Controlling the lag-time and release kinetics of press-coated tablets using process parameters and tablet geometry.

Press-coated tablets are an advantageous technology to achieve delayed releases of active ingredients. They are characterized by a core-shell structure, that makes it possible to tune the lag-time and release kinetics in order to meet the chronotherapeutical goals. Thus, these features are the most important quality attributes to be controlled when designing a press-coated tablet. Many studies have focused on the influence of the formulation on the release attributes. This work aims to study the influence of geometrical and process parameters on the release attributes of press-coated tablets, while keeping a constant formulation. In particular, the variation of compression pressure, layer thickness and band thickness made it possible to vary the lag-time from 1 h to 10 h. These parameters also have an influence on the release kinetics after the lag-time. Indeed, two main opening modes were observed during the dissolution test that correspond to fast or slow release rates. The opening mode obtained depends on the density distribution in the shell, which is directly influenced by the process parameters.

Influence of the punch shape on the core and shell structure of press-coated tablets.

Press-coated tablets are a key technology to achieve delayed releases in chronotherapeutics. The drug release properties of this kind of tablets are linked to its unique core-shell structure. It is thus important to understand the influence of the process parameters on this structure. As different shapes can be used in the industry, we focused, in this study, on understanding the influence of punch shape on the final structure of a press-coated tablet. Experiments were performed using flat, bevel-edged and concave punches for the coating-compression to study the effect of the punch shape on the final properties of the core but also on the density distribution in the shell. The experiments were supported by numerical simulation to understand the mechanical effects in the powder compression process. It was found that the radial and axial stress state in the shell and in the core during compression is very dependent on the punch shape. The use of concave punches results in a more hydrostatic stress state compared to flat punches. The consequences on the structure are a more homogenous shell and less deformation of the core, which confirms that the tooling shape is a critical parameter to consider for the production of press-coated tablets.

Breaking patterns of press-coated tablets during the diametral compression test: Influence of the product, geometry and process parameters.

Press-coated tablets are a high-interest technology in chronopharmaceutics, for modified release applications. As for any kind of tablet, the test of the mechanical resistance is of primary importance at the industrial level during both the development and production steps. For this purpose, the diametral compression test is commonly used in the industry for press-coated tablets. Nevertheless, the result of this test can be much more complex compared to the case of single layer tablets. This work aims to study the applicability of this test to press-coated tablets. Diametral compression tests were performed on press-coated tablets obtained with different products (shell/core), shell sizes and compaction pressures. Four types of breaking profiles were found: total diametral, shell diametral, around the core and laminated depending on the process parameters/products used to obtain the tablet. Digital image correlation was used in order to understand the breaking patterns especially in terms of failure initiation and propagation. The kind of breaking pattern obtained is dependent on the final structure of the tablet in terms of density distribution and thus of elastic properties. To confirm the findings, numerical simulations by the finite element method was used to visualize the stress distribution inside the tablet and confirm the influence of the process parameters. The multiple failure profiles obtained imply that the output value of the diametral compression test applied to press-coated tablets should be taken with caution.

Effect of the compaction parameters on the final structure and properties of a press-coated tablet (Tab-in-Tab): Experimental and numerical study of the influence of core and shell dimensions.

With increasing interest in chronopharmaceutics, press-coated tablets have become a key technology in the field of modified release drug delivery systems. Although their benefits in terms of drug release have been largely studied, the comprehension of the compaction process of press-coated tablets is yet to complete. Particularly, the effects of geometrical parameters like the ratios between the thickness/diameter of the core and the thickness/diameter of the whole tablet were so far not much considered. Moreover, there is only few studies in the literature about the effect of the press-coating compression on the final structure and properties of the core. The present work consists in a joint experimental and numerical study that aims to assess these points. The study revealed high stress concentrations on the core during compression, causing high permanent deformations of the core, especially when the ratio between the core thickness and the total tablet thickness was high. The mechanical properties of the core tablet were also shown to be impacted: its density and strength were found to decrease before increasing again along the coating-compression. This effect was highlighted to be dependent on the triaxiality of the stress state (i.e. the ratio between the stresses in the different directions), itself depending on the two studied geometrical parameters. As the properties of the core affect the release attributes, ratios between the dimensions of the core and the dimensions of the whole tablet (thickness, diameter) should be taken into account as critical parameters for the manufacture of press-coated tablets.

The 1,2,4-triazole as a scaffold for the design of ghrelin receptor ligands: development of JMV 2959, a potent antagonist.

Ghrelin is a 28-residue peptide acylated with an n-octanoyl group on the Ser 3 residue, predominantly produced by the stomach. Ghrelin displays strong growth hormone (GH) releasing activity, which is mediated by the activation of the so-called GH secretagogue receptor type 1a (GHS-R1a). Given the wide spectrum of biological activities of Ghrelin in neuroendocrine and metabolic pathways, many research groups, including our group, developed synthetic peptide, and nonpeptide GHS-R1a ligands, acting as agonists, partial agonists, antagonists, or inverse agonists. In this highlight article, we will focus on the discovery of a GHS-R1a antagonist compound, JMV 2959, which has been extensively studied in different in vitro and in vivo models. We will first describe the peptidomimetic approach that led us to discover this compound. Then we will review the results obtained with this compound in different studies in the fields of food intake and obesity, addictive behaviors, hyperactivity and retinopathy.

Anorexigenic and electrophysiological actions of novel ghrelin receptor (GHS-R1A) antagonists in rats.

Here we provide the first pharmacological exploration of the impact of acute central nervous system exposure to three recently developed ghrelin receptor (GHS-R1A) ligands on food intake and on the electrical activity of the target cells for ghrelin in the hypothalamus. Central (i.c.v) injection of GHS-R1A antagonists to rats suppressed food intake induced by i.c.v ghrelin injection (1 microg) in a dose-dependent manner with a total blockade at concentrations of 0.4 microg and 8 microg for JMV 3002 and JMV 2959 respectively. JMV 2810, a partial agonist, also suppressed ghrelin-induced food intake (range: 0.02-2 microg). Moreover all three compounds reduced fasting-induced food intake in rats (i.e. the amount of food eaten during the first hour of food exposure after a 16 h fast). At the single cell level we also explored the effects of the compounds to suppress ghrelin (0.5 microM)-induced changes in electrical activity of arcuate nucleus cells recorded extracellularly in a slice preparation. Preincubation followed by perfusion with the GHS-R1A ligands suppressed the responsiveness of arcuate cells to ghrelin. Thus, the recently developed GHS-R1A ligands (JMV 3002, 2959 and 2810) suppress ghrelin-induced and fasting-induced food intake at the level of the central nervous system. This appears to be mediated, at least in part, by a modulation of the activity of ghrelin-responsive arcuate nucleus cells. As the central ghrelin signalling system has emerged as an important pro-obesity target, it will be important to establish the efficacy of these GHS-R1A ligands to reduce fat mass in clinical studies.

New trisubstituted 1,2,4-triazole derivatives as potent ghrelin receptor antagonists. 3. Synthesis and pharmacological in vitro and in vivo evaluations.

Ghrelin receptor ligands based on trisubstituted 1,2,4-triazole structure were synthesized and evaluated for their in vitro binding and biological activity. In this study, we explored the replacement of the alpha-aminoisobutyryl moiety by aromatic or heteroaromatic groups. Compounds 5 and 34 acted as potent in vivo antagonists of hexarelin-stimulated food intake. These two compounds did not stimulate growth hormone secretion in rodents and did not antagonize growth hormone secretion induced by hexarelin.

Trisubstituted 1,2,4-triazoles as ligands for the ghrelin receptor: on the significance of the orientation and substitution at position 3.

The synthesis and structure-activity relationships concerning 3,4,5-trisubstituted 1,2,4-triazoles as ghrelin receptor ligands are described. The importance of the starting aminoacid material as well as its configuration was explored and the (D) Trp residue was found to lead to the best agonist or antagonist compounds.

Toward potent ghrelin receptor ligands based on trisubstituted 1,2,4-triazole structure. 2. Synthesis and pharmacological in vitro and in vivo evaluations.

A series of ghrelin receptor ligands based on the trisubstituted 1,2,4-triazole structure were synthesized and evaluated for their in vitro binding and biological activity. In this study, we explored the significance of the aminoisobutyryl (Aib) moiety, a common feature in numerous growth hormone secretagogues described in the literature. Potent agonist and antagonist ligands of the growth hormone secretagogue receptor type 1a (GHS-R1a) were obtained, i.e., compounds 41 (JMV2894) and 17 (JMV3031). The best compounds were evaluated for their in vivo activity on food intake, after sc injection in rodents. Among the tested compounds, few of them were able to stimulate food intake and some others, i.e., compounds 4 (JMV2959), 17, and 52 (JMV3021), acted as potent in vivo antagonist of hexarelin-stimulated food intake. These compounds did not stimulate growth hormone secretion in rats and furthermore did not antagonize growth hormone secretion induced by hexarelin, revealing that it is possible to modulate food intake without altering growth hormone secretion.

Recent developments in ghrelin receptor ligands.

The 28-amino acid peptide ghrelin is a neuroendocrine hormone synthesized primarily in the stomach. It stimulates growth hormone secretion and appetite, thus promoting food intake and body-weight gain. The pharmacological properties of this peptide are mediated by the growth hormone secretagogue receptor type 1a (GHS-R1a). Given its wide spectrum of biological activities, it is evident that the discovery of ghrelin and its receptor has opened up many perspectives in the fields of neuroendocrine and metabolic research and has had an influence on such fields of internal medicine as gastroenterology, oncology, and cardiology. It is therefore increasingly likely that synthetic, peptidyl, and nonpeptidyl GHS-R1a ligands, acting as agonists, partial agonists, antagonists, or inverse agonists, could have both clinical and therapeutic potential. This review summarizes the various types of GHS-R1a ligands that have been described in the literature and discusses the recent progress made in this research area.

Synthesis and pharmacological in vitro and in vivo evaluations of novel triazole derivatives as ligands of the ghrelin receptor. 1.

A new series of growth hormone secretagogue (GHS) analogues based on the 1,2,4-triazole structure were synthesized and evaluated for their in vitro binding and their ability to stimulate intracellular calcium release to the cloned hGHS-1a ghrelin receptor expressed in LLC PK-1 cells. We have synthesized potent ligands of this receptor, some of them behaving as agonists, partial agonists, or antagonists. Some compounds among the most potent, i.e., agonist 29c (JMV2873), partial agonists including 21b (JMV2810), antagonists 19b (JMV2866) and 19c (JMV2844), were evaluated for their in vivo activity on food intake, after sc injection in rodents. Some compounds were found to stimulate food intake like hexarelin; some others were identified as potent hexarelin antagonists in this assay. Among the tested compounds, 21b was identified as an in vitro ghrelin receptor partial agonist, as well as a potent in vivo antagonist of hexarelin-stimulated food intake in rodents. Compound 21b was without effect on GH release from rat. However, in this series of compounds, it was not possible to find a clear correlation between in vitro and in vivo results.

Synthesis of peptide aldehydes.

The functionalization of peptides and proteins by aldehyde groups has become the subject of intensive research since the discovery of the inhibition properties of peptide aldehydes towards various enzymes. Furthermore, peptide aldehydes are of great interest for peptide backbone modification or ligation reactions. This review focuses upon their synthesis, which has been developed following two main strategies. The first strategy consists of prior synthesis of the peptide, followed by the introduction of the aldehyde function. The second possible strategy uses alpha-amino aldehydes as starting materials. After protection of the aldehyde, peptide elongation occurs. At the end of the synthesis, the aldehyde function can be unmasked.

The epimerization of peptide aldehydes--a systematic study.

Peptide aldehydes are interesting targets as enzyme inhibitors, and can be used for pseudopeptide chemistry or ligation. However, they are known to be subjected to epimerization during synthesis or purification. By (1)H NMR, a model dipeptide aldehyde can be used to check the possible epimerization occurring during synthesis. Various purification methods were investigated, but none was free from epimerization.