Solid state stabilisation of the orally delivered drugs atenolol, glibenclamide, memantine and paracetamol through their complexation with cucurbit[7]uril

McInnes, Fiona; Anthony, Nahoum G.; Kennedy, Alan R.; Wheate, Nial J.

doi:10.1039/b918372h

Cited by 86 publications

(45 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…40,41 Therefore, CB [7] is supposed to act as a potential pharmaceutical excipient to improve the solubility and physical stability of drugs. Though the effect of CB [7] in enhancing the solubility 42,43 and physical stability 44,45 has been validated, the underlying mechanism remains poorly understood, particularly at a molecular level, due to the lack of structural information about the drug−excipient interactions. It has been demonstrated that excipients have significant influence on drug dissolution and oral bioavailability, which can be altered by drug−excipient interactions.…”

Section: ■ Introductionmentioning

confidence: 99%

The Delivery of Triamterene by Cucurbit[7]uril: Synthesis, Structures and Pharmacokinetics Study

Chen

Jiang

et al. 2013

Mol. Pharmaceutics

View full text Add to dashboard Cite

In recent years, cucurbit [7]uril (CB [7]) has attracted great attention in drug delivery. Though the effect of CB [7] in enhancing the solubility of water insoluble drugs has been validated, the underlying mechanism remains poorly understood, particularly at a molecular level. This study is designed to evaluate a CB [7]-based pharmaceutical formulation to improve solubility and bioavailability of triamterene (a mild potassium-sparing diuretic). Two polymorphs of triamterene@CB [7] were obtained, and their crystal structures were determined by single crystal X-ray diffraction. The CB [7] molecule forms a stable host−guest complex with triamterene (K a = 1.69 ± 0.34 × 10 4 M −1 ) in aqueous solution (pH = 1.0). The results of dissolution study demonstrate that the apparent solubility value of triamterene@CB [7] complex in 0.1 M HCl is 1.6 times as large as that of triamterene, while free triamterene was released from triamterene@CB [7] complex in phosphate buffer of pH 6.8. Pharmacokinetic studies in rats reveal that the AUC 0−∞ value of triamterene@CB [7] complex increases 2.8-fold compared with that of free triamterene, and t 1/2 is prolonged from 1.42 to 2.61 h (P < 0.05) after oral administration. The increased solubility and oral bioavailability are attributed to the formation of a hydrophilic capsule composed of two CB [7] molecules, in which two insoluble triamterene molecules are encapsulated. These results demonstrate that triamterene@CB [7] complex is a stable and effective pharmaceutical formulation. KEYWORDS: cucurbit [7]uril, triamterene, crystal structure, solubility, pharmacokinetics ■ INTRODUCTIONPoor aqueous solubility is a major bottleneck in drug discovery and drug development: more than 40% of drug candidates are poorly water-soluble, and poor aqueous solubility is the main factor to restrict the bioavailability of drugs.1,2 Various approaches have been investigated to improve solubility of drugs, including cocrystal, 3,4 salts, 5 prodrugs, 6 solid dispersion, 7 macrocyclic hosts (e.g., cyclodextrins, cucurbiturils), 8,9 etc. Triamterene, 2,4,7-triamino-6-phenylpteridine (Scheme 1) is a mild potassium-sparing diuretic used either alone or in combination with potassium-wasting diuretics such as hydrochlorothiazide.10,11 It displays low oral bioavailability, and there exists wide intersubject variation because of its poor aqueous solubility (45 mg/L). 12,13 Though triamterene contains three primary amine groups, various methods to obtain soluble salts failed, probably due to its weak basicity. 12 To date, only a few formulations have been proposed to improve the solubility of triamterene, including cyclodextrins 14,15 and solid dispersions. 16,17 However, parenteral administration of β-cyclodextrin results in renal toxicity, 18 and solid dispersions are often physically unstable upon storage at elevated temperature and humidity, 19 and neither of the two triamterene formulations has been applied for clinical therapy. Therefore, the development of new pharmaceutical formulation of triam...

show abstract

Section: ■ Introductionmentioning

confidence: 99%

The Delivery of Triamterene by Cucurbit[7]uril: Synthesis, Structures and Pharmacokinetics Study

Chen

Jiang

et al. 2013

Mol. Pharmaceutics

View full text Add to dashboard Cite

show abstract

“…1, le) in particular has drawn considerable interest because of both its good watersolubility and its capacity to encapsulate organic molecules of a wide range of sizes. It has been demonstrated by numerous research groups including ours that CB [7] can effectively encapsulate a variety of drugs and bioactive molecules, including atenolol (a beta-blocker), 12 pyrazinamide (a tuberculosis drug), 13 platinum-based anti-cancer drugs such as cisplatin and others, [14][15][16] prilocaine and various other local anaesthetic, 17 as well as ranitidine and coumarin. 18,19 In addition, we have also actively investigated the complexation behaviors of steroidal NMBAs 20 and local anesthetic agents 17 by CB [7] and reviewed the use of CB[n]-type hosts for the reversal of steroidal NMBAs.…”

Section: Introductionmentioning

confidence: 99%

In vivo reversal of general anesthesia by cucurbit[7]uril with zebrafish models

Chen

Chan

et al. 2015

RSC Adv.

View full text Add to dashboard Cite

A general anesthetic is a drug that brings about a reversible loss of consciousness, during a surgical or therapeutic procedure to render the patient free of pain and anxiety. However, the effect of anesthetics may linger far beyond the necessary time required and induce adverse effects. In addition, many surgical patients need to recover to a conscious state that allows them to make important decisions soon after their surgery. Unfortunately, there are currently no clinically-available anti-dotes to reverse the effects of anesthetics. In this study, we demonstrate the in vitro supramolecular host-guest complexations between macrocyclic cucurbit [7]uril (CB [7]) and a commonly used general anesthetic in fish, tricaine mesylate (TM), and we report for the first time the in vivo reversal effect of CB [7] to general anesthesia induced by TM with zebrafish models. These findings might lead to a new approach that may allow patients to regain lucidity much faster than their natural recovery from general anesthesia, and may also be used to reverse potentially life-threatening toxic effects encountered by some patients in response to general anesthesia.

show abstract

“…6,7 They have a hydrophobic cavity, accessible through two hydrophilic oxygen lined portals, and are capable of storing and releasing small molecules. 8,9 Encapsulation of a drug molecule by cucurbituril can provide a range of benefits including: chemical [10][11][12] and thermal stability, [13][14][15] improved drug solubility, 16,17 controlled drug release, 18,19 and potential taste masking of some drugs.…”

Section: Introductionmentioning

confidence: 99%

Cucurbit[7]uril encapsulated cisplatin overcomes cisplatin resistance via a pharmacokinetic effect

et al. 2012

Self Cite

View full text Add to dashboard Cite

The cucurbit [n]uril (CB[n]) family of macrocycles has been shown to have potential in drug delivery where they are able to provide physical and chemical stability to drugs, improve drug solubility, control drug release and mask the taste of drugs. Cisplatin is a small molecule platinum-based anticancer drug that has severe dose-limiting side-effects. Cisplatin forms a host-guest complex with cucurbit [7]uril (cisplatin@CB[7]) with the platinum atom and both chlorido ligands located inside the macrocycle, with binding stabilised by four hydrogen bonds (2.15-2.44 Å ). Whilst CB [7] has no effect on the in vitro cytotoxicity of cisplatin in the human ovarian carcinoma cell line A2780 and its cisplatin-resistant sub-lines A2780/cp70 and MCP1, there is a significant effect on in vivo cytotoxicity using human tumour xenografts. Cisplatin@CB [7] is just as effective on A2780 tumours compared with free cisplatin, and in the cisplatin-resistant A2780/cp70 tumours cisplatin@CB [7] markedly slows tumour growth. The ability of cisplatin@CB [7] to overcome resistance in vivo appears to be a pharmacokinetic effect. Whilst the peak plasma level and tissue distribution are the same for cisplatin@CB [7] and free cisplatin, the total concentration of circulating cisplatin@CB [7] over a period of 24 hours is significantly higher than for free cisplatin when administered at the equivalent dose. The results provide the first example of overcoming drug resistance via a purely pharmacokinetic effect rather than drug design or better tumour targeting, and demonstrate that in vitro assays are no longer as important in screening advanced systems of drug delivery.

show abstract

Solid state stabilisation of the orally delivered drugs atenolol, glibenclamide, memantine and paracetamol through their complexation with cucurbit[7]uril

Cited by 86 publications

References 50 publications

The Delivery of Triamterene by Cucurbit[7]uril: Synthesis, Structures and Pharmacokinetics Study

The Delivery of Triamterene by Cucurbit[7]uril: Synthesis, Structures and Pharmacokinetics Study

In vivo reversal of general anesthesia by cucurbit[7]uril with zebrafish models

Cucurbit[7]uril encapsulated cisplatin overcomes cisplatin resistance via a pharmacokinetic effect

Contact Info

Product

Resources

About