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Peptide Drugs (peptide + drug)
Selected AbstractsQuality specifications for peptide drugs: a regulatory-pharmaceutical approachJOURNAL OF PEPTIDE SCIENCE, Issue 11 2009Valentijn Vergote Abstract Peptide drugs, as all types of pharmaceuticals, require adequate specifications (i.e. quality attributes, procedures and acceptance criteria) as part of their quality assurance to ensure the safety and efficacy of drug substances (i.e. active pharmaceutical ingredients) and drug products (i.e. finished pharmaceutical dosage forms). Compendial monographs are updated regularly to keep up with the most recent advances in peptide synthesis (e.g. reduced by-products) and analytical technology. Nevertheless, currently applied pharmacopoeial peptide specifications are barely harmonized yet (e.g. large differences between the European Pharmacopoeia and the United States Pharmacopeia), increasing the manufacturers' burden of performing analytical procedures in different ways, using different acceptance criteria. Additionally, the peptide monographs are not always consistent within a single pharmacopoeia. In this review, we highlight the main differences and similarities in compendial peptide specifications (including identification, purity and assay). Based on comparison, and together with additional information from peptide drug substance manufacturers and public evaluation reports on registration files of non-pharmacopoeial peptide drugs, a consistent monograph structure is proposed. Copyright © 2009 European Peptide Society and John Wiley & Sons, Ltd. [source] Bioavailability and Biological Efficacy of a New Oral Formulation of Salmon Calcitonin in Healthy Volunteers,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 8 2002Thierry Buclin Abstract Salmon calcitonin (SCT) is a well-tolerated peptide drug with a wide therapeutic margin and is administered parenterally for long-term treatments of bone diseases. Its clinical usefulness would be enhanced by the development of an orally active formulation. In this randomized crossover double-blinded phase I trial, controlled by both a placebo and a parenteral verum, we have tested a new oral formulation of SCT associated with a caprylic acid derivative as carrier. Eight healthy volunteers received single doses of 400, 800, and 1200 ,g of SCT orally, a placebo, and a 10-,g (50 IU) SCT intravenous infusion. SCT was reliably absorbed from the oral formulation, with an absolute bioavailability of 0.5,1.4%, depending on the dose. It induced a marked, dose-dependent drop in blood and urine C-terminal telopeptide of type I collagen (CTX), a sensitive and specific bone resorption marker, with the effects of 1200 ,g exceeding those of 10 ,g intravenously. It also decreased blood calcium and phosphate, and increased the circulating levels of parathyroid hormone (PTH) and, transiently, the urinary excretion of calcium. It was well-tolerated, with some subjects presenting mild and transient nausea, abdominal cramps, diarrheic stools, and headaches. This study shows that oral delivery of SCT is feasible with reproducible absorption and systemic biological efficacy. Such an oral formulation could facilitate the use of SCT in the treatment of osteoporosis and other bone diseases. [source] Site-directed PEGylations of Thymosin , 1 Analogs and Evaluation of Their ImmunoactivityCHINESE JOURNAL OF CHEMISTRY, Issue 4 2009Jiankun QIE Abstract PEGylation is an effective way to improve the pharmacokinetic profiles of pharmaceutical proteins or peptides. But the relatively large and long PEG chains would be likely to shelter the active site of a small peptide because of its small size, compared with a protein. Therefore, the positions and numbers of PEGylation are crucial for the bioactivity of a PEGylated peptide. To elucidate the relationship between the PEGylated positions and bioactivity of a peptide drug, site-specific PEGylations were performed on Zadaxin (Thymosin , 1, T,1), which is a pharmaceutical peptide with an , -helix region, a , -turn region, and random coils. Site-specific mono-PEGylations of T,1 in different conformational regions were realized through introducing one cysteine residue into the desired positions of the peptide, followed by a coupling reaction with a thiol-attached maleimide-PEG reagent. Primary data from IFN- , production of splenocytes induced by Con A showed that the influence of PEGylation on Zadaxin was position-dependent, and mostly, positive effects were observed after PEGylation, which indicated that the position of PEGylation is important for maintaining the bioactivity of a peptide. [source] Quality specifications for peptide drugs: a regulatory-pharmaceutical approachJOURNAL OF PEPTIDE SCIENCE, Issue 11 2009Valentijn Vergote Abstract Peptide drugs, as all types of pharmaceuticals, require adequate specifications (i.e. quality attributes, procedures and acceptance criteria) as part of their quality assurance to ensure the safety and efficacy of drug substances (i.e. active pharmaceutical ingredients) and drug products (i.e. finished pharmaceutical dosage forms). Compendial monographs are updated regularly to keep up with the most recent advances in peptide synthesis (e.g. reduced by-products) and analytical technology. Nevertheless, currently applied pharmacopoeial peptide specifications are barely harmonized yet (e.g. large differences between the European Pharmacopoeia and the United States Pharmacopeia), increasing the manufacturers' burden of performing analytical procedures in different ways, using different acceptance criteria. Additionally, the peptide monographs are not always consistent within a single pharmacopoeia. In this review, we highlight the main differences and similarities in compendial peptide specifications (including identification, purity and assay). Based on comparison, and together with additional information from peptide drug substance manufacturers and public evaluation reports on registration files of non-pharmacopoeial peptide drugs, a consistent monograph structure is proposed. Copyright © 2009 European Peptide Society and John Wiley & Sons, Ltd. [source] Nasal administration of low molecular weight heparinJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 7 2002John Arnold Abstract The main objective of this study was to determine if the systemic absorption of therapeutic amounts of heparin was possible following nasal administration. Sprague-Dawley rats received nosedrops containing a low molecular weight heparin (LMWH) or unfractionated heparin (UFH) formulated with or without tetradecylmaltoside (TDM). TDM is a nonionic surfactant that has been previously shown to be a potent absorption enhancer in studies with peptide drugs. LMWH/UFH absorption was determined by measuring plasma anti-Factor Xa activity. The inclusion of 0.25% TDM in nasal formulations containing LMWH resulted in a significant increase in the Cmax and area under the curve (AUC) of anti-Factor Xa activity when compared to LMWH formulated in saline alone. The addition of TDM to a nasal formulation containing UFH resulted in a much smaller increase in the Cmax and the AUC of anti-Factor Xa activity. The absolute bioavailability of LMWH was increased from 4.0,±,0.4% in the absence of TDM to 19,±,0.3% in the presence of TDM. The reversibility of the absorption enhancing effect of TDM was studied by applying LMWH nasally 60 or 120 min after the enhancer. The effect of TDM on the nasal epithelia appeared to be rapidly reversible. In conclusion, nasal delivery of LMWH, but not UFH, was successful when an absorption enhancer was included to increase nasal permeability. © 2002 Wiley-Liss Inc. and the American Pharmaceutical Association J Pharm Sci 91:1707,1714, 2002 [source] Potential prospects of chitosan derivative trimethyl chitosan chloride (TMC) as a polymeric absorption enhancer: synthesis, characterization and applicationsJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 9 2008Jasjeet K. Sahni ABSTRACT In recent years, researchers have been working extensively on various novel properties of polymers to develop increased efficiency of drug delivery and improve bioavailability of various drug molecules, especially macromolecules. Chitosan, a naturally occurring polysaccharide, because of its protonated/polymeric nature, provides effective and safe absorption of peptide and protein drugs. Its transmucosal absorption is, however, limited to acidic media because of its strong intermolecular hydrogen bonds. A new partially quaternized chitosan derivative, N-trimethyl chitosan chloride (TMC), has been synthesized with improved solubility, safety and effectiveness as an absorption enhancer at neutral pH and in aqueous environment. It enhances the absorption, especially of peptide drugs, by reversible opening of tight junctions in between epithelial cells, thereby facilitating the paracellular diffusion of peptide drugs. This derivative thus opens new perspectives as a biomaterial for various pharmaceutical applications/drug delivery systems. This review deals with the potential use of the quaternized chitosan derivative as a permeation enhancer for the mucosal delivery of macromolecular drugs along with its other biomedical applications. [source] Aminated gelatin as a nasal absorption enhancer for peptide drugs: evaluation of absorption enhancing effect and nasal mucosa perturbation in ratsJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 2 2002Jian Wang This study was carried out to evaluate the potential of aminated gelatin as a nasal absorption enhancer for peptide drugs. The absorption-enhancing effect was investigated in rats using insulin and fluorescein isothiocyanate-dextran with a molecular weight of 4.4 kDa (FD-4) as model drugs. The absorption of insulin was estimated by measuring the changes in plasma glucose levels following intranasal administration, and that of FD-4 was determined by measuring its plasma concentration after dosing. The hypoglycaemic effect after intranasal administration of insulin with aminated gelatin significantly increased compared with that after intranasal administration of insulin in phosphate buffered saline, indicating that aminated gelatin effectively enhanced the nasal absorption of insulin. In contrast, neither kind of native gelatin (isoelectric point = 5.0 and 9.0) showed any absorption-enhancing effect. The pH of the formulations and the concentration of aminated gelatin were found to affect the hypoglycaemic effect. In addition, aminated gelatin at a concentration of 0.2 % significantly enhanced the absorption and the efflux of FD-4 through the rat nasal mucosa. The possible perturbation of aminated gelatin to nasal mucosa was evaluated by measuring the leaching of lactate dehydrogenase (LDH) using an in-situ perfusion rat model. Aminated gelatin presented a concentration-dependent (0.1-0.4 %) but relatively small effect on the LDH leaching from the rat nasal epithelial membrane. These results suggest that positively charged aminated gelatin could be a new absorption enhancer for nasal delivery of peptide drugs. [source] Deamidation of a model hexapeptide in poly(vinyl alcohol) hydrogels and xerogelsCHEMICAL BIOLOGY & DRUG DESIGN, Issue 2 2000M.C. Lai Abstract: Polymeric controlled release systems have been proposed to prolong the half-lives of protein and peptide drugs in vivo and to deliver active drug at a controlled rate. These systems are ineffective, however, if the drug is not stable during storage and release. This study addresses the effect of poly(vinyl alcohol) on the stability and release of an incorporated hexapeptide, VYPNGA, which undergoes deamidation. Two types of peptide-loaded poly(vinyl alcohol) matrices were formed, a semisolid hydrogel and a lower water content ,xerogel', and stored at 50°C for up to 122 days. The hexapeptide was less stable in both poly(vinyl alcohol) matrices than in aqueous buffer or lyophilized polymer-free powders. The type of poly(vinyl alcohol) matrix appeared to influence the degradation mechanism, since the product distributions differ in the hydrogel and the xerogel. The results suggest that, rather than stabilizing this peptide, incorporation in poly(vinyl alcohol) matrices reduces stability relative to solution and lyophilized controls. [source] | |||||||||||||