title: Efficacy and Safety Profile of Diclofenac/Cyclodextrin and Progesterone/Cyclodextrin Formulations: A Review of the Literature Data.
abstract: BACKGROUND
  According 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.
  
  
  OBJECTIVE
  The 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.
  
  
  RESULTS
  The 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.
  
  
  CONCLUSIONS
  As 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.
authors.affiliation: Department of Experimental Medicine, Section of Pharmacology "L. Donatelli", School of Medicine, Second University of Naples, Via De Crecchio, 7, Naples, 80138, Italy. cristina.scavone@unina2.it.
authors.forename: Cristina
authors.initials: C
authors.lastname: Scavone
authors.affiliation: Department of Experimental Medicine, Section of Pharmacology "L. Donatelli", School of Medicine, Second University of Naples, Via De Crecchio, 7, Naples, 80138, Italy.
authors.forename: Angela Colomba
authors.initials: AC
authors.lastname: Bonagura
authors.affiliation: Department of Experimental Medicine, Section of Pharmacology "L. Donatelli", School of Medicine, Second University of Naples, Via De Crecchio, 7, Naples, 80138, Italy.
authors.forename: Sonia
authors.initials: S
authors.lastname: Fiorentino
authors.affiliation: Department of Experimental Medicine, Section of Pharmacology "L. Donatelli", School of Medicine, Second University of Naples, Via De Crecchio, 7, Naples, 80138, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Cimmaruta
authors.affiliation: Department of Experimental Medicine, Section of Pharmacology "L. Donatelli", School of Medicine, Second University of Naples, Via De Crecchio, 7, Naples, 80138, Italy.
authors.forename: Rosina
authors.initials: R
authors.lastname: Cenami
authors.affiliation: Department of Women, Child, General and Specialised Surgery, Second University of Naples, Caserta, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Torella
authors.affiliation: IBSA Pharmaceuticals, Pambio Noranco, Switzerland.
authors.forename: Tiziano
authors.initials: T
authors.lastname: Fossati
authors.affiliation: Department of Experimental Medicine, Section of Pharmacology "L. Donatelli", School of Medicine, Second University of Naples, Via De Crecchio, 7, Naples, 80138, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Rossi
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D001682:Biological Availability; D003505:Cyclodextrins / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D004008:Diclofenac / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D004339:Drug Compounding; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D010146:Pain / Q000188:drug therapy; D010539:Permeability; D011247:Pregnancy; D011374:Progesterone / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D012995:Solubility; D016896:Treatment Outcome; D047392:beta-Cyclodextrins / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*
chemical_list: D003505:Cyclodextrins; D047392:beta-Cyclodextrins; D004008:Diclofenac; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D011374:Progesterone