The synthesis and pharmacological activity of a new series of 1-oxa-4,9-diazaspiro[5.5]undecane derivatives as potent dual ligands for the sigma-1 receptor (σ1R) and the µ-opioid receptor (MOR) are reported. The different positions of the central scaffold, designed using a merging strategy of both targets pharmacophores, were explored using a versatile synthetic approach. Phenethyl derivatives in position 9, substituted pyridyl moieties in position 4 and small alkyl groups in position 2 provided the best profiles. One of the best compounds, 15au, showed a balanced dual profile (i.e. MOR agonism and sigma antagonism) and a potent analgesic activity, comparable to the MOR agonist oxycodone in the paw pressure test in mice. Contrary to oxycodone, as expected from the addition of σ1R antagonism, 15au showed local, peripheral activity in this test, which was reversed by the σ1R agonist PRE-084. At equianalgesic doses, 15au showed less constipation than oxycodone, providing evidence that dual MOR agonism and σ1R antagonism may be a useful strategy for obtaining potent and safer analgesics.

Co-crystal of tramadol -celecoxib (CTC) is a novel active pharmaceutical ingredient API-API co-crystal formed by an intrinsic 1:1 molecular ratio of rac-tramadol.HCl (TRM) and celecoxib (CXB) in late-stage development for the treatment of pain. In line with previous intrinsic dissolution rate (IDR) studies, we report here that the kinetic dissolution profile of CTC in hydroxypropyl methyl cellulose (HPMC) and buffered solutions led to a supersaturation state of CXB and a release significantly faster from CTC than from the free combination, which in turn was quite similar to the release from CXB alone. Inversely, TRM was released much more slowly from CTC than from the free combination and TRM alone. Experimental and predicted solubility-pH curves showed that the thermodynamic solubility of CTC lies in between those of TRM and CXB within the physiologically meaningful pH range. The lattice and solvation contributions to CTC aqueous solubility was studied, showing that the solvation factor is the most important, but it appears to be proportionally lower and more similar to the more soluble component, TRM. These results, together with those obtained in the hygroscopicity studies, show that CTC co-crystal structure provides a clear differential profile versus the free combination or the two APIs alone.

Two parallel artificial membrane permeability assay (PAMPA) systems intended for emulating skin permeability have been characterized through the solvation parameter model of Abraham using multilinear regression analysis. The coefficients of the obtained equations have been compared to the ones already established for other PAMPA membranes using statistical tools. The results indicate that both skin membranes are similar to each other in their physicochemical properties. However, they are different from other PAMPA membranes (e.g., intestinal absorption and blood–brain PAMPAs), mainly in terms of hydrophobicity and hydrogen bonding properties. Next, all PAMPA membranes have been compared to relevant biological processes also characterized through the solvation parameter model. The results highlight that skin-PAMPA membranes are a very good choice to emulate skin permeability.

Five in vitro physicochemical systems have been evaluated in terms of its ability to emulate the skin permeation of neutral compounds: the permeation in two different PAMPA membranes, the classical octanol-water partition coefficient, and two biomimetic chromatography systems, one based in cerasome electrokinetic chromatography and another based in reversed-phase liquid chromatography measurements. The coefficients of the solvation parameter model equation of the mentioned systems have been compared to the ones of the skin permeation process through different comparison parameters. Moreover, a method to predict whether a physicochemical system is able to emulate satisfactorily a biological one, just by the analysis of the equation coefficients has been developed. Results reveal that the two PAMPA systems are a good choice to emulate directly the skin permeation of neutral compounds. Instead, the other three systems need a volume correction term to provide a satisfactory emulation. However, after the correction, all the evaluated systems show a similar ability to emulate well skin permeation, as predicted.