Enhancement of dissolution rate and intestinal stability of candesartan cilexitil

Abstract

The objective of this work was to improve the dissolution rate of candesartan cilexitil, a poorly water soluble prodrug and to reduce its premature degradation in the intestinal lumen. Binary and ternary solid dispersions (SD) of the drug with Pluronic F68, Polyvinyl pyrrolidone (PVP), Hydroxypropyl Methylcellulose (HPMC) and Tween 80 were prepared using the solvent evaporation method. The dissolution rate of the drug was monitored and the prepared SD systems were characterized using thermal analysis and Fourier transform infrared (FTIR) spectroscopy. The stability of candesartan in extracted rabbit intestinal fluids was monitored. This was conducted in absence and presence of tested excipients. SD of the drug with PVP resulted in significant enhancement in the dissolution rate of drug even at the lowest drug to polymer weight ratio. Similarly, SD with HPMC showed enhanced dissolution rate. SD with Pluronic F68 showed promising dissolution enhancement but this was recorded at higher polymer concentrations. Formulation of ternary SD of the drug and PVP with either Pluronic or Tween 80 resulted in rapid drug dissolution. The enhanced dissolution was mainly due to amorphousization of the drug with possible contribution to the micelle formation as reflected from thermal analysis. Incubation of pure candesartan in intestinal fluid resulted in rapid degradation of the drug. This degradation was not affected by 0.1% Pluronic. In presence of Tween 80 the rate of drug degradation was reduced significantly with the efficacy of Tween 80 depending on its concentration. The study developed a system for enhanced dissolution rate of candesartan with better stability in the intestinal lumen.

Investigation of the candesartan cilexetil antihypertensive drug microencapsulation by PLA‐PVP K30 biodegradable polymers: Experimental optimization and release kinetics modelling

“…[3,4] Candesartan is an angiotensin-receptor blocker (ARB) that may be used alone or with other agents to treat hypertension. [5] It is administered orally as the prodrug, CC, which is rapidly converted to its active metabolite, candesartan, during absorption in the gastrointestinal tract. [6] Candesartan lowers blood pressure by antagonizing the renin-angiotensin-aldosterone system (RAAS); it competes with angiotensin II for binding to the type-1 angiotensin II receptor (AT1) subtype and prevents the blood pressure increasing effects of angiotensin II.…”

Comparative Pharmaceutical Evaluation of Candesartan and Candesartan Cilexetil: Physicochemical Properties, In Vitro Dissolution and Ex Vivo In Vivo Studies

“…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).…”

Impact of Solvent Selection and Absorptivity on Dissolution Testing of Acetylsalicylic Acid Enteric-Coated Tablets

“…Q uality control (QC) tests are classified according to United States Pharmacopeia (USP) and British Pharmacopeia (BP) as official or compendial tests and non-official or non-compendial tests (1,2). Dissolution testing is an official test and a significant component of the drug development process (3,4).…”