Improvement of water solubility and dissolution rate of ursodeoxycholic acid and chenodeoxycholic acid by complexation with natural and modified β-cyclodextrins

Ventura, Cinzia Anna; Tirendi, S.; Puglisi, Giovanni; Bousquet, E.; Panza, Luigi

doi:10.1016/s0378-5173(96)04821-1

Cited by 41 publications

(23 citation statements)

References 22 publications

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“…3,4) In the pharmaceutical field this complexation phenomenon has been extensively applied to enhance the solubility, dissolution rate, and bioavailability of sparingly soluble drugs in gastrointestinal fluids. [5][6][7][8][9][10] Because of the increasing interest in CDs and their inherent usefulness, several studies have been conducted to clarify the mechanism of complexation.…”

mentioning

confidence: 99%

Molecular Modelling and 1H-NMR: Ultimate Tools for the Investigation of Tolbutamide: .BETA.-Cyclodextrin and Tolbutamide: Hydroxypropyl-.BETA.-Cyclodextrin Complexes.

et al. 2001

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Cyclodextrins (CDs) are cyclic oligosaccharides composed of ␣-1,4-linked D-glucopyranose units. The most common of these ring-shaped molecules are the a-, b-, and g-CDs formed by six, seven, and eight glucose units, respectively. 1)CDs are toroidal molecules with a truncated cone structure where the secondary hydroxyl groups are located on the wider side of the ring, while the primary hydroxyl groups are positioned on the opposite, narrower side of the torus. The -CH groups carrying the H-1, H-2, and H-4 protons are located on the exterior of the molecule and the hydroxyl groups are oriented to the cone exterior, which makes the external faces of CDs decidedly hydrophilic. The interior of the torus, which offers an environment of much lower polarity than that present in water, is lined by two rings of -CH groups (H-3 and H-5) and by a ring of glycosidic "ether oxygens" (O-4), with H-6 located near the cavity.2) A great variety of "guest" molecules of suitable size and shape may be entirely or partially included in this hydrophobic cavity, resulting in a stable association without formation of covalent bonds. The complexation driving forces have been attributed to hydrophobic interactions, van der Waals-London dispersion forces, and hydrogen bonds. 3,4) In the pharmaceutical field this complexation phenomenon has been extensively applied to enhance the solubility, dissolution rate, and bioavailability of sparingly soluble drugs in gastrointestinal fluids.5-10) Because of the increasing interest in CDs and their inherent usefulness, several studies have been conducted to clarify the mechanism of complexation.In previous studies, the ability of b-CD and hydroxypropyl-b-cyclodextrin (HP-b-CD) to form inclusion complexes with tolbutamide (TBM), in order to increase its solubility, dissolution rate, 11) and oral bioavailability 12) was evaluated. Important information on the solid-phase structure of these complexes may be obtained via X-ray analysis when a suitable crystal of the product is available. However, X-ray diffractograms of the lyophilized TBM:CD complexes previously reported 11) have demonstrated the complete amorphousness of the product obtained, making it impossible to gain more detailed information from them. Although solubility studies indicated the existence of complexation between TBM and b-CD or HP-b-CD in solution, 11) the exact mechanism of complexation could not be deduced.The use of computer-aided molecular modelling and 1 H-NMR studies has proved to hold promise for such purposes, especially for systems or molecules of biological interest which "act" in aqueous medium. These techniques have been used as important tools for investigating the conformation of the most favored complexes and to obtain a better knowledge of the geometry of the system and the topology of the interactions between guest and CDs. [13][14][15][16][17] Therefore in the present study we coupled these techniques, which allowed us to compare and to integrate the theoretical findings obtained in a vacuum (molecular modelling) ...

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confidence: 99%

Molecular Modelling and 1H-NMR: Ultimate Tools for the Investigation of Tolbutamide: .BETA.-Cyclodextrin and Tolbutamide: Hydroxypropyl-.BETA.-Cyclodextrin Complexes.

et al. 2001

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“…Upon complexation, a significant shift in the characteristic peaks of the guest molecule, either to higher or lower frequency, was observed by some authors (20,21). Disappearance and broadening of the peaks of the guest also proves interaction between the drug and b-CD molecules (18).…”

Section: Irmentioning

confidence: 89%

Physicochemical characterization and in vitro dissolution behaviour of celecoxib-β-cyclodextrin inclusion complexes

Sinha¹,

Anitha²,

Ghosh³

et al. 2007

Acta Pharmaceutica

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Cyclodextrins are chemically and physically stable molecules formed by the enzymatic modification of starch (1). They are cyclomalto oligosaccharides composed of six, seven or eight a-D-glucopyranose units (a-, b-, g-CD, respectively). Their hollow structure enables them to host a variety of molecules (guests) partially or entirely in their hydrophobic caving. These inclusion complexes exist both in aqueous solution and in solid state. As a result of complexation of compounds by cyclodextrins, the apparent solubility of the molecule can be altered (2), stability of the compound in the presence of light and oxidizing conditions is increased (3) and volatility of compounds is decreased (4). Many scientists have studied the cyclodextrin complexes of various NSAIDs such as valdecoxib, diclofenac, piroxicam, ketoprofen, etc. and have showed their superiority over physical mixtures (5-8).Celecoxib, 4-[(5-(4-methyl phenyl)-3-trifluoro methyl)-1H-pyrazol-1-yl] benzene sulfonamide is a non steroidal anti-inflammatory drug that is a specific inhibitor of COX-2 enzyme. Celecoxib is widely used in the treatment of rheumatoid and osteoarthritis. According to the biopharmaceutical classification system, celecoxib belongs to class II type In this study, attempts were made to investigate the effects of b-cyclodextrin (b-CD) on the aqueous solubility and dissolution rate of celecoxib. Inclusion complexes were prepared by the kneading method and characterized by SEM, NMR, IR, DSC, and X-ray powder diffraction. Dissolution rate of the complexes was significantly greater than that of the corresponding physical mixtures and pure drug, indicating that the formation of inclusion complex increased the solubility of the poorly soluble drug celecoxib.

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“…Peak biliary UDCA secretion was significantly higher after administration of UDCA-HPßCD complex than when the other two preparations were administered. The complex enhances the aqueous solubilization of UDCA and, therefore, the drug is more rapidly and more extensively absorbed in the intestine [18]. On the other hand, when the drug is given in protonated form, as in the case of suspension or capsule formulation, most of it remains undissolved, high pH values being required for its complete dissolution in aqueous medium [13,23].…”

Section: Discussionmentioning

confidence: 99%

“…HPßCD forms an inclusion complex which has a 1:1 stoichiometric molar ratio of UDCA to ß-cyclodextrin [15][16][17]. Complexation makes UDCA more soluble in aqueous solution at any pH in the gastrointestinal tract than the uncomplexed form of conventional formulations [18]. The enhanced solubility might result in a greater absorption and biliary secretion of UDCA following oral administration.…”

Section: Introductionmentioning

confidence: 99%

Ursodeoxycholic Acid Complexation with 2-Hydroxypropyl-β-Cyclodextrin Increases Ursodeoxycholic Acid Biliary Excretion after Single Oral Administration in Rats

Ventura¹,

Panini²,

Montosi³

et al. 2001

Pharmacology

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Complexation of ursodeoxycholic acid (UDCA) with 2-hydroxypropyl-β-cyclodextrin (HPβCD) improves the water solubility and the dissolution rate of UDCA and may therefore increase its bioavailability. We compared the amount and the rate of biliary excretion of UDCA and biliary lipid secretion after a single oral administration of UDCA in 3 different pharmaceutical formulations [UDCA-HPβCD (‘urso-β-cyclodextrin’), UDCA suspension and UDCA capsule] at 3 different dosages each, in 11 groups (2 control groups) of bile fistula rats. UDCA excretion increased with an increase in dose, biliary UDCA recovery and peak secretion were significantly higher after administration of UDCA-HPβCD than after UDCA in suspension or capsule. This enhancement of biliary excretion may achieve greater UDCA enrichment in the bile acid pool than conventional pharmaceutical UDCA formulations, this giving to UDCA-HPβCD a considerable therapeutical potential.

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Improvement of water solubility and dissolution rate of ursodeoxycholic acid and chenodeoxycholic acid by complexation with natural and modified β-cyclodextrins

Cited by 41 publications

References 22 publications

Molecular Modelling and 1H-NMR: Ultimate Tools for the Investigation of Tolbutamide: .BETA.-Cyclodextrin and Tolbutamide: Hydroxypropyl-.BETA.-Cyclodextrin Complexes.

Molecular Modelling and 1H-NMR: Ultimate Tools for the Investigation of Tolbutamide: .BETA.-Cyclodextrin and Tolbutamide: Hydroxypropyl-.BETA.-Cyclodextrin Complexes.

Physicochemical characterization and in vitro dissolution behaviour of celecoxib-β-cyclodextrin inclusion complexes

Ursodeoxycholic Acid Complexation with 2-Hydroxypropyl-β-Cyclodextrin Increases Ursodeoxycholic Acid Biliary Excretion after Single Oral Administration in Rats

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