Performance tuning of particle engineered mannitol in dry powder inhalation formulations.

Typically, smooth lactose particles are used as carrier in dry powder formulations for inhalation. Two classical approaches to improve their aerodynamic behaviour are the addition of fines (milled lactose) or magnesium stearate (MgSt). Mannitol (Parteck® M DPI) as an alternative carrier was used in this study. It has an irregular particle size distribution and a large and rough surface. This could be challenging for the detachment of micronised drug upon inhalation and it is unclear whether classic strategies for the optimisation of aerodynamic performance can be applied. In contrast, its rough surface could be an advantage in terms of drug load. To address these questions, the mannitol carrier was blended with two different drugs using various concentrations up to 50%. Self-produced mannitol fines and MgSt in different amounts and in combination were added. Blends were investigated regarding their in vitro aerodynamic performance, dosing behaviour and powder rheology. An addition of up to 30% drug load was possible while retaining good flowability and constant dosing behaviour. Despite the rough and indented carrier surface of the mannitol carrier, the addition of fines or MgSt increased the inhalable fraction, but higher concentrations of fines, as used for lactose blends, were necessary.

Content of phenolic compounds and mannitol in olive leaves extracts from six Spanish cultivars: Extraction with the Soxhlet method and pressurized liquids.

Olive leaves are considered a promising source of bioactives such as phenolic compounds and mannitol. The extraction of high added value products is an issue of great interest and importance from the point of view of their exploitation. However, the content of these compounds can differ between cultivars and extraction methods. In this work, six olive leaves cultivars, including three wild cultivars, and two extraction processes (an innovative and alternative technique, pressurized liquid extraction, and a conventional Soxhlet extraction) were evaluated and compared towards the selective recovery of bioactive compounds. The wild cultivars showed the highest content of phenolic and flavonoid compounds, being oleuropein the compound present in higher amount. Findings also revealed that the highest mannitol content in the extracts was observed with the commercial cultivars, specifically in Arbequina. It is thus possible to decide which cultivars to use in order to obtain the highest yield of each bioproduct.

The traditional uses, phytochemistry, and pharmacology of Atractylodes macrocephala Koidz.: A review.

ETHNOPHARMACOLOGICAL RELEVANCE: Atractylodes macrocephala Koidz. (called Baizhu in China) is a medicinal plant that has long been used as a tonic agent in various ethno-medical systems in East Asia, especially in China, for the treatment of gastrointestinal dysfunction, cancer, osteoporosis, obesity, and fetal irritability. AIM OF THE REVIEW: This review aims to provide a systematic summary on the botany, traditional uses, phytochemistry, pharmacology, pharmacokinetics, and toxicology of A. macrocephala to explore the future therapeutic potential and scientific potential of this plant. MATERIALS AND METHODS: A literature search was performed on A. macrocephala using scientific databases including Web of Science, Google Scholar, Baidu Scholar, Springer, PubMed, SciFinder, and ScienceDirect. Information was also collected from classic books of Chinese herbal medicine, Ph.D. and M.Sc. dissertations, unpublished materials, and local conference papers on toxicology. Plant taxonomy was confirmed to the database "The Plant List" (www.theplantlist.org). RESULTS: More than 79 chemical compounds have been isolated from A. macrocephala, including sesquiterpenoids, triterpenoids, polyacetylenes, coumarins, phenylpropanoids, flavonoids and flavonoid glycosides, steroids, benzoquinones, and polysaccharides. Crude extracts and pure compounds of A. macrocephala are used to treat gastrointestinal hypofunction, cancer, arthritis, osteoporosis, splenic asthenia, abnormal fetal movement, Alzheimer disease, and obesity. These extracts have various pharmacological effects, including anti-tumor activity, anti-inflammatory activity, anti-aging activity, anti-oxidative activity, anti-osteoporotic activity, neuroprotective activity, and immunomodulatory activity, as well as improving gastrointestinal function and gonadal hormone regulation. CONCLUSIONS: A. macrocephala is a valuable traditional Chinese medicinal herb with multiple pharmacological activities. Pharmacological investigations support the traditional use of A. macrocephala, and may validate the folk medicinal use of A. macrocephala to treat many chronic diseases. The available literature shows that much of the activity of A. macrocephala can be attributed to sesquiterpenoids, polysaccharides and polyacetylenes. However, there is a need to further understand the molecular mechanisms and the structure-function relationship of these constituents, as well as their potential synergistic and antagonistic effects. Further research on the comprehensive evaluation of medicinal quality, the understanding of multi-target network pharmacology of A. macrocephala, as well as its long-term in vivo toxicity and clinical efficacy is recommended.

Diversity selection, screening and quantitative structure-activity relationships of osmolyte-like additive effects on the thermal stability of a monoclonal antibody.

Solvents used for therapeutic proteins in downstream processing and in formulations often contain stabilizing additives that inhibit denaturation and aggregation. Such additives are mostly selected based on their positive effect on thermal stability of the protein, and are often derived from naturally occuring osmolytes. To better understand the structural basis underlying the effect of additives, we selected a diverse library of compounds comprising 79 compounds of the polyol, amino acid and methylamine chemical classes and determined the effect of each compound on thermal stability of a monoclonal antibody as a function of compound concentration. Thermal stabilization of the antibody was influenced by solution pH. Quantitative structure-activity relationships (QSAR) were derived by partial least squares regression for individual compound classes and globally. The global model suggests that ligands with a phenyl ring will decrease the Tm, while highly soluble, polar compounds with at least two hydrogen bond donors will increase the Tm. This approach may be beneficial for further studies on the influence of other solution conditions like ionic strength and buffer species on additive-mediated protein stabilization.

Development of protocatechualdehyde proliposomes-based sustained-release pellets with improved bioavailability and desired pharmacokinetic behavior for angina chronotherapy.

The present study was aimed to develope a proliposomal formulation to decrease the hepatic first-pass metabolism of protocatechualdehyde (PD), followed by pellet coating to modify the drug release for angina chronotherapy. PD proliposomes were prepared by depositing PD-phospholipid complex on mannitol powders to improve the drug encapsulation. Afterwards, the PD proliposomes were prepared into pellet cores via extrusion-spheronization using 10% κ-carrageenan as pelletization aid prior to the development of PD sustained-release pellets (PD-SRPs). Eudragit® NE 30D was chosen as coating material and the desired drug release profile of PD-SRPs was calculated for formulation optimization by deconvolution based on the circadian rhythm of variant angina. A high similarity factor (f2=85.72) was achieved when the coating weight was 30% and the sustained release behavior also prevented the destruction of liposomes by gastric fluids. Pharmacokinetic studies revealed a basically consistent trend between the actual and the predicted plasma concentration-time curve with absolute percent errors (%PE) of concentrations <10% in 2-12h. Meanwhile, a relative bioavailability of 200% was achieved compared with pure PD. Therefore, the development of proliposomes-based PD-SRPs was an effective strategy to provide both improved oral bioavailability and desired drug plasma concentration-time course for angina chronotherapy.

Paeoniflorin inhibits high glucose-induced macrophage activation through TLR2-dependent signal pathways.

ETHNOPHARMACOLOGICAL RELEVANCE: Paeoniflorin(PF), extracted from the root peeled of Paeonia lactiflora Pall(Family: Ranunculaceae), has therapeutic potential in many animal models of inflammatory diseases. AIM OF THE STUDY: Although the anti-inflammatory efficacy of PF has been well illustrated in several animal models, whether it could attenuate diabetic nephropathy and detailed mechanisms are still obscure. Till now, accumulating evidence has proposed the pivotal role of toll-like receptors (TLRs) in renal inflammation in diabetic patients. In this setting, the current study aimed to investigate the effects and underlying mechanism of PF on high glucose-induced activation of toll like-receptor 2 (TLR2) signaling in macrophages. MATERIALS AND METHODS: Bone marrow-derived macrophages (BMDM) were isolated from male Tlr2tm1kir (TLR2-/-) mice and wild-type littermates (C57BL/6JWT). The level of TLR2 and activation of downstream signaling were evaluated in response to 30mmol/L high glucose (HG)-containing medium. Macrophages behaviors, which include cell viability, migration and inflammatory cytokines production, were also determined. RESULTS: PF suppressed HG-induced production of TLR2, activation of downstream signaling and synthesis of inducible nitric oxide synthase (iNOS). PF could further inhibit MyD88-dependent pathway in HG-induced models in which TLR2 was knocked out. Moreover, deletion of TLR2 inhibited the HG-induced activation of MyD88-dependent pathway, but not TIR domain containing adapter inducing interferon-ß (Trif) signal pathway in BMDMs. As HG stimulation polarizes macrophages into M1 phenotype, treatment of PF or knockout of TLR2 significantly reduces M1 markers on the membrane of macrophages. Additionally, levels of inflammatory cytokines and iNOS were remarkably reduced in response to PF or TLR2 deficiency. CONCLUSION: Collectively, these data demonstrated that HG activated macrophages primarily through TLR2-dependent mechanisms which aggravated the severity of renal inflammation and eventually contributed to DN. Additionally, PF might be applied as a potential therapeutic agent in the battle against progressive DN.

Gastroprotective effects and antimicrobial activity of Lithraea molleoides and isolated compounds against Helicobacter pylori.

ETHNOPHARMACOLOGICAL RELEVANCE: Lithraea molleoides (Vell.) Engl. (Anacardiaceae) is a medicinal plant traditionally used in South America to treat various ailments, including diseases of the digestive system. AIM OF THE STUDY: To evaluate the in vivo antiulcer and antimicrobial activities against Helicobacter pylori of L. molleoides and its isolated compounds. MATERIALS AND METHODS: Methanolic extract 250 and 500 mg/kg, (LmE 250 and LmE 500, respectively) and infusions, 10 g and 20 g en 100mL (LmI 10 and LmI 20, respectively) of L. molleoides was evaluated for antiulcer activity against 0.6N HCl, 0.2N NaOH, 200mg/kg acetilsalicilic acid and absolute ethanol-induced gastric ulcers in rats. The degree of erosion in the glandular part of the stomach was assessed from a scoring system. Acute toxicity in mice was also evaluated. The antiulcer effect of the isolated compounds (catechol, mannitol, rutin, gallic acid, ferulic acid and caffeic acid, 100mg/kg) was evaluated against absolute ethanol-induced gastric ulcers in rats. The anti-Helicobacter pylori activity of L. molleoides and isolated compounds was performed using broth dilution methods. RESULTS: The LmE 250, LmE 500, LmI 10 and LmI 20 produced significant inhibition on the ulcer index in 0.6N HCl, 0.2N NaOH, 200mg/kg acetilsalicilic acid and absolute ethanol- induced gastric ulcers in rats. The isolated compounds, catechol, mannitol, rutin, ferulic acid and caffeic acid were active in absolute ethanol- induced gastric ulcers in rats. L. molleoides and different compounds showed antimicrobial activity in all strains tested. The lowest MIC value (0. 5 µg/mL) was obtained with catechol in six of eleven strains assayed. No signs of toxicity were observed with doses up to 2g/kg in an acute toxicity assay. CONCLUSION: These findings indicate that L. molleoides displays potential antiulcerogenic and antimicrobial activities and the identification of active principles could support the use of this plant for the treatment of digestive affections.