Carvedilol: Solubilization and Cyclodextrin Complexation: A Technical Note

Abstract

Carvedilol (Table I) is a non-selective β-blocker indicated in the treatment of mild to moderate congestive heart failure. It also has vasodilating properties that are mainly attributed to its α1-blocking activity, as well as ability to inhibit oxidative stress in coronary smooth muscle (1). It is marketed under various trade names including Eucardic (Roche), Dilatrend (Roche), Kredex (Roche) and Coreg (GlaxoSmithKline). Carvedilol is well absorbed after oral administration, but is subject to first-pass metabolism in the liver resulting in only about 25% absolute bioavailability. Common oral dosage is 25 mg/day (dose/solubility ratio ≥250 ml; class II drug according to the BCS) with peak plasma concentrations occurring 1 to 2 h after the administration and elimination half-life of 6 to 10 h (2). Low aqueous solubility (S0 ≈ 0.02 mg/ml at pH 7.4) hampers formulation of carvedilol as, for example, nasal spray or sublingual tablet. It has been shown that carvedilol forms 1:2 drug/cyclodextrin complexes with the natural β-cyclodextrin (βCD; 3). 2-Hydroxypropyl-βCD (HPβCD) and sulfobutylether βCD (SBEβCD) have been used as complexing agent in carvedilol buccal and sustained release tablets (4–6). Table 1 Carvedilol ((2RS)-1-(9H-carbazol-4-yloxy)-3-[[2-(2-methoxyphenoxy)ethyl]amino]propan-2-ol): structure and physicochemical properties Cyclodextrins (CDs) are cyclic oligosaccharides that in recent years have been introduced to the pharmaceutical industry as novel enabling excipients, mainly as solubilizing complexing agents for enhanced drug bioavailability (7,8). CDs consist of six (αCD), seven (βCD), eight (γCD) or more α-1,4-linked α-d-glucopyranose units forming a somewhat truncated cone. The hydroxy groups are oriented towards the cone exterior making the external surface hydrophilic while the central cavity is lined by the carbons and ethereal oxygens of the carbohydrate skeleton making it somewhat hydrophobic. CDs form inclusion complexes by taking up lipophilic drug molecule, or more frequently some lipophilic moiety on the drug molecule, into the lipophilic central cavity. Although such inclusion complexes are the most common form of drug/CD complexes the hydroxy groups on the outer surface of the CD molecule are able to form hydrogen bonds with other molecules and CDs can, like non-cyclic oligosaccharides and polysaccharides, form water-soluble non-inclusion complexes with lipophilic water-insoluble drugs (9–11). In saturated aqueous solutions drug/CD complexes frequently consist of a mixture of inclusion and non-inclusion complexes (12). CDs and CD complexes are also known to self-associate to form nanoscale aggregates (12–14) and these aggregates are thought to be able to solubilize lipophilic drug molecules in micellar-like fashion (15). Although CDs are effective solubilizer of drugs their solubilizing efficiency can sometimes be inadequate due to low intrinsic solubility of the drug or low stability constant of the drug/CD complex (16,17). Various methods have successfully been applied to enhance the solubilizing effects of CDs including drug ionization, formation of somewhat water-soluble drug salts and ternary complex formation (8,15,18,19). Salt formation is the most common method of increasing the apparent intrinsic solubility of acidic and basic drugs and frequently enhanced drug solubilization can be obtained by combining salt formation and cyclodextrin complexation. The purpose of this present study is to investigate the effects of ionization and salt formation on CD solubilization of carvedilol.