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This study aims to investigate the effect of the preparation of solid dispersions using supercritical CO 2 (scCO 2 ) on the physicochemical properties and the performance of supramolecular gels based on polymer-cyclodextrin (CD) interactions (named poly(pseudo)rotaxanes, PPR) envisaging a transdermal administration. Solid dispersions containing Soluplus ® , the antihypertensive drug carvedilol (CAR), and CD (αCD or HPβCD) were prepared and characterized by HPLC, XRPD, FTIR, and DSC. PPRs prepared from solid dispersions (SCF gels) and the corresponding physical mixtures (PM gels) were analyzed regarding rheology, morphology, in vitro drug diffusion, and ex vivo drug skin permeation. The application of scCO 2 led to the loss of the crystalline lattice of CAR while preserving its chemical identity. On the contrary, αCD crystals were still present in the SCF solid dispersions. SCF gels were more uniform than their corresponding PM, and the supercritical treatment resulted in changes in the rheological behavior, reducing the viscosity. CAR in vitro diffusion was significantly higher (p < 0.05) for the αCD-based SCF gel than its corresponding PM gel. Drug skin permeation showed a significant increase in drug flux from CD-based SCF gels (containing αCD or HPβCD) compared to corresponding PM gels. Additionally, the pretreatment of the skin with αCD exhibited increased CAR permeation, suggesting an interaction between αCD and the skin membrane. Results evidenced that SCF processing decisively modified the properties of the supramolecular gels, particularly those prepared with αCD., (© 2023. The Author(s).)

Marine biodiversity has emerged as a very promising resource of bioactive compounds and secondary metabolites from different sea organisms. The sponge's secondary metabolites demonstrated various bioactivities and potential pharmacological properties. This systematic review of the literature focuses on the advances achieved in the antioxidant potential of marine sponges in vitro. The review was performed in accordance with PRISMA guidelines. The main inclusion criterion for analysis was articles with identification of compounds from terpene classes that demonstrate antioxidant activity in vitro. Searching in three different databases, two hundred articles were selected. After screening abstracts, titles and evaluating for eligibility of manuscripts 14 articles were included. The most performed analyzes to detect antioxidant activity were scavenging activity 2,2-diphenyl-1-picrylhydrazyl (DPPH) and measurement of intracellular reactive oxygen species (ROS). It was possible to identify 17 compounds of the terpene class with pronounced antioxidant activity in vitro. Scientific evidence of the studies included in this review was accessed by the GRADE analysis. Terpenes play an important ecological role, moreover these molecules have a pharmaceutical and industrial application., (© 2023. Kunming Institute of Botany, CAS.)

This study sought to develop polymer-lipid hybrid solid dispersions containing the poorly soluble drug lopinavir (LPV) by hot-melt extrusion (HME). Hence, the lipid and polymeric adjuvants were selected based on miscibility and compatibility studies. Film casting was used to assess the miscibility, whereas thermal, spectroscopic, and chromatographic analyses were employed to evaluate drug-excipient compatibility. Extrudates were obtained and characterized by physicochemical tests, including in vitro LPV dissolution. Preformulation studies led to select the most appropriate materials, i.e., the polymers PVPVA and Soluplus®, the plasticizers polyethylene glycol 400 and Kolliphor® HS15, phosphatidylcholine, and sodium taurodeoxycholate. HME processing did not result in LPV degradation and significantly increased entrapment efficiency (93.8% ± 2.8 for Soluplus® extrudate against 19.8% ± 0.5 of the respective physical mixture). LPV dissolution was also increased from the extrudates compared to the corresponding physical mixtures (p < 0.05). The dissolution improvement was considerably greater for the Soluplus®-based formulation (24.3 and 2.8-fold higher than pure LPV and PVPVA-based extrudate after 120 min, respectively), which can be attributed to the more pronounced effects of HME processing on the average size and LPV solid-state properties in the Soluplus® extrudates. Transmission electron microscopy and chemical microanalysis suggested that the polymer-lipid interactions in Soluplus®-based formulation depended on thermal processing., (© 2023. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

This study aimed to investigate whether hot-melt extrusion (HME) processing can promote molecular encapsulation of a multi-component natural product composed of volatile and pungent hydrophobic substances (ginger oleoresin (OR)) with cyclodextrins. 6-Gingerol and 6-shogaol, the biomarkers of ginger OR, were quantified by HPLC. Phase-solubility studies were performed using β-cyclodextrin (βCD) and hydroxypropyl-β-cyclodextrin (HPβCD) for ginger OR complexation. Solid complexes were then prepared by thermal (HME)- and solvent (slurry (SL))-based methods. Morphology, thermal behavior, solubility, in vitro dissolution, and in vivo anti-inflammatory activity were evaluated. HPβCD gave rise to AL-type complexes with ginger OR, whereas βCD led to materials with limited solubility. Ginger OR was complexed with HPβCD by HME without significant change in gingerol and shogaol content. Additionally, thermogravimetric analysis (TGA) suggested higher volatile retention in HME complexes than in SL ones. Shogaol and gingerol solubility and dissolution significantly increased from SL and HME complexes compared with ginger OR. In turn, 1:2 OR/HPβCD HME complex showed higher 6-shogaol solubility than SL, associated with a gradual release. The carrageenan-induced pleurisy test showed that the anti-inflammatory activity of ginger OR was maintained after complexation with HPβCD. The complexes significantly decrease the levels of IL-1β and inhibit cell migration. HME complex showed performance equivalent to the positive control and superior to the SL material. Taken together, these results indicate that HME can be useful for promoting the molecular encapsulation of complex natural products that contain volatile and thermolabile substances. HME complexes showed better in vivo and in vitro performance than complexes prepared using the solvent-based method., (© 2022. Controlled Release Society.)

Fused deposition modeling (FDM) 3D printing has demonstrated high potential for the production of personalized medicines. However, the heating at high temperatures inherent to this process causes unknown risks to the drug product's stability. The present study aimed to assess the use of a tailored preformulation protocol involving physicochemical assessments, including the rheological profiles of the samples, to guide the development of medicines by FDM 3D printing. For this, polymers commonly used in FDM printing, i.e., high impact polystyrene (HIPS), polylactic acid (PLA), and polyvinyl alcohol (PVA), and their common plasticizers (mineral oil, triethyl citrate, and glycerol, respectively) were evaluated using the thermolabile model drug isoniazid (INH). Samples were analyzed by chemical and physical assays. The results showed that although the drug could produce polymorphs under thermal processing, the polymeric matrix can be a protective element, and no polymorphic transformation was observed. However, incompatibilities between materials might impact their chemical, thermal, and rheological performances. In fact, ternary mixtures of INH, PLA, and TEC showed a major alteration in their viscoelastic behavior besides the chemical changes. On the other hand, the use of plasticizers for HIPS and PVA exhibited positive consequences in drug solubility and rheologic behavior, probably improving sample printability. Thus, the optimization of the FDM 3D printing based on preformulation studies can assist the choice of compatible components and seek suitable processing conditions to obtain pharmaceutical products., (© 2021. American Association of Pharmaceutical Scientists.)

This study sought to investigate the influence of formulation and process factors of the high shear mixing (HSM) on the properties of solid self-emulsifying drug delivery systems (S-SEDDS) containing the model drug carvedilol (CAR). Firstly, liquid SEDDS (L-SEDDS) were prepared by mixing castor oil with different proportions of surfactant (Solutol or Kolliphor RH40) and cosolvent (Transcutol or PEG400). A miscible L-SEDDS with high drug solubility (124.3 mg/g) was selected and gave rise to 10% (m/m) CAR loaded-emulsion with reduced particle size. Then, a factorial experimental design involving five component's concentration and two process factors was used to study the solidification of the selected L-SEDDS by HSM. CAR content, diffractometric profile, and in vitro dissolution were determined. Morphological and flow analyses were also performed. Porous and spherical particles with mean sizes ranging from 160 to 210 µm were obtained. Particle size was not affected by any formulation factor studied. Powder flowability, in turn, was influenced by L-SEDDS and crospovidone concentration. CAR in vitro dissolution from S-SEDDS was significantly increased compared to the drug as supplied and was equal (pH 1.2) or lower (pH 6.8) than that determined for L-SEDDS. Colloidal silicon dioxide decreased drug dissolution, whereas an increase in water-soluble diluent lactose and L-SEDDS concentration increased CAR dissolution. The proper selection of liquid and solid constituents proved to be crucial to developing an S-SEDDS by HSM. Indeed, the results obtained here using experimental design contribute to the production of S-SEDDS using an industrially viable process., (© 2021. American Association of Pharmaceutical Scientists.)

The aim of this study was to evaluate biocompatibility of hydroxyapatite (HAP) from fish waste using in vitro and in vivo assays. Fish samples (whitemouth croaker - Micropogonias furnieri) from the biowaste was used as HAP source. Pre-osteoblastic MC3T3-E1 cells were used in vitro study. In addition, bone defects were artificially created in rat calvaria and filled with HAP in vivo. The results demonstrated that HAP reduced cytotoxicity in pre-osteoblast cells after 3 and 6 days following HAP exposure. DNA concentration was lower in the HAP group after 6 days. Quantitative RT-PCR did not show any significant differences (p > 0.05) between groups. In vivo study revealed that bone defects filled with HAP pointed out moderate chronic inflammatory cells with slight proliferation of blood vessels after 7 and 15 days. Chronic inflammatory infiltrate was absent after 30 days of HAP exposure. There was also a decrease in the amount of biomaterial, being followed by newly formed bone tissue. All experimental groups also demonstrated strong RUNX-2 immoexpression in the granulation tissue as well as in cells in close contact with biomaterial. The number of osteoblasts inside the defect area was lower in the HAP group when compared to control group after 7 days post-implantation. Similarly, the osteoblast surface as well as the percentage of bone surface was higher in control group when compared with HAP group after 7 days post-implantation. Taken together, HAP from fish waste is a promising possibility that should be explored more carefully by tissue-engineering or biotechnology., (© 2021. The Author(s).)

The effects of excipients on the accuracy of tablet subdivision are severely underinvestigated. In this study, placebo tablets were prepared using a combined mixture design of fillers and binders to evaluate the effect of these excipients on subdivision accuracy. The responses assessed were mass loss, mass variation, tablet fragmentation, and increased friability. Dicalcium phosphate dihydrate (DCP) gave rise to more uniform and denser tablets than microcrystalline cellulose (MCC), thus resulting in greater subdivision accuracy. The binder type, hydroxypropylcellulose (HPC) or polyvinylpyrrolidone (PVP), did not affect the subdivision of DCP tablets. On the contrary, the structural similarity between HPC and MCC led to improved subdivision accuracy for MCC tablets. A less accurate subdivision was observed in tablets prepared with a DCP-MCC combination; this finding could be attributed to irregular binder distribution in this matrix. An optimized response was built using desirability analysis. This study helps to illuminate the relationship between fillers and binders to guide formulation scientists in the development of tablets with better subdivision performance.

Pellet-containing tablets for colon-specific drug delivery present higher targeting efficiency and lower costs when compared with monolithic tablets and pellet-filled capsules, respectively. In this study, pellets containing ketoprofen were coated with different acrylic polymers and submitted to compaction. The influence of formulation and process factors on film integrity was then evaluated. Pellets were prepared via extrusion-spheronization and coated using two acrylic polymers (Eudragit® FS 30 D and Opadry® 94 k28327, PMMA and PMA, respectively). The resulting pellets were mixed with placebo granules and compressed in a hydraulic press. Multiple regression showed that ketoprofen release from pellet-containing tablets is predominantly influenced by pellet content, hardness, friability, and disintegration time. PMA-containing tablets prepared under low compaction force or with low pellet content showed rapid disintegration (<1 min) and ketoprofen release similar to those of uncompressed coated pellets (∼30% at 360 min of experiment). On the other hand, PMMA-containing tablets showed a higher rupture level, and those prepared with higher pellet content gave rise to a non-disintegrating matrix. Coated pellets were shown to be able to target ketoprofen to the colonic region. Targeting capacity was dependent on the physicochemical characteristics of the tablets.

The morphogene bolA plays a significant role in the adaptation of Escherichia coli to general stresses. In general, bacteria can thrive and persist under harsh conditions, counteracting external stresses by using varied mechanisms, including biofilm formation, changes in cell shape, size and protein content, together with alterations in the cell wall structure, thickness and permeability. In E. coli, an increased expression of bolA occurs mainly under stress challenges and when bacterial morphology changes from rod-like to spherical. Moreover, BolA is able to induce biofilm formation and changes in the outer membrane, making it less permeable to harmful agents. Although there has been substantial progress in the description of BolA activity, its role on global cell physiology is still incomplete. Proteins with strong homology to BolA have been found in most living organisms, in many cases also exerting a regulatory role. In this review we summarize current knowledge on the role of BolA, mainly in E. coli, and discuss its implication in global regulation in relation to stress.