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At least 1,243 records · Page 69Linked to original sources

PubMed2000

Dissolution of omeprazole from delayed-release solid oral dosage forms.

The evaluation of the biopharmaceutical quality of omeprazole enteric-coated products (granules in capsules) with respect to its dissolution characteristics is not specifically regulated in any of the most common official pharmacopoeia. USP 23 includes a general monograph for enteric-coated products. This paper reports the evaluation of the medium pH effect on the dissolution rates of omeprazole from four omeprazole-containing products of different manufacturers. It is concluded that the USP 23 recommended dissolution procedure for enteric-coated products is not suitable due to the degradation of omeprazole under such conditions. Furthermore, the medium with pH 8.0 showed different dissolution rates not observed at pH 7.4, allowing discrimination between products of different manufacturers.

Administration, Oral↗

PubMed2001

Development of a mucoadhesive dosage form for vaginal administration.

The antimycotic imidazole derivative clotrimazole is employed locally for the treatment of genitourinary tract mycotic infections and is formulated as creams, foams, tablets, gels, irrigations, or pessaries. In this study, a new dosage form was developed by including bioadhesive polymers (polycarbophyl, hydroxypropylmethylcellulose, and hyaluronic sodium salt) into pessaries made of semisynthetic solid triglycerides. These polymers hold the delivery systems in the vaginal tract for a few days without any toxic effects or important physiological modifications, prolonging the permanence of the drug on the vaginal mucosa. Technological controls (compatibility with differential scanning calorimetry [DSC] studies, particle size analysis, and liquefaction time test) and biopharmaceutics studies for the evaluation of the release of the drug from the dosage form and of the bioadhesive properties were carried out. Moreover, a new test for the evaluation of the permanence of the drug in a simulated application site was developed from a modification of the Satnikar and Fantelli method for the evaluation of the liquefaction time of rectal suppositories. This test simulates the physiological vaginal condition and verifies the efficiency of the polymers in prolonging the permanence of the dosage form in the location where it is applied. The technological controls demonstrated that the presence of the polymers did not have an influence on the characteristics of the pessaries. On the other hand, there was an improvement in adhesivity of the pessaries in the in vitro adhesion test and prolonging of the liquefaction time in the liquefaction time test in the presence of mucoadhesive polymers, which increased with increasing polymer concentration. The presence of the mucoadhesive had a large influence on the permanence of the drug in the simulated application site because it modified the distribution of the drug along the simulated application site. In conclusion, the developed new formulations showed good technological and adhesion properties and the capacity of hold the dosage form in the target site. Among the employed bioadhesive polymers, the best behavior in the performed test was by polycarbophyl at its maximum concentration.

Administration, Intravaginal↗

PubMed2002

Bioavailability assessment of oral coenzyme Q10 formulations in dogs.

The purpose of this investigation was to compare the bioavailability of three coenzyme Q10 (CoQ10) formulations in dogs using an open, randomized, multiple-dose crossover design. The formulations included a powder-filled capsule (A, control) and two soft gelatin formulations (Q-Gel as the water-miscible form of CoQ10, B and Q-Nol as the water-miscible form of ubiquinol, the reduced form of CoQ10, C). Formulations were evaluated in pairs, allowing a washout period of 14 days prior to crossing over. Blood samples were collected from each animal prior to dosing to determine the endogenous plasma CoQ10 concentrations. Serial blood samples were collected for 72 hr and plasma CoQ10 concentrations were determined by high-performance liquid chromatography. Plasma concentration-time profiles were corrected for endogenous CoQ10 concentrations. Results showed that the relative bioavailabilities of formulations B and C were approximately 3.6 and 6.2-fold higher than that of control formulation A. The AUC(microgram.hr/mL) +/- SD, Cmax(microgram/mL) +/- SD, and Tmax(hr) +/- SD for formulations A, B, and C were 1.695 +/- 0.06, 6.097 +/- 0.08, and 10.510 +/- 0.10; 0.096 +/- 0.035, 0.169 +/- 0.038, and 0.402 +/- 0.102; and 4.2 +/- 1.48, 4.1 +/- 1.57, and 4.5 +/- 0.58, respectively. While no significant differences were observed between Tmax values of the three formulations, the AUC and Cmax values for formulations B and C were significantly higher than those of the control (p < 0.05). The present investigation demonstrates that soft gelatin capsules containing water-miscible CoQ10 formulations B (Q-Gel) and C (Q-Nol) are superior to powder-filled formulations with regard to their biopharmaceutical characteristics.

Administration, Oral↗

PubMed2004

Physicochemical characterization of solid dispersions of indomethacin with PEG 6000, Myrj 52, lactose, sorbitol, dextrin, and Eudragit E100.

The purpose of this study was to prepare and characterize solid dispersions of indomethacin with polyethylene glycol (PEG) 6000, Myrj 52, Eudragit E100, and different carbohydrates such as lactose, mannitol, sorbitol, and dextrin. Indomethacin is a class II substance according to the Biopharmaceutics Classification System. It is a poorly water soluble antirheumatic agent. The goal was to investigate whether the solid dispersion can improve the dissolution properties of indomethacin. The solid dispersions were prepared by three different methods depending on the type of carrier. The evaluation of the properties of the dispersions was performed using solubility measurements, dissolution studies, Fourier-transform infrared spectroscopy, and x-ray powder diffractometery. The results indicate that lactose, mannitol, sorbitol, and especially Myrj 52 are suitable carriers to enhance the in vitro dissolution rate of indomethacin at pH 7.2. Eudragit E100, Myrj 52, and mannitol increase the dissolution properties at pH 1.2. The data from the x-ray diffraction showed that the drug was still detectable in its solid state in all solid dispersions except solid dispersions with dextrin and high amounts of mannitol. However, the results from infrared spectroscopy together with those from x-ray diffraction showed well-defined drug-carrier interactions for dextrin coevaporates.

Acrylates↗

PubMed2004

Drug-beta-cyclodextrin containing pellets prepared with a high-shear mixer.

This work was aimed at investigating the preparation of beta-cyclodextrin-microcrystalline cellulose pellets by means of a high-shear mixer, both in the absence or in the presence of ibuprofen as model drug. Drug loading of pellets was accomplished by means of two alternative techniques: 1) solution layering or 2) powder layering. The prepared pellets were characterised in terms of size distribution, shape factor, friability and dissolution rate. The interaction between ibuprofen and beta-cyclodextrin was monitored by Differential Scanning Calorimetry (DSC). Micro Fourier Transform Infrared spectroscopy (MicroFTIR) was applied to determine the distribution of components within each pellet on a micro scale. Pellets with narrow size distribution and containing up to about 90% of BCD were prepared using water as binder. The process yield resulted around 84 and 63% for drug-free and medicate pellets respectively. Drug loaded pellets with favourable technological and biopharmaceutical characteristics can be obtained both by powder or solution layering techniques. The latter proved to be more suitable for producing pellets with high drug contents, reduced friability and high drug dissolution rates.

Cellulose↗

PubMed2001

Effective graphical displays.

A graph is a visual display of data to achieve an understanding of the underlying patterns and interrelationships of the data. Such visual representations of data often form the basis for inferences and decisions. However, a poorly chosen graphical form can lead to erroneous inferences. In this paper previously published graphs depicting biopharmaceutical, drug metabolism, formulation, and pharmacokinetic data are recast using alternate display methods in an attempt to better clarify the data structure. The display methods used include dot plots and trellis plots.

Animals↗

PubMed2002

Drug absorption by the respiratory mucosa: cell culture models and particulate drug carriers.

The inhalation route is of increasing interest for both local and systemic drug delivery, including macromolecular biopharmaceuticals, such as peptides, proteins, and gene therapeutics. In addition to appropriate aerosolization for deposition in relevant areas of the respiratory tract, therapeutic molecules may require an advanced carrier system for safe and efficient delivery to their target. Two approaches to obtain novel carrier systems for pulmonary drug delivery are large porous microparticles with a low aerodynamic diameter and lectin-functionalized liposomes. Epithelial cells of alveolar or bronchial origin, obtained either from patient material or from established cell lines, can be grown on permeable filter supports, resulting in polarized monolayers with functional intercellular junctions. With such in vitro models, transport of drugs into pulmonary epithelial cells and/or across the air-blood barrier, as well as the effect and efficacy of novel drug carrier systems can be systematically studied.

Absorption↗

PubMed1998

Quantitation of host cell DNA contaminate in pharmaceutical-grade plasmid DNA using competitive polymerase chain reaction and enzyme-linked immunosorbent assay.

The rising interest in gene therapy for the treatment of numerous disorders necessitates the need for the large-scale production of therapeutic biopharmaceuticals that meet stringent purity standards. Residual host cell DNA in recombinant pharmaceuticals has been identified as a potential risk factor that must be quantitated carefully both during the manufacturing process and in the final product. We describe a PCR method to quantitate contaminating levels of host cell DNA in clinical plasmid DNA preparations intended for human gene therapy. The quantitation is based on the coamplification of two similar templates, the target DNA and a synthetic competitor, and the quantitation of the resulting PCR products. The competitor is identical to the target DNA PCR product except for a 29-bp internal replacement. As a result, the two PCR products can easily be distinguished from each other. The competitive nature of the assay allows the use of the ratio of the target DNA PCR product to the competitor DNA PCR product to determine the original amount of target DNA in a sample. The primers used in this assay anneal to a conserved region of the E. coli 23S rRNA gene. One of the primers is biotinylated, allowing the PCR products to be detected colorimetrically after their capture on microtiter plates. The capture is accomplished by differential hybridization to target and competitor-specific probes covalently attached to wells of microtiter plates. The entire assay is performed in less than 2 hr postamplification. This method represents an attractive alternative to Southern blot analysis, which is the currently established method for DNA quantitation.

Binding, Competitive↗

PubMed2003

Characterizing proteolytic cleavage site activity using bio-basis function neural networks.

MOTIVATION: In protein chemistry, proteomics and biopharmaceutical development, there is a desire to know not only where a protein is cleaved by a protease, but also the susceptibility of its cleavage sites. The current tools for proteolytic cleavage prediction have often relied purely on regular expressions, or involve models that do not represent biological data well. RESULTS: A novel methodology for characterizing proteolytic cleavage site activities has been developed, which incorporates two fundamental features: activity class prediction and the use of an amino acid similarity matrix for (non-parametric) neural learning. The first solved the problem of predicting proteolytic efficiency. The second significantly improved the robustness in prediction and reduced the time complexity for learning. This study shows that activity class prediction is successful when applying this methodology to the prediction and characterization of Trypsin cleavage sites and the prediction of HIV protease cleavage sites. AVAILABILITY: Requests for software and data should be made respectively to Dr Zheng Rong Yang and Miss Rebecca Thomson.

Amino Acid Sequence↗

PubMed1999

Bovine mammary gland UDP-GalNAc:GlcNAcbeta-R beta1-->4-N-acetylgalactosaminyltransferase is glycoprotein hormone nonspecific and shows interaction with alpha-lactalbumin.

We have identified a novel N -acetylgalactosaminyltransferase activity in lactating bovine mammary gland membranes. Acceptor specificity studies and analysis of products obtained in vitro by 400 MHz1H-NMR spectroscopy revealed that the enzyme catalyses the transfer of N -acetylgalactosamine (GalNAc) from UDP-GalNAc to acceptor substrates carrying a terminal, beta-linked N -acetylglucosamine (GlcNAc) residue and establishes a beta1-->4-linkage forming a GalNAcbeta1-->4GlcNAc ( N, N '-diacetyllactosediamine, lacdiNAc) unit. Therefore, the enzyme can be identified as a UDP-GalNAc:GlcNAcbeta-R beta1-->4-N-acetylgalactosaminyltransferase (beta4-GalNAcT). This enzyme resembles invertebrate beta4-GalNAcT as well as mammalian beta4-galactosyltransferase (beta4-GalT) in acceptor specificity. It can, however, be clearly distinguished from the pituitary hormone-specific beta4-GalNAcT by its incapability of acting with an elevated activity on a glycoprotein substrate carrying a hormone-specific peptide motif. Furthermore, the GalNAcT activity appeared not to be due to a promiscuous action of a beta4-GalT as could be demonstrated by comparing the beta4-GalNAcT and beta4-GalT activities of the mammary gland, bovine colostrum, and purified beta4-GalT, by competition studies with UDP-GalNAc and UDP-Gal, and by use of an anti-beta4-GalT polyclonal inhibiting antibody. Interestingly, under conditions where mammalian beta4-GalT forms with alpha-lactalbumin (alpha-LA) the lactose synthase complex, the mammary gland beta4-GalNAcT was similarly induced by alpha-LA to act on Glc with an increased efficiency yielding the lactose analog GalNAcbeta1-->4Glc. This enzyme thus forms the second example of a mammalian glycosyltransferase the specificity of which can be modified by this milk protein. It is proposed that the mammary gland beta4-GalNAcT functions in the synthesis of lacdiNAc-based, complex-type glycans frequently occurring on bovine milk glycoproteins. The action of this enzyme is to be considered when aiming at the production of properly glycosylated protein biopharmaceuticals in the milk of transgenic dairy animals.

Animals↗

PubMed2002

Immunoreactivity in mammals of two typical plant glyco-epitopes, core alpha(1,3)-fucose and core xylose.

The presence of nonmammalian core alpha(1,3)-fucose and core xylose glyco-epitopes on glycans N-linked to therapeutic glycoproteins produced in plants has raised the question of their immunogenicity in human therapy. We address this question by studying the distribution of these N-glycans in pea, rice, and maize (which are the crops intended for the production of therapeutic proteins) and by reinvestigating their immunogenicity in rodents. We found that immunization with a model glycoprotein, horseradish peroxidase, elicits in C57BL/6 mice and rats the production of antibodies (Abs) specific for core alpha(1,3)-fucose and core xylose epitopes. Furthermore, we demonstrated that about 50% of nonallergic blood donors contains in their sera Abs specific for core xylose, whereas 25% have Abs against core alpha(1,3)-fucose. These Abs probably result from sensitization to environmental antigens. Although the immunological significance of these data is too speculative at the moment, the presence of such Abs might introduce some limitations to the use of plant-derived biopharmaceutical glycoproteins, such as an accelerated clearance during human therapy.

Animals↗

PubMed2004

Influence of lactation parameters on the N-glycosylation of recombinant human C1 inhibitor isolated from the milk of transgenic rabbits.

The large-scale production of recombinant biopharmaceutical glycoproteins in the milk of transgenic animals is becoming more widespread. However, in comparison with bacterial, plant cell, or cell culture production systems, little is known about the glycosylation machinery of the mammary gland, and hence on the glycosylation of recombinant glycoproteins produced in transgenic animals. Here the influence is presented of several lactation parameters on the N-glycosylation of recombinant C1 inhibitor (rhC1INH), a human serum glycoprotein, expressed in the milk of transgenic rabbits. Enzymatically released N-glycans of series of rhC1INH samples were fluorescently labeled and fractionated by HPLC. The major N-glycan structures on rhC1INH of pooled rabbit milk were similar to those on native human C1 inhibitor and recombinant human C1 inhibitor produced in transgenic mouse milk, with only the degree of sialylation and core fucosylation being lower. Analyses of individual animals furthermore showed slight interindividual differences; a decrease in the extent of sialylation, core fucosylation, and oligomannose-type glycosylation with the progress of lactation; and a positive correlation between expression level and oligomannose-type N-glycan content. However, when large quantities of rhC1INH were isolated for preclinical and clinical studies, highly consistent N-linked glycan profiles and monosaccharide compositions were found.

Animals↗

PubMed2005

O-linked glycosylation in maize-expressed human IgA1.

O-Linked glycans vary between eukaryotic cell types and play an important role in determining a glycoprotein's properties, including stability, target recognition, and potentially immunogenicity. We describe O-linked glycan structures of a recombinant human IgA1 (hIgA1) expressed in transgenic maize. Up to six proline/hydroxyproline conversions and variable amounts of arabinosylation (Pro/Hyp + Ara) were found in the hinge region of maize-expressed hIgA1 heavy chain (HC) by using a combination of matrix-assisted laser-desorption ionization mass spectrometry (MALDI MS), chromatography, and amino acid analysis. Approximately 90% of hIgA1 was modified in this way. An average molar ratio of six Ara units per molecule of hIgA1 was revealed. Substantial sequence similarity was identified between the HC hinge region of hIgA1 and regions of maize extensin-family of hydroxyproline-rich glycoproteins (HRGP). We propose that because of this sequence similarity, the HC hinge region of maize-expressed hIgA1 can become a substrate for posttranslational conversion of Pro to Hyp by maize prolyl-hydroxylase(s) with the subsequent arabinosylation of the Hyp residues by Hyp-glycosyltransferase(s) in the Golgi apparatus in maize endosperm tissue. The observation of up to six Pro/Hyp hydroxylations combined with extensive arabinosylation in the hIgA1 HC hinge region is well in agreement with the Pro/Hyp hydroxylation model and the Hyp contiguity hypothesis suggested earlier in literature for plant HRGP. For the first time, the extensin-like Hyp/Pro conversion and O-linked arabinosylation are described for a recombinant therapeutic protein expressed in transgenic plants. Our findings are of significance to the field of plant biotechnology and biopharmaceutical industry-developing transgenic plants as a platform for the production of recombinant therapeutic proteins.

Amino Acid Sequence↗

PubMed2003

Streptomyces-derived quorum-sensing systems engineered for adjustable transgene expression in mammalian cells and mice.

Prokaryotic transcriptional regulatory elements have been adopted for controlled expression of cloned genes in mammalian cells and animals, the cornerstone for gene-function correlations, drug discovery, biopharmaceutical manufacturing as well as advanced gene therapy and tissue engineering. Many prokaryotes have evolved specific molecular communication systems known as quorum-sensing to coordinate population-wide responses to physiological and/or physicochemical signals. A generic bacterial quorum-sensing system is based on a diffusible signal molecule that prevents binding of a repressor to corresponding operator sites thus resulting in derepression of a target regulon. In Streptomyces, a family of butyrolactones and their corresponding receptor proteins, serve as quorum-sensing systems that control morphological development and antibiotic biosynthesis. Fusion of the Streptomyces coelicolor quorum-sensing receptor (ScbR) to a eukaryotic transactivation domain (VP16) created a mammalian transactivator (SCA) which binds and adjusts transcription from chimeric promoters containing an SCA-specific operator module (P(SPA)). Expression of erythropoietin or the human secreted alkaline phosphatase (SEAP) by this quorum-sensor-regulated gene expression system (QuoRex) could be fine-tuned by non-toxic butyrolactones in a variety of mammalian cells including human primary and mouse embryonic stem cells. Following intraperitoneal implantation of microencapsulated Chinese hamster ovary cells transgenic for QuoRex-controlled SEAP expression into mice, the serum levels of this model glycoprotein could be adjusted to desired concentrations using different butyrolactone dosing regimes.

4-Butyrolactone↗

PubMed2004

Effective and robust plasmid topology analysis and the subsequent characterization of the plasmid isoforms thereby observed.

Within the biopharmaceutical industry, recombinant plasmid DNA is used both as a raw material (e.g. in lentiviral and AAV vector production) as well as an active ingredient (e.g. in DNA vaccines). Consequently, many analytical laboratories are routinely involved with plasmid DNA topoisoform qualitative analysis and quantification. In order to reliably determine plasmid topology, one must ensure that the methodology employed can reliably, precisely and accurately measure qualitatively and quantitatively all topological isoforms. Presented here are an anion-exchange high-performance liquid chromatography (AEC) and an agarose gel electrophoresis (AGE)-based method developed for this purpose. The strategies undertaken to overcome the respective typical problems of limited linear range of quantitation (for AGE) and isoform resolution (for AEC) are described. Also presented is a subsequent direct comparison (for assay precision/accuracy) of these two methods, as well as a package of species characterization [by chloroquine-AGE, enzymatic digestion, multi-angle laser light-scattering (MALLS) and electron microscopy] undertaken to confirm the identity of a minor supercoiled dimeric concatamer observed by both approaches.

Chromatography, High Pressure Liquid↗

PubMed2005

A novel mammalian expression system derived from components coordinating nicotine degradation in arthrobacter nicotinovorans pAO1.

We describe the design and detailed characterization of 6-hydroxy-nicotine (6HNic)-adjustable transgene expression (NICE) systems engineered for lentiviral transduction and in vivo modulation of angiogenic responses. Arthrobacter nicotinovorans pAO1 encodes a unique catabolic machinery on its plasmid pAO1, which enables this Gram-positive soil bacterium to use the tobacco alkaloid nicotine as the exclusive carbon source. The 6HNic-responsive repressor-operator (HdnoR-O(NIC)) interaction, controlling 6HNic oxidase production in A.nicotinovorans pAO1, was engineered for generic 6HNic-adjustable transgene expression in mammalian cells. HdnoR fused to different transactivation domains retained its O(NIC)-binding capacity in mammalian cells and reversibly adjusted transgene transcription from chimeric O(NIC)-containing promoters (P(NIC); O(NIC) fused to a minimal eukaryotic promoter [P(min)]) in a 6HNic-responsive manner. The combination of transactivators containing various transactivation domains with promoters differing in the number of operator modules as well as in their relative inter-O(NIC) and/or O(NIC)-P(min) spacing revealed steric constraints influencing overall NICE regulation performance in mammalian cells. Mice implanted with microencapsulated cells engineered for NICE-controlled expression of the human glycoprotein secreted placental alkaline phosphatase (SEAP) showed high SEAP serum levels in the absence of regulating 6HNic. 6HNic was unable to modulate SEAP expression, suggesting that this nicotine derivative exhibits control-incompatible pharmacokinetics in mice. However, chicken embryos transduced with HIV-1-derived self-inactivating lentiviral particles transgenic for NICE-adjustable expression of the human vascular endothelial growth factor 121 (VEGF121) showed graded 6HNic response following administration of different 6HNic concentrations. Owing to the clinically inert and highly water-soluble compound 6HNic, NICE-adjustable transgene control systems may become a welcome alternative to available drug-responsive homologs in basic research, therapeutic cell engineering and biopharmaceutical manufacturing.

Animals↗

PubMed2006

Therapeutic protein transduction of mammalian cells and mice by nucleic acid-free lentiviral nanoparticles.

The straightforward production and dose-controlled administration of protein therapeutics remain major challenges for the biopharmaceutical manufacturing and gene therapy communities. Transgenes linked to HIV-1-derived vpr and pol-based protease cleavage (PC) sequences were co-produced as chimeric fusion proteins in a lentivirus production setting, encapsidated and processed to fusion peptide-free native protein in pseudotyped lentivirions for intracellular delivery and therapeutic action in target cells. Devoid of viral genome sequences, protein-transducing nanoparticles (PTNs) enabled transient and dose-dependent delivery of therapeutic proteins at functional quantities into a variety of mammalian cells in the absence of host chromosome modifications. PTNs delivering Manihot esculenta linamarase into rodent or human, tumor cell lines and spheroids mediated hydrolysis of the innocuous natural prodrug linamarin to cyanide and resulted in efficient cell killing. Following linamarin injection into nude mice, linamarase-transducing nanoparticles impacted solid tumor development through the bystander effect of cyanide.

Animals↗

PubMed2003

Evaluation of different linker regions for multimerization and coupling chemistry for immobilization of a proteinaceous affinity ligand.

Alkaline conditions are generally preferred for sanitization of chromatography media by cleaning-in-place (CIP) protocols in industrial biopharmaceutical processes. The use of such rigorous conditions places stringent demands on the stability of ligands intended for use in affinity chromatography. Here, we describe efforts to meet these requirements for a divalent proteinaceous human serum albumin (HSA) binding ligand, denoted ABD*dimer. The ABD*dimer ligand was constructed by genetic head-to-tail linkage of two copies of the ABD* moiety, which is a monovalent and alkali-stabilized variant of one of the serum albumin-binding motifs of streptococcal protein G. Dimerization was performed to investigate whether a higher HSA-binding capacity could be obtained by ligand multimerization. We also investigated the influence on alkaline stability and HSA-binding capacity of three variants (VDANS, VDADS and GGGSG) of the inter-domain linker. Biosensor binding studies showed that divalent ligands coupled using non-directed chemistry demonstrate an increased molar HSA-binding capacity compared with monovalent ligands. In contrast, equal molar binding capacities were observed for both types of ligands when using directed ligand coupling chemistry involving the introduction and recruitment of a unique C-terminal cysteine residue. Significantly higher molar binding capacities were also detected when using the directed coupling chemistry. These results were confirmed in affinity chromatography binding capacity experiments, using resins containing thiol-coupled ligands. Interestingly, column sanitization studies involving exposure to 0.1 M NaOH solution (pH 13) showed that of all the tested constructs, including the monovalent ligand, the divalent ligand construct containing the VDADS linker sequence was the most stable, retaining 95% of its binding capacity after 7 h of alkaline treatment.

Bacterial Proteins↗