Patent Publication Number: US-2020289523-A1

Title: Fixed dosed pharmaceutical composition comprising amiodipine, candesartan cilexetil and hydrochlorothiazide for the treatment of hypertension

Description:
BACKGROUND OF THE INVENTION 
     The present invention relates to fixed dose pharmaceutical compositions comprising the three active pharmaceutical ingredients (APIs) Amlodipine, Candesartan cilexetil and Hydrochlorothiazide for the treatment of hypertension. 
     Candesartan is the international nonproprietary name (INN) of 2-ethoxy-1-({4-[2-(2H-1,2,3,4-tetrazol-5-yl)phenyl]phenyl}methyl)-1H-1,3-benzodiazole-7-carboxylic acid which has the following chemical structure: 
     
       
         
         
             
             
         
       
     
     Hydrochlorothiazide (abbreviated “HCTZ” or “HCT”) is the INN of 6-chloro-1,1-dioxo-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide having the following chemical structure: 
     
       
         
         
             
             
         
       
     
     Amlodipine is the INN of (RS)-3-ethyl-5-methyl-2-[(2-aminoethoxy)methyl]-4-(2-chloro-phenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate with the following chemical structure: 
     
       
         
         
             
             
         
       
     
     Pharmaceutical compositions of the angiotensin II antagonist Candesartan in the modification of its prodrug Candesartan cilexetil are registered for the treatment of congestive heart failure, diabetic nephropathies, diabetic retinopathy and hypertension, being marketed under the trade name ATACAND®. Pharmaceutical compositions of the diuretic Hydrochlorothiazide are registered and marketed under the trade name ESIDRIX® for the treatment of hypertension, edema and heart failure. Pharmaceutical compositions of the calcium channel blocker Amlodipine in the modification of its benzene sulfonate (“besilate”) salt are registered and marketed under the trade name NORVASC® for the treatment of coronary artery disease and hypertension. 
     A fixed-dose combination of Candesartan cilexetil and Hydrochlorothiazide is registered and marketed under the trade name ATACAND® PLUS for the treatment of hypertension. 
     No fixed-dose pharmaceutical formulation comprising Candesartan cilexetil, Hydrochlorothiazide and Amlodipine has been registered and marketed yet. 
     
       
         
           
               
               
               
               
               
             
               
                 TABLE 1 
               
               
                   
               
             
            
               
                 Brand name(s) 
                 NORVASC ® 
                 ATACAND ® 
                 ATACAND PLUS ® 
                 ESIDRIX ® 
               
            
           
           
               
               
               
               
            
               
                 Originator 
                 Pfizer 
                 Astra Zeneca 
                 Novartis 
               
            
           
           
               
               
               
               
               
            
               
                 company 
                   
                   
                   
                   
               
               
                 Active(s) 
                 Amlodipine 
                 Candesartan  
                 Candesartan 
                 Hydrochlorothiazide 
               
               
                   
                 besilate 
                 cilexetil 
                 cilexetil 
                   
               
               
                   
                   
                   
                 Hydrochlorothiazide 
                   
               
               
                 Composition 
                 Microcrystalline 
                 Carmellose- 
                 Carmellose- 
                 Lactose 
               
               
                 (qualitative) 
                 cellulose, 
                 Calcium, 
                 Calcium, 
                 monohydrate, 
               
               
                   
                 Calcium hydrogen 
                 Hyprolose, 
                 Hyprolose, 
                 Magnesium 
               
               
                   
                 phosphate 
                 Lactose 
                 Lactose 
                 stearate, 
               
               
                   
                 anhydrous, 
                 monohydrate, 
                 monohydrate, 
                 Highly dispersed 
               
               
                   
                 Sodium starch 
                 Magnesium 
                 Magnesium 
                 silicon dioxide, 
               
               
                   
                 glycolate Type A, 
                 stearate, 
                 stearate, 
                 Wheat starch, 
               
               
                   
                 Magnesium stearate 
                 Maize starch, 
                 Maize starch, 
                 Talc 
               
               
                   
                   
                 Macrogol 8000, 
                 Macrogol 8000, 
                   
               
               
                   
                   
                 Ferric oxide 
                 Ferric oxide 
                   
               
               
                 Strengths 
                 5, 10 mg 
                 4, 8, 16, 32* mg 
                  8/12.5 mg,  
                 12.5 mg,  
               
               
                   
                   
                   
                 16/12.5 mg, 
                   25 mg 
               
               
                   
                   
                   
                 32/12.5 mg, 
                   
               
               
                   
                   
                   
                   32/25 mg 
               
               
                   
               
               
                 *marketed as ATACAND PROTECT ®  
               
            
           
         
       
     
     In the development of such triple-fixed-dose combinational products several problems have to be overcome: 
     Candesartan cilexetil is known for its low bioavailability and high tendency to undergo hydrolysis and dealkylation. Amlodipine besilate, on the other hand, is highly hygroscopic and sensitive to hydrolysis, transesterification of the ester groups and oxidation of the dihydropyrine ring. Candesartan cilexetil and Amlodipine besilate are susceptible to static electricity, whereas all three APIs exhibit poor flow properties. 
     As visualized in  FIG. 1 , all three active substances exhibit quite different solubility profiles. Candesartan cilexetil, for example, is barely soluble at low pH-values, whereas the solubility of Hydrochlorothiazide decreases with increasing pH-values. 
     As assembled in table 1, the excipients and compositions of NORVASC® (active: Amlodipine besilate) ESIDRIX® (active: HCTZ) and ATACAND® (active: Candesartan cilexetil) are quite different from each other. 
     As can be seen in  FIG. 2 , the three different (mono) brand products also show different dissolution characteristics in standard media, i.e. in HCl at pH 1.2, in acetate buffer at pH 4.5, and phosphate buffer at pH 6.5. The solubility of Candesartan cilexetil is so low that a detergent has to be added to allow the media to show any discriminatory effect. The respective recommended standard media are displayed in table 7. 
     As can be deducted from  FIG. 3 , a comparison of the release rates of Candesartan cilexetil from ATACAND® and Candesartan cilexetil from ATACAND PLUS®—both having the same qualitative composition of excipients—reveals that the dissolution profiles are significantly different. 
     As can be seen in table 1 and table 2, sixteen (16) different fixed-dose combinations with different strengths of Amlodipine, Candesartan cilexetil and Hydrochlorothiazide are theoretically possible. 
     
       
         
           
               
               
               
               
             
               
                 TABLE 2 
               
               
                   
               
               
                 Fixed dose  
                   
                 Candesartan  
                 Hydro- 
               
               
                 combination 
                 Amlodipine 
                 cilexitil 
                 chlorothiazide 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
            
               
                  1. 
                  5 mg 
                  4 mg 
                 12.5  
                 mg 
               
               
                  2. 
                 10 mg 
                   
                   
                   
               
               
                  3. 
                  5 mg 
                  8 mg 
                   
                   
               
               
                  4. 
                 10 mg 
                   
                   
                   
               
               
                  5. 
                  5 mg 
                 16 mg 
                   
                   
               
               
                  6. 
                 10 mg 
                   
                   
                   
               
               
                  7. 
                  5 mg 
                 32 mg 
                   
                   
               
               
                  8. 
                 10 mg 
                   
                   
                   
               
               
                  9. 
                  5 mg 
                  4 mg 
                 25  
                 mg 
               
               
                 10. 
                 10 mg 
                   
                   
                   
               
               
                 11. 
                  5 mg 
                  8 mg 
                   
                   
               
               
                 12. 
                 10 mg 
                   
                   
                   
               
               
                 13. 
                  5 mg 
                 16 mg 
                   
                   
               
               
                 14. 
                 10 mg 
                   
                   
                   
               
               
                 15. 
                  5 mg 
                 32 mg 
                   
                   
               
               
                 16. 
                 10 mg 
               
               
                   
               
            
           
         
       
     
     For several technical, regulatory and commercial reasons it is economically not attractive to develop, register and manufacture all 16 different fixed-dose combinations of Amlodipine, Candesartan cilexetil and Hydrochlorothiazide. It is thus necessary to focus on those fixed-dose combinations which allow for a cost efficient registration process as well as economical manufacturing. 
     In summary, it can be concluded that there is no guidance in the prior art how to design, develop and manufacture a fixed dose combination of Amlodipine, Candesartan cilexetil and Hydrochlorothiazide and to deal with all the obstacles described above. 
     It has now been found that fixed dose pharmaceutical formulations of Amlodipine, Candesartan cilexetil and Hydrochlorothiazide according to the present invention satisfy all requirements as regards the stability and the processability of all three active substances as well as their release and dissolution profile compared to their respective brand products. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG. 1  shows the solubility of Hydrochlorothiazide, Candesartan cilexetil and Amlodipine besilate in various standard dissolution media. 
         FIG. 2  shows the dissolution of ESIDRIX® (Hydrochlorothiazide), ATACAND® (Candesartan cilexetil) and NORVASC® (Amlodipine besilate) in various standard dissolution media. 
         FIG. 3  shows a comparison of the dissolution profiles of ATACAND PROTECT® (32 mg Candesartan mono) versus ATACAND PLUS FORTE® (32 mg Candesartan+25 mg Hydrochlorothiazide) under the respective recommended standard conditions. 
         FIG. 4 a    shows a comparison of the dissolution profiles of Amlodipine besilate from formulation I, formulation II and NORVASC®. 
         FIG. 4 b    shows a comparison of the dissolution profiles of Candesartan cilexetil from formulation I, formulation II and ATACAND®. 
         FIG. 5  shows a comparison of the dissolution profiles of Candesartan cilexetil having different particle size distributions from formulation I. 
         FIG. 6  shows a flow chart of the manufacturing process for formulations I, Ia, Ib and Ic. 
     
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     The present invention relates to fixed dose pharmaceutical compositions comprising the three active pharmaceutical ingredients (APIs) Amlodipine, Candesartan cilexetil and Hydrochlorothiazide for the treatment of hypertension. In a preferred embodiment of the present invention, Amlodipine is utilized in the form of its benzenesulfonate (besilate) salt. 
     Amlodipine besilate may be manufactured according to processes known in the art, e.g. as disclosed in patent application EP 0 244 944 A2. Candesartan cilexetil may also be manufactured according to processes known in the art, e.g. as disclosed in patent application EP 0 459 136 A1. Hydrochlorothiazide may also be manufactured according to processes known in the art, e.g. as disclosed in U.S. Pat. No. 3,163,645. 
     The pharmaceutical compositions according to the present invention, preferably in the form of tablets, comprise Candesartan cilexetil and a first matrix of excipients, Amlodipine and a second matrix of excipients, comprising at least one filler and Hydrochlorothiazide which may be present in either matrix. 
     Preferably, the first matrix is in the form of granules comprising Candesartan cilexetil, one or more disintegrants, one or more binders, one or more fillers, one or more stabilizers and optionally one or more glidants and other pharmaceutically acceptable excipients; whereas the second extragranular matrix comprises Amlodipine, one or more fillers, one or more lubricants and optionally other pharmaceutically acceptable excipients. Hydrochlorothiazide may be present either in the first granular matrix or in the second extragranular matrix. 
     In the context of the present invention, the terms actives, fillers, disintegrants, stabilizers, binders, lubricants, glidants etc. shall be understood as including a single compound but also multiple compounds. 
     Pharmaceutically acceptable disintegrants include, but are not limited to, carboxymethyl cellulose (carmellose), sodium starch glycolate, polyvinylpyrrolidone, crospovidone, croscarmellose, low substituted hydroxypropyl cellulose (L-HPC) and mixtures thereof. The preferred disintegrant is carmellose calcium. 
     In a preferred embodiment of the present invention, the one or more disintegrants are completely intragranular. It was found that the amount of intragranular disintegrant should be kept in a certain range. If the amount of disintegrant is below 1.0 wt.-%, Candesartan cilexetil is released too slowly. On the other hand, an amount of disintegrant of 5.0 wt.-% or higher results in too fast a dissolution of Candesartan cilexetil. Accordingly, the amount of disintegrants is preferably in the range from 1.5 wt.-% to 4.0 wt.-%, relative to the total weight of the composition. 
     Pharmaceutically acceptable binders include, but are not limited to, hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), dihydroxypropyl cellulose, methyl cellulose, hydroxyethyl cellulose, ethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol, maltodextrin, pregelatinized starch, polymethacrylates, sodium alginate, polyvinylpyrrolidone (povidone) and vinylpyrrolidone/vinylacetate copolymer (copovidone) and mixtures thereof. The preferred binder is hydroxypropyl cellulose (HPC). 
     It has been found that a certain minimum of binder is necessary for the formation of granules, whereas too high amounts lead to poor dissolution of the API(s). Accordingly, in a preferred embodiment of the invention, the amount of one or more binder(s) is in the range from 1 wt.-% to 10.0 wt.-%, more preferably in the range from 6.0 wt.-% to 9.0 wt.-%. In a particularly preferred embodiment of the invention, the binder is incorporated into the granular matrix only. 
     To match the different dissolution profiles of the three different active substances at the same time with a fixed dose combination/formulation is not trivial, as already indicated in  FIG. 2 . 
     It has been found that not only the total amount of disintegrants and binders does matter, but also their relative proportions. 
     For some reason, changes of the composition of the granular matrix appear to affect also the dissolution of Amlodipine being located in the extragranular matrix. 
     As demonstrated in  FIG. 4 a   , the release of Amlodipine from formulation I, having a ratio of about 1.0:1.5 between disintegrant and binder, is slower compared to the reference product NORVASC®. However, the release of Candesartan cilexetil from this formulation is faster compared to the reference product ATACAND®, as demonstrated in  FIG. 4   b.    
     In order to slow down the release of Candesartan cilexetil, the amount of disintegrant was reduced whereas the amount of binder was increased in formulation II compared to formulation I, resulting in a ratio of about 1.0:4.0 between disintegrant and binder. 
     As demonstrated in  FIG. 4 b   , the release of Candesartan cilexetil from formulation II is faster compared to formulation I. However, the release of Amlodipine from formulation II is slower compared to formulation I, as demonstrated in  FIG. 4 a   . This finding is unexpected because the change of binder and disintegrant occurred in the granular matrix, whereas the composition of the extragranular matrix, comprising the Amlodipine, was not changed. 
     Interestingly, it appears that the dissolution profile of Hydrochlorothiazide is not influenced by changes of the composition. On the contrary, even the transfer of the full amount of Hydrochlorothiazide from the granular matrix into the extragranular matrix does not change its dissolution profile significantly. 
     As a result from the observations above, it can be said that both formulations are satisfactory as regards the approach of the dissolution profiles of all reference products NORVASC®, ATACAND® and ESIDRIX® in order to achieve bioequivalence for all active substances. However, special attention has to be drawn towards the ratio between the amount of disintegrants relative to the amount of binders in the formulation, which should be kept in the range of from 1.0:1.5 to 1.0:4.0 by weight. 
     Accordingly, preferred embodiments of the present invention are characterized by a ratio between the amount of disintegrants and the amount of binders in the formulation that is in the range of from 1.0:1.5 to 1.0:4.0 by weight. 
     Pharmaceutically acceptable fillers include, but are not limited to, lactose, starch, microcrystalline cellulose (MCC), sucrose, mannitol, dicalcium phosphate, calcium carbonate, magnesium carbonate, low substituted hydroxypropyl cellulose (L-HPC), powder cellulose, calcium silicate, calcium phosphate, sorbitol, dextrin, kaolin, magnesium oxide, calcium sulfate, xylitol, isomalt, glucose, fructose, maltose and mixtures thereof. Preferred filler(s) are lactose monohydrate and maize starch, microcrystalline cellulose (MCC) and mixtures thereof. 
     The total amount of fillers is preferably in the range between 30 wt.-% and 85 wt.-%, based on the total weight of the composition. 
     In view of the finding that the composition of the granular matrix impacts also the characteristics of the extragranular matrix, it was quite surprising that even high amounts of lactose in the granular matrix appears not to have any impact on the stability of extragranular Amlodipine, which is known to readily form colored impurities when exhibited to lactose because of the Maillard reaction. Accordingly, a preferred embodiment of the present invention is characterized by a content of 50 wt.-% or more of lactose monohydrate. 
     Preferred pharmaceutical compositions according to the present invention comprise one or more stabilizers. The most preferred stabilizing agent for Candesartan cilexetil is polyethylene glycol (PEG). Since high amounts of PEG are known to result in increased amlodipine-related impurities (i.e. Impurity D), the amount of PEG should be kept as low as possible. It has now been found that PEG in amounts (by weight) of as low as a ratio of 1.0:6.0 to 1.0:8.0 relative to Candesartan cilexetil does not only sufficiently stabilize Candesartan cilexetil (table 8a-d), but furthermore leads to formulations with an even improved processability. 
     Accordingly, preferred pharmaceutical formulations according to the present invention comprise PEG in amounts (by weight) of as low as a ratio of 1.0:6.0 to 1.0:8.0 relative to Candesartan cilexetil. 
     Suitable lubricants include, but are not limited to, magnesium stearate, calcium stearate, sodium stearate, stearic acid, sodium glyceryl behenate, hexanedioic acid, hydrogenated vegetable oil sodium, stearyl fumarate, glycerin fumarate and mixtures thereof. The preferred lubricant is magnesium stearate. The amount of lubricants is preferably in the range between 0.5 wt.-% and 2.0 wt.-%, relative to the total weight of the composition, preferably being present in the extragranular matrix only. 
     The pharmaceutical compositions according to the present invention may optionally comprise pharmaceutically acceptable glidants such as colloidal silicon dioxide, talcum, magnesium carbonate and mixtures thereof. The amount of glidant(s) is preferably in the range between 0.1 wt.-% and 1.5 wt.-%, relative to the total weight of the composition. 
     The dissolution profile of pharmaceutical formulations of Candesartan cilexetil is somewhat affected by the size of the Candesartan cilexetil particles. As indicated in  FIG. 5 , formulation I equipped with Candesartan cilexetil having a particle size distribution with a D 90 -value of about 10.8 μm shows an incomplete total drug release, whereas the drug release from formulation I equipped with Candesartan cilexetil particles having a particle size distribution with a D 90 -value of about 5.9 μm is complete. The particle size analyses were performed according to the test method as described in table 10. 
     Accordingly, in a preferred embodiment of the present invention the D 90 -value of the particle size distribution of Candesartan cilexetil, being measured by laser diffraction, ranges from 1.0 μm to 10.0 μm. More preferred, the D 90 -value of the particle size distribution of Candesartan cilexetil ranges from of 4.0 μm to 8.0 μm. 
     As already indicated above, it is economically not attractive to develop, register and manufacture all of the 16 theoretically possible fixed dose compositions of Amlodipine, Candesartan cilexetil and Hydrochlorothiazide. 
     It has been found that the set of fixed dose pharmaceutical compositions containing 5 mg/16 mg/12.5 mg, 10 mg/16 mg/12.5 mg, 5 mg/32 mg/25 mg, 10 mg/32 mg/25 mg Amlodipine/Candesartan cilexetil/Hydrochlorothiazide is advantageous from a regulatory and economically point of view. 
     The advantages are as follows:
         Only the amount of the active Amlodipine besilate is amended, whereas the amounts (in wt.-%) of the actives Candesartan cilexetil and Hydrochlorothiazide remain constant. As can be seen from table 4, this allows to produce all four different combinations of strengths from only one granular matrix for each composition, rendering the manufacturing process much more cost efficient.   If the total weight of the composition is 285 mg or more, the relative amount of Amlodipine besilate remains below 5 wt.-% compared to the total weight of the composition. If, in addition, Amlodipine besilate is solely replaced by a filler so that the total weight of the composition remains constant, there is no need to perform additional bioequivalence studies.       

     
       
         
           
               
               
               
               
               
             
               
                 TABLE 3 
               
               
                   
               
               
                   
                 formulations 
                 formulations 
                 formulations 
                 formulations 
               
               
                   
                 Ic, IIc, IIIc 
                 Ib, IIb, IIIb 
                 Ia, IIa, IIIa 
                 I, II, III 
               
               
                   
                 5/16/12.5 
                 10/16/12.5 
                 5/32/25 
                 10/32/25 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                 Total weight 
                 285.00 mg 
                 570.00 mg 
               
            
           
           
               
               
            
               
                 Candesartan cilexetil 
                 5.7% 
               
               
                 Hydrochlorothiazide 
                 4.4% 
               
            
           
           
               
               
               
               
               
            
               
                 Amlodipine besilate 
                 2.45% 
                 4.9% 
                 1.23% 
                 2.45% 
               
               
                 APIs in total 
                  35.45 mg 
                  42.40 mg 
                  63.95 mg 
                  70.90 mg 
               
               
                 Excipients in total 
                 249.55 mg 
                 242.60 mg 
                 506.05 mg 
                 499.10 mg 
               
               
                 Restriction fulfilled 
                 quantitatively 
                 Amlo: (i) + (iii) 
                 Amlo: (i) + (iii) 
                 Reference (supposed 
               
               
                   
                 to formulation IV 
                   
                   
                 BE-strength) 
               
               
                   
               
            
           
         
       
     
     In an especially preferred embodiment of the present invention, HCT is only present in the granular matrix of the pharmaceutical composition. A further advantage of this embodiment is that the granular matrix comprising Candesartan cilexetil and HCT remains the same for all 4 combinations of strengths, which represents a major advantage for the manufacturing since only one kind of granules (instead of four different kinds of granules) has to be produced to satisfy all 4 combinations. 
     The invention also relates to a process for the manufacture of pharmaceutical compositions comprising Candesartan cilexetil, Hydrochlorothiazide and Amlodipine. 
     Tablets containing Candesartan cilexetil, Hydrochlorothiazide and Amlodipine besilate were prepared by compression of a blend comprising a granulate of Candesartan cilexetil, Hydrochlorothiazide and a first set of excipients with an admixed extragranular matrix comprising Amlodipine Besilate and a second set of excipients. 
     The dry components of the granulate, i.e. Candesartan cilexetil, polyethylene glycol, maize starch, lactose monohydrate, carboxymethyl cellulose (carmellose) calcium, hydroxypropyl cellulose (hyprolose, HPC) and Hydrochlorothiazide were sifted and mixed in a high shear rapid mixer and granulator (RMG) until a homogenous blend was obtained (Steps 1 to 3), then wetted with purified water and granulated (Step 4). The wet granulate was then subjected to a fluidized bed drying process to obtain a moisture level corresponding approximately to the starting moisture content of the dry ingredients mixture (Step 5). 
     The dry granulate was then milled through a Quadro® Comil® to obtain granules of uniform size (Step 6). The resulting granulate was mixed with the extragranular matrix components, i.e. Amlodipine besilate, microcrystalline cellulose and magnesium stearate (Steps 7 to 12), and then compressed using a rotary tablet machine (Step 13). The tablets were packed in opaque PVC/PVdC blisters and Alu-Alu blisters and charged on stability at 40 PC/75% RH, 30° C./65% RH, and 25° C./60% RH, for up to 6 months. 
     A detailed process for the manufacture of pharmaceutical compositions according to formulations I and Ia-c of the present invention is displayed in  FIG. 6 . The manufacture of pharmaceutical compositions according to formulations II and IIa-c and III and IIIa-c of the present invention is practically identical with the exception that Hydrochlorothiazide is not added together with the other components of the granulate such as Candesartan cilexetil, but added together with the other extragranular matrix components such as Amlodipine besilate. 
     An in-vivo pilot bioequivalence (BE) study with medications according to formulation I (table 4) and formulation II (table 5) and the respective mono brand products (ATACAND®, ESIDRIX® and NORVASC®) as references revealed that the maximum plasma concentration (c max ) of Candesartan was above of the acceptable upper limit, whereas the release profiles of Amlodipine and Hydrochlorothiazide perfectly hit the optimum range as regards c max  and area under the curve (AUC). 
     Consequently, the composition of the medication had to be adapted in order to lower c max  of Candesartan without affecting its AUC and also the pharmacokinetic parameters of Amlodipine and Hydrochlorothiazide. This was achieved by the development of medications prepared according to formulation III (table 5). Two batches of this formulation (batch IIIA and batch IIIB) containing Candesartan cilexetil having particle size distributions with D 90 -values of about 14 μm and about 24 μm, respectively, revealed acceptable values of c max  and AUC of all three actives when applied in a follow-up BE study (table 9). 
     Accordingly, another preferred embodiment of the present invention is described in the following: 
     The present invention relates to a fixed dose pharmaceutical composition comprising the active substances Candesartan cilexetil, Amlodipine and Hydrochlorothiazide for the treatment of hypertension. 
     In particular, the fixed dose pharmaceutical composition is in the form of a tablet, comprising
         Candesartan cilexetil and a first matrix of excipients, and   Amlodipine and a second matrix of excipients,
 
wherein Hydrochlorothiazide may be comprised in either matrix.
       

     Preferably, the first matrix is in the form of granules comprising Candesartan cilexetil, one or more disintegrants, one or more binders, one or more fillers, one or more stabilizers and optionally one or more glidants and/or other pharmaceutically acceptable excipients and the second, extragranular matrix comprises Amlodipine, one or more fillers, one or more lubricants and optionally other pharmaceutically acceptable excipients. 
     In a preferred embodiment, the fixed dose pharmaceutical composition comprises polyethylene glycol (PEG) as stabilizer in a ratio of from 1.0:6.0 to 1.0:8.0 by weight relative to Candesartan cilexetil. 
     In a particularly preferred embodiment, the D 90 -value of the particle size distribution of Candesartan cilexetil, being measured by laser diffraction, ranges from 11.0 μm 50.0 μm. More preferred, the D 90 -value of the particle size distribution of Candesartan cilexetil ranges from 12.0 μm to 40.0 μm. Even more preferred, the D 90 -value of the particle size distribution of Candesartan cilexetil ranges from 13.0 μm to 30.0 μm. Most preferred, the D 90 -value of the particle size distribution of Candesartan cilexetil is 14.0 μm or 24.0 μm. 
     The fixed dose pharmaceutical composition may preferably comprise 5 mg or 10 mg Amlodipine, 4 mg, 8 mg, 16 mg or 32 mg Candesartan cilexetil, and 12.5 mg or 25 mg Hydrochlorothiazide. 
     Also within the scope of the present invention is a set of fixed dose pharmaceutical compositions comprising 5 mg/16 mg/12.5 mg, 10 mg/16 mg/12.5 mg, 5 mg/32 mg/25 mg and 10 mg/32 mg/25 mg Amlodipine/Candesartan cilexetil/Hydrochlorothiazide, respectively, wherein
         the relative amounts of Candesartan cilexetil and Hydrochlorothiazide in wt.-% compared to the total weight of the composition remain constant in each composition   Amlodipine besilate is solely replaced by a filler, so that the total weight of the composition remains constant, and   the total weight of the composition is 285 mg or more, so that the relative amount of Amlodipine besilate remains below 5 wt.-% compared to the total weight of the composition.       

     EXAMPLES 
     Pharmaceutical Compositions 
     Tablets containing Amlodipine besilate, Candesartan cilexetil and Hydrochlorothiazide were prepared according to the process as shown in  FIG. 6 . 
     
       
         
           
               
               
               
               
               
               
             
               
                 TABLE 4 
               
             
            
               
                   
               
               
                   
                   
                 formulation Ic 
                 formulation Ib 
                 formulation Ia 
                 formulation I 
               
               
                   
                   
                 5/16/12.5 
                 10/16/12.5 
                 5/32/25 
                 10/32/25 
               
            
           
           
               
               
               
            
               
                 Ingredients 
                 Function 
                 Qty/Tab [mg] (wt.-%*) 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 Intragranular 
                   
                   
                   
               
               
                 Candesartan cilexetil 
                 Active 
                 16.00 (5.61) 
                 32.00 (5.61) 
               
               
                   
                 substance 
                   
                   
               
               
                 PEG 8000 PF 
                 Stabilizer 
                  2.60 (0.91) 
                  5.20 (0.91) 
               
               
                 Lactose monohydrate 
                 Filler 
                 155.90 (54.70) 
                 311.80 (54.70) 
               
               
                 Pharmatose 200M 
                   
                   
                   
               
               
                 Maize starch B 
                 Filler 
                 28.00 (9.82) 
                 56.00 (9.82) 
               
               
                 Carmellose calcium 
                 Disintegrant 
                 11.50 (4.04) 
                 23.00 (4.04) 
               
               
                 (ECG-505) 
                   
                   
                   
               
               
                 Hydroxypropyl 
                 Binder 
                 18.50 (6.49) 
                 37.00 (6.49) 
               
               
                 cellulose (Klucel) 
                   
                   
                   
               
               
                 Hydrochlorothiazide 
                 Active 
                 12.50 (4.39) 
                 25.00 (4.39) 
               
               
                   
                 substance 
                   
                   
               
               
                 Total intragranular 
                 — 
                    245 (85.96) 
                   490 (85.96) 
               
               
                 Extragranular 
                   
                   
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 Amlodipine besilate 
                 Active 
                  6.95 (2.45) 
                 13.90 (4.90) 
                  6.95 (1.23) 
                 13.90 (2.45) 
               
               
                   
                 substance 
                   
                   
                   
                   
               
               
                 Microcrystalline 
                 Filler 
                 31.50 (11.05) 
                 24.55 (8.60) 
                 69.95 (12.27) 
                 63.00 (11.05) 
               
               
                 cellulose PH102 
                   
                   
                   
                   
                   
               
            
           
           
               
               
               
               
            
               
                 Magnesium stearate 
                 Lubricant 
                  1.55 (0.54) 
                  3.10 (0.54) 
               
               
                 Total 
                 — 
                  285.00 (100.00) 
                  570.00 (100.00) 
               
               
                   
               
               
                 *Relative amount, based on the weight of the total composition 
               
            
           
         
       
     
     As apparent from table 4, the set of up to four pharmaceutical compositions I, Ia, Ib and Ic may be manufactured by using the same granular matrix. In other words, there is no need to produce a different granular matrix for each composition of strengths, rendering the manufacturing process much more cost efficient. Only the amount of one active (i.e. Amlodipine besilate) in the extragranular matrix has to be adapted. 
     
       
         
           
               
               
               
               
               
               
             
               
                 TABLE 5 
               
             
            
               
                   
               
               
                   
                   
                 formulation IIc 
                 formulation IIb 
                 formulation IIa 
                 formulation II 
               
               
                   
                   
                 5/16/12.5 
                 10/16/12.5 
                 5/32/25 
                 10/32/25 
               
            
           
           
               
               
               
            
               
                 Ingredients 
                 Function 
                 Qty/Tab [mg] (wt.-%*) 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 Intragranular 
                   
                   
                   
               
               
                 Candesartan cilexetil 
                 Active 
                 16.00 (5.61) 
                 32.00 (5.61) 
               
               
                   
                 substance 
                   
                   
               
               
                 PEG 8000 PF 
                 Stabilizer 
                  2.60 (0.91) 
                  5.20 (0.91) 
               
               
                 Lactose monohydrate 
                 Filler 
                 155.90 (54.70) 
                 311.80 (54.70) 
               
               
                 Pharmatose 200M 
                   
                   
                   
               
               
                 Maize starch B 
                 Filler 
                 28.00 (9.82) 
                 56.00 (9.82) 
               
               
                 Carmellose calcium 
                 Disintegrant 
                  5.50 (1.93) 
                 11.00 (1.93) 
               
               
                 (ECG-505) 
                   
                   
                   
               
               
                 Hydroxypropyl 
                 Binder 
                 24.50 (8.60) 
                 49.00 (8.60) 
               
               
                 cellulose (Klucel) 
                   
                   
                   
               
               
                 Total lntragranular 
                 — 
                 232.50 (81.58) 
                 465.00 (81.58) 
               
               
                 Extragranular 
                   
                   
                   
               
               
                 Hydrochlorothiazide 
                 Active 
                 12.50 (4.39) 
                 25.00 (4.39) 
               
               
                   
                 substance 
                   
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 Amlodipine besilate 
                 Active 
                 6.95 (2.44) 
                 13.90 (4.88) 
                 6.95 (1.22) 
                 13.90 (2.44)  
               
               
                   
                 substance 
                   
                   
                   
                   
               
               
                 Microcrystalline 
                 Filler 
                 31.50 (11.05) 
                 24.55 (8.61) 
                 69.95 (12.27) 
                 63.00 (11.05) 
               
               
                 cellulose PH102 
                   
                   
                   
                   
                   
               
            
           
           
               
               
               
               
            
               
                 Magnesium stearate 
                 Lubricant 
                  1.55 (0.54) 
                  3.10 (0.54) 
               
               
                 Total 
                 — 
                  285.00 (100.00) 
                  570.00 (100.00) 
               
               
                   
               
               
                 *Relative amount, based on the weight of the total composition 
               
            
           
         
       
     
     As apparent from table 5, the complete set of up to four pharmaceutical compositions II, IIa, IIb and IIc may be manufactured by using only one granular matrix. Again, there is no need to produce a different granular matrix for each composition of strengths, rendering the manufacturing process much more cost efficient. However, the amount of two actives (i.e. Amlodipine besilate and Hydrochlorothiazide) in the extragranular matrix has to be adapted. 
     
       
         
           
               
               
               
               
               
               
             
               
                 TABLE 6 
               
             
            
               
                   
               
               
                   
                   
                 formulation IIIc 
                 formulation IIIb 
                 formulation IIIa 
                 formulation III 
               
               
                   
                   
                 5/16/12.5 
                 10/16/12.5 
                 5/32/25 
                 10/32/25 
               
            
           
           
               
               
               
            
               
                 Ingredients 
                 Function 
                 Qty/Tab [mg] (wt.-%*) 
               
               
                   
               
            
           
           
               
               
               
               
            
               
                 Intragranular 
                   
                   
                   
               
               
                 Candesartan cilexetil 
                 Active 
                 16.00 (5.61) 
                 32.00 (5.61) 
               
               
                   
                 substance 
                   
                   
               
               
                 PEG 8000 PF 
                 Stabilizer 
                  2.60 (0.91) 
                  5.20 (0.91) 
               
               
                 Lactose monohydrate 
                 Filler 
                 151.75 (53.25) 
                 303.50 (53.25) 
               
               
                 Pharmatose 200M 
                   
                   
                   
               
               
                 Maize starch B 
                 Filler 
                 13.68 (4.80) 
                 27.36 (4.80) 
               
               
                 Carmellose calcium 
                 Disintegrant 
                  5.50 (1.93) 
                 11.00 (1.93) 
               
               
                 (ECG-505) 
                   
                   
                   
               
               
                 Hydroxypropyl 
                 Binder 
                  40.47 (14.20) 
                  80.94 (14.20) 
               
               
                 cellulose (Klucel EXF) 
                   
                   
                   
               
               
                 Hydroxypropyl 
                 Binder 
                  2.50 (0.88) 
                  5.00 (0.88) 
               
               
                 cellulose (Klucel LF) 
                   
                   
                   
               
               
                 Total lntragranular 
                 — 
                 232.50 (81.58) 
                  465.0 (81.58) 
               
               
                 Extragranular 
                   
                   
                   
               
               
                 Hydrochlorothiazide 
                 Active 
                 12.50 (4.39) 
                 25.00 (4.39) 
               
               
                   
                 substance 
                   
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 Amlodipine besilate 
                 Active 
                 6.95 (2.44) 
                 13.90 (4.88) 
                 6.95 (1.22) 
                 13.90 (2.44) 
               
               
                   
                 substance 
                   
                   
                   
                   
               
               
                 Microcrystalline 
                 Filler 
                 31.50 (11.05) 
                 24.55 (8.61) 
                 69.95 (12.27) 
                  63.00 (11.05) 
               
               
                 cellulose PH102 
                   
                   
                   
                   
                   
               
            
           
           
               
               
               
               
            
               
                 Magnesium stearate 
                 Lubricant 
                  1.55 (0.54) 
                  3.10 (0.54) 
               
               
                 Total 
                 — 
                  285.00 (100.00) 
                  570.00 (100.00) 
               
               
                   
               
               
                 *Relative amount, based on the weight of the total composition 
               
            
           
         
       
     
     Dissolution Testing 
     The in-vitro dissolution of tablets was analyzed according to Ph. Eur. 2.9.3/USP &lt;711&gt;—Method 2 (Paddle Apparatus) with the settings as displayed in table 7. 
     
       
         
           
               
               
               
               
               
               
               
             
               
                 TABLE 7 
               
               
                   
               
               
                   
                   
                   
                   
                   
                   
                 Recom- 
               
               
                   
                   
                   
                   
                   
                   
                 mended 
               
               
                   
                   
                   
                   
                   
                   
                 Sampling  
               
               
                 Drug  
                   
                 USP 
                 Speed 
                   
                 Volume 
                 Times 
               
               
                 Name 
                 Reference 
                 Apparatus 
                 [RPM] 
                 Medium 
                 [ml] 
                 [minutes] 
               
               
                   
               
             
            
               
                 Amlodipine 
                 OGD and 
                 II  
                 75 
                 0.01N HCl 
                 500 
                 10, 20, 30,  
               
               
                 besylate 
                 USP 
                 (Paddle) 
                   
                   
                   
                 45 and 60 
               
               
                 Candesartan 
                 BP draft 
                 II  
                 50 
                 0.03% w/v 
                 900 
                 45 min  
               
               
                 cilexetil 
                 mono- 
                 (Paddle) 
                   
                 polysorbate 80 in 
                   
                 (75%) 
               
               
                   
                 graph 
                   
                   
                 buffer solution 
                   
                   
               
               
                   
                   
                   
                   
                 pH 7.2 
                   
                   
               
               
                 Candesartan 
                 OGD 
                 II  
                 50 
                 0.35% 
                 900 
                 10, 20, 30,  
               
               
                 cilexetil/ 
                   
                 (Paddle) 
                   
                 polysorbate 20 in 
                   
                 45 and 60 
               
               
                 HCTZ 
                   
                   
                   
                 phosphate buffer 
                   
                   
               
               
                 (16/12.5 mg) 
                   
                   
                   
                 pH 6.5 
                   
                   
               
               
                 Candesartan 
                 OGD 
                 II  
                 50 
                 0.70% 
                 900 
                 10, 20, 30,  
               
               
                 cilexetil 
                   
                 (Paddle) 
                   
                 polysorbate 20 in 
                   
                 45 and 60 
               
               
                 (32 mg); 
                   
                   
                   
                 0.05M phosphate 
                   
                   
               
               
                 Candesartan 
                   
                   
                   
                 buffer pH 6.5 
                   
                   
               
               
                 Cilexetil/ 
                   
                   
                   
                   
                   
                   
               
               
                 HCTZ 
                   
                   
                   
                   
                   
                   
               
               
                 (32/12.5 mg  
                   
                   
                   
                   
                   
                   
               
               
                 and 
                   
                   
                   
                   
                   
                   
               
               
                 32/25 mg) 
                   
                   
                   
                   
                   
                   
               
               
                 Hydrochloro- 
                 USP 
                 I  
                 100  
                 0.1N hydro- 
                 900 
                 60 min 
               
               
                 thiazide 
                   
                 (basket) 
                   
                 chloric acid 
                   
                 (NLT 60%) 
               
               
                   
               
            
           
         
       
     
     Stability 
     Samples of formulation IIIb and formulation IIIa were stored under controlled conditions and analyzed for related substances and assay at certain time points. The results revealed excellent stability. 
     
       
         
           
               
             
               
                 TABLE 8a 
               
             
            
               
                   
               
               
                 RELATED SUBSTANCE DATA 
               
            
           
           
               
               
               
            
               
                   
                   
                 Conditions 
               
               
                   
                   
                 40° C./75% RH, Blister 
               
               
                   
                   
                 Formulation 
               
            
           
           
               
               
               
               
            
               
                   
                   
                 Formulation IIIb  
                 Formulation IIIa  
               
               
                   
                   
                 (10/16/12.5 mg) 
                 (5/32/25 mg) 
               
            
           
           
               
               
               
            
               
                   
                   
                 Time Point [Months] 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
            
               
                   
                 LIMITS 
                 0 
                 1 
                 3 
                 6 
                 0 
                 1 
                 3 
                 6 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
            
               
                 Amlodipine  
                 Imp D 
                 1 
                 0.06 
                 &lt;LoQ 
                 &lt;LoQ 
                 &lt;LoQ 
                 0.09 
                 &lt;LoQ 
                 0.09 
                 0.09 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                 Besilate  
                 Max  
                 % Impurity 
                 0.2 
                 &lt;LoQ 
                 &lt;LoQ 
                 0.08 
                 0.09 
                 &lt;LoQ 
                 0.23 
                 0.35 
                 0.36 
               
               
                 Impurities 
                 Single  
                 RRT 
                 N/A 
                 N/A 
                 N/A 
                 0.84 
                 0.80 
                 N/A 
                 0.79 
                 0.84 
                 0,79 
               
               
                   
                 Unknown 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
            
               
                   
                 Total Known 
                 N/A 
                 0.06 
                 &lt;LoQ 
                 &lt;LoQ 
                 &lt;LoQ 
                 0.09 
                 &lt;LoQ 
                 0.09 
                 0.09 
               
               
                   
                 Total Unknown 
                 0.2 
                 &lt;LoQ 
                 &lt;LoQ 
                 0.08 
                 0.09 
                 &lt;LoQ 
                 0.41 
                 0.43 
                 0.46 
               
               
                   
                 Total Impurities 
                 N/A 
                 0.06 
                 &lt;LoQ 
                 0.08 
                 0.09 
                 0.09 
                 0.41 
                 0.52 
                 0.55 
               
               
                 Candesartan  
                 Imp B 
                 0.5 
                 0.14 
                 0.20 
                 0.24 
                 0.32 
                 0.13 
                 0.21 
                 0.27 
                 0.33 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                 Cilexetil  
                 Max  
                 % Impurity 
                 0.2 
                 0.09 
                 0.14 
                 0.18 
                 0.23 
                 0.09 
                 0.15 
                 0.21 
                 0,25 
               
               
                 Impurities 
                 Single  
                 RRT 
                 N/A 
                 1.09 
                 1.09 
                 1.09 
                 1.09 
                 1.09 
                 1.09 
                 1.09 
                 1,09 
               
               
                   
                 Unknown 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
            
               
                   
                 Total Known 
                 N/A 
                 0.14 
                 0.20 
                 0.24 
                 0.32 
                 0.13 
                 0.21 
                 0.27 
                 0.33 
               
               
                   
                 Total Unknown 
                 0.2 
                 0.12 
                 0.19 
                 0.29 
                 0.30 
                 0.09 
                 0.20 
                 0.32 
                 0.33 
               
               
                   
                 Total Impurities 
                 N/A 
                 0.26 
                 0.39 
                 0.53 
                 0.62 
                 0.22 
                 0.41 
                 0.59 
                 0.66 
               
               
                 HCTZ  
                 Imp B 
                 1 
                 0.16 
                 0.30 
                 0.52 
                 0.65 
                 0.17 
                 0.30 
                 0.47 
                 0.55 
               
               
                 Impurities 
                 Imp A 
                 0.5 
                 &lt;LoQ 
                 &lt;LoQ 
                 &lt;LoQ 
                 &lt;LoQ 
                 &lt;LoQ 
                 &lt;LoQ 
                 &lt;LoQ 
                 &lt;LoQ 
               
               
                   
                 HCTZ-Dimer 
                 0.5 
                 &lt;LoQ 
                 &lt;LoQ 
                 &lt;LoQ 
                 0.06 
                 &lt;LoQ 
                 &lt;LoQ 
                 0.05 
                 &lt;LoQ 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                   
                 Max  
                 % Impurity 
                 0.2 
                 &lt;LoQ 
                 &lt;LoQ 
                 &lt;LoQ 
                 &lt;LoQ 
                 &lt;LoQ 
                 &lt;LoQ 
                 0.05 
                 &lt;LoQ 
               
               
                   
                 Single  
                 RRT 
                 N/A 
                 N/A 
                 N/A 
                 N/A 
                 N/A 
                 N/A 
                 N/A 
                 2.85 
                 N/A 
               
               
                   
                 Unknown 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
            
               
                   
                 Total Known 
                 N/A 
                 0.16 
                 0.30 
                 0.52 
                 0.71 
                 0.17 
                 0.30 
                 0.52 
                 0.55 
               
               
                   
                 Total Unknown 
                 0.2 
                 &lt;LoQ 
                 &lt;LoQ 
                 &lt;LoQ 
                 &lt;LoQ 
                 LoQ 
                 &lt;LoQ 
                 0.05 
                 0.07 
               
               
                   
                 Total Impurities 
                 N/A 
                 0.16 
                 0.30 
                 0.52 
                 0.71 
                 0.17 
                 0.30 
                 0.57 
                 0.55 
               
               
                   
               
               
                 N/A: not applicable 
               
               
                 RRT: relative retention time 
               
               
                 &lt;LoQ: below level of quantification (0.05%) 
               
               
                 Note: 
               
               
                 Amlodipine besilate impurity at RRT ca. 0.8 is considered as amlodipine adduct (to be confirmed). The limit of impurity is actually 0.5%. 
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 8b 
               
             
            
               
                   
               
               
                 RELATED SUBSTANCE DATA 
               
            
           
           
               
               
               
            
               
                   
                   
                 Conditions 
               
               
                   
                   
                 30° C./65% RH, Blister 
               
               
                   
                   
                 Formulation 
               
            
           
           
               
               
               
               
            
               
                   
                   
                 Formulation  
                 Formulation  
               
               
                   
                   
                 IIIb 
                 IIIa 
               
               
                   
                   
                 (10/16/ 
                 (5/32/ 
               
               
                   
                   
                 12.5 mg) 
                 25 mg) 
               
            
           
           
               
               
               
            
               
                   
                   
                 Time Point [Months] 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 LIMITS 
                 0 
                 6 
                 0 
                 6 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 Amlodipine  
                 Imp D 
                 1 
                 0.06 
                 &lt;LoQ 
                 0.09 
                 &lt;LoQ 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 Besilate  
                 Max  
                 %  
                 0.2 
                 &lt;LoQ 
                 &lt;LoQ 
                 &lt;LoQ 
                 0.15 
               
               
                 Impurities 
                 Single  
                 Impurity 
                   
                   
                   
                   
                   
               
               
                   
                 Unknown 
                 RRT 
                 N/A 
                 N/A 
                 N/A 
                 N/A 
                 0.84 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                 Total Known 
                 N/A 
                 0.06 
                 &lt;LoQ 
                 0.09 
                 &lt;LoQ 
               
               
                   
                 Total Unknown 
                 0.2 
                 &lt;LoQ 
                 &lt;LoQ 
                 &lt;LoQ 
                 0.15 
               
               
                   
                 Total Impurities 
                 N/A 
                 0.06 
                 &lt;LoQ 
                 0.09 
                 0.15 
               
               
                 Candesartan  
                 Imp B 
                 0.5 
                 0.14 
                 0.20 
                 0.13 
                 0.23 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 Cilexetil  
                 Max  
                 %  
                 0.2 
                 0.09 
                 0.14 
                 0.09 
                 0.17 
               
               
                 Impurities 
                 Single  
                 Impurity 
                   
                   
                   
                   
                   
               
               
                   
                 Unknown 
                 RRT 
                 N/A 
                 1.09 
                 1.09 
                 1.09 
                 1.09 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                 Total Known 
                 N/A 
                 0.14 
                 0.20 
                 0.13 
                 0.23 
               
               
                   
                 Total Unknown 
                 0.2 
                 0.09 
                 0.20 
                 0.09 
                 0.23 
               
               
                   
                 Total Impurities 
                 N/A 
                 0.23 
                 0.40 
                 0.22 
                 0.46 
               
               
                 HCTZ  
                 Imp B 
                 1 
                 0.16 
                 0.16 
                 0.17 
                 0.15 
               
               
                 Impurities 
                 Imp A 
                 0.5 
                 &lt;LoQ 
                 &lt;LoQ 
                 &lt;LoQ 
                 &lt;LoQ 
               
               
                   
                 HCTZ-Dimer 
                 0.5 
                 &lt;LoQ 
                 &lt;LoQ 
                 &lt;LoQ 
                 &lt;LoQ 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 Max  
                 %  
                 0.2 
                 &lt;LoQ 
                 &lt;LoQ 
                 &lt;LoQ 
                 &lt;LoQ 
               
               
                   
                 Single  
                 Impurity 
                   
                   
                   
                   
                   
               
               
                   
                 Unknown 
                 RRT 
                 N/A 
                 N/A 
                 N/A 
                 N/A 
                 N/A 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                 Total Known 
                 N/A 
                 0.16 
                 0.16 
                 0.17 
                 0.15 
               
               
                   
                 Total Unknown 
                 0.2 
                 &lt;LoQ 
                 &lt;LoQ 
                 &lt;LoQ 
                 &lt;LoQ 
               
               
                   
                 Total Impurities 
                 N/A 
                 0.16 
                 0.16 
                 0.17 
                 0.15 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 8c 
               
             
            
               
                   
               
               
                 RELATED SUBSTANCE DATA 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                   
                   
                 Conditions 
               
               
                   
                   
                   
                   
                 25° C./60% RH, Blister 
               
               
                   
                   
                   
                   
                 Formulation 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                 Formulation  
                 Formulation  
               
               
                   
                   
                   
                   
                 IIIb 
                 IIIa 
               
               
                   
                   
                   
                   
                 (10/16/ 
                 (5/32/ 
               
               
                   
                   
                   
                   
                 12.5 mg) 
                 25 mg) 
               
            
           
           
               
               
               
               
               
            
               
                   
                   
                   
                   
                 Time Point [Months] 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                   
                   
                 LIMITS 
                 0 
                 6 
                 0 
                 6 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 Amlodipine  
                 Imp D 
                 1 
                 0.06 
                 &lt;LoQ 
                 0.09 
                 &lt;LoQ 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 Besilate  
                 Max  
                 %  
                 0.2 
                 &lt;LoQ 
                 &lt;LoQ 
                 &lt;LoQ 
                 0.07 
               
               
                 Impurities 
                 Single  
                 Impurity 
                   
                   
                   
                   
                   
               
               
                   
                 Unknown 
                 RRT 
                 N/A 
                 N/A 
                 N/A 
                 N/A 
                 0.79 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                 Total Known 
                 N/A 
                 0.06 
                 &lt;LoQ 
                 0.09 
                 &lt;LoQ 
               
               
                   
                 Total Unknown 
                 0.2 
                 &lt;LoQ 
                 &lt;LoQ 
                 &lt;LoQ 
                 0.07 
               
               
                   
                 Total Impurities 
                 N/A 
                 0.06 
                 &lt;LoQ 
                 0.09 
                 0.07 
               
               
                 Candesartan  
                 Imp B 
                 0.5 
                 0.14 
                 0.21 
                 0.13 
                 0.20 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 Cilexetil  
                 Max  
                 %  
                 0.2 
                 0.09 
                 0.15 
                 0.09 
                 0.15 
               
               
                 Impurities 
                 Single  
                 Impurity 
                   
                   
                   
                   
                   
               
               
                   
                 Unknown 
                 RRT 
                 N/A 
                 1.09 
                 1.09 
                 1.09 
                 1.09 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                 Total Known 
                 N/A 
                 0.14 
                 0.21 
                 0.13 
                 0.20 
               
               
                   
                 Total Unknown 
                 0.2 
                 0.09 
                 0.20 
                 0.09 
                 0.20 
               
               
                   
                 Total Impurities 
                 N/A 
                 0.23 
                 0.41 
                 0.22 
                 0.40 
               
               
                 HCTZ  
                 Imp B 
                 1 
                 0.16 
                 0.17 
                 0.17 
                 0.15 
               
               
                 Impurities 
                 Imp A 
                 0.5 
                 &lt;LoQ 
                 &lt;LoQ 
                 &lt;LoQ 
                 &lt;LoQ 
               
               
                   
                 HCTZ-Dimer 
                 0.5 
                 &lt;LoQ 
                 &lt;LoQ 
                 &lt;LoQ 
                 &lt;LoQ 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 Max  
                 %  
                 0.2 
                 &lt;LoQ 
                 &lt;LoQ 
                 &lt;LoQ 
                 &lt;LoQ 
               
               
                   
                 Single  
                 Impurity 
                   
                   
                   
                   
                   
               
               
                   
                 Unknown 
                 RRT 
                 N/A 
                 N/A 
                 N/A 
                 N/A 
                 N/A 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                 Total Known 
                 N/A 
                 0.16 
                 0.17 
                 0.17 
                 0.15 
               
               
                   
                 Total Unknown 
                 0.2 
                 &lt;LoQ 
                 &lt;LoQ 
                 &lt;LoQ 
                 &lt;LoQ 
               
               
                   
                 Total Impurities 
                 N/A 
                 0.16 
                 0.17 
                 0.17 
                 0.15 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
               
               
               
             
               
                 TABLE 8d 
               
             
            
               
                   
               
               
                   
                 Time Point 
                   
                 Assay 
               
            
           
           
               
               
               
               
               
               
            
               
                 Formulation 
                 [Months] 
                 Condition 
                 Amlodipine 
                 Candesartan 
                 HCTZ 
               
               
                   
               
               
                 Formulation IIIb 
                 0 
                   
                 99.1 
                 102.5 
                 103.2 
               
               
                 (10 mg/16 mg/12.5 mg) 
                 6M 
                 40° C./75% RH 
                 97.2 
                 102.0 
                  96.1 
               
               
                   
                   
                 25° C./60% RH 
                 97.0 
                 100.7 
                  99.2 
               
               
                 Formulation IIIa 
                 0 
                   
                 96.5 
                 100.1 
                 100.5 
               
               
                 (5 mg/32 mg/25 mg) 
                 6M 
                 40° C./75% RH 
                 96.2 
                 101.9 
                  99.5 
               
               
                   
                   
                 25° C./60% RH 
                 98.1 
                 100.1 
                 102.8 
               
               
                   
               
            
           
         
       
     
     Bioequivalence 
     Table 9 shows the results of the follow-up BE study. 
     
       
         
           
               
               
               
               
             
               
                 TABLE 9 
               
             
            
               
                   
               
               
                   
                   
                   
                 90% Confidence Intervals of Parametric Means (n = 18) 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                   
                 Pharmacokinetic 
                 Point  
                 Lower Bound [%] 
                 Upper Bound [%] 
               
               
                 Batch 
                 Active 
                 Parameter 
                 estimate [%] 
                 (≥80.00%) 
                 (≤125.00%) 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 IIIA 
                 Amlodipine 
                 c max   
                 104.42 
                 97.85 
                 111.44 
               
               
                 (Candesartan 
                   
                 AUC (0-72 h)   
                 101.29 
                 96.48 
                 106.35 
               
               
                 cilexetil 
                 Candesartan 
                 c max   
                 105.01 
                 92.79 
                 118.82 
               
               
                 D 90  ≈ 14 μm) 
                   
                 AUC (0-72 h)   
                 108.88 
                 98.42 
                 120.44 
               
               
                   
                 HCTZ 
                 c max   
                 102.38 
                 92.71 
                 113.05 
               
               
                   
                   
                 AUC (0-72 h)   
                 97.12 
                 91.16 
                 103.48 
               
               
                 IIIB 
                 Amlodipine 
                 c max   
                 106.41 
                 99.71 
                 113.56 
               
               
                 (Candesartan 
                   
                 AUC (0-72 h)   
                 101.50 
                 96.67 
                 106.56 
               
               
                 cilexetil 
                 Candesartan 
                 c max   
                 94.51 
                 83.52 
                 106.94 
               
               
                 D 90  ≈ 24 μm) 
                   
                 AUC (0-72 h)   
                 95.77 
                 86.57 
                 105.94 
               
               
                   
                 HCTZ 
                 c max   
                 108.68 
                 98.42 
                 120.01 
               
               
                   
                   
                 AUC (0-72 h)   
                 97.40 
                 91.42 
                 103.77 
               
               
                   
               
            
           
         
       
     
     Particle Size Analysis 
     The particle size analyses were performed as described in table 10. 
     
       
         
           
               
               
               
             
               
                 TABLE 10 
               
               
                   
               
             
            
               
                 Apparatus 
                 Model: 
                 Mastersizer 2000, Malvern 
               
               
                   
                 Accessory: 
                 Scirocco 2000 (A) 
               
               
                 Parameters 
                 Particle RI: 
                 1.63 
               
               
                   
                 Absorption: 
                 0.1 
               
               
                   
                 Analysis model: 
                 General purpose 
               
               
                   
                 Measurement time  
                 8 seconds 
               
               
                   
                 (Sample): 
                   
               
               
                   
                 Background: 
                 8 seconds 
               
               
                   
                 Sampling frequency: 
                 50% 
               
               
                   
                 Scattering pressure: 
                 3.0 bar 
               
               
                   
                 Obscuration: 
                 0.5~6% 
               
            
           
           
               
               
            
               
                 Test  
                 1) Clean the sample plate Scirocco2000 (A) and  
               
               
                 method 
                 dispersing funnel 
               
               
                   
                 2) Sample preparation: Make samples to be well mixed  
               
               
                   
                 for 3 minutes (from top to bottom, left and right) 
               
               
                   
                 3) Take appropriate sample into injector plate and start  
               
               
                   
                 CANDESARTAN CILEXETIL standard measurement  
               
               
                   
                 procedure edited, repeat the testing 3 times. In each test  
               
               
                   
                 intervals, vacuum purge 60 seconds with gas pressure 
               
               
                   
                 to 3.0 bar 
               
               
                   
                 4) After the testing, clean the sample plate and dispersing  
               
               
                   
                 funnel with pressure to 2.0 bar and scattering sampling  
               
               
                   
                 frequency to 50% 
               
               
                   
                 5) Measure the sample of each batch for three times