Host-Guest Interaction Study of Olmesartan Medoxomil with ß-Cyclodextrin Derivatives.

Olmesartan medoxomil (OLM) is a selective angiotensin II receptor antagonist used in the treatment of hypertension. Its therapeutic potential is limited by its poor water solubility, leading to poor bioavailability. Encapsulation of the drug substance by two methylated cyclodextrins, namely randomly methylated ß-cyclodextrin (RM-ß-CD) and heptakis(2,3,6-tri-O-methyl)-ß-cyclodextrin (TM-ß-CD), was carried out to overcome the limitation related to OLM solubility, which, in turn, is expected to result in an improved biopharmaceutical profile. Supramolecular entities were evaluated by means of thermoanalytical techniques (TG-thermogravimetry; DTG-derivative thermogravimetry), spectroscopic methods including powder X-ray diffractometry (PXRD), universal-attenuated total reflectance Fourier-transform infrared (UATR-FTIR) and UV spectroscopy, saturation solubility studies, and by a theoretical approach using molecular modeling. The phase solubility method reveals an AL-type diagram for both inclusion complexes, indicating a stoichiometry ratio of 1:1. The values of the apparent stability constant indicate the higher stability of the host-guest system OLM/RM-ß-CD. The physicochemical properties of the binary systems are different from those of the parent compounds, emphasizing the formation of inclusion complexes between the drug and CDs when the kneading method was used. The molecular encapsulation of OLM in RM-ß-CD led to an increase in drug solubility, thus the supramolecular adduct can be the subject of further research to design a new pharmaceutical formulation containing OLM, with improved bioavailability.

Antimicrobial Potential and Phytochemical Profile of Wild and Cultivated Populations of Thyme (Thymus sp.) Growing in Western Romania.

The purpose of this study was to analyze the chemical composition and antimicrobial activity of some thymus populations collected from five different locations in Western Romania. The chemical compositions of the essential oils (EOs) were studied through GC-MS, and the biological activities were evaluated using the microdilution method. The EO yield ranged between 0.44% and 0.81%. Overall, 60 chemical compounds were identified belonging to three chemotypes: thymol (three populations), geraniol (one population) and carvacrol (one population). Thymus vulgaris L. is distinguished by a high content of thymol, while species of spontaneous flora (Th. odoratissimus and Th. pulegioides) contain, in addition to thymol, appreciable amounts of carvacrol and geraniol. The antimicrobial activity of each the five oils was tested on Staphylococcus aureus (ATCC 25923), Streptococcus pyogenes (ATCC 19615), Esherichia coli (ATCC 25922), Pseudomonas aeruginosa (ATCC 27853), Shigella flexneri (ATCC 12022), Salmonella typhimurium (ATCC 14028), Haemophilus influenzae type B (ATCC 10211), Candida albicans (ATCC 10231) and Candida parapsilopsis (ATCC 22019). The EOs showed biological activity on Gram-positive/Gram-negative/fungal pathogens, the most sensitive strains proving to be S. pyogenes, S. flexneri, S. typhimurium and C. parapsilopsis with an MIC starting at 2 µL EO/100 µL. The species sensitive to the action of Thymus sp. from culture or spontaneous flora are generally the same, but it should be noted that T. odoratissimus has a positive inhibition rate higher than other investigated EOs, regardless of the administered oil concentration. To date, there is no research work presenting the chemical and antimicrobial profiling of T. odoratissimus and the correlations between the antimicrobial potential and chemical composition of wild and cultivated populations of thyme (Thymus sp.) growing in Western Romania.

Risperidone/Randomly Methylated ß-Cyclodextrin Inclusion Complex-Compatibility Study with Pharmaceutical Excipients.

Risperidone (RSP) is an atypical antipsychotic drug used in treating schizophrenia, behavioral, and psychological symptoms of dementia and irritability associated with autism. The drug substance is practically insoluble in water and exhibits high lipophilicity. It also presents incompatibilities with pharmaceutical excipients such as magnesium stearate, lactose, and cellulose microcrystalline. RSP encapsulation by randomly methylated ß-cyclodextrin (RM-ß-CD) was performed in order to enhance drug solubility and stability and improve its biopharmaceutical profile. The inclusion complex formation was evaluated using thermal methods, powder X-ray diffractometry (PXRD), universal-attenuated total reflectance Fourier transform infrared (UATR-FTIR), UV spectroscopy, and saturation solubility studies. The 1:1 stoichiometry ratio and the apparent stability constant of the inclusion complex were determined by means of the phase solubility method. The compatibility between the supramolecular adduct and pharmaceutical excipients starch, anhydrous lactose, magnesium stearate, and cellulose microcrystalline was studied employing thermoanalytical tools (TG-thermogravimetry/DTG-derivative thermogravimetry/HF-heat flow) and spectroscopic techniques (UATR-FTIR, PXRD). The compatibility study reveals that there are no interactions between the supramolecular adduct with starch, magnesium stearate, and cellulose microcrystalline, while incompatibility with anhydrous lactose is observed even under ambient conditions. The supramolecular adduct of RSP with RM-ß-CD represents a valuable candidate for further research in developing new formulations with enhanced bioavailability and stability, and the results of this study allow a pertinent selection of three excipients that can be incorporated in solid dosage forms.

Encapsulation of Risperidone by Methylated ß-Cyclodextrins: Physicochemical and Molecular Modeling Studies.

Risperidone (RSP) is an atypical antipsychotic drug which acts as a potent antagonist of serotonin-2 (5TH2) and dopamine-2 (D2) receptors in the brain; it is used to treat schizophrenia, behavioral and psychological symptoms of dementia and irritability associated with autism. It is a poorly water soluble benzoxazole derivative with high lipophilicity. Supramolecular adducts between drug substance and two methylated ß-cyclodextrins, namely heptakis(2,6-di-O-methyl)-ß-cyclodextrin (DM-ß-CD) and heptakis(2,3,6-tri-O-methyl)-ß-cyclodextrin (TM-ß-CD) were obtained in order to enhance RSP solubility and improve its biopharmaceutical profile. The inclusion complexes were evaluated by means of thermoanalytical methods (TG-thermogravimetry/DTG-derivative thermogravimetry/HF-heat flow), powder X-ray diffractometry (PXRD), universal-attenuated total reflectance Fourier transform infrared (UATR-FTIR), UV spectroscopy and saturation solubility studies. Job's method was employed for the determination of the stoichiometry of the inclusion complexes, which was found to be 2:1 for both guest-host systems. Molecular modeling studies were carried out for an in-depth characterization of the interaction between drug substance and cyclodextrins (CDs). The physicochemical properties of the supramolecular systems differ from those of RSP, demonstrating the inclusion complex formation between drug and CDs. The RSP solubility was enhanced as a result of drug encapsulation in the CDs cavity, the higher increase being obtained with DM-ß-CD as host; the guest-host system RSP/DM-ß-CD can thus be a starting point for further research in developing new formulations containing RSP, with enhanced bioavailability.

Solid Polymeric Nanoparticles of Albendazole: Synthesis, Physico-Chemical Characterization and Biological Activity.

Albendazole is a benzimidazole derivative with documented antitumor activity and low toxicity to healthy cells. The major disadvantage in terms of clinical use is its low aqueous solubility which limits its bioavailability. Albendazole was incorporated into stable and homogeneous polyurethane structures with the aim of obtaining an improved drug delivery system model. Spectral and thermal analysis was used to investigate the encapsulation process and confirmed the presence of albendazole inside the nanoparticles. The in vitro anticancer properties of albendazole encapsulated in polyurethane structures versus the un-encapsulated compound were tested on two breast cancer cell lines, MCF-7 and MDA-MB-231, in terms of cellular viability and apoptosis induction. The study showed that the encapsulation process enhanced the antitumor activity of albendazole on the MCF-7 and MDA-MB-23 breast cancer lines. The cytotoxic activity manifested in a concentration-dependent manner and was accompanied by changes in cell morphology and nuclear fragmentation.

Stability and Compatibility Studies of Levothyroxine Sodium in Solid Binary Systems-Instrumental Screening.

The influence of excipients on the stability of sodium levothyroxine pentahydrate (LTSS) under ambient conditions and thermal stress was evaluated. Since LTSS is a synthetic hormone with a narrow therapeutic index, the interactions of LTSS with excipients can lead to a drastic diminution of therapeutic activity. Ten commonly used pharmaceutical excipients with different roles in solid formulations were chosen as components for binary mixtures containing LTSS, namely, starch, anhydrous lactose, D-mannitol, D-sorbitol, gelatin, calcium lactate pentahydrate, magnesium stearate, methyl 2-hydroxyethyl cellulose (Tylose), colloidal SiO2 (Aerosil) and talc. As investigational tools, universal attenuated total reflectance- Fourier transform infrared spectroscopy UATR-FTIR spectroscopy and thermal analysis were chosen and used as follows: UATR-FTIR spectra were drawn up for samples kept under ambient conditions, while thermoanalytical tools (TG/DTG/HF data) were chosen to evaluate the inducing of interactions during thermal stress. The corroboration of instrumental results led to the conclusion that LTSS is incompatible with lactose, mannitol and sorbitol, and these excipients should not be considered in the development of new generic solid formulations.