WO 2007/ Al PCT. (19) World Intellectual Property Organization International Bureau

Transcription

1 (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (43) International Publication Date (10) International Publication Number 12 July 2007 ( ) PCT WO 2007/ Al (51) International Patent Classification: JUNG, Hyun [KR/KR]; , Ssangyong Apt., A61K 31/44 ( ) A61P 9/12 ( ) Yeongtong-dong, Yeongtong-gu, Suwon-si, Gyeonggi-do, (KR). (21) International Application Number: PCT/KR2006/ (74) Agent: KOO, Hyun-Seo; 4f., Byukcheon Bldg., , Seocho-dong, Seocho-gu, Seoul (KR). (22) International Filing Date: 28 December 2006 ( ) (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, (25) Filing Language: Korean AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI, (26) Publication Language: English GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KZ, LA, LC, LK, LR, LS, LT, (30) Priority Data: LU, LV,LY,MA, MD, MG, MK, MN, MW, MX, MY, MZ, January 2006 ( ) KR NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, SV, SY, TJ, TM, TN, TR, (71) Applicant (for all designated States except US): TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW NEOMEDICS CO., LTD. [KR/KR]; 303, 3f., , Guui-dong, Gwangjin-gu, Seoul, (KR). (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (72) Inventors; and GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, (75) Inventors/Applicants (for US only): JUNG, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), Kwang-Yong [KR/KR]; , Doosan Weve Apt., European (AT,BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, 222, Hawolgok-dong, Seongbuk-gu, Seoul, (KR). FR, GB, GR, HU, IE, IS, IT, LT, LU, LV,MC, NL, PL, PT, CHOO, Hyun-Kwang [KR/KR]; 3-601, Hansin Apt., RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, 256-5, Hagye-dong, Nowon-gu, Seoul, (KR). GN, GQ, GW, ML, MR, NE, SN, TD, TG). OH, Woo-Seok [KR/KR]; , Olympic Seonsu Gija-chon Apt., 89, Bangi-dong, Songpa-gu, Seoul, Published: (KR). JEON, Hong-Ryeol [KR/KR]; , with international search report Jugong Greenvill Apt., Maetan-dong, Yeongtong-gu, Suwon-si, Gyeonggi-do, (KR). LEE, Bong-Sang [KR/KR]; , Jugong Apt., 35, Woncheon-dong, Yeongtong-gu, Suwon-si, Gyeonggi-do, (KR). For two-letter codes and other abbreviations, refer to the "G uid ance Notes on Codes and Abbreviations" appearing at the beg in ning of each regular issue of the PCT Gazette. (54) Title: PHARMACEUTICAL FORMULATION CONTAINING AMLODIPINE AND ASPIRIN (57) Abstract: The present invention relates to a pharmaceutical formulation or kit comprising amlodipine or its pharmaceutically acceptable salt; and aspirin. The pharmaceutical formulation and kit according to the present invention have a good stability because the amlodipine and the aspirin are separated from each other. The amlodipine and aspirin exert a bad effect on each other's stability.

2 PHARMACEUTICAL FORMULATION CONTAINING AMLODIPINE AND ASPIRIN [Technical Field] The present invention relates to a pharmaceutical formulation or kit comprising amlodipine and aspirin; and a pharmaceutical composition comprising amlodipine maleate. [Background Art] Amlodipine, a dihydropyridine calcium channel blocker, is a drug relaxing the smooth muscle in the coronary arteries, expanding the coronary arteries, and increasing oxygen supply to vasoconstriction-induced ischemic heart muscle by suppressing influx of calcium ion into calcium channel located in the smooth muscle and heart muscle. Aspirin is a drug often used as an analgesic or antipyretic. In addition, aspirin is discovered to be effective for decreasing risk of non-fatal myocardial infarction and ischemic attack, and preventing re-infarction after the outset of cardiac infarction in patient having instable angina pectoris by suppressing aggregation of platelet. Recently, combination therapy of the two drugs has been studied because it shows a synergic effect in suppressing activity of platelet (Inhibition of platelet activity in vivo by amlodipine alone and combined with aspirin, Int J Cardiol, 1997; 62: Sl Il - Sl 17 and End Organ Protection by Calcium-Channel Blockers, Clin. Cardiol., 2001; 24: ). However, a formulation comprising the two drugs has not been discovered until now. [Disclosure of the Invention] [Technical Problem] Therefore, the object of the present invention is to provide a pharmaceutical formulation or kit comprising both amlodipine and aspirin. Another object of the present invention is to provide an amlodipine maleatecontaining pharmaceutical composition having improved stability.

3 [Technical Solution] The present invention is based on a surprising fact that if amlodipine and aspirin are mixed or in contact with each other, the amlodipine and aspirin do a bad effect on each other's stability. In addition, the present invention is based on another surprising fact that if amlodipine maleate is used as the amlodipine, some ingredient can much increase the stability of amlodipine maleate. Therefore, to achieve the object, the present invention provides a pharmaceutical formulation comprising (a) amlodipine freebase or its pharmaceutically acceptable salt; and (b) aspirin, wherein the amlodipine and the aspirin are separated from each other to block contact between the amlodipine and the aspirin. When amlodipine and aspirin are separated from each other, the stability of amlodipine and aspirin are improved about 5 times and 10 times, respectively, compared to when amlodipine and aspirin are mixed. It is expected for the specific molecular structure of amlodipine and aspirin to cause this difference of stability, and thus amlodipine and aspirin should be separated when a pharmaceutical formulation comprising both active ingredients together is developed. It is conventional to mix both active ingredients in a formulation for combination therapy because of manufacturing cost, but the stability of amlodipine and aspirin is more important factor than the manufacturing cost. In the pharmaceutical formulation according to the present invention, preferably, the content of aspirin and amlodipine are mg and 1-30 mg per formulation, respectively, but the scope of the present invention is not limited to this content range. More preferably, the content of aspirin and amlodipine are mg and 2-30 mg per formulation, and most preferably, the content of aspirin and amlodipine are mg and 3-10 mg per formulation. The pharmaceutical formulation or kit according to the present invention can comprise amlodipine freebase or it's pharmaceutically acceptable salt as the amlodipine ingredient. The pharmaceutically acceptable salt of amlodipine includes, but is not limited to, amlodipine maleate, amlodipine besylate, amlodipine camsylate, amlodipine

4 adipate, amlodipine mesylate or amlodipine nicotinate. More preferably, the present invention provides a pharmaceutical formulation comprising (a) amlodipine freebase or its pharmaceutically acceptable salt; and (b) aspirin, wherein the (a) ingredient or the (b) ingredient; or a granule comprising the (a) ingredient or the (b) ingredient is coated by polymer to block contact between the amlodipine and the aspirin. For example, the pharmaceutical formulation is a capsule comprising both the (a) ingredient (or the granule comprising the (a) ingredient) which is coated by polymer and the (b) ingredient (or the granule comprising the (b) ingredient). Similarly, the pharmaceutical formulation may be a capsule comprising both the (a) ingredient (or the granule comprising the (a) ingredient) and the (b) ingredient (or the granule comprising the (b) ingredient) which is coated by polymer. As said polymer according to the present invention, any polymer can be used if the polymer forms a coating layer to physically block the contact between the (a) ingredient and the (b) ingredient by surrounding any one ingredient or a granule comprising any one ingredient. Examples of the polymer include, but are not limited to, alkylcellulose, hydroxyalkylcellulose, carboxyalkylcellulose, polyvinylalcohol, polyvinylpyrrolidone, polyvinylacetate, polyalkeneoxide, polyalkeneglycol, polyethylene-polypropylene polymer, polyoxyethylene-polyoxypropylene polymer, zein, shellac, diethylaminoacetate, aminoalkylmethacrylate copolymer, sodium alginate, chitosan, gelatin, gum or poly-l-lysine. At lease one polymer selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, methacrylate copolymer, aminoalkylmethacrylate copolymer and ethylcellulose is more preferable when considering the easiness of manufacturing and the stability of amlodipine. In particular, it is preferable to coat aspirin with enteric polymer or polymer for sustained-release compared to coating amlodipine because aspirin can cause stomach side effect. In addition, if amlodipine maleate is used as the (a) ingredient, it is preferable to coat amlodipine maleate because the coating layer can prevent amlodipine maleate from being contact with water as well as aspirin, which can improve the stability of amlodipine maleate. Coating amlodipine, aspirin or granule comprising any one can be performed by

5 any machine or apparatus if the machine or apparatus can spray a coating solution after fluidizing the ingredient powder or granule. For example, fluidized bed coater can be used for coating of the present invention. More preferably, the present invention provides a pharmaceutical formulation comprising (a) amlodipine freebase or its pharmaceutically acceptable salt; and (b) aspirin, wherein the pharmaceutical formulation comprises a tablet or granule comprising any one between the (a) ingredient and the (b) ingredient; first coating layer surrounding the tablet or granule; and second coating layer surrounding the first coating layer and comprising the other ingredient. When considering the compliance of patient taking two different drugs, it is preferred that only one tablet or granule comprises both drugs together. It can be achieved by making a tablet or granule comprising any one between amlodipine and aspirin, making a coating layer for separation with said polymer, and then again coating the tablet or granule having the first coating layer with the other active ingredient and a coating material. This method can make one tablet or granule having two different drugs together without contacting each other. When considering the fact that a dose of aspirin is much more than that of amlodipine, it is more preferable to make a tablet or granule comprising aspirin, make a coating layer for separation, and then make another coating layer with coating solution comprising amlodipine. Conventional tablet-coating machine used for making conventional filmcoating tablet can be used for the coating of said tablet in the present invention. Preferably, the present invention provides a pharmaceutical formulation comprising (a) amlodipine freebase or its pharmaceutically acceptable salt; and (b) aspirin, wherein the pharmaceutical formulation is a multilayered tablet comprising first layer comprising the (a) ingredient; and second layer comprising the (b) ingredient. More preferably, the present invention provides said multilayered tablet comprising a layer or membrane for separating between the first layer and the second layer. Multilayered tablet means a tablet having, for example, two or three separate layers made by the following exemplary processes: tabletting granules having one active ingredient, adding another granules to the prepared tablet having and again

6 tabletting the granules on the prepared tablet; or supplying one kind of granules and another kind of granules into punch hole of tabletting machine one after the other, and tabletting two kinds of granules at a time. The contact between the amlodipine and the aspirin can be prevented because the active ingredients are contained in different layers, respectively. Furthermore, it is more preferable for the multilayered tablet to comprise a layer or membrane for separating each layer from another layer to completely block the contact between the amlodipine and the aspirin. Preferably, the present invention provides a pharmaceutical formulation comprising (a) amlodipine freebase or its pharmaceutically acceptable salt; and (b) aspirin, wherein the pharmaceutical formulation is a press-coated tablet comprising a core tablet comprising any one between the (a) ingredient and the (b) ingredient; and an exterior layer surrounding the core tablet and comprising the other ingredient. More preferably, the present invention provides said press-coated tablet, wherein the core tablet is coated by polymer. Press-coated tablet means a tablet manufactured by preparing a small tablet (the core tablet) with conventional tabletting methods, putting the small tablet into punch hole having some amount of granules, filling punch hole with granules, and then tabletting them. In the press-coated tablet, there is little contact between amlodipine and aspirin because the amlodipine and the aspirin are separately contained in the core tablet or the layer surrounding the core tablet. Furthermore, it is more preferable for the core tablet to be coated with said polymer to completely block the contact. More preferably, the present invention provides a pharmaceutical formulation comprising (a) amlodipine freebase or its pharmaceutically acceptable salt; and (b) aspirin, wherein the pharmaceutical formulation is a capsule comprising a small tablet comprising the (a) ingredient; and another small tablet comprising the (b) ingredient. The present invention also provides a kit comprising (a) a formulation comprising amlodipine freebase or its pharmaceutical acceptable salt; and (b) another formulation comprising aspirin, wherein the formulations are separated from each other to block contact between the amlodipine and the aspirin. Preferably, the present invention provides the kit, wherein the formulation is capsule, microcapsule, tablet or granule. The formulation according to the present invention can further comprise diluent,

7 binder, disintegrant, lubricant and so on except amlodipine and aspirin. Conventional diluent, binder, disintegrant and lubricant can be used if they have a bad effect on the stability of amlodipine and aspirin. For example, the ingredients said in the following "mode for carrying out the invention" are preferable. The present invention also provides a pharmaceutical composition comprising amlodipine maleate and stabilizing ingredient. If amlodipine maleate is used as the amlodipine ingredient, amlodipine maleate is unstable because of creation of impurity D, Michael reaction, etc. This instability can be improved by addition of the stabilizing ingredient. As the stabilizing ingredient, at least one selected from the group consisting of sodium citrate, butylated hydroxy toluene, succinic acid, fumaric acid, tartaric acid and ascorbic acid is preferable, and butylated hydroxy toluene is most preferable. [Mode for carrying out the Invention] Hereinafter, a preferred embodiment of the present invention will be described in detail. Prior to the description, it should be understood that various modifications are possible to the embodiments of the present invention, and it should be understood that the scope of the invention is not limited to the following embodiments. <Example 1> Contact stability test of aspirin and amlodipine maleate Aspirin (10 g), amlodipine maleate (0.642 g), and mixture of aspirin (10 g) and amlodipine maleate (0.642 g) were put in high-density polyethylene (HDPE) plastic bottle, respectively, and stored for stability test at an accelerated condition (40±2 C, 75+5% RH). After 90 days and 180 days, samples were analyzed with change of color and impurities using HPLC as follows. HPLC measuring condition for impurities of amlodipine maleate 50 mg of amlodipine was accurately weighed and put in a flask. The below mobile phase was added in the flask to make 50 ml. Detector: UV-Visible spectrophotometer (detection wavelength: 237 nm) Column: Capcellpak C18 4.5X150 mm, 5 urn Mobile phase: ph 3.0 buffered solution:acetonitrile:methanol = 60:20:20 (ph

8 3.0 buffered solution: 7.0 ml of triethylamine was added in some amount of water, and water was added to make volume 1 liter, and then ph of the prepared solution was adjusted to 3.0 with phosphoric acid.) Flow rate: 2.0 ml/minute Injection volume: 20 ul Calculation method: Impurity (%) = (Peak area of impurity X 100) / Peak area of amlodipine (Percent value of impurity D was multiplied by adjustment factor (3.03)). Measuring condition of free salicylic acid in aspirin 100 mg of aspirin was accurately weighed and put in a flask. After that, samples were tested according to the U.S. Pharmacopeia guidelines for measuring free salicylic acid in enteric coating tablet of aspirin. Results were shown in the below table 1. [Table 1] In the above table 1 and the below tables, N.D. means 'not detected' in the used analysis condition. As shown in table 1, mixing of amlodipine, especially amlodipine maleate, and aspirin accelerated degradation of each other and increased the amounts of impurities. This means the two active ingredients have a bad effect on the stability of each other. <Example 2> Mixing stability test of formulation additives Amlodipine maleate and usually used formulation additives were mixed as weight ratio shown in the below tables, and subject to stability test in the accelerated condition (40+2 C, 75+5% RH) like the method used in example 1. After 90 days

9 and 180 days, samples were analyzed using change of color and impurities like the method of example 1. Diluent and amlodipine maleate were mixed as ratio of 9:1. Effect of each diluent on the stability of amlodipine maleate was evaluated. Results were shown in table 2. [Table 2] In the above table 2 and the below tables, N.C. means 'not changed.' As shown in the above table 2, lactose, mannitol and pre-gelatinized starch were preferable when considering the stability of amlodipine maleate. Binder and amlodipine maleate were mixed as ratio of 1:1. Effect of each binder on the stability of amlodipine maleate was evaluated. Results were shown in table 3. [Table 3]

10 As shown in the above table 3, hydroxypropylcellulose and carbopol were preferable when considering the stability of amlodipine maleate. Disintegrant and amlodipine maleate were mixed as ratio of 1:1. Effect of each disintegrator on the stability of amlodipine maleate was evaluated. Results were shown in table 4. [Table 4] As shown in the above table 4, sodium starch glycolate, cross-povidone and Crosscarmellose sodium were preferable when considering the stability of amlodipine maleate. Lubricant and amlodipine maleate were mixed as ratio of 0.5 :1. Effect of each lubricant on the stability of amlodipine maleate was evaluated. Results were shown in table 5. [Table 5]

11 As shown in the above table 5, colloidal silicon dioxide and talc had a bad effect on the stability of amlodipine maleate. Stabilizing ingredient and amlodipine maleate were mixed as ratio of 0.05:1. Effect of each stabilizing ingredient on the stability of amlodipine maleate was evaluated. Results were shown in table 6. [Table 6] As shown in the above table 6, propyl gallate and sodium metabisulfite had a

12 bad effect on the stability of amlodipine maleate. Film-coating material and amlodipine maleate were mixed as ratio of 3:1. Effect of each film-coating material on the stability of amlodipine maleate was evaluated. Results were shown in table 7. [Table 7] As shown in the above table 7, polyvinylalcohol had a bad effect on the stability of amlodipine maleate. <Stability test according to formulation> Based on the results of the stability tests of the example 2, capsules and tablets were manufactured according to the below components and manufacturing method. A. Aspirin/amlodipine maleate capsule

13 Example 3: Manufacturing granules of amlodipine maleate Based on the effects of additives on the stability of amlodipine maleate, granules according to the below table 8 were manufactured. Butylated hydroxy toluene and hydroxypropylcellulose were dissolved in ethanol to make a binding solution. Amlodipine maleate, pre-gelatinized starch and mannitol were put in a mixer and mixed for about 10 minutes. Granules were manufactured with the binding solution and the mixture through conventional wet granulation method. [Table 8] Examples 4-6: Manufacturing enteric-coated granules of aspirin Enteric-coated granules of aspirin were manufactured like the below table 9. Example 4 was manufactured as follows: First of all, (Sl) propylene glycol and hydroxypropylmethylcellulose 2910 were dissolved in mixture of methylene chloride and ethanol to make a sub-coating solution. After that, (S2) aspirin was put in a fluidized bed coater, and coated (and dried simultaneously) with the coating solution of (Sl) step on condition of C of inlet air, C of outlet air, bar of spraying pressure and ml/minute of spraying rate to prepare the sub-coated pellet of aspirin. (S3) Propylene glycol was dissolved in purified water, and then talc was added to the solution and suspended. (S4) Methacrylic acid copolymer was added to the suspension of (S3) step and mixed well to make a coating solution. (S5) The subcoated pellet of aspirin was put in the fluidized bed coater, coated (and dried simultaneously) with the coating solution of (S4) step on condition of C of inlet air, C of outlet air, bar of spraying pressure and ml/minute of spraying rate to make an enteric-coated pellets of aspirin. Example 5 was manufactured as follows: First of all, (Sl) sub-coated pellets of aspirin were made like example 4. (S2) Fatty acid glycerin ester was dissolved in mixture of purified water and ethanol, and then talc was added to the solution and

14 suspended. (S3) Hydroxypropylmethylcellulose phthalate was added to the suspension of (S2) step and mixed well to make a coating solution. (S4) The sub-coated pellet of aspirin was put in the fluidized bed coater, coated (and dried simultaneously) with the coating solution of (S3) step on condition of C of inlet air, C of outlet air, bar of spraying pressure and ml/minute of spraying rate to make an enteric-coated pellets of aspirin. Example 6 was manufactured as follows: First of all, (Sl) sub-coated pellets of aspirin were made like example 4. (S2) Fatty acid glycerin ester was dissolved in mixture of purified water and ethanol, and then talc was added to the solution and suspended. (S3) Hydroxypropylmethylcellulose acetate succinate was added to the suspension of (S2) step and mixed well to make a coating solution. (S4) The subcoated pellet of aspirin was put in the fluidized bed coater, coated (and dried simultaneously) with the coating solution of (S3) step on condition of C of inlet air, C of outlet air, bar of spraying pressure and ml/minute of spraying rate to make an enteric-coated pellets of aspirin. [Table 9] Comparative example 1: combination capsule of amlodipine maleate/aspirin Amlodipine maleate and aspirin enteric pellets of example 4 were mixed and filled into empty hard capsule. Comparative example 2: combination capsule of amlodipine maleate/aspirin

15 Amlodipine maleate granules of example 3 and aspirin were mixed and filled into empty hard capsule. Formulation example 1: combination capsule of amlodipine maleate/aspirin Amlodipine maleate granules of example 3, aspirin enteric pellets of example 4 and magnesium stearate were mixed for 10 minutes, and filled into empty hard capsule for one capsule to have 185 mg of mixture. Formulation example 2: combination capsule of amlodipine maleate/aspirin Amlodipine maleate granules of example 3, aspirin enteric pellets of example 5 and magnesium stearate were mixed for 10 minutes, and filled into empty hard capsule for one capsule to have 185 mg of mixture. Formulation example 3: combination capsule of amlodipine maleate/aspirin Amlodipine maleate granules of example 3, aspirin enteric pellets of example 6 and magnesium stearate were mixed for 10 minutes, and filled into empty hard capsule for one capsule to have 185 mg of mixture. Example 7: Manufacturing coating layer comprising amlodipine maleate (Sl) Butylated hydroxy toluene, propylene glycol and hydroxypropylmethylcellulose 2910 were dissolved in mixture of ethanol and methylene chloride. (S2) Amlodipine maleate was dissolved in ethanol, and mixed with the solution of (Sl) step to make a coating solution. (S3) Aspirin enteric granules of example 4 were coated with the coating solution comprising amlodipine maleate according to the coating condition of example 6. Example 8: Manufacturing coating layer comprising amlodipine maleate Coating layer comprising amlodipine maleate was manufactured like example 7 except that aspirin enteric pellets of example 5 were used as core instead of aspirin enteric pellets of example 4. Example 9: Manufacturing coating layer comprising amlodipine maleate Coating layer comprising amlodipine maleate was manufactured like example 7 except that aspirin enteric pellets of example 6 were used as core instead of aspirin enteric pellets of example 4. The ingredients and contents of the examples 7-9 were collectively shown in table 10. [Table 10]

16 Formulation example 4: combination capsule of amlodipine maleate/aspirin Granules of example 7 were filled into empty hard capsule. Formulation example 5: combination capsule of amlodipine maleate/aspirin Granules of example 8 were filled into empty hard capsule. Formulation example 6: combination capsule of amlodipine maleate/aspirin Granules of example 9 were filled into empty hard capsule. Example 10: As shown in the below table 11, granules of example 3, microcrystalline cellulose, croscarmellose sodium, fumaric acid and low-substituted hydroxypropylcellulose were mixed for 10 minutes, and magnesium stearate was add to the mixture as lubricant and mixed for 5 minutes. The final mixture was tabletted. [Table 11] Formulation example 7 Amlodipine maleate tablet of example 10 and aspirin enteric-coated pellets of example 4 were filled into empty hard capsule. Formulation example 8 Amlodipine maleate tablet of example 10 and aspirin enteric-coated pellets of example 5 were filled into empty hard capsule. Formulation example 9 Amlodipine maleate tablet of example 10 and aspirin enteric-coated pellets of

17 example 6 were filled into empty hard capsule. B. Combination tablet of aspirin/amlodipine maleate Comparative example 3 Aspirin, amlodipine maleate granules of example 3, microcrystalline cellulose, pre-gelatinized starch and stearic acid were mixed for 15 minutes and tabletted. Comparative example 4 (Sl) Aspirin, microcrystalline cellulose, pre-gelatinized starch and stearic acid were mixed for 15 minutes and tabletted. (S2) The tablet made in the (Sl) step was coated with the coating solution comprising methacrylic acid copolymer like example 4 to make an aspirin enteric-coated tablet. Formulation example 10 The aspirin enteric-coated tablet of the comparative example 4 was coated with the coating solution comprising amlodipine maleate like example 9. Formulation example 11 (Sl) An aspirin enteric-coated tablet was manufactured like formulation example 10 with a coating solution comprising hydroxypropylmethylcellulose phthalate described in example 5. (S2) The aspirin enteric-coated tablet of the (Sl) step was coated with the coating solution comprising amlodipine maleate like example 9. Formulation example 12 (Sl) An aspirin enteric-coated tablet was manufactured like formulation example 10 with a coating solution comprising hydroxypropylmethylcellulose acetate succinate described in example 6. (S2) The aspirin enteric-coated tablet of the (Sl) step was coated with the coating solution comprising amlodipine maleate like example 9. Formulation example 13 Amlodipine maleate granules of example 3, aspirin enteric-coated pellets of example 4, microcrystalline cellulose, pre-gelatinized starch, low-substituted hydroxypropylcellulose and stearic acid were mixed for 10 minutes and tabletted. C. Stability test of each formulation Example 11: Stability test of each formulation Formulation examples and manufactured formulations were packed in HDPE

18 bottle by 100 capsules or 100 tablets per bottle. Bottles were stored in an accelerated condition (40±2 C, 75±5%RH) for 90 days, and then impurities were evaluated. Analyzing methods of the example 1 were used in this test. 1) Stability test of capsules Results were shown in the below table 12. [Table 12] As shown in comparative example 2 of the table 12, the stabilities of both amlodipine maleate and aspirin were bad when aspirin was contacted with amlodipine maleate. However, comparative example 1 and all formulation examples had good stabilities compared to the comparative example 2 because the contact between amlodipine and aspirin was blocked. 2) Stability test of tablets Results were shown in the below table 13. [Table 13]

19 As shown in comparative example 3 of the table 13, the stabilities of both amlodipine maleate and aspirin were bad when aspirin was contacted with amlodipine maleate. However, all formulation examples had good stabilities compared to the comparative example 3 because the contact between amlodipine and aspirin was blocked. In addition, the stability of the comparative example 3 was worse than that of comparative example 2, which is thought to be caused by the difference (capsule vs. tablet) of type of formulation. Tablet, the comparative example 3, usually causes much contact between amlodipine and aspirin compared to capsule, which has a bad effect on the stability of each other. The stability of formulation example 13 was bad, which is thought to be caused by break of coating layer happening due to tabletting pressure. The break causes the contact between amlodipine and aspirin. [Advantageous Effects] The present invention provides a pharmaceutical formulation or kit comprising amlodipine and aspirin, wherein the stabilities of both amlodipine and aspirin are improved. The present invention also provides a pharmaceutical composition comprising amlodipine maleate and having an improved stability.

20 [CLAIMS] 1. A pharmaceutical formulation comprising (a) amlodipine freebase or its pharmaceutically acceptable salt; and (b) aspirin, wherein the amlodipine and the aspirin are separated from each other to block contact between the amlodipine and the aspirin. 2. The pharmaceutical formulation of claim 1, wherein the pharmaceutically acceptable salt of amlodipine is amlodipine maleate. 3. The pharmaceutical formulation of claim 1 or 2, wherein the (a) ingredient or the (b) ingredient; or a granule comprising the (a) ingredient or the (b) ingredient is coated by polymer to block contact between the amlodipine and the aspirin. 4. The pharmaceutical formulation of claim 3, wherein the pharmaceutical formulation is a capsule. 5. The pharmaceutical formulation of claim 1 or 2, wherein the pharmaceutical formulation comprises a tablet or granule comprising any one between the (a) ingredient and the (b) ingredient; first coating layer surrounding the tablet or granule; and second coating layer surrounding the first coating layer and comprising the other ingredient. 6. The pharmaceutical formulation of claim 1 or 2, wherein the pharmaceutical formulation is a multilayered tablet comprising first layer comprising the (a) ingredient; and second layer comprising the (b) ingredient. 7. The pharmaceutical formulation of claim 6, wherein the multilayered tablet comprises a layer or membrane for separating between the first layer and the second

21 layer. 8. The pharmaceutical formulation of claim 1 or 2, wherein the pharmaceutical formulation is a press-coated tablet comprising a core tablet comprising any one between the (a) ingredient and the (b) ingredient; and an exterior layer surrounding the core tablet and comprising the other ingredient. 9. The pharmaceutical formulation of claim 8, wherein the core tablet is coated by polymer. 10. The pharmaceutical formulation of claim 1 or 2, wherein the pharmaceutical formulation is a capsule comprising a small tablet comprising the (a) ingredient; and another small tablet comprising the (b) ingredient. 11. A kit comprising (a) a formulation comprising amlodipine freebase or its pharmaceutically acceptable salt; and (b) a formulation comprising aspirin, wherein the formulations are separated from each other to block contact between the amlodipine and the aspirin. tablet or granule. 12. The kit of claim 11, wherein the formulation is capsule, microcapsule, 13. A pharmaceutical composition comprising amlodipine maleate and stabilizing ingredient. 14. The pharmaceutical composition of claim 13, wherein the stabilizing ingredient is at least one selected from the group consisting of sodium citrate, butylated hydroxy toluene, succinic acid, fumaric acid, tartaric acid and ascorbic acid. 15. The pharmaceutical composition of claim 14, wherein the stabilizing

22 ingredient is butylated hydroxy toluene.

23 A. CLASSIFICATION OF SUBJECT MATTER A61K 31/44( )i, A61P 9/12( )i According to International Patent Classification (IPC) or to both national classification and IPC B. FIELDS SEARCHED Minimum documentation searched (classification system followed by classification symbols) IPC8 A61K, A61P Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched Electronic data base consulted during the intertnational search (name of data base and, where practicable, search terms used) ekipass, Pubmed (amlodipine, aspirin, formulation, coat, antioxidant) C. DOCUMENTS CONSIDERED TO BE RELEVANT Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No X US 2004/ A l (HURD, W R et al ) 02 September See page 3 right column, lines and claim 1 A FOLTS, J D Inhibition of platelet activity in vivo by amlodipine alone and combined with 1-12 aspirin International Journal Cardiology, 1997, VoI 62, Suppl 2 pages Sl I l-sl 17 See abstract X WO 97/37640 A2 (ALZA CORPORATION) 16 October See examples 8, 10 MASON, R P et al Inhibition of excessive neuπnal apoptosis by the calcium antagonist amlodipine and antioxidants in cerebellar granule cells, Journal of Neurochemistry, 1999, VoI 72, pages See the whole document Further documents are listed in the continuation of Box C See patent family annex * Special categories of cited documents "T" later document published after the international filing date or priority "A" document defining the general state of the art which is not considered date and not in conflict with the application but cited to understand to be of particular relevance the principle or theory underlying the invention "E" earlier application or patent but published on or after the international "X" document of particular relevance, the claimed invention cannot he filing date considered novel or cannot be considered to involve an inventive "L" document which may throw doubts on priority claim(s) or which is step when the document is taken alone cited to establish the publication date of citation or other "Y" document of particular relevance, the claimed invention cannot be special reason (as specified) considered to involve an inventive step when the document is "O" document referring to an oral disclosure, use, exhibition or other combined with one or more other such documents,such combination means being obvious to a person skilled in the art "P" document published prior to the international filing date but later "&" document member of the same patent family than the priority date claimed Date of the actual completion of the international search Date of mailing of the international search report 06 MARCH 2007 ( ) 09 MARCH 2007 ( ) Name and mailing address of the ISA/KR Authorized officer Korean Intellectual Property Office 920 Dunsan-dong, Seo-gu, Daejeon , LEE, Mi Jeong Republic of Korea Facsimile No Telephone No Form PCT/ISA/210 (second sheet) (April 2005)

24 INTERNATIONAL SEARCH REPORT International application No PCT/KR2006/ Box No. II Observations where certain claims were found unsearchable (Continuation of item 2 of first sheet) This international search report has not been established in respect of certain claims under Article 17(2)(a) for the following reasons 1 I I Claims Nos because they relate to subject matter not required to be searched by this Authority, namely Claims Nos because they relate to parts of the international application that do not comply with the prescribed requirements to such an extent that no meaningful international search can be carried out, specifically Claims Nos because they are dependent claims and are not drafted in accordance with the second and third sentences of Rule 6 4(a) Box No. Ill Observations where unity of invention is lacking (Continuation of item 3 of first sheet) This International Searching Authority found multiple inventions in this international application, as follows Group I Claims 1-12 relate to a pharmaceutical composition comprising amlodipine and aspirin, where the two drugs are separately formulated to prevent reactive contact Group II Claims relate to a pharmaceutical composition comprising amlodipine and a stabilizer As seen before, the essential components of Group I are different from those of Group II Thus, Group I and Group II are considered to have no common technical feature 1 As all required addtional search fees were timely paid by the applicant, this international search report covers all searchable claims 2 [ \ \ As all searchable claims could be searched without effort justifying an additional fee, this Authority did not invite payment of any additional fee 3 As only some of the required additional search fees were timely paid by the applicant, this international search report covers only those claims for which fees were paid, specifically claims Nos No required additional search fees were timely paid by the applicant Consequently, this international search report is restπcted to the invention first mentioned in the claims, it is covered by claims Nos Remark on Protest The additional search fees were accompanied by the applicant's protest and, where applicable, the payment of a protest fee I I The additional search fees were accompanied by the applicant's protest but the applicable protest fee was not paid within the time limit specified in the invitation I I No protest accompanied the payment of additional search fees Form PCT/ISA/210 (continuation of first sheet (2)) (April 2005)

25 INTERNATIONAL SEARCH REPORT International application No Information on patent family members PCT/KR2006/ Patent document Publication Patent family Publication cited in search report date member(s) date US 2004/ A None WO 97/37640 A US A JP T EP A CA AA AU A Form PCT/ISA/210 (patent family annex) (April 2005)