DEVELOPMENT OF NOVEL MULTI-RESPONSIVE MATERIALS CHARACTERIZED BY POTENTIAL CONTROLLED RELEASE PROPERTIES

With the emergence of novel and more effective drug therapies, increased importance is being placed upon the methods by which these drugs are being delivered to the body. In conventional drug delivery systems, there is very little control over the release of drug. The effective concentration at the target site can be achieved by intermittent administration of grossly excessive doses, which, often results in constantly, unpredictable variations in plasma concentrations, with the risk of reaching levels below or above the therapeutic range leading to marked side effects. A plethora of formulation strategies mainly based on polymeric/lipid nanoparticles, are described in literature. Even though these systems are therapeutically advantageous in comparison to conventional systems, they remain insensitive to the changing metabolic states of the body although the symptoms of most metabolic diseases follow a rhythmic pattern.A more appropriate and effective approach of managing some of these conditions lies in the chronotherapy. This approach allows for pulsed or self-regulated drug delivery which is adjusted to the staging of biological rhythms, since the onset of certain diseases exhibits strong circadian temporal dependence. In order to reach the objective of mimicking the biophysical and biochemical processes of pathological states, many innovations in material design for drug delivery systems (DDS) that are able to release the therapeutic payload-on-demand were done to release the therapeutic agent only when it is required, according to the physiological need. The development of multidisciplinary research teams has brought huge advantages in the design, fabrication and utilization of such smart systems, especially in the pharmaceutical field. Interestingly, numerous smart polymeric materials exhibit a response to a specific stimulus. A step further, the elaboration of purpose-built monomers can give rise to compounds with tunable sensitivities or multi-stimuli responsiveness. These smart polymers demonstrate an active responsiveness to environmental (or external) signals and change their physicochemical properties as designed (e.g. conformation, solubility, shape, charge or size). As far as the stimuli are concerned, they consist of physical (e.g. temperature, ultrasound, light, electricity, magnetic or mechanical stress), chemical (e.g. pH, ionic strength) and biological signals (e.g. enzymes, biomolecules). Due to the intrapersonal variabilities which may make internal stimuli hazardous, externally controlled systems rely on externally applied stimuli that are produced by stimuli-generating devices, which results in pulsed drug delivery. This type of delivery may be rapid and allows a transient release of a determined amount of drug within a short period of time immediately after a pre-determined off-release period. A novel strategy for the formation of multi-stimuli responsive materials endowed with pH, magnetic and light sensitivity was achieved. The approach relied on the incorporation of magnetic tetrahalogenoferrate(III) anions along a polymeric backbone based on poly(2-(N,N-dimethylamino) ethyl meth-acrylate) (PDMAEMA). Starting from the same PDMAEMA, quaternized pending amine groups with various halide derivatives gave rise to magnetic materials after anion metathesis. Measuring the magnetic susceptibility of these materials exhibited that the magnetic susceptibility increased as the substituted group size decreased (become smaller) which was apparently related to the steric hindrance around the ionic pendants. Additionally, a good correlation between the magnetic susceptibility and ferric content was found. Additional experimental and theoretical Raman analyses allowed the determination of the nature of the magnetic species constituting the materials. This strategy further offers the opportunity to tailor the magnetic response through partial ammonium salt formation. In order to merge the magnetic properties of ferric-based materials with another stimuli-responsive functionality, random copolymers containing DMAEMA (D) with diazobenzene (A) unit were prepared. So, three copolymers PDA were synthesized (with targeted D/A ratios 4/6 (PDA4), 6/4 (PDA6) and 8/2 (PDA8)). Meanwhile, different degrees of amine quaternization (10, 50 and 100 %) were applied, which led to the following polymeric salts PDAX/Y where X = 4, 6, 8 (referring to the percentage of the DMAEMA unit) and Y = 10, 50 and 100 (referring to the percentage of quaternized amine groups). Finally, the aforementioned materials were converted into magnetic polymers by anion exchange. As a result, magnetic responses correlated well with amount of iron oxide in these compounds and the amount of ionic pending groups along the backbone. Moreover, the remaining tertiary amines conferred pH sensitivity to the polymers whereas the diazobenzene units ensured light responsiveness through the well-established trans-to-cis isomerization.In order to functionalize these materials in the pharmaceutical field, an intelligent delivery system was prepared. Firstly, an attempt to formulate riboflavin-5’-phosphate sodium (RPS) loaded on PDA8 microspheres was made using double emulsion evaporation method. Meanwhile, prednisolone (PRD) microspheres were prepared using s/o/w emulsion technique. Subsequently, coating systems of cochineal red tablets were developed. These tablets were coated with polymer solution (using each of three types of copolymers: PDA8, PDA6, and PDA4) until the desired percentage of the coating was achieved (10, 15, and 20 % w/w). The cumulative release profiles of cochineal red tablets coated with PDA8, PDA6, and PDA4 showed a pH-sensitive release behavior. The release in the neutral media (pH ≈ 7.0) was very slow (less than 3 % after one hour). Then, after changing the pH to 1.2, an increase in the release of cochineal was observed. Furthermore, the cumulative release of cochineal red was at the highest value for the PDA8 and the lowest for PDA4 depending on the percentage of PDMAEMA moieties. Moreover, by increasing the percentage of the coating from (10, 15 to 20 % w/w), the cumulative release of cochineal decreased. Therefore, the copolymer PDAX can be used for controlling the release of drug by changing the pH value.Finally, the cochineal tablets coated with PDA6 (10 %) showed features of light sensitivity. The release of cochineal red from coated tablets was only due to the switching in the conformational trans/cis isomerization of azobenzene moieties upon irradiation, which was confirmed by comparing the release of coated tablets with uncoated tablets upon irradiation.Doctorat en Sciences biomédicales et pharmaceutiques (Pharmacie)info:eu-repo/semantics/nonPublishe

Mechanical energies associated with compaction of form I and form II paracetamol powder

Paracetamol solid state has three known polymorphic forms; monoclinic form (Form I), orthorhombic form (Form II) and Form III. In this work Form II was successfully produced in appreciable quantities by controlled crystallization of melted Form I. The moisture content of both forms stored for 3 weeks at 25 °C at different relative humidity conditions was investigated. It was found that neither form acquires any significant amount of moisture in any of the storage conditions. The results showed that Form II is stable for 3 weeks of storage at relative humidities of 23%, 43%, and 58%. Work of compression, work of decompression, plasticity index (ψ), and elastic energy/plastic energy (EE/PE) ratio associated with the compaction of both forms were determined at maximum applied compression forces of 35 kN, 27 kN, 18 kN, 11 kN, and 5 kN. It was found that both forms have high magnitude of elastic energy recovery during decompression. Moreover, it was found that for generating compacts of equal volumes of the two forms the plasticity index is larger for Form II and the EE/PE ratio is larger for Form I.info:eu-repo/semantics/publishe

Type 2 17-β hydroxysteroid dehydrogenase as a novel target for the treatment of osteoporosis

Low estradiol level in postmenopausal women is implicated in osteoporosis, which occurs because of the high bone resorption rate. Estrogen formation is controlled by 17-β hydroxysteroid dehydrogenase 17-β HSD enzymes, where 17-β HSD type 1 contributes in the formation of estradiol, while type 2 catalyzes its catabolism. Inhibiting 17-β HSD2 can help in increasing estradiol concentration. Several promising 17-β HSD2 inhibitors that can act at low nanomolar range have been identified. However, there are some specific challenges associated with the application of these compounds. Our review provides an up-to-date summary of the current status and recent progress in the production of 17-β HSD2 inhibitors as well as the future challenges in their clinical application.SCOPUS: re.jinfo:eu-repo/semantics/publishe

Antioxidant effects and bioavailability evaluation of propolis extract and its content of pure polyphenols

Propolis is a resinous mixture which honey bees collect from buds and bark of some trees. It contains several antioxidant compounds such as polyphenols and flavonoids. This paper describes the antioxidant capacity of propolis extracts and pure polyphenols in vivo. Several biological parameters were measured after promoting oxidative stress. All the homeostasis changes and liver, kidney, and lung damage were restored by propolis extract. Propolis extracts directly modulated lipid peroxidation where LDL level decreased from 1.3 to 0.8 g/L after giving propolis, illustrating the antioxidant contribution of propolis. Finally, orally administered pure antioxidant compounds such as caffeic acid, quercetin, and kaempferol at the doses corresponding to in vitro antioxidant capacity of the propolis extract did not restore the physiological parameters. Bioavailability study demonstrated that the isolated polyphenols have lower absorption (plasma Cmax of polyphenols = 15–20 µg/mL) than the complex extract of propolis (plasma Cmax of polyphenols = 40–50 µg/mL). Practical applications: Extracts of propolis showed significant reduction of oxidative damages from oxidative stress. The complexity of propolis has an antioxidant capacity more than its isolated polyphenols. Monitoring the concentrations of the compounds in serum after orally administering of propolis and isolated polyphenols demonstrated that these antioxidant compounds have higher bioavailability when applied as crude extracts. These results make the propolis extracts a promising antioxidant which could be used as a food supplement.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Triple-stimuli responsive polymers with fine tuneable magnetic responses

The formation of multi-stimuli responsive polymers exhibiting magnetic, pH and light sensitivity is reported. After quaternization of tertiary amines along poly(2-(N,N-dimethylamino) ethyl methacrylate) (PDMAEMA) with varied alkyl and benzyl halides, a series of tetrahalogenoferrate(iii) salts were obtained by anion metathesis, conferring tailored and high magnetic responses. Experimental and theoretical Raman analyses allowed one to distinguish between the different magnetic anions present in the materials. This strategy was then implemented to the formation of multi-responsive compounds, by using random copolymers that incorporate various amounts of DMAEMA (∼40, 65 and 80%) and diazobenzene units. Partial or total quaternization of the dimethylamino end groups (10, 50 and 100%) followed by magnetic anion exchange afforded the magnetic-responsive copolymers, as evidenced by their magnetic susceptibility. Free ternary amino groups and diazobenzene moieties further brought pH and light sensitivity, giving rise to triple-stimuli responsive materials. This simple and rapid procedure offers the opportunity to fine tune the magnetic properties of remotely controlled smart devices.SCOPUS: ar.jSCOPUS: ar.jinfo:eu-repo/semantics/publishe

Novel bis-arylalkylamines as myeloperoxidase inhibitors: Design, synthesis, and structure-activity relationship study

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Discovery of Novel Potent Reversible and Irreversible Myeloperoxidase Inhibitors Using Virtual Screening Procedure

The heme enzyme myeloperoxidase (MPO) participates in innate immune defense mechanism through formation of microbicidal reactive oxidants. However, evidence has emerged that MPO-derived oxidants contribute to propagation of inflammatory diseases. Because of the deleterious effects of circulating MPO, there is a great interest in the development of new efficient and specific inhibitors. Here, we have performed a novel virtual screening procedure, depending on ligand-based pharmacophore modeling followed by structure-based virtual screening. Starting from a set of 727842 compounds, 28 molecules were selected by this virtual method and tested on MPO in vitro. Twelve out of 28 compounds were found to have an IC50 less than 5 μM. The best inhibitors were 2-(7-methoxy-4-methylquinazolin-2-yl)guanidine (28) and (R)-2-(1-((2,3-dihydro-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-5-fluoro-1H-benzo[d]imidazole (42) with IC50 values of 44 and 50 nM, respectively. Studies on the mechanism of inhibition suggest that 28 is the first potent mechanism-based inhibitor and inhibits irreversibly MPO at nanomolar concentration.SCOPUS: ar.jinfo:eu-repo/semantics/publishe