the present invention provides a pharmaceutical combination formulation for the prevention or treatment of a cardiovascular disorder , comprising : ( 1 ) a first discrete part comprising amlodipine or a pharmaceutically acceptable salt thereof , rosuvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive ; and ( 2 ) a second discrete part comprising losartan or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive , wherein said discrete parts are physically separated from each other . the combination formulation according to the present invention comprises the first and the second discrete parts in which said discrete parts are physically separated , i . e ., amlodipine and losartan are separately contained . thus , an interaction between amlodipine and losartan is prevented , thereby exhibiting improved stability . in one embodiment of the present invention , the first discrete part and the second discrete part in the combination formulation may be a first layer and a second layer , respectively . in other words , the combination formulation may be in the form of a bilayer tablet comprising : ( 1 ) a first layer comprising amlodipine or a pharmaceutically acceptable salt thereof , rosuvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive ; and ( 2 ) a second layer comprising losartan or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive ( see fig1 ). besides a bilayer tablet , in another embodiment of the present invention , the combination formulation may be prepared in various forms where a first discrete part and a second discrete part are physically separated from each other ( for example , core - shell structure ). the combination formulation of the present invention comprises amlodipine or a pharmaceutically acceptable salt thereof in the first discrete part ( or the first layer ). the pharmaceutically acceptable salt of amlodipine employed in the present invention may be prepared by using an acid containing a pharmaceutically acceptable anion which can form a non - toxic acid addition salt , e . g ., hydrogen chloride , hydrogen bromide , sulfate , phosphate , acetate , malate , furmarate , lactate , tartrate , citrate , gluconate , besylate and camsylate , but are not limited thereto . preferably , the pharmaceutically acceptable salt of amlodipine is amlodipine besylate and camsylate , more preferably camsylate . also , amlodipine of the present invention includes a racemic mixture and ( s )- amlodipine . amlodipine or a pharmaceutically acceptable salt thereof may be administered at a daily dose of from 5 to 10 mg . the combination formulation of the present invention comprises rosuvastatin or a pharmaceutically acceptable salt thereof in the first discrete part ( or the first layer ). examples of the pharmaceutically acceptable salt of rosuvastatin include inorganic salts having polycation , preferably rosuvastatin calcium , but are not limited thereto . rosuvastatin or a pharmaceutically acceptable salt thereof may be administered at a daily dose of from 10 to 20 mg . the combination formulation of the present invention comprises losartan or a pharmaceutically acceptable salt thereof in the second discrete part ( or the second layer ). examples of the pharmaceutically acceptable salt of losartan include losartan potassium , but are not limited thereto . losartan or a pharmaceutically acceptable salt thereof may be administered at a daily dose of from 45 to 100 mg . in the combination formulation of the present invention , amlodipine or a pharmaceutically acceptable salt thereof , rosuvastatin or a pharmaceutically acceptable salt thereof and losartan or a pharmaceutically acceptable salt thereof may be admixed in a weight ratio of 1 : 1 ˜ 4 : 10 ˜ 20 , but not limited thereto . in the present invention , the first discrete part ( or the first layer ) and the second discrete part ( or the second layer ) of the combination formulation may further comprise a pharmaceutically acceptable additive , e . g ., a pharmaceutically acceptable carrier or excipient . examples of the pharmaceutically acceptable carrier or excipient include lactose ( lactose hydrate ), micro - crystalline cellulose , mannitol , sodium citrate , calcium citrate , calcium phosphate , glycine and starch , a disintegrant ( e . g ., crospovidone , copovidone , sodium starch glycolate , croscarmellose sodium , and combination silicates ) and a binder ( e . g ., polyvinylpyrrolidone , hydroxypropyl methyl cellulose ( hpmc ), hydroxypropyl cellulose ( hpc ), sucrose , gelatin and acacia gum . in one embodiment , the combination formulation of the present invention comprises lactose hydrate and micro - crystalline cellulose in the first discrete part ( or the first layer ) as additives . the lactose hydrate may be comprised in an amount of from 20 to 40 wt % based on the total weight of the first discrete part ( or the first layer ). the micro - crystalline cellulose may be comprised in an amount of from 50 to 70 wt % based on the total weight of the first discrete part ( or the first layer ). in another embodiment , the lactose hydrate and micro - crystalline cellulose may be employed in a ratio of 1 : 1 . 5 to 1 : 3 . when the lactose hydrate is employed in said range , the lactose hydrate may form hydrophilic channels which promote dissolution of active ingredients , thereby allowing a fast dissolution . a fast dissolution profile cannot be obtained if the amount falls below said range , and if the amount exceeds said range , time required for complete dissolution of the lactose hydrate is extended and thereby slowing down the dissolution of active ingredients . in case of micro - crystalline cellulose , the tableting process becomes easy if the micro - crystalline cellulose is employed in said range . however , an amount smaller than said range may cause some difficulties during the tableting process , whereas an excessive amount may lead to an excessively large size of formulation . accordingly , dissolution rates of amlodipine , rosuvastatin and losartan may be improved significantly by employing the lactose hydrate and micro - crystalline cellulose in said range . in one embodiment , the second discrete part ( or the second layer ) of the inventive combination formulation may be prepared in a conventional manner , e . g ., compaction granulation followed by tableting . in another embodiment , the second discrete part is in the form of granules prepared by a dry roller compaction process . according to the experimental results of the present invention , a combination formulation exhibited improved dissolution rate of amlodipine , rosuvastatin and losartan , as well as excellent dissolution profiles of amlodipine and rosuvastatin when the combination formulation was prepared by tableting a simply mixed first discrete part and a second discrete part prepared by compaction granulation . a problem of gelation of losartan occurs when a combination formulation is prepared by simply mixing amlodipine , rosuvastatin and losartan . losartan readily dissolves in purified water and is easily released at a relatively high ph ( e . g ., ph 4 . 0 , ph 6 . 8 ), but is released very slowly at a low ph ( e . g ., ph 1 . 2 , ph 2 . 0 ) because of the gelation . this problem significantly imparts undesired effects on the dissolution rate and bioavailability of formulation because the formulation is first exposed to the acidic gastric juice having a low ph value when orally administered . as the gelation of losartan progresses in the formulation , amlodipine and rosuvastatin are trapped within the losartan gel and dissolve poorly , which is demonstrated in comparative example 1 . the dissolution result of a single layer tablet of comparative example 1 prepared by simply mixing said three ingredients was significantly lower than “ 80 % dissolution at the time of 30 minutes in ph 1 . 2 .” in comparison , the combination formulation of the present invention separates the first discrete part comprising amlodipine and rosuvastatin from the second discrete part comprising losartan , thereby reducing the contact area of losartan . as a result , the gelation of losartan can be prevented under a low ph condition and thus exhibit improved stability and dissolution rate of amlodipine , rosuvastatin and losartan . meanwhile , the present invention also provides a fixed - dose combination formulation for the prevention or treatment of a cardiovascular disorder , comprising : ( 1 ) a first discrete part comprising amlodipine or a pharmaceutically acceptable salt thereof , rosuvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive ; and ( 2 ) a second discrete part comprising losartan or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive , wherein said discrete parts are physically separated from each other . in one embodiment of the fixed - dose combination formulation , the amount of amlodipine or a pharmaceutically acceptable salt thereof , as converted to amlodipine free base form , is 5 to 10 mg . in one embodiment of the fixed - dose combination formulation , the amount of rosuvastatin or a pharmaceutically acceptable salt thereof , as converted to rosuvastatin free acid form , is 10 to 20 mg . also , in one embodiment of the fixed - dose combination formulation , the amount of losartan or a pharmaceutically acceptable salt thereof , as converted to losartan free base form , is 45 to 100 mg . moreover , in accordance with another aspect thereof , the present invention provides a method for preparing a pharmaceutical combination formulation for the prevention or treatment of a cardiovascular disorder , comprising : a ) admixing amlodipine or a pharmaceutically acceptable salt thereof , rosuvastatin or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive ; b ) admixing losartan or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive ; and c ) loading a discrete part prepared in step a ) and a discrete part prepared in step b ) into a formulation , wherein said discrete parts are physically separated from each other . in one embodiment , step b ) further comprises a granulizing step , and in step c ) the discrete part obtained in step a ) and the granules obtained in step b ) are tableted to obtain a bilayer tablet . in the present invention , the cardiovascular disorder is selected from the group consisting of angina pectoris , hypertension , arteriospasm , cardiac arrhythmia , cardiomegaly , cerebral infarction , congestive heart failure and myocardial infarction , but not limited thereto . hereinafter , the present invention is described more specifically by following examples . however , these examples are provided only for illustration purposes , and the present invention is not limited thereto . examples 1 to 3 : preparation of combination bilayer tablet by using compaction granulation in accordance with the ingredients as described in table 1 below , amlodipine camsylate , rosuvastatin calcium , lactose hydrate , micro - crystalline cellulose and crospovidone were admixed , sieved through a 30 mesh screen , added with magnesium stearate and finally admixed in a mixer to obtain a discrete part comprising amlodipine and rosuvastatin . meanwhile , losartan potassium , micro - crystalline cellulose , hydroxypropyl cellulose and crospovidone were admixed , and sieved through a 30 mesh screen . then , the sieved powder was pressed using a roller compactor ( wp200 , alexanderwerk ) at a minimum compaction force of 20 kn with a roll speed of from 2 to 10 rpm to form granules in the form of flakes . granules thus obtained were pulverized by using a fitz mill ( bas 06 , fitzpatrick , usa ), sieved through a 20 mesh screen , added with magnesium stearate and finally admixed in a mixer to obtain a discrete part comprising losartan . subsequently , the discrete parts were formulated into a combination bilayer tablet comprising the discrete part comprising amlodipine and rosuvastatin ( first layer , upper layer ) and the discrete part comprising losartan ( second layer , lower layer ) by using a tablet press ( kilian synthesis 700 , germany ). in accordance with the ingredients as described in table 2 below , amlodipine camsylate , rosuvastatin calcium , losartan potassium , lactose hydrate , micro - crystalline cellulose and crospovidone and hydroxypropyl cellulose were admixed , sieved through a 30 mesh screen , added with magnesium stearate and finally admixed in a mixer . the mixed powder was formulated to obtain a single - layer tablet . in accordance with the ingredients as described in table 3 below , amlodipine camsylate , rosuvastatin calcium , lactose hydrate , micro - crystalline cellulose , and crospovidone were admixed , sieved through a 30 mesh screen , added with magnesium stearate and finally admixed in a mixer to obtain a discrete part comprising amlodipine and rosuvastatin . meanwhile , losartan potassium , micro - crystalline cellulose , hydroxypropyl cellulose and crospovidone were admixed , sieved through a 30 mesh screen , added with magnesium stearate and finally admixed in a mixer to obtain a discrete part comprising losartan . subsequently , the discrete parts were formulated into a combination bilayer tablet comprising the discrete part comprising amlodipine and rosuvastatin ( first layer , upper layer ) and the discrete part comprising losartan ( second layer , lower layer ) by using a tablet press . the procedure of example 1 was repeated except for changing the ratio of lactose and cellulose in accordance with the ingredients as described in table 4 below to obtain a combination bilayer tablet . the procedure of example 1 was repeated except for employing the ingredients as described in table 5 below to obtain a combination bilayer tablet which comprises amlodipine and losartan in the first discrete part and rosuvastatin in the second discrete part . the procedure of example 1 was repeated except for employing the ingredients as described in table 6 below to obtain a combination bilayer tablet which comprises amlodipine in the first discrete part and losartan and rosuvastatin in the second discrete part . in accordance with the ingredients as described in table 7 below , combination bilayer tablets which have different amounts of active ingredients than examples 1 to 3 were prepared . sampling : dissolution media were taken 5 , 10 , 15 , 30 , 45 , 60 , 90 and 120 minutes after the test was commenced . the paddle speed was raised from 50 rpm to 150 rpm , and after 30 minutes , i . e ., 150 minutes after the test was commenced , dissolution media was taken for final analysis . column : stainless steel column ( inner diameter : about 4 . 6 mm , length : 15 cm ) packed with 3 μm of octadecylsilylated silica gel for liquid chromatography mobile phase : 6 mm sodium hexanesulfonate monohydrate / 0 . 05 % v / v phosphoric acid : acetonitrile ( 60 : 40 , v / v ) ( 6 mm sodium hexanesulfonate monohydrate / 0 . 05 % v / v phosphoric acid : 1 . 24 g of sodium 1 - hexanesulfonate monohydrate was added to an 1 l flask , and 0 . 5 ml of phosphoric acid was carefully added . distilled water was added and thoroughly stirred .) dissolution rate of 80 % or greater after 30 minutes ( amlodipine , rosuvastatin ) the results of the dissolution test are shown in fig2 to 4 . as shown in fig2 and 3 , the bilayer tablet of example 1 in which the discrete part comprising amlodipine and rosuvastatin and the discrete part comprising losartan are physically separated from each other exhibited a high dissolution rate as compared with the single layer tablet of comparative example 1 prepared by dry direct tableting . also , unlike the single layer tablet of comparative example 1 , the bilayer tablet of example 1 showed a good dissolution profile of amlodipine and rosuvastatin , while satisfying the test criterion . moreover , as shown in fig4 , the bilayer tablet of example 1 showed a significantly high dissolution rate of losartan compared with the single layer tablet of comparative example 1 which had dissolution rate of 40 % or lower after 60 minutes . the above results show that the gelation of losartan slows down the dissolution of amlodipine or rosuvastatin when losartan is present with amlodipine or rosuvastatin in the same layer . experimental example 2 : dissolution test of bilayer tablet with compaction - granulated losartan part and bilayer tablet prepared by dry direct tableting the bilayer tablet of example 1 prepared by compaction granulation and the bilayer tablet of comparative example 2 prepared by simple mixing followed by dry direct tableting were each subjected to a dissolution test by using the same conditions as described in experimental example 1 to evaluate dissolution rate of amlodipine , rosuvastatin and losartan . the results are shown in fig5 to 7 . as shown in fig7 , the bilayer tablet of example 1 which was prepared by using a roller compactor and the bilayer tablet of comparative example 2 which was prepared without using a roller compactor did not show much difference in dissolution rate of losartan . however , as shown in fig5 and 6 , the bilayer tablet of comparative example 2 which was prepared by simple mixing and dry direct tableting without using roller compactor exhibited a large deviation in dissolution , and a relatively low dissolution rate . also , the bilayer tablet of comparative example 2 did not satisfy the test criterion ( dissolution rate of 80 % or greater after 30 minutes ) in terms of amlodipine and rosuvastatin . moreover , the losartan layer of comparative example 2 which was prepared without going through compaction granulation process , suffered from low productivity due to a problem associated with capping of the tablet . on the other hand , the bilayer tablet of example 1 prepared by using a roller compactor showed an excellent dissolution rate of amlodipine and rosuvastatin , and also satisfied the test criterion . the above results demonstrate that the roller compaction process of losartan granules not only affects dissolution profiles of three active ingredients , but also can affect the productivity of tableting process . experimental example 3 : changes in dissolution rate depending on the ratio of additives in amlodipine - rosuvastatin layer a dissolution test was performed by using the same conditions as described in experimental example 1 on the bilayer tablets of examples 1 to 3 and comparative examples 3 to 5 to evaluate dissolution rate of amlodipine , rosuvastatin and losartan . the results are shown in fig8 to 10 . as shown in fig1 , the bilayer tablets of examples 1 to 3 and comparative examples 3 to 5 did not show much difference in dissolution rate of losartan . however , as shown in fig8 and 9 , the bilayer tablets of examples 1 to 3 exhibited good dissolution profiles that satisfied the test criterion , whereas the bilayer tablets of comparative examples 3 to 5 failed to satisfy the test criterion . the test results suggest that it is preferable , in terms of dissolution rate , to employ lactose hydrate and micro - crystalline cellulose in weight ratios of 20 to 40 wt % and 50 to 70 wt %, respectively , in the amlodipine - rosuvastain layer . experimental example 4 : dissolution test of comparative examples 6 ( tablet comprising amlodipine - losartan layer and rosuvastatin layer ) and 7 ( tablet comprising amlodipine layer and losartan - rosuvastatin layer ) a dissolution test was performed by using the same conditions as described in experimental example 1 on the bilayer tablet of example 1 and the bilayer tablets of comparative examples 6 and 7 to evaluate dissolution rate of amlodipine , rosuvastatin and losartan . the results are shown in fig1 to 13 . as shown in fig1 to 13 , the bilayer tablet of example 1 which comprises the amlodipine - rosuvastatin layer and the losartan layer exhibited a fast and high dissolution rate , and showed a good dissolution profile of amlodipine and rosuvastatin by meeting the test criterion . in contrast , the bilayer tablet of comparative example 6 having the amlodipine - losartan layer and the rosuvastatin layer and the bilayer tablet of comparative example 7 having the amlodipine layer and the losartan - rosuvastatin layer failed to pass the test criterion in terms of dissolution rate of all three ingredients . the above results demonstrate that it is preferable to prepare a bilayer tablet comprising the amlodipine - rosuvastatin layer and the losartan layer , because a delay in dissolution is expected due to the gelation of losartan when a bilayer tablet comprises an amlodipine - losartan layer and a rosuvastatin layer or an amlodipine layer and a losartan - rosuvastatin layer . thus , the results also show that a separation mode of said three drugs is critical in terms of dissolution rate . a stability test was performed for the tablets of examples 1 to 3 under the following conditions to evaluate the stability of the tablets by analyzing the content change in amlodipine , rosuvastatin and losartan . the results are shown in table 9 . storage condition : stored in an hdpe bottle at 40 ° c ., 75 % rh column : stainless steel column ( inner diameter : about 4 . 6 mm , length : 15 cm ) packed with 3 μm of octadecylsilylated silica gel for liquid chromatography mobile phase : 6 mm sodium hexanesulfonate monohydrate / 0 . 05 % ( v / v ) phosphoric acid : acetonitrile ( 6 : 4 , v / v ) as shown in table 9 above , the bilayer tablets of examples 1 to 3 exhibited insignificant changes in the content of amlodipine , rosuvastatin and losartan under 6 month accelerated storage , thereby indicating exceptionally good storage stability . experimental example 6 : stability test under accelerated light and heat conditions a stability test was performed for the tablets prepared in examples 1 to 3 and comparative examples 1 to 7 under the following conditions to analyze the changes in production rate of related substances of amlodipine , rosuvastatin and losartan under accelerated light and heat conditions . the results are shown in table 10 . column : stainless steel column ( inner diameter : about 4 . 6 mm , length : 25 cm ) packed with 5 μm of octadecylsilylated silica gel for liquid chromatography mobile phase : 6 mm sodium hexanesulfonate monohydrate / 0 . 05 % ( v / v ) phosphoric acid : acetonitrile ( 6 : 4 , v / v ) as shown in table 10 above , the tablets of examples 1 to 3 exhibited high stability under accelerated light and heat conditions , while producing a very small amount of amlodipine -, rosuvastatin - and losartan - related substances . on the other hand , the tablet obtained in comparative example 1 , which was prepared by simple mixing of three ingredient followed by direct - compaction , produced related substances at least 5 to 10 times greater than the tablets obtained in examples 1 to 3 . this result indicates that tablets prepared by simple mixing have poor stability under accelerated light and heat conditions . additionally , the tablets obtained in comparative examples 6 and 7 produced related substances as much as comparative example 1 . the test result of comparative example 6 shows that the bilayer tablet having the amlodipine - losartan layer and the rosuvastatin layer exhibits poor stability under accelerated light and heat conditions . similarly , the test result of comparative example 7 shows that the bilayer tablet having the amlodipine layer and the losartan - rosuvastatin layer also exhibits poor stability under accelerated light and heat conditions . this result indicates that the bilayer tablet having the amlodipine - rosuvastatin layer and the losartan layer of examples 1 to 3 have significantly improved stability . experimental example 7 : stability test of bilayer tablets having different amounts of active ingredient a stability test was performed for the tablets prepared in examples 4 to 6 and comparative examples 8 to 10 , which had different amounts of active ingredients , to evaluate dissolution rate of amlodipine , rosuvastatin and losartan . the results are shown in fig1 to 16 . as shown in fig1 to 16 , the tablets of examples 4 to 6 , which contained 50 mg of losartan and 10 mg of rosuvastatin , exhibited similar dissolution profiles as those of examples 1 to 3 and satisfied the test criterion . on the other hand , the tablets of comparative examples 8 to 10 failed to pass the test criterion in terms of dissolution rates of amlodipine and rosuvastatin . this result indicates that a tablet can maintain a good dissolution rate even if the amount of active ingredient changes , as long as the amlodipine - rosuvastatin layer contains the lactose hydrate in an amount of 20 to 40 wt %, and micro - crystalline cellulose in an amount of 50 to 70 wt %.
disclosed is a pharmaceutical combination formulation comprising a first discrete part containing amlodipine and rosuvastatin and a second discrete part containing losartan , which exhibits improved dissolution rate and stability . the inventive combination formulation comprising amlodipine , losartan and rosuvastatin having different action mechanisms from one another can be effectively used to prevent or treat a cardiovascular disorder . designed to minimize an interaction among active ingredients , the pharmaceutical combination formulation exhibits excellent storage stability and dissolution rates of amlodipine , losartan and rosuvastatin , and thus can be useful in pharmaceutical industries .