Effects of Injectable HPβCD-Diclofenac on the Human Delayed Rectifier Potassium Channel Current In Vitro and on Proarrhythmic QTc In Vivo

Carr, Daniel B.; Moorehead, Tara McDonnell; Bouchard, André; Sprenger, Craig R.; Hamilton, Douglas A.; Lang, Eric; Madden, Donna; Lacouture, Peter G.; Wright, Curtis

doi:10.1016/j.clinthera.2013.03.014

Cited by 7 publications

(4 citation statements)

References 26 publications

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“…In a thorough QT study in healthy volunteers (n = 70), diclofenac HPbCD did not produce proarrhythmic corrected QT interval prolongation when administered as intravenous bolus doses of 37.5 and 75 mg. [8].…”

Section: Pharmacodynamic Profilementioning

confidence: 95%

Diclofenac Sodium Injection (Akis®, Dicloin®): A Review of Its Use in the Management of Pain

Blair

Plosker

2015

Clin Drug Investig

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A novel formulation of diclofenac sodium suitable for subcutaneous or intramuscular injection (Akis(®), Dicloin(®)) has been developed using the complexing agent hydroxypropyl-β-cyclodextrin (HPβCD) as a solubility enhancer. Diclofenac HPβCD is available in several European countries, where it is indicated for use in adults with acute forms of pain, including postoperative pain. Clinical trials have demonstrated the analgesic efficacy of diclofenac HPβCD in terms of relieving moderate to severe postoperative pain in patients undergoing dental surgery or minor orthopaedic surgery. Subcutaneous diclofenac HPβCD also effectively relieved moderate to severe neuropathic pain, related to cancer or not. Diclofenac HPβCD was generally well tolerated in clinical trials, with injection-site reactions among the most commonly reported adverse events. The local tolerability of diclofenac HPβCD was consistently rated as 'good' or 'excellent' across all studies. Subcutaneous administration of diclofenac is a valid alternative to intramuscular delivery, with the advantages of easier administration, the availability of additional body sites suitable for injection and the potential for self-administration. Thus, diclofenac HPβCD 25, 50 or 75 mg/mL solution for subcutaneous or intramuscular injection extends the treatment options available for use in the management of pain in adults.

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Section: Pharmacodynamic Profilementioning

confidence: 95%

Diclofenac Sodium Injection (Akis®, Dicloin®): A Review of Its Use in the Management of Pain

Blair

Plosker

2015

Clin Drug Investig

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“…In addition, diclofenac, one of the more prescribed NSAIDs worldwide [ 23 – 25 ], was associated with cyclodextrins, and was marketed in formulations for subcutaneous, intramuscular, and intravenous administration. The drug, not associated with cyclodextrins, is also available in formulations for oral and topical administration.…”

Section: Association Of Hydroxypropyl-β-cyclodextrin (Hpβcd) and Diclmentioning

confidence: 99%

Efficacy and Safety Profile of Diclofenac/Cyclodextrin and Progesterone/Cyclodextrin Formulations: A Review of the Literature Data

et al. 2016

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BackgroundAccording to health technology assessment, patients deserve the best medicine. The development of drugs associated with solubility enhancers, such as cyclodextrins, represents a measure taken in order to improve the management of patients. Different drugs, such as estradiol, testosterone, dexamethasone, opioids, non-steroidal anti-inflammatories (NSAIDs; i.e. diclofenac), and progesterone are associated with cyclodextrins. Products containing the association of diclofenac/cyclodextrins are available for subcutaneous, intramuscular, and intravenous administration in doses that range from 25 to 75 mg. Medicinal products containing the association of progesterone/cyclodextrins are indicated for intramuscular and subcutaneous injection at a dose equal to 25 mg.Objectives and MethodsThe effects of cyclodextrins have been discussed in the solubility profile and permeability through biological membranes of drug molecules. A literature search was performed in order to give an overview of the pharmacokinetic characteristics, and efficacy and safety profiles of diclofenac/hydroxypropyl-β-cyclodextrin (HPβCD) and progesterone/HPβCD associations.ResultsThe results of more than 20 clinical studies were reviewed. It was suggested that the new diclofenac/HPβCD formulation gives a rapid and effective response to acute pain and, furthermore, has pharmacokinetic and efficacy/safety profiles comparable to other medicinal products not containing cyclodextrins. One of the principal aspects of these new diclofenac formulations is that in lowering the dose (lower than 50 mg) the drugs could be more tolerable, especially in patients with comorbid conditions. Moreover, results of studies investigating the characteristics of progesterone and cyclodextrins showed that the new formulation (progesterone/HPβCD 25 mg solution) has the same bioavailability as other products containing progesterone. It is more rapidly absorbed and allows the achievement of peak plasma concentrations in a shorter time. Finally, the new formulation of progesterone was shown to be safe and not inferior to other products already on the market, with the exception of progesterone administered vaginally.ConclusionsAs shown by the results of clinical studies presented in this review, the newly approved medicines containing cyclodextrins have been found to be as effective and as well-tolerated as other medicinal products that do not contain cyclodextrins. Moreover, the newly approved lower dose of diclofenac associated with cyclodextrins is consistent with the European Medicines Agency recommendations reported in the revision of the Assessment Report for Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) and Cardiovascular Risk. Finally, the use of cyclodextrins led to significant increases in solubility and bioavailability of drugs, such as diclofenac and progesterone, and improvement in the efficacy and safety of these drugs.

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“…54 Several published data on the cardiac safety of cyclodextrins demonstrated interference with the hERG. 55,56 In contrast, clinical evaluation of γ-CD, marketed as sugammadex, indicated no relevant effects of the compound on QT interval. 57 The fact that Captisol is the excipient for several FDA-approved drug formulations that have not resulted in cardiac toxicity in patients speaks for its biosafety.…”

Section: ■ Discussionmentioning

confidence: 99%

“…Nevertheless, further testing in vivo using higher concentrations of M1 and an electrocardiogram (ECG) analysis will need to be conducted in order to confirm that M1 does not have inhibitory effects on the cardiac muscle . Several published data on the cardiac safety of cyclodextrins demonstrated interference with the hERG. , In contrast, clinical evaluation of γ-CD, marketed as sugammadex, indicated no relevant effects of the compound on QT interval . The fact that Captisol is the excipient for several FDA-approved drug formulations that have not resulted in cardiac toxicity in patients speaks for its biosafety…”

Section: Discussionmentioning

confidence: 99%

Acyclic Cucurbit[n]uril-Type Molecular Container Enables Systemic Delivery of Effective Doses of Albendazole for Treatment of SK-OV-3 Xenograft Tumors

Hettiarachchi

Samanta²,

Falcinelli

et al. 2016

Mol. Pharmaceutics

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Approximately, 40–70% of active pharmaceutical ingredients (API) are severely limited by their extremely poor aqueous solubility and consequently there is a high demand for excipients that can be used to formulate clinically relevant doses of these drug candidates. Here, proof-of-concept studies demonstrate the potential of our recently discovered acyclic cucurbit[n]uril-type molecular container Motor1 (M1) as a solubilizing agent for insoluble drugs. M1 did not induce significant rates of mutations in various Salmonella typhimurium test strains during the Ames test, suggesting low genotoxicity. M1 also has low risk of causing cardiac toxicity in humans since it did not inhibit the human Ether-á-go-go-Related Gene channel as tested on transfected CHO cell lines via patch clamp analysis. Albendazole (ABZ) is a widely used anti-helminthic agent but that has also shown promising efficacy against cancerous cells in vitro. However, due to its low aqueous solubility (2.7 micromolar) and poor pharmacokinetics, ABZ is clinically limited as an anti-cancer agent. Here we investigated the potential of M1 as a solubilizing excipient for ABZ formulation. A pharmacokinetic study indicated that ABZ escapes the peritoneal cavity resulting in 78% absolute bioavailability while its active intermediate metabolite, albendazole sulfoxide, achieved 43% absolute bioavailability. The daily dosing of 681 mg/kg M1 complexed with 3.2 mg/kg of ABZ for 14 days did not result in significant weight loss or pathology in Swiss Webster mice. In vivo efficacy studies using this M1•ABZ inclusion complex showed significant decreases in tumor growth rates and increases in survival of mice bearing SK-OV-3 xenograft tumors. In conclusion, we provide substantial new evidence demonstrating that M1 is a safe and efficient excipient that enables in vivo parenteral delivery of poorly water-soluble APIs.

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Effects of Injectable HPβCD-Diclofenac on the Human Delayed Rectifier Potassium Channel Current In Vitro and on Proarrhythmic QTc In Vivo

Abstract: The findings from the present study suggest that HPβCD-diclofenac does not have a dose-dependent effect in the in vitro hERG assay system and does not produce proarrhythmic QTc prolongation in vivo. ClinicalTrials.gov identifier: NCT01812538.

Cited by 7 publications

References 26 publications

Diclofenac Sodium Injection (Akis®, Dicloin®): A Review of Its Use in the Management of Pain

Diclofenac Sodium Injection (Akis®, Dicloin®): A Review of Its Use in the Management of Pain

Efficacy and Safety Profile of Diclofenac/Cyclodextrin and Progesterone/Cyclodextrin Formulations: A Review of the Literature Data

Acyclic Cucurbit[n]uril-Type Molecular Container Enables Systemic Delivery of Effective Doses of Albendazole for Treatment of SK-OV-3 Xenograft Tumors

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