Interactions and incompatibilities of pharmaceutical excipients with active pharmaceutical ingredients: a comprehensive review

Studies of active drug/excipient compatibility represent an important phase in the preformulation stage of the development of all dosage forms. The potential physical and chemical interactions between drugs and excipients can affect the chemical nature, the stability and bioavailability of drugs and, consequently, their therapeutic efficacy and safety. The present review covers the literature reports of interaction and incompatibilities of commonly used pharmaceutical excipients with different active pharmaceutical ingredients in solid dosage forms. Examples of active drug/excipient interactions, such as transacylation, the Maillard browning reaction, acid base reactions and physical changes are discussed for different active pharmaceutical ingredients belonging to different therapeutic categories viz antiviral, anti-inflammatory, antidiabetic, antihypertensive, anti-convulsant, antibiotic, bronchodialator, antimalarial, antiemetic, antiamoebic, antipsychotic, antidepressant, anticancer, anticoagulant and sedative/hypnotic drugs and vitamins. Once the solid-state reactions of a pharmaceutical system are understood, the necessary steps can be taken to avoid reactivity and improve the stability of drug substances and products

Cytotoxicity Screening of Selected Indian Medicinal Plants using Brine-Shrimp Lethality Bioassay

ABSTRACT In the present work, ethanolic extracts of fourteen Indian medicinal plants viz. Acorus calamus (Araceae) stem, Asparagus racemosus (Asparagaceae) root, Aegle marmelos (Rutaceae) leaves and fruits, Cassia fistula (Fabaceae) fruits, Gymnema sylvestre (Asclepiadaceae) leaves, Holarrhena antidysenterica (Apocynaceae) bark, Mimusops elengi (Sapotaceae) bark, Ocimum sanctum (Lamiaceae) leaves, Piper longum (Piperaceae) leaves, Sapindus trifoliatus (Sapindaceae) fruits, Terminalia arjuna (Combretaceae) bark, Terminalia bellerica (Combretaceae) fruits, Terminalia chebula (Combretaceae) fruits and Withania somnifera (Solanaceae) roots were tested for brine shrimp lethality in order to detect potential sources of novel cytotoxic, antitumor and pesticidal compounds. Amongst tested extracts, ethanolic extracts of Piper longum, Holarrhena antidysenterica and Terminalia chebula showed most potent cytotoxic activity with LC 50 of 10, 104 and 107 μg/mL respectively

Crocus sativus Extract Tightens the Blood-Brain Barrier, Reduces Amyloid β Load and Related Toxicity in 5XFAD Mice

Crocus sativus, commonly known as saffron or Kesar, is used in Ayurveda and other folk medicines for various purposes as an aphrodisiac, antispasmodic, and expectorant. Previous evidence suggested that Crocus sativus is linked to improving cognitive function in Alzheimer’s disease (AD) patients. The aim of this study was to in vitro and in vivo investigate the mechanism(s) by which Crocus sativus exerts its positive effect against AD. The effect of Crocus sativus extract on Aβ load and related toxicity was evaluated. In vitro results showed that Crocus sativus extract increases the tightness of a cell-based blood-brain barrier (BBB) model and enhances transport of Aβ. Further in vivo studies confirmed the effect of Crocus sativus extract (50 mg/kg/day, added to mice diet) on the BBB tightness and function that was associated with reduced Aβ load and related pathological changes in 5XFAD mice used as an AD model. Reduced Aβ load could be explained, at least in part, by Crocus sativus extract effect to enhance Aβ clearance pathways including BBB clearance, enzymatic degradation and ApoE clearance pathway. Furthermore, Crocus sativus extract upregulated synaptic proteins and reduced neuroinflammation associated with Aβ pathology in the brains of 5XFAD mice. Crocin, a major active constituent of Crocus sativus and known for its antioxidant and anti-inflammatory effect, was also tested separately in vivo in 5XFAD mice. Crocin (10 mg/kg/day) was able to reduce Aβ load but to a lesser extent when compared to Crocus sativus extract. Collectively, findings from this study support the positive effect of Crocus sativus against AD by reducing Aβ pathological manifestations

Biphenyl-4-carboxylic Acid [2-(1<i>H</i>‑Indol-3-yl)-ethyl]-methylamide (CA224), a Nonplanar Analogue of Fascaplysin, Inhibits Cdk4 and Tubulin Polymerization: Evaluation of in Vitro and in Vivo Anticancer Activity

Biphenyl-4-carboxylic acid-[2-(1<i>H</i>-indol-3-yl)-ethyl]-methylamide <b>1</b> (CA224) is a nonplanar analogue of fascaplysin (<b>2</b>) that specifically inhibits Cdk4–cyclin D1 in vitro. Compound <b>1</b> blocks the growth of cancer cells at G₀/G₁ phase of the cell cycle. It also blocks the cell cycle at G₂/M phase, which is explained by the fact that it inhibits tubulin polymerization. Additionally, it acts as an enhancer of depolymerization for taxol-stabilized tubulin. Western blot analyses of p53-positive cancer cells treated with compound <b>1</b> indicated upregulation of p53, p21, and p27 proteins together with downregulation of cyclin B1 and Cdk1. Compound <b>1</b> selectively induces apoptosis of SV40 large T-antigen transformed cells and significantly reduces colony formation efficiency, in a dose-dependent manner, of lung cancer cells. It is efficacious at 1/10th of the MTD against human tumors derived from HCT-116 and NCI-H460 cells in SCID mouse models. The promising efficacy of compound <b>1</b> in human xenograft models as well as its excellent therapeutic window indicates its potential for clinical development

Discovery and characterization of novel CYP1B1 inhibitors based on heterocyclic chalcones: Overcoming cisplatin resistance in CYP1B1-overexpressing lines

© 2017 Elsevier Masson SAS The structure of alpha-napthoflavone (ANF), a potent inhibitor of CYP1A1 and CYP1B1, mimics the structure of chalcones. Two potent CYP1B1 inhibitors 7k (DMU2105) and 6j (DMU2139) have been identified from two series of synthetic pyridylchalcones. They inhibit human CYP1B1 enzyme bound to yeast-derived microsomes (Sacchrosomes™) with IC 50 values of 10 and 9nM, respectively, and show a very high level of selectivity towards CYP1B1 with respect to the IC 50 values obtained with CYP1A1, CYP1A2, CYP3A4, CYP2D6, CYP2C9 and CYP2C19 Sacchrosomes™. Both compounds also potently inhibit CYP1B1 expressed within ‘live’ recombinant yeast and human HEK293 kidney cells with IC 50 values of 63, 65, and 4, 4nM, respectively. Furthermore, the synthesized pyridylchalcones possess better solubility and lipophilicity values than ANF. Both compounds overcome cisplatin–resistance in HEK293 and A2780cells which results from CYP1B1 overexpression. These potent cell-permeable and water-soluble CYP1B1 inhibitors are likely to have useful roles in the treatment of cancer, glaucoma, ischemia and obesity

Discovery of 7‑(Prolinol‑<i>N</i>‑yl)-2-phenylamino-thiazolo[5,4‑<i>d</i>]pyrimidines as Novel Non-Nucleoside Partial Agonists for the A_2A Adenosine Receptor: Prediction from Molecular Modeling

We describe the identification of 7-(prolinol-<i>N</i>-yl)-2-phenylamino-thiazolo­[5,4-<i>d</i>]­pyrimidines as a novel chemotype of non-nucleoside partial agonists for the A_2A adenosine receptor (A_2AAR). Molecular-modeling indicated that the (<i>S</i>)-2-hydroxymethylene-pyrrolidine could mimic the interactions of agonists’ ribose, suggesting that this class of compounds could have agonistic properties. This was confirmed by functional assays on the A_2AAR, where their efficacy could be associated with the presence of the 2-hydroxymethylene moiety. Additionally, the best compound displays promising affinity, selectivity profile, and physicochemical properties

Discovery of 7‑(Prolinol‑<i>N</i>‑yl)-2-phenylamino-thiazolo[5,4‑<i>d</i>]pyrimidines as Novel Non-Nucleoside Partial Agonists for the A_2A Adenosine Receptor: Prediction from Molecular Modeling

We describe the identification of 7-(prolinol-<i>N</i>-yl)-2-phenylamino-thiazolo­[5,4-<i>d</i>]­pyrimidines as a novel chemotype of non-nucleoside partial agonists for the A_2A adenosine receptor (A_2AAR). Molecular-modeling indicated that the (<i>S</i>)-2-hydroxymethylene-pyrrolidine could mimic the interactions of agonists’ ribose, suggesting that this class of compounds could have agonistic properties. This was confirmed by functional assays on the A_2AAR, where their efficacy could be associated with the presence of the 2-hydroxymethylene moiety. Additionally, the best compound displays promising affinity, selectivity profile, and physicochemical properties

Pyrano-isochromanones as IL‑6 Inhibitors: Synthesis, in Vitro and in Vivo Antiarthritic Activity

Bergenin (<b>1</b>), a unique fused <i>C</i>-glycoside isolated from Bergenia species, possesses interesting anti-inflammatory and antipain activities. To study SAR of this scaffold, first-generation derivatives were synthesized and evaluated for inhibition of lymphocyte proliferation and production of pro-inflammatory cytokines. The C-7 substituted derivatives showed inhibition of IL-6 as well as TNF-α production. Bergenin and its most potent IL-6 inhibitor derivatives <b>4e</b> and <b>4f</b> were then investigated in a panel of in vitro and in vivo inflammation/arthritis models. These compounds significantly decreased the expression of NF-kB and IKK-β in THP-1 cells. In in vivo study in BALB/c mice, a dose-dependent inhibition of SRBC-induced cytokines, reduction in humoral/cell-mediated immunity, and antibody titer was observed. The CIA study in DBA/1J mice indicated that compounds led to reduction in swelling of paws, cytokine levels, and anticollagen IgG1/IgG2a levels. The significant in vivo immunosuppressive efficacy of pyrano-isochromanones demonstrates the promise of this scaffold for development of next-generation antiarthritic drugs