Showing papers in "Pharmaceutical Research in 2000"
TL;DR: The purpose of this report is to represent the progress in analytical methodologies over the last decade and assessment of the major agreements and issues discussed with regard to small molecules at both the conference and the workshop.
Abstract: This report is a synthesis of (1) the earlier conference on Analytical Methods Validation−Bioavailability, Bioequivalence and Pharmacokinetic Studies (Conference held in Arlington, VA, December 3–5, 1990 and the report published in Pharmaceutical Research, 9: 588-592, 1992) and (2) the workshop on “Bioanalytical Methods Validation—A Revisit with a Decade of Progress,” (Workshop held in Arlington, VA, January 12–14, 2000), sponsored by the American Association of Pharmaceutical Scientists and the U. S. Food and Drug Administration. The bioanalytical method validation workshop of January 12–14, 2000 was directed towards small molecules. A separate workshop was held in March 1–3, 2000 to discuss validation principles for macromolecules. The purpose of this report is to represent the progress in analytical methodologies over the last decade and assessment of the major agreements and issues discussed with regard to small molecules at both the conference and the workshop. The report is also intended to provide guiding principles for validation of bioanalytical methods employed in support of bioavailability, bioequivalence, and pharmacokinetic studies in man and in animals.
1,588 citations
TL;DR: Amorphous pharmaceuticals are markedly more soluble than their crystalline counterparts, however, their experimental solubility advantage is typically less than that predicted from simplethermodynamic considerations.
Abstract: Purpose To evaluate the magnitude of the solubility advantage foramorphous pharmaceutical materials when compared to their crystallinecounterpartsMethods The thermal properties of several drugs in their amorphousand crystalline states were determined using differential scanningcalorimetry From these properties the solubility advantage for theamorphous form was predicted as a function of temperature using a simplethermodynamic analysis These predictions were compared to theresults of experimental measurements of the aqueous solubilities of theamorphous and crystalline forms of the drugs at several temperaturesResults By treating each amorphous drug as either an equilibriumsupercooled liquid or a pseudo-equilibrium glass, the solubilityadvantage compared to the most stable crystalline form was predicted to bebetween 10 and 1600 fold The measured solubility advantage wasusually considerably less than this, and for one compound studied indetail its temperature dependence was also less than predicted It wascalculated that even for partially amorphous materials the apparentsolubility enhancement (theoretical or measured) is likely to influencein-vitro and in-vivo dissolution behaviorConclusions Amorphous pharmaceuticals are markedly more solublethan their crystalline counterparts, however, their experimental solubility advantage is typically less than that predicted from simplethermodynamic considerations This appears to be the result of difficulties indetermining the solubility of amorphous materials under trueequilibrium conditions Simple thermodynamic predictions can provide a useful indication of the theoretical maximum solubility advantage foramorphous pharmaceuticals, which directly reflects the driving forcefor their initial dissolution
1,322 citations
TL;DR: This papermarizes recent physicochemical and biological information on polyplexes and aims to provide new insights with respect to thistype of gene delivery system and describes the in vitro and in vivo genetransfection behavior of polyplexe.
Abstract: Gene transfer to humans requires carriers for the plasmid DNA which can efficiently and safely carry the gene into the nucleus of the desired cells. A series of chemically different cationic polymers are currently being investigated for these purposes. Although many cationic polymers indeed condense DNA spontaneously, which is a requirement for gene transfer in most types of cells, the physicochemical and biopharmaceutical behavior of the current generation of polyplexes severely limits an efficient gene transfer in vitro and especially in vivo. This paper summarizes recent physicochemical and biological information on polyplexes and aims to provide new insights with respect to this type of gene delivery system. Firstly, the chemical structure of frequently studied cationic polymers is represented. Secondly, the parameters influencing condensation of DNA by cationic polymers are described. Thirdly, the surface properties, solubility, aggregration behavior, degradation and dissociation of polyplexes are considered. The review ends by describing the in vitro and in vivo gene transfection behavior of polyplexes.
910 citations
TL;DR: A pH gradient is shown, with the most acidic environment at the center of the spheres and higher pH near the edges, which is characteristic of diffusion-controlled release of the acidicdegradation products.
Abstract: Purpose In the past decade, biodegradable polymers have becomethe materials of choice for a variety of biomaterials applications Inparticular, poly(lactic-co-glycolic acid) (PLGA) microspheres havebeen extensively studied for controlled-release drug delivery However,degradation of the polymer generates acidic monomers, andacidification of the inner polymer environment is a central issue in thedevelopment of these devices for drug delivery
Methods To quantitatively determine the intrapolymer acidity, weentrapped pH-sensitive fluorescent dyes (conjugated to 10,000 Dadextrans) within the microspheres and imaged them with confocalfluorescence microscopy The technique allows visualization of thespatial and temporal distribution of pH within the degradingmicrospheres (1)
Results Our experiments show the formation of a very acidicenvironment within the particles with the minimum pH as low as 15
Conclusions The images show a pH gradient, with the most acidicenvironment at the center of the spheres and higher pH near the edges,which is characteristic of diffusion-controlled release of the acidicdegradation products
755 citations
TL;DR: The use of various stabilization approaches has rendered some success in increasing protein stability, but, still, full preservation of the native protein structure remains a major challenge in the formulation of protein-loaded PLGA microparticles.
Abstract: In this review the current knowledge of protein degradation during preparation, storage and release from poly(lactic-co-glycolic acid) (PLGA) microparticles is described, as well as stabilization approaches. Although we have focussed on PLGA microparticles, the degradation processes and mechanisms described here are valid for many other polymeric release systems. Optimized process conditions as well as stabilizing excipients need to be used to counteract several stress factors that compromise the integrity of protein structure during preparation, storage, and release. The use of various stabilization approaches has rendered some success in increasing protein stability, but, still, full preservation of the native protein structure remains a major challenge in the formulation of protein-loaded PLGA microparticles.
721 citations
TL;DR: The characteristic properties of growth factors are described to provide a biological basis for their use in tissue engineered devices and a review of experimental evidence illustrates examples of growth factor delivery from devices such as micropaticles, scaffolds, and encapsulated cells, for theirUse in the application of musculoskeletal tissue, neural tissue, and hepatic tissue.
Abstract: A tissue-engineered implant is a biologic-biomaterial combination in which some component of tissuehas been combined with a biomaterial to create a device for the restoration or modification of tissue ororgan function. Specific growth factors, released from a delivery device or from co-transplanted cells,would aid in the induction of host paraenchymal cell infiltration and improve engraftment of co-deliveredcells for more efficient tissue regeneration or ameliorate disease states. The characteristic properties ofgrowth factors are described to provide a biological basis for their use in tissue engineered devices. Theprinciples of polymeric device development for therapeutic growth factor delivery in the context of tissueengineering are outlined. A review of experimental evidence illustrates examples of growth factor deliveryfrom devices such as micropaticles, scaffolds, and encapsulated cells, for their use in the applicationareas of musculoskeletal tissue, neural tissue, and hepatic tissue.
454 citations
TL;DR: ROI play a key role in cationic lipid-mediated toxicity, cause a release of ROI which are responsible for the pulmonary toxicity and cause oxidative burst induced by the liposomes.
Abstract: Purpose. The objectives of this study are to investigate the toxicityassociated with polycationic liposomes and to elucidate the underlyingmechanism. We tested the hypothesis that the positive charge of liposomesis a key determinant of toxicity by testing differently chargedliposomes in mice.
311 citations
TL;DR: A pragmatic, statistically sound and clinically relevant approach to dose-proportionality analyses that is compatible with common study designs and helps to standardize decision rules is proposed.
Abstract: Purpose. The aim of this work was a pragmatic, statistically sound and clinically relevant approach to dose-proportionality analyses that is compatible with common study designs.
302 citations
TL;DR: This paper summarizes literature studies on these combinations of iontophoresis, chemicals, ultrasound, and electroporation that have been found to enhance transdermal transport more effectively than each of them alone.
Abstract: Transdermal drug delivery offers a non-invasive route of drug administration, although its applications are limited by low skin permeability. Various enhancers including iontophoresis, chemicals, ultrasound, and electroporation have been shown to enhance transdermal drug transport. Although all these methods have been individually shown to enhance transdermal drug transport, their combinations have often been found to enhance transdermal transport more effectively than each of them alone. This paper summarizes literature studies on these combinations with respect to their efficacy and mechanisms.
266 citations
TL;DR: The new potentiometric method was shown to be reliable for determining the solubility-pH profiles of uncharged ionizable drugsubstances and an attractive addition to traditional approaches used byformulation and development scientists.
Abstract: Purpose. The objective of this study was to compare the results of anormal saturation shake-flask method to a new potentiometricacid-base titration method for determining the intrinsic solubility and thesolubility-pH profiles of ionizable molecules, and to report thesolubility constants determined by the latter technique.
Methods. The solubility-pH profiles of twelve generic drugs (atenolol,diclofenac.Na, famotidine, flurbiprofen, furosemide,hydrochlorothiazide, ibuprofen, ketoprofen, labetolol.HCl, naproxen, phenytoin, andpropranolol.HCl), with solubilities spanning over six orders ofmagnitude, were determined both by the new pH-metric method and by atraditional approach (24 hr shaking of saturated solutions, followed byfiltration, then HPLC assaying with UV detection).
Results. The 212 separate saturation shake-flask solubilitymeasurements and those derived from 65 potentiometric titrations agreed well.The analysis produced the correlation equation:log(1/S)titration = ±0.063(± 0.032)+ 1.025(±0.011) log(1/S)shake-flask,s = 0.20, r2 = 0.978.The potentiometrically-derived intrinsic solubilities of the drugs were:atenolol 13.5 mg/mL, diclofenac.Na 0.82 μg/mL, famotidine 1.1mg/mL, flurbiprofen 10.6 μg/mL, furosemide 5.9 μg/mL,hydrochlorothiazide 0.70 mg/mL, ibuprofen 49 μg/mL, ketoprofen 118 μg/mL,labetolol.HCl 128 μg/mL, naproxen 14 μg/mL, phenytoin 19 μg/mL, andpropranolol.HCl 70 μg/mL.
Conclusions. The new potentiometric method was shown to be reliablefor determining the solubility-pH profiles of uncharged ionizable drugsubstances. Its speed compared to conventional equilibriummeasurements, its sound theoretical basis, its ability to generate the fullsolubility-pH profile from a single titration, and its dynamic range (currentlyestimated to be seven orders of magnitude) make the new pH-metricmethod an attractive addition to traditional approaches used bypreformulation and development scientists. It may be useful even todiscovery scientists in critical decision situations (such as calibratingcomputational prediction methods).
247 citations
TL;DR: Respirable rifampicin loaded PLGAmicrospheres were produced by both solvent evaporation and spray drying methods, and were evaluated in an animal model oftuberculosis.
Abstract: Purpose. Particles with aerodynamic diameters of 1–5μm deposit in the periphery of the lungs and are phagocytized by alveolarmacrophages, the primary site of Mycobacterium tuberculosisinfection. Aerosols of biodegradable polymeric microspheres containingantitubercular agents may be delivered to the lungs to improve the treatmentof tuberculosis.
TL;DR: A genetically engineered chimeric HIRMAb has been produced, and the chimeric antibody has identical reactivity to the human and primate BBB HIR as the original murine antibody.
Abstract: Purpose Brain drug targeting may be achieved by conjugating drugs,that normally do not cross the blood-brain barrier (BBB), to brain drugdelivery vectors The murine 83-14 MAb to the human insulin receptor(HIR) is a potential brain drug targeting vector that could be used inhumans, if this MAb was genetically engineered to form a chimericantibody, where most of the immunogenic murine sequences arereplaced by human antibody sequence
TL;DR: As the anionic PAMAM dendrimers displayed serosal transfer rates that were faster than observed for other syntheticand natural macromolecules (including tomato lectin) studied in the evertedsac system, these interesting nanoscale structures may have potential for further development as oral drug delivery systems.
Abstract: Purpose. To investigate systematically the effect ofpolyamidoamine (PAMAM) dendrimer size, charge, and concentration on uptakeand transport across the adult rat intestine in vitro using theeverted rat intestinal sac system.
TL;DR: Vascular endothelial growth factor (VEGF)-binding assays demonstrated that the NX1838 remaining in the vitreous humor after 28 days was fully active and support monthly 1 or 2 mg/eye dose regimens in human clinical trials.
Abstract: Purpose. The objective of this study was to determine the pharmacokinetics and safety for NX1838 following injection into the vitreous humor of rhesus monkeys.
TL;DR: An improved design model is developed that can be used to predict accurately the required composition and dimensions of drug-loaded hydrophilic matrices in order to achieve desired release profiles, thus facilitating the development of new pharmaceutical products.
Abstract: Purpose. The aims of this study were (i) to elucidate the transport mechanisms involved in drug release from hydrophilic matrices; and (ii) to develop an improved mathematical model allowing quantitative predictions of the resulting release kinetics.
Methods. Our previously presented model has been substantially modified, by adding: (i) inhomogeneous swelling; (ii) poorly water-soluble drugs; and (iii) high initial drug loadings. The validity of the improved model has been tested experimentally using hydroxypropyl methylcellulose (HPMC)-matrices, containing either a poorly or a freely water-soluble drug (theophylline or chlorpheniramine maleate) at various initial loadings in phosphate buffer pH 7.4 and 0.1 N HCl, respectively.
Results. By overcoming the assumption of homogeneous swelling we show that the agreement between theory and experiment could be significantly improved. Among others, the model could describe quantitatively even the very complex effect on the resulting relative release rates (first slowing down, then accelerating drug release) observed when increasing the initial loading of poorly water-soluble drugs.
Conclusions. The practical benefit of this work is an improved design model that can be used to predict accurately the required composition and dimensions of drug-loaded hydrophilic matrices in order to achieve desired release profiles, thus facilitating the development of new pharmaceutical products.
TL;DR: The efficacy of 5-ALA-PDT may be improved by (a) development of adequate drug delivery systems; (b) use of enhancers of PpIX production and accumulation in target tissue, and (c) modifications of the 5- ALA molecule.
Abstract: Photodynamic therapy (PDT) is a new modality of skin cancer treatment. It involves the administration of photosensitizing drugs which, when localized in tumor tissue can produce its destruction by absorbing an adequate dose of light of an appropriate wavelength. A large number of photosensitizing agents have been tested in PDT experiments. Topical application of 5-aminolevulinic acid (5-ALA) followed by light irradiation is the most commonly used method. 5-ALA is a prodrug converted in situ via the heme cycle into protoporphyrin IX, an effective photosensitizer agent. Treatment of nonmelanoma skin cancers by PDT has met with varying degrees of success. In the case of 5-ALA, this therapy's main limitation is the poor penetration of 5-ALA into skin, due to hydrophilic and charge characteristics. However, the efficacy of 5-ALA-PDT may be improved by (a) development of adequate drug delivery systems; (b) use of enhancers of PpIX production and accumulation in target tissue, and (c) modifications of the 5-ALA molecule. Optimal timing, light sources, doses, and number of applications are also important factors for topical 5-ALA therapy and must be well defined. The aim of this review is to highlight recent progress in 5-ALA-PDT of skin cancer, and to present ways holding promise for its improvement.
TL;DR: The formation of hollow porous particles provides anew formulation technology for stabilizing suspensions of drugs in hydrofluoroalkane propellants with improved physical stability, content uniformity, and aerosolization efficiency.
Abstract: Purpose. To assess the physical stability and aerosol characteristicsof suspensions of hollow porous microspheres (PulmoSpheres™) inHFA-134a.
Methods. Cromolyn sodium, albuterol sulfate, and formoterol fumaratemicrospheres were prepared by a spray-drying method. Particle sizeand morphology were determined via electron microscopy. Particleaggregation and suspension creaming times were assessed visually,and aerosol performance was determined via Andersen cascadeimpaction and dose uniformity studies.
Results. The hollow porous particle morphology allows the propellantto permeate freely within the particles creating a novel form ofsuspension termed a homodispersion™, wherein the dispersed and continuousphases are identical, separated by an insoluble interfacial layer of drugand excipient. Homodispersion formation improves suspension stabilityby minimizing the difference in density between the particles andthe medium, and by reducing attractive forces between particles. Theimproved physical stability leads to excellent dose uniformity. Excellentaerosolization efficiencies are also observed with PulmoSpheresformulations, with fine particle fractions of about 70%.
Conclusions. The formation of hollow porous particles provides anew formulation technology for stabilizing suspensions of drugs inhydrofluoroalkane propellants with improved physical stability, contentuniformity, and aerosolization efficiency.
TL;DR: This study demonstrated that atorvastatin was secreted across the apical surface of Caco-2 cell monolayers via P-glycoprotein-mediated efflux and transported across theApical membrane in theabsorptive direction via a H+-monocarboxylic acid cotransporter(MCT).
Abstract: Purpose. The purpose of this study was to elucidate the mechanismsby which an HMG-CoA reductase inhibitor, atorvastatin (an organicacid with a pKa of 4.46), was transported in the secretory and absorptivedirections across Caco-2 cell monolayers.
TL;DR: The use of the biodegradable poly-cation, PAGA, as aDNA condensing agent will be useful in safe gene delivery because of its degradability and the biocompatibility of the monomer.
Abstract: Purpose. The aim of this study was to develop a non-toxic polymericgene carrier. For this purpose, biodegradable cationic polymer,poly[α-(4-aminobutyl)-l-glycolic acid] (PAGA) was synthesized. PAGA wasdesigned to have ester linkage because polyesters usually showbiodegradability.
TL;DR: The most significant atomization parameter affecting particle size was the mass flow ratio (mass of atomization N2 relative to that for liquid feed).
Abstract: Purpose. To investigate the effect of atomization conditions on particle size and stability of spray-freeze dried protein.
TL;DR: The mechanism by which Mg(OH)2 stabilizes encapsulated BSA in PLGA implants is through neutralizing the acidicmicroclimate pH in the polymer, which suggests a potential approach to optimize the stability of encapsulated pharmaceuticals inPLGA including therapeutic proteins.
Abstract: Purpose. A previous study from our group has shown that in theacidic microclimate of poly(lactide-co-glycolide) (PLGA) implants,encapsulated BSA forms insoluble noncovalent aggregates and ishydrolyzed during in vitro release. Incorporation of Mg(OH)2 stronglyinhibits these mechanisms of instability and facilitates continuousprotein release. The purpose of this study was to determine the proteinstabilization mechanism in the presence of basic additives.
TL;DR: Although dog has been commonly employed as ananimal model for studying oral absorption in drug discovery and development, the present study suggests that one may need to exercise caution in the interpretation of data obtained.
Abstract: Purpose. To conduct a retrospective evaluation of using dog as ananimal model to study the fraction of oral dose absorbed (F) of 43drugs in humans and to briefly discuss potential factors that mighthave contributed to the observed differences in absorption.
Methods. Mean human and dog absorption data obtained under fastedstate of 43 drugs with markedly different physicochemical andpharmacological properties and with mean F values ranging from 0.015 to1.0 were obtained from the literature. Correlation of F values betweenhumans and dogs was studied. Based on the same references, additionalF data for humans and rats were also obtained for 18 drugs.
Results. Among the 43 drugs studied, 22 drugs were virtuallycompletely absorbed in both dogs and humans. However, the overallcorrelation was relatively poor (r2 = 0.5123) as compared to the earlier ratvs. human study on 64 drugs (r2 = 0.975). Several drugs showed muchbetter absorption in dogs than in humans. Marked differences in thenonliner absorption profiles between the two species were found forsome drugs. Also, some drugs had much longer Tmax values andprolonged absorption in humans than in dogs that might be theoreticallypredicted. Data on 18 drugs further support great similarity in F betweenhumans and rats reported earlier from our laboratory.
Conclusions. Although dog has been commonly employed as ananimal model for studying oral absorption in drug discovery anddevelopment, the present study suggests that one may need to exercise cautionin the interpretation of data obtained. Exact reasons for the observedinterspecies differences in oral absorption remain to be explored.
TL;DR: By optimizing lipid composition and charge ratio, galactosylated liposome/DNA complexes allow superior in vivo genetransfection in the liver via asialoglycoprotein receptor-mediatedendocytosis.
Abstract: Purpose. The purpose of this study is to elucidate the in vivo genetransfer for galactosylated liposomes containingcholesten-5-yloxy-N-(4-((1-imino-2-β-D-thiogalactosylethyl)amino)butyl)formamide(Gal-C4-Chol)in relation to lipid composition and charge ratio.
TL;DR: Interfacial polymerization of spontaneously formingwater-in-oil microemulsions represents a convenient method for thepreparation of poly(alkylcyanoacrylate) nanocapsules suitable for theentrapment of bioactive peptides.
Abstract: Purpose. To prepare poly(ethyl 2-cyanoacrylate) nanocapsulescontaining insulin by interfacial polymerization of spontaneously forming,biocompatible microemulsions.
Methods. A pseudo-ternary phase diagram of a mixture of mediumchain glycerides (caprylic/capric triglycerides and mono-/diglycerides),a mixture of surfactants (polysorbate 80 and sorbitan mono-oleate) andwater was constructed. Polarizing light microscopy was used to identifycombinations forming microemulsions. Microemulsions werecharacterized by conductivity and viscosity to select systems suitable for thepreparation of poly(ethyl 2-cyanoacrylate) nanocapsules by interfacialpolymerization. Nanocapsules were prepared by addition of 100 mgof ethyl 2-cyanoacrylate to a stirred water-in-oil microemulsioncontaining 1 g of water, 7.6 g of oil, and 1.4 g of surfactant. Thenanocapsules formed were characterized by photon correlation spectroscopy,freeze fracture transmission and scanning electron microscopy. Insulinnanocapsules were prepared by using an aqueous solution of insulin(100 units/ml) as the dispersed phase of the microemulsion. Theentrapment and the release of insulin from the nanocapsules were determined.
Results. Three regions were identified in the pseudo-ternary phasediagram; a microemulsion region, a region in which liquid crystallinestructures were present and a coarse emulsion region. All systems inthe microemulsion region were water-in-oil dispersions.Poly(ethyl 2-cyanoacrylate) nanocapsules having a mean particle size of 150.9 nmwere formed upon interfacial polymerization of the microemulsion.Nanocapsules were found to have a central cavity surrounded by apolymer wall. In excess of 80;pc of the insulin present in themicroemulsion was encapsulated upon interfacial polymerization.
Conclusions. Interfacial polymerization of spontaneously formingwater-in-oil microemulsions represents a convenient method for thepreparation of poly(alkylcyanoacrylate) nanocapsules suitable for theentrapment of bioactive peptides.
TL;DR: This paper describes, for the first time, ananotechnologyable to encapsulate oligonucleotides rather than adsorbing them at thesurface of a solid support, such a formulation has great potential foroligonucleotide delivery.
Abstract: Purpose. The goal of the present paper was to encapsulateoligonucleotides in a new particulate carrier in order to protect them fromenzymatic degradation.
TL;DR: C-terminal lysine microheterogeneity and deamidation of Asn141 in the heavy chain and Asn161 in the light chain are the major causes of MMA383 charge heterogeneity.
Abstract: Purpose. The aim of this study was to elucidate the molecular basis of charge heterogeneity found in a purified monoclonal IgG1 antibody, MMA383.
Methods. Cation exchange chromatography (CEX) and isoelectric focusing (IEF) were used to monitor charge heterogeneity. CEX in conjunction with carboxypeptidase B digests of the antibody was used to determine the contribution of C-terminal lysines to MMA383 charge heterogeneity. Potential chemical degradation sites were identified by peptide mapping of individual chains, with peptide identification by mass spectrometry (MALDI-TOF MS). Peptide sequencing was used to determine specific deamidation sites. Binding constants of predominant isoforms were compared by surface plasmon resonance (SPR).
Results. Extensive charge heterogeneity of purified MMA383 was detected by CEX and IEF. Removal of C-terminal lysines simplified the IEF pattern to nine predominant isoforms. Quantitation of isoaspartate in each of the isoforms indicated deamidation of MMA383 as a major cause of charge heterogeneity. CEX of the individual isoform chains suggested the presence of one deamidation site on each of the heavy and light chains. The two sites of deamidation were identified using peptide mapping, sequencing and mass spectrometry. SPR results showed no significant difference in the binding parameters among the isoforms.
Conclusions. C-terminal lysine microheterogeneity and deamidation of Asn141 in the heavy chain and Asn161 in the light chain are the major causes of MMA383 charge heterogeneity. Identification of the two deamidation sites will allow replacement of these amino acids in order to create a product less susceptible to degradation.
TL;DR: Both the in vitro and in vivo results indicate that TMCs are potent mucosal permeation enhancers of the peptide drug buserelin at neutral pH values.
Abstract: Purpose. To evaluate N-trimethyl chitosan chloride (TMC) of highdegrees of substitution as intestinal permeation enhancers for thepeptide drug buserelin in vitro using Caco-2 cell monolayers, and toinvestigate TMCs as enhancers of the intestinal absorption of buserelinin vivo, in rats.
Methods. TMCs were tested on Caco-2 cells for their efficiency toincrease the paracellular permeability of the peptide buserelin. For thein vivo studies male Wistar rats were used and buserelin wasadministered with or without the polymers intraduodenally. Both types ofexperiments were performed at pH 7.2.
Results. Transport studies with Caco-2 cell monolayers confirmed thatthe increase in buserelin permeation is dependent on the degree oftrimethylation of TMC. In agreement with the in vitro results, in vivodata revealed highly increased bioavailability of buserelin followingintraduodenal co-administration with 1.0% (w/v) TMCs.Intraduodenally applied buserelin resulted in 0.8% absolute bioavailability,whereas co-administrations with TMCs resulted in mean bioavailabilityvalues between 6 and 13 %. Chitosan HCl (1.0% pH = 7.2) did notsignificantly increase the intestinal absorption of buserelin.
Conclusions. Both the in vitro and in vivo results indicate that TMCsare potent mucosal permeation enhancers of the peptide drug buserelinat neutral pH values.
TL;DR: QW8184, a stable sub-micron o/w emulsion of paclitaxel has been developed that can be filter-sterilized and administered i.v. as a bolus dose and exhibited reduced toxicity and improved efficacy most likely due to the composition and dependent physicochemical characteristics of the emulsion.
Abstract: Purpose. Paclitaxel is currently administered i.v. as a slow infusion of asolution of the drug in an ethanol:surfactant:saline admixture. However,poor solubilization and toxicity are associated with this drug therapy.Alternative drug delivery systems, including parenteral emulsions, areunder development in recent years to reduce drug toxicity, improveefficacy and eliminate premedication.
TL;DR: Ten HIFs and five human gastric fluids were used and originated from 13 healthy male and female subjects who had fasted for 10 hours.
Abstract: Betty Lomstein Pedersen,1,3 Anette Müllertz,1 Dissolution Media Helle Brøndsted,2 and Henning Gjelstrup Ten HIFs and five human gastric fluids (HGFs) were used. Kristensen1 The fluids originated from 13 healthy male and female subjects who had fasted for 10 hours. For two subjects both the intestinal and gastric fluid were included in the study. The method for Received February 17, 2000; accepted April 11, 2000 aspiration has been described in detail by Lindahl et al. (1) and
TL;DR: ESCA provides a direct, quantitative measure of the surface composition of spray-dried trehalose/protein/surfactant particles and shows how and why the addition of a surfactant reduces protein adsorption, and by thisMechanism could reduce protein instability during Spray-drying.
Abstract: Purpose. To characterize via electron spectroscopy for chemical analysis(ESCA) the surface of spray-dried particles of trehalose plus aprotein (bovine serum albumin). Additionally, to show how and whythe addition of a surfactant reduces protein adsorption, and by thismechanism could reduce protein instability during spray-drying.