AAPS PharmSciTech ( # 2017) DOI: 10.1208/s12249-017-0879-x
Research Article Comparative Pharmaceutical Evaluation of Candesartan and Candesartan Cilexetil: Physicochemical Properties, In Vitro Dissolution and Ex Vivo In Vivo Studies Ahmed M. Amer,1 Ahmed N. Allam,2,3 and Ossama Y. Abdallah2
Received 10 June 2017; accepted 14 September 2017 Abstract.
The aim of the present work is to answer the question is it possible to replace the ester prodrug candesartan cilexetil (CC) by its active metabolite candesartan (C) to bypass the in vivo variable effect of esterase enzymes. A comparative physicochemical evaluation was conducted through solubility, dissolution, and stability studies; additionally, ex vivo permeation and in vivo studies were assessed. C demonstrated higher solubility over CC at alkaline pH. Moreover, dissolution testing using the pharmacopeial method showed better release profile of C even in the absence of surfactant in the testing medium. Both drugs demonstrated a slight degradation in acidic pH after short-term stability. Instead, shifting to alkaline pH of 6.5 and 7.4 showed superiority of C solution stability compared to CC solution. The ex vivo permeation results demonstrated that the parent compound C has a significant (P < 0.05) enhanced permeation compared to its prodrug from CC, that agreed with in vivo results in which C suspension reached significantly (P < 0.05) higher Cmax of 1.39 ± 0.59 μg/mL at Tmax of 0.66 ± 0.11 h, while CC suspension reached Cmax of 0.47 ± 0.22 μg/mL at Tmax of 2.00 ± 0.27 h, a lag period of 40 min is needed prior to detection of any absorbed CC in plasma. Those findings are not in agreement with the previously reported rationale on the prodrug formation owing to the poor permeability of the parent compound, suggesting the possibility of marketing the parent drug candesartan for clinical use similarly to azilsartan and its prodrug.
KEY WORDS: candesartan; candesartan cilexetil; permeation; solubility; bioavailability; prodrug.
INTRODUCTION During the past three decades, prodrug strategy has been implemented to improve the physicochemical, biopharmaceutical, and pharmacokinetic properties of active pharmaceutical candidates (1). It is appraised that presently about 10% of global marketed drugs can be classified as prodrugs which can be defined as bio reversible derivatives of drug candidate that undergo a chemical and/or enzymatic conversion in vivo to release the active parent component, which can then exert the anticipated pharmacological effect (1,2). Esters of active agents with different functional groups are the most commonly used prodrugs. Approximately half of the prodrugs currently available on the market are activated via enzymatic hydrolysis by universal esterases which are present throughout the body. However, the prodrug approach 1
Pharonia Pharmaceutical Company Alexandria, Alexandria, Egypt. Department of Pharmaceutics, Faculty of Pharmacy, University of Alexandria, El-Khartoum Square, El-Azarita, Alexandria, 21521, Egypt. 3 To whom correspondence should be addressed. (e-mail:
[email protected]) 2
was not always the optimal strategy to increase oral bioavailability of problematic drugs and many factors should be considered (2). For instance, several aryl and alkyl ester prodrugs including angiotensin converting enzyme inhibitors such as enalaprilate showed a relatively slow and incomplete bioconversion resulting in much lower bioavailability than expected (3). Fosinopril is another antihypertensive prodrug of the active form of fosinoprilat that was developed to exhibit much lipophilicity than its former drug ramipril and expected to demonstrate a greater bioavailability. However, it showed a lower oral absorption that was attributed to the increased molecular weight and lipophilic nature over ramipril (4). Thus, the balance of lipophilicity and aqueous solubility is an important factor in the design of an oral prodrug (3,4). Despite the many successful examples of phosphate prodrugs for parenteral administration, only a few phosphate prodrugs have reached the market as oral dosage forms due to the challenges that may be encountered in the development phase and observation of suboptimal enzymatic bioconversion by phosphatases (5), others may fail due to reduced enzymatic bioconversion, as phosphate esters of taxol (6). Moreover, some oral prodrugs failed owing to absent of 1530-9932/17/0000-0001/0 # 2017 American Association of Pharmaceutical Scientists
Amer et al. clinically relevant benefit over the parent drug, such as oral etoposide (7). Candesartan cilexetil (CC) has been developed to improve the permeation and absorption of the parent drug, candesartan (C), responsible for the antihypertensive activity, by increasing its lipophilicity, it is rapidly and completely bioactivated by ester hydrolysis during absorption from the gastrointestinal tract to candesartan (8,9). CC was not detected in plasma after oral administration and only the active metabolite C was detected (9). In spite of the verified potency and selectivity of CC for angiotensin-II receptors, contradiction about its effectiveness as an antihypertensive drug to attain the targeted blood pressure has been developed (10,11). Some literatures justified the low and irregular bioavailability of CC (15 to 40%) by its high lipophilicity and low aqueous solubility (12,13), while others justified it by the early degradation of the prodrug CC by the esterase enzymes existing in the intestinal lumen before its absorption yielding the parent compound C which is poorly permeable (14). It was reported that the rate of bioconversion of ester prodrugs to the active moiety is unpredictable and erratic based on the availability of the esterase enzymes in the body and the differences in the substrate specificity resulting in pharmacological and toxicological variations (15). Gender, genetic differences, age, drug interaction, food effect, environmental factors, lifestyle, and disease are some of the factors that may be sources for interindividual variations affecting the rate of ester prodrug hydrolysis (15). Recently, azilsartan medoxomil, an ester prodrug of the most recently introduced angiotensin receptor blocker azilsartan which has a very similar structure to C, was developed. Although an early publication from the manufacturer concluded that azilsartan does not need a prodrug formation, both the drug and its prodrug form are available for clinical use, where azilsartan is marketed in Japan while the prodrug azilsartan medoxomil is marketed in the European Union and USA. Even that, literature reports a slightly greater bioavailability and pharmacokinetics after oral administration of azilsartan rather than the prodrug azilsartan medoxomil (16). Similarly, it is an interesting point to investigate the credibility of this claim and the possibility of using C parallel with or even instead of CC, as an approach to bypass the controversial effect of esterase enzymes. The aim of the present work is an attempt to reveal the reason for prodrug formation by conducting a comparative physicochemical evaluation, ex vivo permeation and in vivo pharmacokinetic study for both C and CC. The novelty of the present work is being the first attempt to answer the question if it is possible to replace the ester prodrug CC by its active metabolite C to bypass the in vivo variable inconsistent effect of esterase enzymes. MATERIALS AND METHODS Materials C was obtained from Linhai Tianyu Pharmaceutical CO., China. CC was obtained from Weihai Disu Pharmaceutical CO., China. All other chemicals and reagents used were of analytical grade.
Saturated Solubility Studies The solubility of C and CC was determined in different aqueous media with pH ranging from 1.2 to 7.4 resembling the pH range of the gastrointestinal tract. Briefly, excess amount of C and CC were added to 25 mL of either 0.1 N HCl (pH 1.2) or different phosphate buffers (pH 4.5, 6.8, and 7.4). Samples were stirred at 100 rpm temperature (37° ± 0.5°C) in a controlled water bath for 24 h. After equilibrium, samples were then filtered through 0.22-μm syringe filters (Sartorious, Germany), and an aliquot of 100 μL was injected into HPLC system (Agilent 1200 Series HPLC, Germany). Experiments were done in triplicate. Dissolution Studies In vitro dissolution study was conducted for both drugs using the compendial dissolution conditions for a CC 32 mg tablet in USP39 (17) using phosphate buffer pH 6.5 with 0.7% Tween® 20 as dissolution medium. Moreover, dissolution testing was also performed in a 0.1 N HCl pH 1.2, phosphate buffer (pH 4.5 and pH 6.5). Briefly, 23 mg C powder and 32 mg CC powder (equivalent weight to 23 mg C) were accurately weighed and placed in the dissolution vessel of USP apparatus type II (Hanson, USA) containing a 900-mL dissolution medium at 37° ± 0.5° and stirred at 50 rpm. A sample of 5 mL was withdrawn at 5, 10, 20, 30, 45, and 60 min, filtered using a 0.22-μm syringe filter, replaced by a fresh corresponding medium and analyzed using the same validated HPLC method. Short-term Stability Evaluation Short-term stability evaluation of C and CC in different pH ranges was done. One-millimeter stock solution (1 mg/ mL) of either CC or C in acetonitrile: water (3:2), which is the official solvent for related substance testing of CC in USP39 (17), was diluted in a 50-ml volumetric flask using either 0.1 N HCl (pH 1.2) or different phosphate buffers (pH 4.5, 6.5, and 7.4). Samples were kept at room temperature protected from light for 1 week and percent recovered of both drugs were analyzed using HPLC and compared to zero time as 100%. HPLC Assay HPLC for related substance analysis of CC raw material in the British Pharmacopeia (BP) was used for determination of C and CC (18). The HPLC instrument supplied with a reversed-phase C18 column (X-Terra C18, 4.6 × 150 mm, 5 μm), equipped with a security guard ULTRA cartridges HPLC C18 (4.6 mm) (Phenomenex Co., USA) was used. A gradient method with mobile phase A (acetonitrile: water 57:43) and mobile phase B (acetonitrile: water 90:10). The pH of both mobile phase A and B was adjusted to 3 by addition of 2% glacial acetic acid and the mixture was delivered at flow rate 0.8 mL/min at room temperature. In addition, acetonitrile: water (3:2 v/v) was utilized as analysis solvent. Samples were detected at 254 nm with an injection volume of 100 μL at a retention time of 5.3 and 11.73 min for C and CC, respectively. The method was validated for detection of both C and CC. The linearity range of the method was 0.5–100 μg/
Comparative evaluation of candesartan and candesartan cilexetil mL, with a correlation coefficient (R2) of 0.9998 and 0.9997, respectively. Intra-day and inter-day precision were represented by % relative SD, which ranged from 0.34 to 1.87% and from 0.05 to 1.67%, respectively. Accuracy of the method, demonstrated by intra-day and inter-day % recovery, ranged from 98.27 to 100.72% and from 98.51 to 100.42% for C, while for CC ranged from 99.53 to 101.93% and from 99.24 to 101.06%, respectively. Ex Vivo Permeation Healthy male rats, weighing approximately 200–250 g were kept at 25 ± 1°C and 45–55% RH. The animals were fasted with free access to water, overnight before starting of the experiment. Rats were sacrificed by spinal dislocation and the small intestine was immediately removed and washed with warm Ringer’s solution using a syringe equipped with blunt end. The upper end of the duodenum and lower end of the ileum were separated into sacs having a diameter of 0.4 cm. Each sac was tied at one end, filled with 1 mL of either 1 mg/mL CC suspension or 0.72 mg/mL C suspension, both were dispersed in 0.3% carboxy methylcellulose (CMC) in ringer pH 7.4, via a 1 mL micropipette and was sealed by tying the other end keeping effective sac length 10 cm for permeation. Another parallel experiment was conducted for CC and C solubilized from using 10% dimethylsulphoxide (DMSO) to study the effect of solubility on drug permeation. Each non-everted rat intestinal sac was placed in a 100-mL glass beaker containing 50 mL ringer’s solution pH 7.4 at 37°C in a shaking water bath (Kottermann®, Germany) operating at 100 rpm and constantly aerated with oxygen using laboratory aerator. At predetermined intervals (10, 20, 30, 60, 90, 120, 150, and 180 min), samples of 5 mL were collected from outside of sac and replaced with fresh medium. After samples filtration through a 0.22-μm millipore syringe filter, an aliquot of 100 μL was injected into HPLC system. Permeability flux (F) and apparent permeability coefficient (Papp) were calculated for quantification of amount of drug permeated through the intestinal mucous membrane using the following Eq. (19) Papp ¼
F SA C0
Where, F is permeation flux (μg/min) is the slope of linear portion of the graph obtained by plotting the cumulative
amount (μg) of C permeated versus time (min) and Papp is apparent permeability coefficient (cm/min), SA is the surface area of intestinal membrane assuming it to be of cylindrical shape (cm2); C0 is the initial drug concentration (μg/ml) in the mucosal compartment. In vivo Studies Experimental Animal Protocol The animal experimental protocols were performed in accordance with the European Community guidelines for the use of experimental animals and were approved by the Animal Care and Use Committee, Faculty of Pharmacy, Alexandria University. Healthy male rats, weighing approximately 200–250 g were kept at 25 ± 1°C and 45–55% RH. The animals were fasted providing free access to water, overnight before the start of the experiment. Ten rats were divided into two groups, each comprising five rats. They were administrated either CC or C powder in a dose corresponding to 10 mg/kg (13,20) or 7.2 mg/kg, respectively. Doses were suspended in 2 mL of 0.3% CMC in deionized water and orally administered using an oral gavage passed through the esophagus into the stomach by a stainless steel catheter with blunt ends. Each rat was anesthetized in an ether chamber, and 1-mL blood samples were collected by puncture at the retro-orbital vein at the following intervals: 0.33, 0.66, 1, 1.5, 2, 4, 6, and 8 h. Preparation of Plasma Samples Blood samples were centrifuged at 6000 rpm for 15 min, 200 μL of plasma was mixed with 100 μL of 20% acetic acid, and was vortexed (vortex mixer VM-300; Taipei, Taiwan) for 2 min. After standing for 5 min, 400 μL acetonitrile was added and vortexed for another 2 min then centrifuged (Model 3K-30; Sigma Laboratory; Germany) at 6000 rpm for 15 min at − 20°C and the supernatant was separated, filtered with a 0.22-μm syringe filter and injected in HPLC system. Pharmacokinetic Study Pharmacokinetic analysis of the data was performed using PKSolver, an add-in program for Microsoft excel (21). The area under the plasma concentration-time profile (AUC0-t) was calculated using the linear trapezoidal method. Maximum
Fig. 1. Solubility study results of candesartan in different media at 37°C (n = 3)
Amer et al. Similarly, calibration curve of C concentration plasma was plotted in plasma for quantification purpose. The linearity range of the method was 0.25–10 μg/mL, with a correlation coefficient (R2) of 0.9995. Intra-day and inter-day precision were represented by % relative SD, which ranged from 1.19 to 4.85% and from 1.27 to 4.83%, respectively. Accuracy of the method, demonstrated by intra-day and inter-day % recovery, ranged from 99.73 to 102.71% and from 99.97 to 102.78%, respectively. Statistical Analysis Analysis of variance was conducted using SPSS 20.0 software (SPSS Inc., Chicago, IL, USA, 2012). A P value of ≤ 0.05 was considered statistically significant. Fig. 2. In vitro dissolution of candesartan (C) and candesartan cilexetil (CC) in phosphate buffer pH 6.5 with and without Tween 20
plasma concentration (Cmax) and the time for maximum plasma concentration (Tmax) were obtained directly from the concentration versus time curve. Data were expressed as the mean ± SD. HPLC Assay The same BP stability indicating HPLC method was utilized with slight modification for determination of C in ex vivo and in vivo studies (18). An isocratic mobile phase was a mixture of water and acetonitrile in a ratio of 55:45. The pH of the mobile phase was adjusted to 3 by addition of 2% glacial acetic acid, and the mixture was delivered at flow rate 0.8 mL/min at room temperature. C was detected at 254 nm with an injection volume of 100 μL at a retention time of 5.3 min. Calibration curve of C concentration in Ringer’s solution pH 7.4 was plotted for quantification purpose. The linearity range of the method was 0.5–100 μg/mL, with a correlation coefficient (R2) of 0.9998. Intra-day and inter-day precision were represented by % relative SD, which ranged from 0.29 to 1.63% and from 0.25 to 1.87%, respectively. Accuracy of the method, demonstrated by intra-day and inter-day % recovery, ranged from 98.75 to 102.54% and from 98.86 to 101.07%, respectively.
RESULTS AND DISCUSSION C is a white crystalline powder with pKa of 5.4 and a molecular weight of 440 (22). It is classified as biopharmaceutical classification system (BCS) IV drug with both low solubility and permeability (23). There is insufficient data about its bioavailability and only one study is available; it was reported from this study that the bioavailability is very low with less than 5% after oral administration (24). On the other hand, CC is a white crystalline powder with molecular weight of 610 and pKa = 6.0, it is practically insoluble in water and sparingly soluble in methanol (22). It is supposed to be classified as BCS II drug with both low solubility and high permeability (20). Saturated Solubility Studies Unlike CC which showed poor aqueous solubility (lower than 0.1 mg%) over the pH range from 1.2 to 7.4, C exhibited a pH dependent solubility pattern with a dramatic significant increase by shifting the pH from 4.5 to 6.5 above its pKa as illustrated in Fig. 1. It was reported that the pH dependent solubility pattern of C could be attributed to the presence of acidic carboxylic and tetrazole groups in C structure (25). Despite the increased solubility of C in slightly alkaline buffers above its pKa, it is still considered a poorly soluble
Fig. 3. Short-term stability of C and CC for 1 week at room temperature in different pH range presented as percent recovery
Comparative evaluation of candesartan and candesartan cilexetil drug according to the BCS guidelines where a drug is considered highly soluble when the highest dose is soluble in 250 mL or less of aqueous buffers over the pH range of the gastrointestinal tract (23).
Table I. Permeation Parameters of CC Suspension, CC solution, C Suspension, and C Solution
Formula
CAP/3 h (μg)
F ± SD (μg/min)
Papp ± SD (cm/min)
CC suspension CC solution C suspension C solution
50.48 346.40 369.60 385.91
0.25 2.06 1.97 2.02
1.6 × 10–2 ± 0.02 13.1 × 10–2 ± 0.18 17.4 × 10–2 ± 0.21 17.9 × 10–2 ± 0.31
Dissolution Studies The dissolution study was conducted for C and CC powder in different media with pH 1.2, 4.5, and 6.5, in addition to, the USP medium of CC 32 mg tablets (phosphate buffer pH 6.5 with 0.7% Tween® 20). Dissolution testing in pH 1.2 and 4.5 demonstrated a very low dissolution rate with nearly less than 5% dissolved after 60 min for both C and CC powder, which in accordance with the solubility studies, previously conducted. Dissolution profile of C and CC powder in pH 6.5 and the compendial medium were illustrated in Fig. 2. CC powder showed a very poor dissolution with less than 5% dissolved after 30 min compared to 95.41% dissolved of C powder at pH 6.5; instead, the addition of Tween® 20 to the dissolution medium markedly increased the dissolution of CC powder resulting in 67.43% dissolved after 30 min. Tween® 20 is a non-ionic surfactant suggested by US-FDA and USP39 to increase the solubility of CC and achieve the sink conditions for dissolution testing of CC tablets (26). On the other hand, Tween® 20 had no effect on dissolution pattern of C powder with a superimposed profile after 30 min. However, a slight enhancement in % dissolved after, 5 min was observed that could be explained by the ability of the surfactant to reduce the surface tension and time needed for the powder to be wetted. Short-term Stability Evaluation C and CC samples were analyzed using validated BPrelated substance HPLC method, which is considered a stability indicating method as it can detect the different degradation products of C and CC without any interference. Short-term stability study of C and CC for 1 week at room temperature was presented in Fig. 3. The gathered data proved their chemical stability but with different degree depending on pH of the
Fig. 4. Permeation profile of CC suspension, CC solution, C suspension, and C solution through non-everted rat intestine in Ringer’s solution saline pH 7.4 at 37°C for 3 h (n = 3)
± ± ± ±
1.41 3.31 6.39 9.61
± ± ± ±
1.51 0.69 1.21 0.68
CAP cumulative amount permeated, F permeation flux, Papp apparent permeability coefficient
medium. Both drugs demonstrated degradation in acidic pH range after 1 week with percent recovery of 86.5 and 88.1% for C and 87.4% and 88.3% for CC in pH 1.2 and 4.5, respectively. Instead, shifting to alkaline pH of 6.5 and 7.4 showed superiority of C solution stability with percent recovery of 97.8 and 99.3% compared to CC solution which showed percent recovery of 90.4 and 92.3%, respectively. It was observed that the percentage of CC degradation in alkaline pH was recovered in the form of the active metabolite C which could be explained by the hydrolysis of the ester linkage in the alkaline medium resulting in formation of the carboxylic acid active form of the compound. Those results are supported by findings of Hoppe and Sznitowska (26) who performed stability study for CC in different pH range over a time of 2 weeks. They found that degradation rate of CC is decreased by increasing the pH from 1.2 to 7.4 by 14-fold. They also reported the formation of the active metabolite C after degradation of CC in alkaline pH above 6 while degradation of CC in acidic pH resulted in formation of the inactive degradation product desethyl CC by cleavage of the ether bond between the ethyl group and benzimidazole moiety. Ex vivo Permeation Due to the reported assumption in literature justifying the use of prodrug CC instead of the active form C owing to its poor permeability and low bioavailability (24), it was
Fig. 5. Plasma concentration-time curve of candesartan after oral administration of CC suspension and C suspension to rats, in a dose equivalent to 10 mg CC/kg body weight
Amer et al. Table II. Pharmacokinetics Parameters of C After Oral Administration of CC Suspension and C Suspension to Rats, in a Dose Equivalent to 10 mg CC/kg
Pharmacokinetic parameters
CC suspension C suspension
Cmax (μg/mL)
Tmax (h)
0.47 ± 0.22 1.39 ± 0.59
2.00 ± 0.27 0.66 ± 0.11
AUC 8 (μg h/mL) 1.86 ± 0.83 4.44 ± 1.54
Values are expressed as mean ± SD C candesartan, CC candesartan cilexetil, SD standard deviation, Cmax peak plasma concentrations, Tmax time to reach peak plasma concentrations, AUC 24 area under the plasma concentration-time curve
necessary to evaluate the permeation of both drugs through rat intestine. Ex vivo permeation studies were reported in literature for evaluation of CC where only C was detected in the samples collected from the outer receiver medium (9). CC is completely hydrolyzed by the intestinal esterase enzymes yielding the active form C that is absorbed through the intestinal membrane reaching the blood. As shown in Fig. 4, the cumulative amounts permeated after 180 min for C suspension and CC suspension were 369.60 ± 6.39 μg and 50.48 ± 1.41 μg, respectively. It was also noticed that the permeation profile of C suspension was characterized by an initial faster rate compared to CC suspension which could be related to the in vitro burst release, more drug will be available on the mucosal surface resulting in rapid intestinal permeation. Likewise, C suspension has higher permeability flux (F) and apparent permeability (Papp) compared to CC suspension as presented in Table I. Permeation flux reflects the quantity of drug permeated per unit time while permeation coefficient (P) is another parameter, which measures the rate of movement of molecule through intestinal mucosa. To obtain more relevant results and to demonstrate the difference in permeation of both drugs in the absence of solubility factor, both C and CC were solubilized by the addition of DMSO to compare the permeation of the dissolved molecular state of both drugs. It was reported that using DMSO in concentration up to 10% does not cause any significant damage to the intestinal epithelium or significant effect on the permeation rate (27). For CC solution, a significant enhancement (P < 0.05) in cumulative amount permeated after a lag period of 40 min was observed compared to CC suspension, CC solution demonstrated 6fold increase with 346.4 ± 3.3 μg permeated at the end of experiment indicating the influence of solubility on permeation and bioavailability of CC. On the other hand, C permeation was not significantly (P 0.05) affected after solubilization with DMSO where the two permeation profiles were nearly superimposed. Despite the presence of C in saturated suspension at the beginning of the experiment, as soon as C starts to permeate though the intestinal wall to the receiver medium, its concentration in the intestinal lumen starts to decrease below the saturation level allowing more drug to be dissolved which could be attributed to the high solubility of C in pH 7.4. The ex vivo permeation results demonstrated that the parent compound C has a significantly (P < 0.05) enhanced permeation compared to its prodrug from CC which are not
in agreement with the previously reported rationale on the prodrug formation owing to the poor permeability of the parent compound (24). In vivo Studies The candesartan mean plasma concentration-time curve after oral administration of tested formulae to rats were shown in Fig. 5 and corresponding pharmacokinetics parameters were summarized in Table II. Despite the reported data on formation of CC prodrug owing to the poor bioavailability of the active parent compound C (23,24), C suspension reached significantly (P < 0.05) higher Cmax of 1.39 ± 0.59 μg/mL at Tmax of 0.66 ± 0.11 h, while CC suspension reached Cmax of 0.47 ± 0.22 μg/mL at Tmax of 2.00 ± 0.27 h. A lag period of 40 min is needed prior to detection of any absorbed CC in plasma as shown in Fig. 5, which could be the time needed for bioconversion of CC to active metabolite C by intestinal esterase enzyme that is in accordance with ex vivo results. Also, the mean AUC values of C suspension showed significantly (P < 0.05) higher values compared to CC suspension of 4.44 ± 1.54 μg h/mL and 1.86 ± 0.83 μg h/mL, respectively, which resulted in a relative bioavailability of 238.7%. CONCLUSION Despite of the insufficient data on candesartan to draw any firm conclusions on the reasons behind the formation of an ester prodrug and the previous literature theories about its poor permeability and solubility, data gathered from this work are not in agreement with those speculations, where, the results proved that candesartan is comparable or even superior to its prodrug. Candesartan demonstrated a better stability, solubility, in vitro dissolution, ex vivo permeation and bioavailability in comparison to its prodrug candesartan cilexetil suggesting the possibility of marketing the parent drug candesartan along with candesartan cilexetil for clinical use similarly to azilsartan and its prodrug.
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