Amorphous solid dispersions and nanocrystal technologies for poorly water-soluble drug delivery – An update

Poor water-solubility remains a typical property of drug candidates in pharmaceutical development pipelines today. Various processes have been developed to increase the solubility, dissolution rate, and bioavailability of these active ingredients belonging to biopharmaceutical classification system (BCS) II and IV classifications. Since the early 2000s, nanocrystal delivery and amorphous solid dispersions are more established techniques to overcome the limitations of poorly-water soluble drugs in FDA available products. This article provides an updated review of nanocrystal and amorphous solid dispersion techniques primarily for orally delivered medicaments. The thermodynamic and kinetic theories relative to these technologies are presented along with marketed product evaluations and a survey of commercially relevant scientific literature.     

Nanoemulsions as self-emulsified drug delivery carriers for enhanced permeability of the poorly water-soluble selective β₁-adrenoreceptor blocker Talinolol

To enhance the bioavailability of the poorly water-soluble drug talinolol, a self-nanoemulsifying drug delivery system (SNEDDS) comprising 5% (w/v) Brij-721 ethanolic solution (Smix), triacetin, and water, in the ratio of 40:20:40 (% w/w) was developed by constructing pseudo-ternary phase diagrams and evaluated for droplet size, polydispersity index, and surface morphology of nanoemulsions. The effect of nanodrug carriers on drug release and permeability was assessed using stripped porcine jejunum and everted rat gut sac method and compared with hydroalcoholic drug solution, oily solution, and conventional emulsion and suspension. The SNEDDS showed a significant (P < 0.001) increase in drug release, permeability, and in vivo bioavailability as compared to drug suspension. This may be attributed to increased solubility and enhanced permeability of the drug from nanosized emulsion. FROM THE CLINICAL EDITOR: In this study, a self-nanoemulsifying drug delivery system was utilized to enhance the bioavailability of the poorly water-soluble beta-blocker talinolol. Significant increase in drug release, permeability, and in vivo bioavailability were demonstrated as compared to standard drug suspension.     

Molecular requirements for inhibition of the chemokine receptor CCR8 – probe-dependent allosteric interactions

BACKGROUND AND PURPOSE

Here we present a novel series of CCR8 antagonists based on a naphthalene-sulfonamide structure. This structure differs from the predominant pharmacophore for most small-molecule CC-chemokine receptor antagonists, which in fact activate CCR8, suggesting that CCR8 inhibition requires alternative structural probes.

EXPERIMENTAL APPROACH

The compounds were tested as inverse agonists and as antagonists against CCL1-induced activity in Gα_i signalling and chemotaxis. Furthermore, they were assessed by heterologous competition binding against two radiolabelled receptor ligands: the endogenous agonist CCL1 and the virus-encoded antagonist MC148.

KEY RESULTS

All compounds were highly potent inverse agonists with EC₅₀ values from 1.7 to 23 nM. Their potencies as antagonists were more widely spread (EC₅₀ values from 5.9 to 1572 nM). Some compounds were balanced antagonists/inverse agonists whereas others were predominantly inverse agonists with >100-fold lower potency as antagonists. A correspondingly broad range of affinities, which followed the antagonist potencies, was disclosed by competition with [¹²⁵I]-CCL1 (K_i 3.4–842 nM), whereas the affinities measured against [¹²⁵I]-MC148 were less widely spread (K_i 0.37–27 nM), and matched the inverse agonist potencies.

CONCLUSION AND IMPLICATIONS

Despite highly potent and direct effects as inverse agonists, competition-binding experiments against radiolabelled agonist and tests for antagonism revealed a probe-dependent allosteric effect of these compounds. Thus, minor chemical changes affected the ability to modify chemokine binding and action, and divided the compounds into two groups: predominantly inverse agonists and balanced antagonists/inverse agonists. These studies have important implications for the design of new inverse agonists with or without antagonist properties.     

Block copolymer micelles as delivery vehicles of hydrophobic drugs: Micelle–cell interactions

One-third of drugs in development are water insoluble and one-half fail in trials because of poor pharmacokinetics. Block copolymer micelles are nanosized particles that can solubilize hydrophobic drugs and alter their kinetics in vitro and in vivo. However, block copolymer micelles are not solely passive drug containers that simply solubilize hydrophobic drugs; cells internalize micelles. To facilitate the development of advanced, controlled, micellar drug delivery vehicles, we have to understand the fate of micelles and micelle-incorporated drugs in cells and in vivo. With micelle-based drug formulations recently reaching clinical trials, the impetus for answers is ever so strong and detailed studies of interactions of micelles and cells are starting to emerge. Most notably, the question arises: Is the internalization of block copolymer micelles carrying small molecular weight drugs an undesired side effect or a useful means of improving the effectiveness of the incorporated drugs?     

Low Molecular Weight Proteins as Carriers for Renal Drug Targeting: Naproxen–Lysozyme

Low molecular weight proteins (LMWPs), such as lysozyme, may be suitable carriers to target drugs to the kidney. In this study the antiinflammatory drug naproxen was covalently bound to lysozyme (1:1). Pharmacokinetics of the conjugate, naproxen–lysozyme (nap-LYSO), were compared to that of an equimolar mixture of uncoupled naproxen with lysozyme in freely moving rats. Similar plasma kinetics and organ distribution for native lysozyme and the drug conjugate were observed (Cl_p = 1.2 and 1.1 ml/min; = 85 and 75 min, respectively). In case of the uncoupled naproxen–lysozyme mixture, a monoexponential plasma disappearance of naproxen with a of 2.8 hr was observed, coinciding with urinary excretion of naproxen metabolites (mainly 6-desmethylnaproxen sulfate; 6-DMN-S) between 2 and 8 hr after injection. Urinary recovery of total metabolites was 59% of the naproxen dose. In contrast, after injection of covalently bound naproxen, plasma levels of the parent drug were below the detection level, whereas naproxen was recovered as 6-DMN-S in urine over a period from 4 to 30 hr. However, only 8% of the administered dose was recovered as 6-DMN-S in urine, whereas 50% of the dose was recovered as naproxen metabolites in feces. Incubation experiments using purified renal tubular lysosomal lysates revealed that naproxen–lysozyme degradation ultimately results in a stable naproxen amino acid catabolite, naproxen–lysine (nap-lys). Hepatic uptake and biliary excretion of this catabolyte were demonstrated in isolated perfused rat livers. Further, an equipotent pharmacological activity relative to parent naproxen was observed. We conclude that LMWPs such as lysozyme are indeed suitable carriers for site-specific delivery of drugs to the kidney. Although naproxen covalently bound to lysozyme did not release the parent drug, it did result in renal release of a stable and active catabolite, naproxen–lysine.     

Neuropeptide receptor ligands as drugs for psychiatric diseases: the end of the beginning?

The search for novel drugs for treating psychiatric disorders is driven by the growing medical need to improve on the effectiveness and side-effect profile of currently available therapies. Given the wealth of preclinical data supporting the role of neuropeptides in modulating behaviour, pharmaceutical companies have been attempting to target neuropeptide receptors for over two decades. However, clinical studies with synthetic neuropeptide ligands have been unable to confirm the promise predicted by studies in animal models. Here, we analyse preclinical and clinical results for neuropeptide receptor ligands that have been studied in clinical trials for psychiatric diseases, including agents that target the receptors for tachykinins, corticotropin-releasing factor, vasopressin and neurotensin, and suggest new ways to exploit the full potential of these candidate drugs.     

Anti-TNF-α therapy for chronic inflammation: reconsidering pentoxifylline as an alternative to therapeutic protein drugs

Pentoxifylline is a useful inhibitor of TNF- production, thus resembling anti-inflammatory corticosteroids. The combination of pentoxifylline with Lyprinol^® is an effective treatment for chronic inflammation in rats, in this respect mimicking low dose prednisone with Lyprinol^®.     

Plant lectins as carriers for oral drugs: is wheat germ agglutinin a suitable candidate?

Wheat germ agglutinin (WGA) is a plant protein that binds specifically to sugars expressed also by gastrointestinal epithelial cells. WGA is currently investigated as an anti-tumor drug and as a carrier for oral drugs. Information on whether it can cross the gastrointestinal epithelium and on its possible effects on the integrity of the epithelial layer is however scanty or lacking, and herein we address these issues. Differentiated Caco2 cells have been used as a model of polarized intestinal epithelium. WGA concentration at both the apical and the basolateral side of the epithelium has been quantified using a sensitive ELISA assay (sensitivity threshold 0.84 nM). Trans epithelial electrical resistance (TEER) has been measured to evaluate the integrity of the epithelium upon treatments with WGA. (3)H-Mannitol (182.2 Da) and FITC-dextran (3000 Da) have been used to measure the permeability of the epithelium. Cell viability has been measured by the MTT, by 7-AAD uptake, and Annexin-V binding assays. Up to a concentration of 5.6 microM, approximately 0.1% of intact WGA molecules only could cross the epithelial layer. WGA perturbed the integrity of the epithelium and increased the permeability of the tissue in a dose- and time-dependent manner. WGA did not induce cell death but increased the permeability of individual cells to 7-AAD which is normally not uptaken by viable cells. These data allowed us to define a toxicity threshold for WGA on epithelial cells. WGA suitability as a carrier for oral drugs can therefore be evaluated on a rational basis.     

Tropomyosin receptor kinase inhibitors: an updated patent review for 2010-2016 – Part I

Introduction: Tropomyosin receptor kinases (TrkA/B/C) play crucial roles in the development and maintenance of the nervous system, and aberrant expression of Trk has been implicated in neurological disorders as well as neural and non-neural neoplasms. Patent activity encompassing Trk inhibitors has grown substantially over the last 6 years, recognized by a rise in the number of pharmaceutical entrants to the field and the escalation of novel inhibitor chemotypes.

Area covered: In Part I of this two part review, a biological and structural overview of Trk is provided in the context of Trk as a therapeutic target for cancer and pain, followed by the report of recent patent literature claiming small molecule inhibitors of Trk family kinases or which describe inhibitors developed for other kinase targets but include noteworthy Trk inhibition/application. The discussion of the patent literature continues in Part II of this review, which includes an in-depth view of the current clinical applications of Trk inhibitors.

Expert opinion: Substantial synthetic efforts in Trk inhibitor development has propagated numerous and diverse inhibitor chemotypes, including TrkA-specific inhibitors. While many novel Trk inhibitors remain the original progeny of Trk-specific development programs, kinase inhibitors initially developed for other kinases have also been successfully repositioned for Trk.     

Nrf2: a potential therapeutic target for naturally occurring anticancer drugs?

Introduction: Nuclear factor (erythroid-derived-2)-like 2 is one of the most efficient cytoprotective rheostats against exogenous or endogenous oxidative insults. At present, the modulation of the Nrf2 pathway represents an interesting and highly explored strategy in the oncological area.

Area covered: In this review, we present and discuss the different modulation of the Nrf2 pathway by some natural compounds with a well demonstrated anticancer activity, and critically analyze the challenges associated with the development of an Nrf2-based anticancer strategy.

Expert opinion: Many natural compounds with a well-defined anticancer activity are able to modulate this pathway. Both Nrf2 inducers and inhibitors can be useful as anticancer strategy. However, since Nrf2 modulates many networks potentially involved in the detoxification process of anticancer drugs, its activation in cancer cells could lead to chemoresistance. The switch between a beneficial or detrimental role of Nrf2 in cancer cells essentially depends on the tight control of its activity, the specific conditions of tumor microenvironment, and cell type. In line with the paucity of clear data related to the mechanisms underpinning the role of Nrf2 in cancer development and chemoresistance, discovery and development of Nrf2-based strategies is one of the most critical and challenging assignments for fighting cancers.     

Tropomyosin receptor kinase inhibitors: an updated patent review for 2010-2016 – Part II

Introduction: TrkA/B/C receptor activation supports growth, survival, and differentiation of discrete neuronal populations during development, adult life, and ageing but also plays numerous roles in human disease onset and progression. Trk-specific inhibitors have therapeutic applications in cancer and pain and thus constitute a growing area of interest in oncology and neurology. There has been substantial growth in the number of structural classes of Trk inhibitors and the number of industrial entrants to the Trk inhibitor field over the past six years.

Areas covered: In Part II of this two-part review, the discussion of recent patent literature covering Trk family inhibitors is continued from Part I and clinical research with Trk inhibitors is considered.

Expert opinion: Trk has been molecularly targeted for over a decade resulting in the progressive evolution of structurally diversified Trk inhibitors arising from scaffold hopping and HTS efforts. Correspondingly, there have been a growing number of clinical investigations utilizing Trk inhibitors in recent years, with a particular focus on the treatment of NTRK-fusion positive cancers and chronic pain. The observed potential of Trk inhibitors to cause adverse CNS side effects however suggests the need for a more rigorous consideration of BBB permeation capabilities during drug development.     

Proteins, polysaccharides, and their complexes used as stabilizers for emulsions: Alternatives to synthetic surfactants in the pharmaceutical field?

Emulsions are widely used in pharmaceutics for the encapsulation, solubilization, entrapment, and controlled delivery of active ingredients. In order to answer the increasing demand for clean label excipients, natural polymers can replace the potentially irritative synthetic surfactants used in emulsion formulation. Indeed, biopolymers are currently used in the food industry to stabilize emulsions, and they appear as promising candidates in the pharmaceutical field too. All proteins and some polysaccharides are able to adsorb at a globule surface, thus decreasing the interfacial tension and enhancing the interfacial elasticity. However, most polysaccharides stabilize emulsions simply by increasing the viscosity of the continuous phase. Proteins and polysaccharides may also be associated either through covalent bonding or electrostatic interactions. The combination of the properties of these biopolymers under appropriate conditions leads to increased emulsion stability. Alternative layers of oppositely charged biopolymers can also be formed around the globules to obtain multi-layered "membranes". These layers can provide electrostatic and steric stabilization thus improving thermal stability and resistance to external treatment. The novel biopolymer-stabilized emulsions have a great potential in the pharmaceutical field for encapsulation, controlled digestion, and targeted release although several challenging issues such as storage and bacteriological concerns still need to be addressed.     

Natural Products as Promising Drug Candidates for the Treatment of Alzheimer’s Disease: Molecular Mechanism Aspect

Alzheimer’s disease (AD) is the most common neurodegenerative disorder to date, with no curative or preventive therapy. Histopathological hallmarks of AD include deposition of β-amyloid plaques and formation of neurofibrillary tangles. Extent studies on pathology of the disease have made important discoveries regarding mechanism of disease and potential therapeutic targets. Many cellular changes including oxidative stress, disruption of Ca2+ homeostasis, inflammation, metabolic disturbances, and accumulation of unfolded/misfolded proteins can lead to programmed cell death in AD. Despite intensive research, only five approved drugs are available for the management of AD. Hence, there is a need to look at alternative therapies. Use of natural products and culinary herbs in medicine has gained popularity in recent years. Several natural substances with neuroprotective effects have been widely studied. Most of these compounds have remarkable antioxidant properties and act mainly by scavenging free radical species. Some of them increase cell survival and improve cognition by directly affecting amyloidogenesis and programmed cell death pathways. Further studies on these natural products and their mechanism of action, parallel with the use of novel pharmaceutical drug design and delivery techniques, enable us to offer an addition to conventional medicine. This review discussed some natural products with potential neuroprotective properties against Aβ with respect to their mechanism of action.Keyword: Alzheimer’s disease, Amyloid β, Apoptosis, Natural products, Neuroprotection, Tau protein.     

New drugs for type 2 diabetes mellitus: what is their place in therapy?

Oral therapy for type 2 diabetes mellitus, when used appropriately, can safely assist patients to achieve glycaemic targets in the short to medium term. However, the progressive nature of type 2 diabetes usually requires a combination of two or more oral agents in the longer term, often as a prelude to insulin therapy. Issues of safety and tolerability, notably weight gain, often limit the optimal application of anti-diabetic drugs such as sulfonylureas and thiazolidinediones. Moreover, the impact of different drugs, even within a single class, on the risk of long-term vascular complications has come under scrutiny. For example, recent publication of evidence suggesting potential detrimental effects of rosiglitazone on myocardial events generated a heated debate and led to a reduction in use of this drug. In contrast, current evidence supports the view that pioglitazone has vasculoprotective properties. Both drugs are contraindicated in patients who are at risk of heart failure. An additional recently identified safety concern is an increased risk of fractures, especially in postmenopausal women.Several new drugs with glucose-lowering efficacy that may offer certain advantages have recently become available. These include (i) injectable glucagon-like peptide-1 (GLP-1) receptor agonists and oral dipeptidyl peptidase-4 (DPP-4) inhibitors; (ii) the amylin analogue pramlintide; and (iii) selective cannabinoid receptor-1 (CB1) antagonists. GLP-1 receptor agonists, such as exenatide, stimulate nutrient-induced insulin secretion and reduce inappropriate glucagon secretion while delaying gastric emptying and reducing appetite. These agents offer a low risk of hypoglycaemia combined with sustained weight loss. The DPP-4 inhibitors sitagliptin and vildagliptin are generally weight neutral, with less marked gastrointestinal adverse effects than the GLP-1 receptor agonists. Potential benefits of GLP-1 receptor stimulation on beta cell neogenesis are under investigation. Pancreatitis has been reported in exenatide-treated patients. Pramlintide, an injected peptide used in combination with insulin, can reduce insulin dose and bodyweight. The CB1 receptor antagonist rimonabant promotes weight loss and has favourable effects on aspects of the metabolic syndrome, including the hyperglycaemia of type 2 diabetes. However, in 2007 the US FDA declined approval of rimonabant, requiring more data on adverse effects, notably depression. The future of dual peroxisome proliferator-activated receptor-alpha/gamma agonists, or glitazars, is presently uncertain following concerns about their safety.In conclusion, several new classes of drugs have recently become available in some countries that offer new options for treating type 2 diabetes. Beneficial or neutral effects on bodyweight are an attractive feature of the new drugs. However, the higher cost of these agents, coupled with an absence of long-term safety and clinical outcome data, need to be taken into consideration by clinicians and healthcare organizations.     

Detecting drug–drug interactions using a database for spontaneous adverse drug reactions: an example with diuretics and non-steroidal anti-inflammatory drugs

OBJECTIVE: Drug-drug interactions are relatively rarely reported to spontaneous reporting systems (SRSs) for adverse drug reactions. For this reason, the traditional approach for analysing SRS has major limitations for the detection of drug-drug interactions. We developed a method that may enable signalling of these possible interactions, which are often not explicitly reported, utilising reports of adverse drug reactions in data sets of SRS. As an example, the influence of concomitant use of diuretics and non-steroidal anti-inflammatory drugs (NSAIDs) on symptoms indicating a decreased efficacy of diuretics was examined using reports received by the Netherlands Pharmacovigilance Foundation Lareb. METHODS: Reports received between 1 January 1990 and 1 January 1999 of patients older than 50 years were included in the study. Cases were defined as reports with symptoms indicating a decreased efficacy of diuretics, non-cases as all other reports. Exposure categories were the use of NSAIDs or diuretics versus the use of neither of these drugs. The influence of the combined use of both drugs was examined using logistic regression analysis. RESULTS: The odds ratio of the statistical interaction term of the combined use of both drugs was increased [adjusted odds ratio 2.0, 95% confidence interval (CI) 1.1-3.7], which may indicate an enhanced effect of concomitant drug use. CONCLUSION: The findings illustrate that spontaneous reporting systems have a potential for signal detection and the analysis of possible drug-drug interactions. The method described may enable a more active approach in the detection of drug-drug interactions after marketing.     

HepaRG cell line as an in vitro model for screening drug–drug interactions mediated by metabolic induction: Amiodarone used as a model substance

The prediction of drug–drug interactions mediated by the induction or inhibition of cytochrome P450 enzymes is of great relevance in the development of new drugs. Due to the fact that HepaRG, a new human cell line derived from a hepatocellular carcinoma, is being considered a promising model to evaluate the in vitro metabolism of drugs, it was herein used for investigating metabolic-based drug–drug interactions mediated by metabolic induction. In this study, rifampicin and phenytoin were used as probe inducers and amiodarone (AM) as a model drug. HepaRG cells were firstly seeded in the supplemented Williams’ E, and then differentiated in the same culture medium, supplemented with 2% dimethyl sulfoxide for 2 weeks. For metabolic induction studies AM was incubated during 12 h in HepaRG cells which were pre-incubated with phenytoin or rifampicin for 72 h. The concentrations of AM and its main metabolite, mono-N-desethylamiodarone, were quantified by HPLC-DAD. This study evidenced that rifampicin and phenytoin are powerful inducers of the metabolism of AM, including at therapeutic drug concentrations. These experimental findings demonstrated, for the first time, the applicability of HepaRG cells as a useful in vitro model for the prediction of metabolic-based drug–drug interactions, namely those mediated by metabolic induction. Thus, this model could potentially be a worthy alternative to the primary human hepatocytes.     

HepaRG cell line as an in vitro model for screening drug–drug interactions mediated by metabolic induction: Amiodarone used as a model substance

The prediction of drug–drug interactions mediated by the induction or inhibition of cytochrome P450 enzymes is of great relevance in the development of new drugs. Due to the fact that HepaRG, a new human cell line derived from a hepatocellular carcinoma, is being considered a promising model to evaluate the in vitro metabolism of drugs, it was herein used for investigating metabolic-based drug–drug interactions mediated by metabolic induction. In this study, rifampicin and phenytoin were used as probe inducers and amiodarone (AM) as a model drug. HepaRG cells were firstly seeded in the supplemented Williams’ E, and then differentiated in the same culture medium, supplemented with 2% dimethyl sulfoxide for 2 weeks. For metabolic induction studies AM was incubated during 12 h in HepaRG cells which were pre-incubated with phenytoin or rifampicin for 72 h. The concentrations of AM and its main metabolite, mono-N-desethylamiodarone, were quantified by HPLC-DAD. This study evidenced that rifampicin and phenytoin are powerful inducers of the metabolism of AM, including at therapeutic drug concentrations. These experimental findings demonstrated, for the first time, the applicability of HepaRG cells as a useful in vitro model for the prediction of metabolic-based drug–drug interactions, namely those mediated by metabolic induction. Thus, this model could potentially be a worthy alternative to the primary human hepatocytes.