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PubMed2000

Microbial biotechnology.

For thousands of years, microorganisms have been used to supply products such as bread, beer and wine. A second phase of traditional microbial biotechnology began during World War I and resulted in the development of the acetone-butanol and glycerol fermentations, followed by processes yielding, for example, citric acid, vitamins and antibiotics. In the early 1970s, traditional industrial microbiology was merged with molecular biology to yield more than 40 biopharmaceutical products, such as erythropoietin, human growth hormone and interferons. Today, microbiology is a major participant in global industry, especially in the pharmaceutical, food and chemical industries.

Amino Acids↗
PubMed2002

The biotech equipment and supplies sector in Europe-is it European?

Socio-economic research on biotechnology is dealing mainly with the sectors of biopharmaceuticals, agro-food or environmental technologies. In contrast, the equipment and supplies sector seems to be largely ignored. This is surprising because this sector provides important input in terms of technology and material for the development of biotechnology in general. Our comparative analysis of the sector in eight countries indicates that there exists no specific science base for the sector and that it is largely neglected by public research funding. Commercial activities are concentrated in countries with a large general science base in biotechnology and strong multinational pharmaceutical or chemical companies. There is a rather broad diversity in the way the sector has developed in the eight countries. Our data support the notion that national peculiarities seem dominant for explaining this picture. We anticipate growing business opportunities for European firms to step into large markets of equipment and supplies for functional genomics and protein analyses where Europe maintains a strong science base.

Biotechnology↗
PubMed2002

Artificial mammalian gene regulation networks-novel approaches for gene therapy and bioengineering.

Recently developed strategies for targeted molecular interventions in mammalian cells have created novel opportunities in biotechnological and biomedical research with huge economic and therapeutic impact: the design of mammalian cells with desired phenotypes for biopharmaceutical manufacturing, tissue engineering and gene therapy. These advances have been enabled by constructing artificial gene regulation systems with control modalities similar to those evolved in key regulatory networks of mammalian cells. This review highlights recurring cellular regulation strategies and artificial gene regulation technology currently in use for rational reprogramming of cellular key events including metabolism, growth, differentiation and cell death to achieve sophisticated bioprocess and therapeutic goals.

Animals↗
PubMed2002

Integrated process optimization: lessons from retrovirus and virus-like particle production.

The optimization of production and purification processes is usually approached by engineers from a strictly biotechnological point of view. The present paper envisages the definition and application of an optimization model that takes into account the impact of both biological and technological issues upon the optimization protocols and strategies. For this purpose, the optimization of three analogous but different systems comprising animal cell growth and bioparticle production is presented. These systems were: human immunodeficiency 1 (HIV-1) and porcine parvovirus (PPV) virus-like particles (VLPs) produced in insect cells and retrovirus produced in mammalian cells. For the systematization of the optimization process four levels of optimization were defined-product, technology, design and integration. In this paper, the limits of each of the optimization levels defined are discussed by applying the concept to the systems described. This analysis leads to decisions regarding the production of VLPs and retrovirus as well as on the points relevant for further process development. Finally, the definition of the objective function or performance index, the possible strategies and tools for bioprocess optimization are described. Although developed from the three described processes, this approach can, based on the recent literature evidence reviewed here, be applied more universally for the process development of complex biopharmaceuticals.

Animals↗
PubMed2003

Evaluation of phenylboronate agarose for industrial-scale purification of erythropoietin from mammalian cell cultures.

The search for novel, cost-effective ways to produce erythropoietin (Epo), the world top-selling biopharmaceutical, is a major challenge for today's biotechnology industry. However, Epo's high glycosylation content (almost 40% of total mass) and the requirement for sialic acid for optimal in vivo activity still make mammalian cells the expression system of choice. In contrast to the abundance of reports on Epo production, robust, cost-effective methods for large-scale Epo purification can hardly be found in literature. To fill this gap, we describe here a process specifically studied for industrial-scale purification of the protein. Our method is based on the ability of phenylboronate agarose (PBA) to form reversible complexes with 1,2-cis-diol-containing molecules, like sugars in glycoproteins. Finding that additional factors (i.e., ionic and hydrophobic interactions) contribute to the Epo-PBA binding reaction, chromatography conditions have been optimized in scale-down experiments to improve selectivity and yield. As a result, the high performance of affinity chromatography has been achieved using a support possessing the robustness, chemical stability and low cost of a small synthetic ligand. By adding an anion exchange chromatography step and gel filtration for polishing, a pure and active product can easily be obtained by an integrated, start-to-end process optimized for industrial-scale operations.

Animals↗
PubMed1998

Cation-exchange displacement chromatography for the purification of recombinant protein therapeutics from variants.

Removal of low level impurities that are closely related to the bioproduct is a commonly encountered challenge in the purification of biopharmaceuticals. These separations are typically carried out by using shallow linear salt gradients at relatively low column loadings, significantly limiting the throughput of the purification process. In this manuscript we examine the utility of displacement chromatography for the purification of recombinant human brain-derived neurotrophic factor, rHuBDNF. The utility of displacement chromatography is compared to gradient elution for the removal of variants of the rHuBDNF. The results demonstrate that displacement chromatography is capable of achieving high yields and purity at high column loadings. Displacements developed on 20 microns and 50 microns cation-exchange resins are shown to provide 8-fold and 4.5-fold increases in production rates, respectively, when compared to an existing linear gradient elution operation. These results demonstrate the efficacy of displacement chromatography for the purification of therapeutic proteins from complex feed streams.

Brain-Derived Neurotrophic Factor↗
PubMed2000

A novel approach for constant rate delivery of highly soluble bioactives from a simple monolithic system.

A novel monolithic drug delivery system for highly water-soluble bioactive agents to follow pH-independent zero-order kinetics is described. The system utilizes a hydrophilic gel-based swellable polymeric material (polyethylene oxide), a model drug (metoprolol tartrate, 100% water soluble at 25 degrees C) and different electrolytes, such as sodium carbonate and/or pentasodium tripolyphosphate. Based on the induction of in situ intra-gel chemical reactions between different ionic species, drug and polymer, a heterogeneous structure manifested as 'peripheral boundary stiffening,' is accomplished. The consequence of these interactions essentially include the development of gradient-controlled matrix swelling as elucidated through textural profiling, which may contribute to inhibition of drug solubility and its outward diffusion. Analysis of textural profiles and photomicroscopy distinctly provides information on the disposition of peripheral boundary densification for the electrolyte-containing matrices. Electrolytic conductivity measurements performed with the simultaneous analysis of matrix swelling showed that sodium carbonate forms a highly reactive matrix within the first 3 h of medium penetration. On the other hand, larger molecules such as pentasodium tripolyphosphate maintain a constant conductivity level, which may be related to its lower solubility and diffusion in comparison to sodium carbonate. Based on model fitting and statistical analysis, it is shown that drug release kinetics were adequately described by M(t)/M(infinity)=k(0)t, with zero-order release rate constant k(0) of 0.054 h(-1). This novel approach in formulation development could potentially be used for constant rate delivery of highly soluble bioactive agents over an extended period for specific biopharmaceutical needs.

Calcium Carbonate↗
PubMed2003

Optimising the therapeutic trinity of active ingredient, delivery system and functional packaging.

This paper introduces the "therapeutic trinity" concept for formulating and developing optimal drug products. It starts with the recognition that all drug products are constituted of three distinct elements: the active ingredient, the delivery system and the packaging. Union of these three elements into one trinity will bring therapeutic value to the patient under the condition that active ingredient, delivery system and packaging are developed and optimised interdependently. Optimisation should be performed with the patient in mind, taking into account the relevant efficacy and safety parameters, and the relevant quality and cost parameters. Since the patient plays the central role in the performance of the drug product, biopharmaceutical robustness of and patient compliance towards the active ingredient/delivery system/packaging trinity should be considered important determinants of therapeutic success.

Chemistry, Pharmaceutical↗
PubMed2003

Pulmonary deposition of a budesonide/gamma-cyclodextrin complex in vitro.

Cyclodextrins (CDs) may be potential excipients in inhalation powders; e.g., to increase drug stability, dissolution rate and bioavailability, or to decrease local irritation of an inhaled drug. The aim of this study was to investigate the effect of CD complexation on the pulmonary deposition of drugs. Studies were performed by using novel Taifun multi-dose dry powder inhalers and budesonide as a model compound. A precipitation method was developed to prepare solid budesonide/gamma-CD complexes. Inhalation powders containing either budesonide/gamma-CD complexes (15 microg/dose; complex:carrier ratio 1:15) or budesonide (10 microg/dose and 100 microg/dose; drug:carrier ratio 1:159 and 1:15, respectively) with a lactose carrier, were prepared by dry mixing. The in vitro pulmonary depositions of budesonide and budesonide/gamma-CD complexes were determined initially and after 1 month's storage (40 degrees C, 75% RH) using an Andersen cascade impactor. The respirable fraction (RF) of the budesonide/gamma-CD complex was 35% initially and 31% after storage. The RF of budesonide was 35% (10 microg/dose) and 45% (100 microg/dose) initially, and 31% (10 microg/dose) and 51% (100 microg/dose) after storage, respectively. In conclusion, CDs may be used in inhalation powders to improve pharmaceutical and biopharmaceutical properties of drugs without lowering their pulmonary deposition.

Administration, Inhalation↗
PubMed1999

Improving the pharmacokinetic and pharmacodynamic properties of a drug by chemical conversion to a chimera drug.

The purpose of the present study is to investigate a new concept which involves the conjugation of two drugs having different pharmacological activities which is termed a 'chimera drug (mutual prodrug)', in drug delivery optimization using a chemical modification approach. The conjugates of FP, an NSAID, with histamine H(2) antagonists were synthesized, in order to investigate the reduction in gastric damage by NSAID, and their pharmaceutical, pharmacokinetic and pharmacological properties were examined. The limited data obtained herein indicate that the chimera drug composed of FP and PPA was effective in reducing gastric damage by FP, with no changes in its biopharmaceutical properties, compared with the conventional prodrugs such as ester-type prodrugs.

Absorption↗
PubMed1999

Optimizing oral absorption of peptides using prodrug strategies.

Prodrug strategies applied to peptides have tended to focus on modification of a single functional group (e.g., N-terminal end). Recently, our laboratory introduced the concept of making cyclic prodrugs of peptides as a way to modify their physicochemical properties sufficiently to allow them to permeate biological barriers (i.e., intestinal mucosa). This cyclization strategy required the development of new 'chemical linkers,' including an acyloxyalkoxy linker, a phenylpropionic acid linker, and a coumarinic acid linker. All three chemical linkers were designed to be susceptible to esterase metabolism (slow step), leading to a cascade of chemical reactions (fast steps) that result in release of the peptide. These cyclic prodrug strategies have been applied to opioid peptides in an attempt to stabilize them to metabolism and/or improve their intestinal mucosal permeation. Specifically, we prepared acyloxyalkoxy-, phenylpropionic acid- and coumarinic acid-based cyclic prodrugs of [Leu(5)]-enkephalin (H-Tyr-Gly-Gly-Phe-Leu-OH) and its metabolically stable analog DADLE (H-Tyr-D-Ala-Gly-Phe-D-Leu-OH) and determined their metabolic and biopharmaceutical properties. The cyclic prodrugs of these opioid peptides were shown to have: (i) favorable physicochemical properties (e.g., increased lipophilicity) for membrane permeation; (ii) unique solution structures (e.g., beta-turns) that reduce their hydrogen bonding potential; and (iii) metabolic stability to exo- and endopeptidases. The cell membrane permeation characteristics of [Leu(5)]-enkephalin, DADLE and the cyclic peptide prodrugs were evaluated using Caco-2 cell monolayers, a cell culture model of the intestinal mucosa. The phenylpropionic acid- and coumarinic acid-based cyclic prodrugs of [Leu(5)]-enkephalin and DADLE were shown to have significantly better cell permeation characteristics than the parent opioid peptides. Furthermore, these cyclic prodrugs were shown to be transcellular permeants (in contrast to the opioid peptides, which are paracellular permeants), and were not substrates for polarized efflux systems. Surprisingly, the acyloxyalkoxy-based prodrugs of [Leu(5)]-enkephalin and DADLE were shown to exhibit very low permeation through Caco-2 cell monolayers, which could be attributed to their substrate activity for efflux systems.

Administration, Oral↗
PubMed2000

Lectin-mediated drug delivery: the second generation of bioadhesives.

This paper reviews some recent developments in the area of bioadhesive drug delivery systems. The area of bioadhesion in drug delivery had started some 20 years ago by using so-called mucoadhesive polymers. Many of these polymers were already used as excipients in pharmaceutical formulations. This has facilitated the development of the first bioadhesive drug products, which are now commercially available. A major disadvantage of the hitherto known mucoadhesives, however, is their non-specificity with respect to the substrate. In particular for gastro-intestinal applications, this may cause some premature inactivation and moreover limits the duration of mucoadhesive bonds to the relatively fast mucus turnover. Nevertheless, for some mucoadhesive polymers other interesting functionalities were discovered, such as their ability to modulate epithelial permeability and to inhibit proteolytic enzymes. In contrast to the mucoadhesive polymers, lectins and some other adhesion molecules specifically recognize receptor-like structures of the cell membrane and therefore bind directly to the epithelial cells themselves ("cytoadhesion") rather than to the mucus gel layer. Furthermore, when bioadhesion is receptor-mediated, it is not only restricted to mere binding, but may subsequently trigger the active transport of large molecules or nanoscalic drug carrier systems by vesicular transport processes (endo-/transcytosis). Rather than only acting as a platform for controlled release systems, the concept of lectin-mediated bioadhesion therefore bears the potential for the controlled delivery of macromolecular biopharmaceuticals at relevant biological barriers, such as the epithelia of the intestinal or respiratory tract.

Adhesives↗
PubMed2000

Development of predictive pharmacokinetic simulation models for drug discovery.

As discovery chemistry produces increased numbers of potential drug compounds, the use of ADME (absorption, distribution, metabolism, and excretion) properties is becoming increasingly important in the drug selection and promotion process. A computer simulation model has been developed and validated to predict ADME outcomes, such as rate of absorption, extent of absorption, etc. using a limited number of in vitro data inputs. The oral bioavailability of ganciclovir in dogs and humans was simulated using a physiologically based model that utilized many biopharmaceutically relevant parameters, such as the concentration of ganciclovir in the duodenum, jejunum, ileum, and colon at various dose levels and solubility values. The simulations were run and compared to dog and human in vivo data. The simulation results demonstrated that the low bioavailability of ganciclovir is limited by compound solubility rather than permeability due to partitioning as previously speculated. This technology provides a breakthrough in in silico prediction of absorption and with its continued development and improvement, will aid drug discovery and development scientists to produce better pharmaceutical products.

Animals↗
PubMed2003

Pharmacokinetic and biodistribution properties of poly(ethylene glycol)-protein conjugates.

Peptide and protein PEGylation is usually undertaken to improve the biopharmaceutical properties of these drugs and, to date, several examples of conjugates with long permanence in the body as well as with localization ability in disease sites have been reported. Although a number of studies on the in vivo behavior and fate of conjugates have been performed, forecasting their pharmacokinetics is a difficult task since the pharmacokinetic profile is determined by a number of parameters which include physiological and anatomical aspects of the recipient and physico-chemical properties of the derivative. The most relevant perturbations of the protein molecule following PEG conjugation are: size enlargement, protein surface and glycosylation function masking, charge modification, and epitope shielding. In particular, size enlargement slows down kidney ultrafiltration and promotes the accumulation into permeable tissues by the passive enhanced permeation and retention mechanism. Charge and glycosylation function masking is revealed predominantly in reduced phagocytosis by the RES and liver cells. Protein shielding reduces proteolysis and immune system recognition, which are important routes of elimination. The specific effect of PEGylation on protein physico-chemical and biological properties is strictly determined by protein and polymer properties as well as by the adopted PEGylation strategy. Relevant parameters to be considered in protein-polymer conjugates are: protein structure, molecular weight and composition, polymer molecular weight and shape, number of linked polymer chains and conjugation chemistry. The examples reported in this review show that general considerations could be useful in developing a target product, although significant deviations from the expected results can not be excluded.

Animals↗
PubMed1998

Intranasal drug delivery.

In recent years the nasal route has received a great deal of attention as a convenient and reliable method for the systemic administration of drugs. Although this route is currently being marketed for the systemic administration of several drugs, it has only recently been studied. This chapter deals with animal techniques to study nasal absorption and the effect of physico-chemical and biopharmaceutical properties of drugs on the rate and extent of absorption. It also discusses factors affecting peptide absorption and methods to improve the nasal bioavailability of peptides. In the last part of the chapter the utility of the nasal route for the delivery of drugs to the brain is discussed.

Journal Article↗
PubMed1997

Preparation of peptide and protein powders for inhalation.

Innovations in biotechnology and recombinant techniques have led to a large increase in the number of macromolecule drugs developed over the last several years. These molecules are enabling new therapies for many previously untreated or poorly treated diseases. Due to poor oral absorption, most biopharmaceuticals are delivered by injection. Medical science, health care providers and consumers have been searching for alternative methods of delivering macromolecule drugs. Animal and human clinical studies have demonstrated that pharmacological doses of bioactive peptides and proteins pass, by a natural biological process, from the lungs into the bloodstream or local tissue. New macromolecule drugs are also being developed for treatment of respiratory diseases such as cystic fibrosis, adult and infant respiratory distress syndromes, asthma and emphysema. This paper reviews formulations for delivering therapeutic aerosols to the lungs. Particular emphasis will be placed on preparing fine powders containing macromolecule drugs.

Journal Article↗
PubMed1990

Chromatographic methods for the bioanalysis of antiviral agents.

The present review has concentrated on chromatographic techniques for the quantitative determination of antiviral drugs in biological samples. Special attention has been paid to the elements of chromatographic assays that are essential to ensure selectivity, sensitivity, accuracy and precision of the various methods. Wherever possible, attempts have been made to determine the suitability of the methods for application to investigations in pharmacokinetics in man and experimental animals, biopharmaceutics, therapeutic drug monitoring, metabolism and pharmacology. Because of the serious consequences of infection from material contaminated with viruses, special consideration has been given to the handling of contaminated samples. It was convenient to divide the antiviral drugs for the purpose of this review into two groups, the nucleoside and the non-nucleoside antiviral drugs. The nucleosides discussed are vidarabine, cytarabine, ribavirin, riboxamide, acyclovir, ganciclovir, desciclovir, carbovir, 2',3'-dideoxyadenosine, 2',3'-dideoxycytidine, zidovudine, 2',3'-dideoxyinosine, 2',3'-didehydro-3'-deoxythymidine, idoxuridine, 5-(2-bromovinyl)-2'-deoxyuridine, 2'-fluoro-5-iodoaracytidine and 5-iodo-2'-deoxycytidine. The non-nucleoside antiviral drugs discussed are arildone, amantidine, rimantidine, moroxydine, enviroxime, foscarnet and ampligen.

Antiviral Agents↗