Drugs R D (2016) 16:129–140 DOI 10.1007/s40268-016-0123-2 REVIEW ARTICLE Efficacy and Safety Profile of Diclofenac/Cyclodextrin and Progesterone/Cyclodextrin Formulations: A Review of the Literature Data 1 1 1 Cristina Scavone • Angela Colomba Bonagura • Sonia Fiorentino • 1 1 2 3 Daniela Cimmaruta • Rosina Cenami • Marco Torella • Tiziano Fossati • Francesco Rossi1 Published online: 3 March 2016 Ó The Author(s) 2016. This article is published with open access at Springerlink.com Abstract pain and, furthermore, has pharmacokinetic and efficacy/ Background According to health technology assessment, safety profiles comparable to other medicinal products not patients deserve the best medicine. The development of containing cyclodextrins. One of the principal aspects of drugs associated with solubility enhancers, such as these new diclofenac formulations is that in lowering the cyclodextrins, represents a measure taken in order to dose (lower than 50 mg) the drugs could be more tolerable, improve the management of patients. Different drugs, such especially in patients with comorbid conditions. Moreover, as estradiol, testosterone, dexamethasone, opioids, non- results of studies investigating the characteristics of pro- steroidal anti-inflammatories (NSAIDs; i.e. diclofenac), gesterone and cyclodextrins showed that the new formu- and progesterone are associated with cyclodextrins. Prod- lation (progesterone/HPbCD 25 mg solution) has the same ucts containing the association of diclofenac/cyclodextrins bioavailability as other products containing progesterone. It are available for subcutaneous, intramuscular, and intra- is more rapidly absorbed and allows the achievement of venous administration in doses that range from 25 to peak plasma concentrations in a shorter time. Finally, the 75 mg. Medicinal products containing the association of new formulation of progesterone was shown to be safe and progesterone/cyclodextrins are indicated for intramuscular not inferior to other products already on the market, with and subcutaneous injection at a dose equal to 25 mg. the exception of progesterone administered vaginally. Objectives and Methods The effects of cyclodextrins have Conclusions As shown by the results of clinical studies been discussed in the solubility profile and permeability presented in this review, the newly approved medicines through biological membranes of drug molecules. A literature containing cyclodextrins have been found to be as effective search was performed in order to give an overview of the and as well-tolerated as other medicinal products that do not pharmacokinetic characteristics, and efficacy and safety pro- contain cyclodextrins. Moreover, the newly approved lower files of diclofenac/hydroxypropyl-b-cyclodextrin (HPbCD) dose of diclofenac associated with cyclodextrins is consis- and progesterone/HPbCD associations. tent with the European Medicines Agency recommendations Results The results of more than 20 clinical studies were reported in the revision of the Assessment Report for Non- reviewed. It was suggested that the new diclofenac/HPbCD Steroidal Anti-Inflammatory Drugs (NSAIDs) and Cardio- formulation gives a rapid and effective response to acute vascular Risk. Finally, the use of cyclodextrins led to sig- nificant increases in solubility and bioavailability of drugs, & Cristina Scavone such as diclofenac and progesterone, and improvement in the [email protected] efficacy and safety of these drugs. 1 Department of Experimental Medicine, Section of Pharmacology ‘‘L. Donatelli’’, School of Medicine, Second University of Naples, Via De Crecchio, 7, Naples 80138, 1 Introduction Italy 2 Department of Women, Child, General and Specialised As a result of the introduction of Health Technology Surgery, Second University of Naples, Caserta, Italy Assessment (HTA) in healthcare systems, the evaluation of 3 IBSA Pharmaceuticals, Pambio Noranco, Switzerland a patient’s health and proper use of resources are becoming 130 C. Scavone et al. more important. Accordingly, HTA processes aim to hydrophobic drugs, thus causing an increase in their water ensure the choice of the best drug, in terms of safety and solubility. The complexes are easily absorbed. Studies efficacy, and hence the development of drugs associated suggest that cyclodextrins are able to increase the oral with solubility enhancers, such as cyclodextrins, represents bioavailability of drugs belonging to BCS Class II, but to one of the measures taken in order to improve patient reduce the bioavailability of the drugs of Class I and III [6, management. When cyclodextrins are associated with 7]. Cyclodextrins can enhance the permeation of lipophilic drugs, the pharmacokinetic characteristics of these drugs drugs through biological membranes, and increase the can be modified, leading to an increase in the dissolution chemical stability of drugs at the aqueous membrane profile, solubility, and bioavailability. exterior. Specifically, only the free drug permeates the The Biopharmaceutics Classification System (BCS) lipophilic membranes, while cyclodextrins, except for an guidance stipulated by the US FDA categorizes drugs into insignificant amount, cannot penetrate through biological four classes according to their solubility and permeability: membranes. These effects can be explained by different Class I: high permeability, high solubility; Class II: high mechanisms. First, the development of inclusion com- permeability, low solubility; Class III: low permeability, plexes increase the amount of dissolved drug molecules in high solubility; Class IV: low permeability, low solubility the aqueous donor phase, with a consequent increase in the [1]. In order to improve the solubility, dissolution rate and, concentration gradient of the drug over the unstirred water therefore, the bioavailability of compounds belonging to the layer (UWL). The rapid release of the drug from the classes BCS II and IV, many techniques can be used. In complex increases the availability of free drug molecules particular, these include micronization, self-emulsification, close to the lipophilic membrane surface. Moreover, complexation with cyclodextrins, co-crystallization, super- cyclodextrin complexation of drug may reduce the inter- critical fluid technology, and several other techniques [2]. action between drug molecules and other molecules in the UWL, enhancing the global delivery of the drug to the membrane surface. Additional mechanisms of action are 2 Cyclodextrins, Solubility Enhancers not excluded [8]. Cyclodextrins have multiple effects on the body’s organs. Cyclodextrins, described for the first time in 1891, are In particular, they increase the transendothelial permeability cyclic oligosaccharides, characterized by an outer hydro- of hydrophobic drugs and boost the effects of estradiol, philic portion and a central lipophilic cavity [3]. As shown testosterone, and dexamethasone on the central nervous in Table 1, each cyclodextrin is characterized by the system (in rats). Cyclodextrins also prolong the analgesic presence of a specific functional group. Among these, the effects of opioid peptides, morphine, lofentanil, alfentanil most widely used are a-, b- and c-cyclodextrin. In 1976, b- and sulfentanil, and enhance the intestinal penetration of cyclodextrin was used for the first time in a pharmaceutical peptides. Absorption through the nasal mucosa and the formulation. In the year 2014, several medicines containing bioavailability of hydrophobic drugs, oligopeptides, and cyclodextrins, in formulations for oral, parenteral, oph- peptides is also enhanced, while the irritant effects on the thalmic, and topical administration, were authorized oral cavity, throat, and pharynx are reduced [9]. worldwide (Table 2)[3–5]. In the lungs, cyclodextrins reduce smells, taste, and Cyclodextrins are used in the pharmaceutical industry local irritation associated with the drugs administered by because of their ability to form inclusion complexes with inhalation. Solubility and the degree of permeation of drugs through the skin with minimal occurrence of adverse events are also influenced [9]. Moreover, cyclodextrins Table 1 Functional groups of main cyclodextrins used in the phar- increase the shelf-life of the product they are complexed maceutical industry with [10]. Cyclodextrin Functional group Data obtained from scientific literature confirm that cyclodextrins reduce drug toxicity. In particular, the asso- a-Cyclodextrin (a-CD) H4 ciation of hydroxypropyl-b-cyclodextrin (HPbCD)/flur- b-Cyclodextrin (b-CD) H5 biprofen showed a reduction in gastroduodenal toxicity in c-Cyclodextrin (c-CD) H6 rats. The association of 5-fluorouracil and folinic acid/b- Diethyl-ethyl-b-cyclodextrin (DE-b-CD) CH2CH3 or H Dimethyl-ethyl-b-cyclodextrin (DM-b-CD) CH3 or H cyclodextrin resulted in a reduced phlebitis in a rabbit ear vein model [11, 12]. Moreover, other preclinical studies Hydroxypropyl-b-cyclodextrin (HP-b-CD) CH2CH0HCH3 or H suggested that the administration of complexes HPbCD or Hydroxypropyl-c-cyclodextrin (HP-c-CD) CH2CH0HCH3 or H b-cyclodextrin and ketorolac, meloxicam, or naproxen led Methyl-b-cyclodextrin (M-b-CD) CH3 or H to a reduction in the risk of ulcers and gastric damage [11, Sulfobutylether-b-cyclodextrin (SBE-b-CD) (CH ) SO Na or H 2 4 3 13, 14]. Efficacy and Safety Profile of Diclofenac/Cyclodextrin and Progesterone/Cyclodextrin 131 Table 2 Examples of drugs Active ingredient Cyclodextrin Route of administration associated with cyclodextrins in medicinal products Alprostadil a-CD Intracavernous