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

Abstract

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.

Cyclodextrin Enhances Corneal Tolerability and Reduces Ocular Toxicity Caused by Diclofenac

“…CDs have gained much popularity and are widely used in the pharmaceutical industry for systemic routes such as oral and parenteral dosage forms [ 4 ]. Orally administered CDs are considered to be nontoxic because of their lack of absorption from the gastrointestinal tract and γ - and hydroxypropyl- (HP-) β -CD having been used safely via the parenteral route [ 5 ].…”

“…Orally administered CDs are considered to be nontoxic because of their lack of absorption from the gastrointestinal tract and γ - and hydroxypropyl- (HP-) β -CD having been used safely via the parenteral route [ 5 ]. It is well-known that faster onset of action and less gastrointestinal side effects are attributed to oral piroxicam- β -CD than piroxicam alone [ 4 ]. In addition, Dyloject® and Akis® are two relatively new commercially available injectable Diclo-HP- β -CD complexes that gave rapid and effective analgesia comparable to Voltaren® IM injection not containing CDs [ 4 ].…”

“…It is well-known that faster onset of action and less gastrointestinal side effects are attributed to oral piroxicam- β -CD than piroxicam alone [ 4 ]. In addition, Dyloject® and Akis® are two relatively new commercially available injectable Diclo-HP- β -CD complexes that gave rapid and effective analgesia comparable to Voltaren® IM injection not containing CDs [ 4 ].…”

Hydroxypropyl‐β‐cyclodextrin hybrid nanogels as nano‐drug delivery carriers to enhance the solubility of dexibuprofen: Characterization, in vitro release, and acute oral toxicity studies

“…[4] Recently, several kinds of the hydrophilic CD derivatives have been utilized in drug delivery, that is, methyl, hydroxypropyl, and sulfobutyl CD derivatives. [7] However, efficiency of complexation is often not very high, and therefore, relatively large amounts of CDs must be used to complex small amounts of drugs. Hydroxypropyl derivatives have high water solubility (i.e., >90%) and low hygroscopicity as compared to natural CDs.…”

Cyclodextrin Cationic Polymer-Based Nanoassemblies to Manage Inflammation by Intra-Articular Delivery Strategies

“…Unfortunately, similarly to other NSAIDs, DCF use is associated with some gastrointestinal (GI) side effects, including ulceration and hemorrhage. In order to mitigate such side effects, DCF has been successfully administered by controlled release systems based on CDs and their supramolecular assemblies [ 32 , 33 ]. The inclusion of DCF inside the CD cavity helps reducing its GI mucosal toxicity and improves the solubility of the drug, enhancing its bioavailability in the site of action and anti-inflammatory effect.…”