and a mixture thereof. 12. The pharmaceutical composition of claim 9, wherein the binding agent is selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose and a mixture thereof. 13. The pharmaceutical composition of claim 9, wherein the lubricating agent is selected from the group consisting of tale, stearic acid, magnesium stearate and a mixture thereof, 14, The pharmaceutical composition of claim 9, wherein the dispersing agent is contained in an amount of 15 to 70% by weight, based on the total weight of the composition; the disintegrating agent is contained in an amount of 3 to 20% by weight, based on the total weight of the composition; the binding agent is contained in an amount of 1 to 10% by weight, based on the total weight of the composition; and the lubricating agent is contained in an amount of 0.5 to 5% by weight, based on the total weight of the composition, 15, A pharmaceutical formulation prepared by using the pharmaceutical composition of any one of claims | to 9. 16. The pharmaceutical formulation of claim 15, which is in the form of an 1920 25 30 WO 2013/108 PCT/KR2013/000253 oral solid formulation selected from the group consisting of a powder, a granule, a pellet, a tablet and a capsule. 17, The pharmaceutical formulation of claim 16, which is in the form of a tablet. 18. A method for preparing the pharmaceutical formulation of claim 15, comprising the steps of: (@ preparing granules comprising eperisone or a pharmaceutically acceptable salt thereof, an acidifying agent and a pharmaceutical acceptable excipient; and (ii) mixing the granules obtained from step (i) with a pharmaceutically acceptable excipient. 19, The method of claim 18, wherein each ingredient of step (i) is sifted through a 30 to 80 mesh sieve, and then is mixed to prepare granules, 20. The method of claim 18, wherein step (i) is conducted by a dry granulation process comprising the steps of a) mixing eperisone or @ pharmaceutically acceptable salt thereof with an acidifying agent and a pharmaceutically acceptable excipient; ) compressing the mixture obtained from step (a) into agglomerates; and ©) pulverizing the compressed agglomerates obtained from step (b) into dry granules. 21, The method of claim 18, wherein step (i) is conducted by a wet granulation process comprising the steps of: a) dissolving and dispersing an acidifying agent and a pharmaceutically acceptable excipient in a binding solution to prepare a mixed binding solution; b) combining a mixture of eperisone or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient with the mixed binding solution prepared in step (a); and ©) drying and pulverizing the combined material obtained from step (b) to obtain wet granules 20WO 2013/108 PCT/KR2013/000253 22. The method of claim 18, which further comprises formulating the mixture obtained from step (ii) into an oral solid formulation in a form selected from the group consisting of a powder, a granule, a pellet, a tablet and a capsule. 21WO 2013/105819 PCT/KR2013/000253 1/6 FIG. 1 Forced degradation test 8.07 6.05 Related substances 2.07 0.04 3) aN aot go? xe Oo . so Wi ws cS cH ood «s ro ‘ GOO eon soe 98 i gt Ga pe oe on wor oo% WO 2013/105819 2/6 FIG. 2 Severe conditions 5.00 4.00 3.00 2.00 1.00 0.00 Related substances a 4 Time (week) PCT/KR2013/000253 DExample 1 DExample 2 Example 3 DExample 4 GExample 5WO 2013/105819 PCT/KR2013/000253 3/6 FIG. 3 Severe conditions Related substances 0.15 ~ -- 0.10 % DExample 6 CiComp. Ex. 2 0.05 | -- - 000 +8 AS Time (week)WO 2013/105819 PCT/KR2013/000253 4/6 FIG. 4 Severe conditions Related substances 030 7 ——— — | R 020 - a GExample 1 % Gexample 7 GeExample 8 COR a INGE 0 SComp. Ex. 1 RY 0.00 + - - 0 2 4 Time (week)WO 2013/105819 PCT/KR2013/000253 5/6 FIG. 5 Severe conditions Related substances 030 + | 0.20 |———— DeExample 2 % | DExample 10 | CeExample 11 010 + BExample 12 | Comp. Ex. 1 N wo aoa FIA 0 2 4 Time (week)WO 2013/105819 Accelerated conditions 0.40 0.30 0.20 010 +- 0.00 6/6 FIG. 6 Related substances 2 4 Time (month) PCT/KR2013/000253 GExample 1 example 2 Comp. Ex 1INTERNATIONAL SEARCH REPORT International application No. PCT/KR2013/000253 ‘A. CLASSIFICATION OF SUBJECT MATTER AGIK 31/145(2006.01)i, AGIK 31/435(2006.01)i, AOIK 9/20(2006.01)i, AGIK 9/48(2006.01)i According to International Patent Classification (IPC) oF to both national classification and IPC B_ FIELDS SEARCHED ‘Minimum documentation searched (clasiication system Tollowed by classification symbols) AGIK 31/445; AGIK 9/22; AGIK 31/404; AGLP 29100, AGIK 31/335, AGIK 31/185; AGTK 924 Dovumentaivon searched oiher than minimum documentation To he extent that such documents are meladed tn the TMs Searched ‘Korean uility models and applications For uility models Japanese utility models and applications for utility models i the inlematfonal search (name of data base and, where practicable, search terms wsed) eKOMPASS(KIPO internal) & Keywords: eporisone, aeidiving agent, phosphor avi, alginic acid ‘G__DOCUMENTS CONSIDERED TO BE RELEVANT Category® Citation of document, with indieation, where appropriate, of the relevant passages Relevant to elaim No. A US 2008-0014268 AI (CHERLKURI, 8. B.) 17 January 2008 i See paragraphs [0010]-[0011}, [o024)~[0025], [0088], [0049)-{0052]. [0071]. [o100}-[0103], (0138) and [0136]; and examples 1-4 A US 6136846 A (RUBINFELD, J. et al.) 24 October 2000 re See claims 16-19. A KR 10-2004-0029082 A (ANOREPACTPIC CORPORATION) 21 Apri 2008 re See claims 1-13. A JP 2000-143510 A (TAISHO PHARMACEUTICAL CD., LTD.) 28 May 2000, See clains 1-3. Px | KR 10-1156054 BL (NAVIPHARN. CO., LTD.) 20 June 2012 ree See claims 1, 8, 4, 6 and 7: and paragrapns {0012]-[0015] Further document are listed in the continustion of Box €, DX] See patent family annes. 7 Spas napus of Sa dam TP ter dosument published arth intrmatonal ling date or prion "A" document defining the general stats ofthe ant which sno coms dies not in confit with the pplication butted to understand toe of particular relevance {he principle or thory undying he invention “B* _earier ppication open bu published on rafter th inemationsl °° document of particular elvanse the claimed ivstion cannot Bs filing date ‘sotsidersd novel oe sannot be considered to mole an inventive dlcent which may throw doubs on pry bis) or which i epson the document stan lone cited establish the publication date oF citation or ether "Y> document of particular relevance the chimed invention cannot be special reason (as spsiticd) ‘consideidto involve an inventive stp when the document. is "O" document referring to an onl disclosure, use, exibition or ote ‘combined with one or more other such documentsuch combination meas ‘hing obiodsto a person shill in the art "P*document published poe tothe iateational Filing date but ate ‘han the prority date claimed document member ofthe sme patent Fai Date ofthe actual completion ofthe Intemational search Date of mailing of the Intemational sarch report 30 April 2013 (30.04.2013) 30 April 2013 (30.04.2013) ame and mailing address of he SAIKR ‘Ruthorzed officer Korean Intellectual Property Office 189 Cheongsa-ro, Seo-gu, Daejeon Metropolitan CHOI, Sung Hee City, 302-701, Republie of Korea Facsimile No $2-82-472-7140 Telephone No $2-42-481-8740 Fonm PCTIISA/210 (second sheet) (July 2009)INTERNATIONAL SEARCH REPORT Information on patent family members Intemational application No, PCT/KR2013/000253 Patent document cited in search report Publication date Patent family Publication member(s) date US 2008-0014268 Al US 6136846 A KR 10-2004~0033082 A JP 2000-143510 A KR 10-1156054 Bt 17.01.2008 24, 10.2000 21,04,2004 23,05 .2000 20.06.2012 EP 2084953 AZ Wo 2008-002529 A2 23 SE88 SESSSRRRERES 88 AU 2000-74902 MI CA 2388613 AI ch 1382038 4 EP 1225872 At JP 2003-512416 A Us 2002-0103254 At Us 2003-0191179 At Us 6319943 81 Us 6509370 81 Us 6538020 82 Us 6828346 82 WO 01-90319 AT & FSSLmsSesrsase AU 2003-26951 At ch 1703219 A JP 2006-50387 A WO 2004-092927 A1 BSS SSR28SSS288e8 8S 28 None None Form PCTVISA/210 (patent family annex) (uly 2009)