Showing papers in "Pharmaceutical Research in 1999"
TL;DR: The LMW-PEI described here is a new, highly efficient, and non-cytotoxic vector with a favorable efficiency/toxicity profile for gene therapeutic applications.
Abstract: Purpose. Low molecular weight branched polyethylenimine (LMW-PEI) was synthesized and studied as a DNA carrier for gene delivery with regard to physico-chemical properties, cytotoxicity, and transfection efficiency.
1,131 citations
TL;DR: The polar molecular surface area is a dominating determinant for oral absorption and brain penetration of drugs that are transported by the transcellular route and should be considered in the early phase of drug screening.
Abstract: Purpose. To study oral absorption and brain penetration as a function of polar molecular surface area.
745 citations
TL;DR: Insulin association was found to be highly mediated by an ionic interaction mechanism and its release in vitro occurred rapidly in sink conditions, and chitosan nanoparticles are efficient vehicles for the transport of insulin through the nasal mucosa.
Abstract: Purpose To investigate the potential of chitosan nanoparticles as a system for improving the systemic absorption of insulin following nasal instillation
573 citations
TL;DR: It is demonstrated that the brain concentration of systemically administered doxorubicin can be enhanced over 60-fold by binding to biodegradable poly(butyl cyanoacrylate) nanoparticles, overcoated with the nonionic surfactant polysorbate 80.
Abstract: Purpose. To investigate the possibility of delivering of anticancer drugs into the brain using colloidal carriers (nanoparticles).
Methods. Rats obtained 5 mg/kg of doxorubicin by i v. injection in form of 4 preparations : 1. a simple solution in saline, 2. a simple solution in polysorbate 80 1% in saline, 3. bound to poly (butyl cyanoacrylate) nanoparticles, and 4. bound to poly(butyl cyanoacrylate) nanoparticles overcoated with 1% polysorbate 80 (Tween® 80). After sacrifice of the animals after 10 min, 1, 2, 4, 6, and 8 hours, the doxorubicin concentrations in plasma, liver, spleen, lungs, kidneys, heart and brain were determined after extraction by HPLC.
Results. No significant difference in the body distribution was observed between the two solution formulations. The two nanoparticle formulations very significantly decreased the heart concentrations. High brain concentrations of doxorubicin (>6 μg/g) were achieved with the nanoparticles overcoated with polysorbate 80 between 2 and 4 hours. The brain concentrations observed with the other three preparations were always below the detection limit (< 0.1 |μg/g).
Conclusions. The present study demonstrates that the brain concentration of systemically administered doxorubicin can be enhanced over 60-fold by binding to biodegradable poly(butyl cyanoacrylate) nanoparticles, overcoated with the nonionic surfactant polysorbate 80. It is highly probable that coated particles reached the brain intact and released the drug after endocytosis by the brain blood vessel endothelial cells.
517 citations
TL;DR: The results indicate that the overlap in substrate specificities of CYP3A and P-gp appears to be fortuitous rather than indicative of a more fundamental relationship.
Abstract: Purpose. CYP3A and P-gp both function to reduce the intracellular concentration of drug substrates, one by metabolism and the other by transmembrane efflux. Moreover, it has been serendipitously noted that the two proteins have many common substrates and inhibitors. In order to test this notion more fully, systematic studies were undertaken to determine the P-gp-mediated transport and inhibitory characteristics of prototypical CYP substrates.
470 citations
TL;DR: The major basis for crystal inhibition of indomethacin at 30°C at the 5% w/w polymer level in molecular dispersions is not related to polymer molecular weight and to the glass transition temperature, and is more likely related to the ability to hydrogen bond with indometHacin and to inhibit the formation of carboxylic acid dimers that are required for nucleation and growth to the γ crystal form of indometrichacIn.
Abstract: Purpose. To measure solid-state features of amorphous molecular dispersions of indomethacin and various molecular weight grades of poly(vinylpyrrolidone), PVP, and poly(vinylpyrrolidone-co-vinylacetate), PVP/VA, in relation to isothermal crystallization of indomethacin at 30°C
437 citations
TL;DR: Data demonstrate that TPGS acts as a reversal agent for P-glycoprotein mediated multidrug resistance and inhibits P-gp mediated drug transport and suggests that enhanced oral bioavailability of drugs co-administered with T PGS may, in part, be due to inhibition of P- glycoprotein in the intestine.
Abstract: Purpose. To investigate whether d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) functions as an inhibitor of P-glycoprotein (P-gp), the multidrug resistance transporter.
404 citations
TL;DR: The practical benefit of the presented model is to identify the required shape and dimensions of drug-loaded HPMC-matrices in order to achieve desired release profiles, thus facilitating the development of new controlled drug delivery products.
Abstract: Purpose. The purpose of this study was to investigate the drug release mechanisms from hydroxypropyl methylcellulose (HPMC)-matrices, and to develop a new model for quantitative predictions of controlled drug delivery.
Methods. The dissolved mass of pure HPMC-matrices and the drug release rate from propranolol HCl-loaded HPMC-matrices were determined experimentally. Based on Fick's second law of diffusion for cylinders, the transport of water and drug were modeled considering (i) both radial and axial diffusion, (ii) concentration-dependent drug diffusivities, (iii) matrix swelling and (iv) HPMC dissolution.
Results. Good agreement between theory and experiment (dissolved mass and drug release studies) was obtained, proving the validity of the presented model. The water and drug diffusivities are strongly dependent on the matrix swelling ratio. Diffusion, swelling and dissolution are the governing mechanisms involved in the overall drug release process.
Conclusions. The practical benefit of the presented model is to identify the required shape and dimensions of drug-loaded HPMC-matrices in order to achieve desired release profiles, thus facilitating the development of new controlled drug delivery products. This will be demonstrated in a future study.
359 citations
TL;DR: Spray freeze drying produced protein particles with light and porous characteristics, which offered powders with superior aerosol performance due to favorable aerodynamic properties.
Abstract: Purpose. To develop a new technique, spray freeze drying, for preparing protein aerosol powders. Also, to compare the spray freeze-dried powders with spray-dried powders in terms of physical properties and aerosol performance.
Methods. Protein powders were characterized using particle size analysis, thermogravimetric analysis, scanning electron microscopy, X-ray powder diffractometry, and specific surface area measurement. Aerosol performance of the powders was evaluated after blending with lactose carriers using a multi-stage liquid impinger or an Anderson cascade impactor. Two recombinant therapeutic proteins currently used for treating respiratory tract-related diseases, deoxyribonuclase (rhDNase) and anti-IgE monoclonal antibody (anti-IgE MAb), were employed and formulated with different carbohydrate excipients.
Results. Through the same atomization but the different drying process, spray drying (SD) produced small (∼3 μm), dense particles, but SFD resulted in large (∼8−10 μm), porous particles. The fine particle fraction (FPF) of the spray freeze-dried powder was significantly better than that of the spray-dried powder, attributed to better aerodynamic properties. Powders collected from different stages of the cascade impactor were characterized, which confirmed the concept of aerodynamic particle size. Protein formulation played a major role in affecting the powder's aerosol performance, especially for the carbohydrate excipient of a high crystallization tendency.
Conclusions. Spray freeze drying, as opposed to spray drying, produced protein particles with light and porous characteristics, which offered powders with superior aerosol performance due to favorable aerodynamic properties.
353 citations
TL;DR: Polymers with thiol groups might represent a new generation of mucoadhesive polymers displaying comparatively stronger adhesive properties.
Abstract: Purpose. To improve the mucoadhesive properties of polycarbophil by the introduction of sulfhydryl groups.
327 citations
TL;DR: Dry powders engineered as large and light particles, and prepared with combinations of GRAS (generally recognized as safe) excipients, may be broadly applicable to inhalation therapy.
Abstract: Purpose. Relatively large (>5 µm) and porous (mass density < 0.4 g/cm3) particles present advantages for the delivery of drugs to the lungs, e.g., excellent aerosolization properties. The aim of this study was, first, to formulate such particles with excipients that are either FDA-approved for inhalation or endogenous to the lungs; and second, to compare the aerodynamic size and performance of the particles with theoretical estimates based on bulk powder measurements.
Methods. Dry powders were made of water-soluble excipients (e.g., lactose, albumin) combined with water-insoluble material (e.g., lung surfactant), using a standard single-step spray-drying process. Aerosolization properties were assessed with a Spinhaler TM device in vitro in both an Andersen cascade impactor and an AerosizerTM..
Results. By properly choosing excipient concentration and varying the spray drying parameters, a high degree of control was achieved over the physical properties of the dry powders. Mean geometric diameters ranged between 3 and 15 µm, and tap densities between 0.04 and 0.6 g/cm3. Theoretical estimates of mass mean aerodynamic diameter (MMAD) were rationalized and calculated in terms of geometric particle diameters and bulk tap densities. Experimental values of MMAD obtained from the AerosizerTM most closely approximated the theoretical estimates, as compared to those obtained from the Andersen cascade impactor. Particles possessing high porosity and large size, with theoretical estimates of MMAD between 1−3 µm, exhibited emitted doses as high as 96% and respirable fractions ranging up to 49% or 92%, depending on measurement technique.
Conclusions. Dry powders engineered as large and light particles, and prepared with combinations of GRAS (generally recognized as safe) excipients, may be broadly applicable to inhalation therapy.
TL;DR: Pharmacokinetic/pharmacodynamic (PK/PD)-modeling links dose-concentration relationships (PK) and concentration-effect relationships (PD), thereby facilitating the description and prediction of the time course of drug effects resulting from a certain dosing regimen as discussed by the authors.
Abstract: Pharmacokinetic/pharmacodynamic (PK/PD)-modeling links dose-concentration relationships (PK) and concentration-effect relationships (PD), thereby facilitating the description and prediction of the time course of drug effects resulting from a certain dosing regimen. PK/PD-modeling approaches can basically be distinguished by four major attributes. The first characterizes the link between measured drug concentration and the response system, direct link versus indirect link. The second considers how the response system relates effect site concentration to the observed outcome, direct versus indirect response. The third regards what clinically or experimentally assessed information is used to establish the link between concentration and effect, hard link versus soft link. And the fourth considers the time dependency of pharmacodynamic model parameters, distinguishing between time-variant versus time-invariant. Application of PK/PD-modeling concepts has been identified as potentially beneficial in all phases of preclinical and clinical drug development. Although today predominantly limited to research, broader application of PK/PD-concepts in clinical therapy will provide a more rational basis for patient-specific dosage individualization and may thus guide applied pharmacotherapy to a higher level of performance.
TL;DR: SLN could be a promising sustained release and targeting system for camptothecin or other lipophilic antitumor drugs after oral administration and show significant changes in body distribution through incorporation into solid lipid nanoparticles by peroral route.
Abstract: Purpose. The aim of this study was to investigate the specific changes in body distribution of camptothecin (CA) through incorporation into solid lipid nanoparticles (SLN) by peroral route.
TL;DR: The relationship between the structure of Pluronic block copolymers and their biological response modifying effects in MDR cells is useful for determining formulations with maximal efficacy with respect to MDR tumors.
Abstract: Purpose. Previous studies have demonstrated that Pluronic block copolymers hypersensitize multiple drug resistant (MDR) cancer cells, drastically increasing the cytotoxic effects of anthracyclines and other anticancer cytotoxics in these cells. This work evaluates the dose dependent effects of these polymers on (i) doxorubicin (Dox) cytotoxicity and (ii) cellular accumulation of P-glycoprotein probe, rhodamine 123 (R123) in MDR cancer cells.
TL;DR: The conjugation approach of doxorubicin to PLGA was potentially useful for nanoparticle formulations that require high drug loading and sustained release.
Abstract: Purpose. Doxorubicin was chemically conjugated to a terminal end group of poly(D,L-lactic-co-glycolic acid) [PLGA] and the doxorubicin-PLGA conjugate was formulated into nanoparticles to sustain the release of doxorubicin.
TL;DR: Varying the drug lipophilicity and loading revealed that the precipitation of the lactone could also stabilize CPT, which may be neutralized by co-encapsulating a base such as Mg(OH)2, as suggested by previous work with poly(ortho esters) (2).
Abstract: Purpose. The camptothecin (CPT) analogue, 10-hydroxycamptothecin (10-HCPT) has been shown previously to remain in its acid-stable (and active) lactone form when encapsulated in poly(lactide-co-glycolide) (PLGA) microspheres (1). The purpose of this study was to determine the principal mechanism(s) of 10-HCPT stabilization.
TL;DR: Vitamin E-TPGS inhibits the efflux system and enhances the permeability of amprenavir, a potent HIV protease inhibitor, by increasing its solubility and permeability and is essential to the development of the novel soft gelatin capsule formulation of amp Renavir for use in the clinic.
Abstract: Purpose. To investigate the effect of vitamin E-TPGS, d-α-tocopheryl polyethylene glycol 1000 succinate, on the solubility and permeability of amprenavir, a potent HIV protease inhibitor.
TL;DR: Evidence is provided that amprenavir and other HIV PIs are Pgp substrates and that co-administration of a specific Pgp inhibitor will enhance amprenvir's CNS penetration in vivo, which will have an important therapeutic impact in the treatment of AIDS dementia.
Abstract: Purpose. To determine the role of P-glycoprotein (Pgp) on the CNS penetration of the HIV protease inhibitor (PI) amprenavir (141W94) and to test the hypothesis that co-administration of a second HIV PI (ritonavir) could enhance amprenavir's brain penetration in vivo.
TL;DR: Gd-nanoCPs might be useful as an i.t. injectable device for gadolinium neutron-capture therapy and their ability for long-term retention of Gd-DTPA in the tumor indicated that.
Abstract: Purpose. The gadopentetic acid (Gd-DTPA)-loaded chitosan nanoparticles (Gd-nanoCPs) were prepared for gadolinium neutron-capture therapy (Gd-NCT) and characterized and evaluated as a device for intratumoral (i.t.) injection.
TL;DR: The basics of fluorescence recovery after photobleaching (FRAP) are introduced from a theoretical and an instrumentational approach and the possibility of performing FRAP in microscopic dosage forms (microspheres) using a high resolution variant of FRAP is illustrated.
Abstract: This review introduces the basics of fluorescence recovery after photobleaching (FRAP) from a theoretical and an instrumentational approach The most interesting and innovative applications with a pharmaceutical point of view are briefly discussed and possible future applications are suggested These future applications include research on the mobility of macromolecular drugs in macro- or microscopic pharmaceutical dosage forms, mobility, and binding of antitumor drugs in tumor tissue, intracellular trafficking of gene complexes and mobility of drugs in membranes prior to transmembrane penetration The paper is also intended to be an introductory guideline to those who would like to get involved in FRAP related experimental techniques Therefore, comprehensive details on different setups and data analysis are given, as well as a brief outline of the problems that may be encountered when performing FRAP Overall, this review shows the great potential of FRAP in pharmaceutical research This is complemented by our own results illustrating the possibility of performing FRAP in microscopic dosage forms (microspheres) using a high resolution variant of FRAP
TL;DR: P85 increases AP to BL permeability in BBMEC and Caco-2 monolayers with respect to a broad panel of structurally diverse compounds, that were previously shown to be affected by P-gp and/ or multidrug resistance associated protein (MRP) efflux systems.
Abstract: Purpose. Previous studies demonstrated that inhibition of P glycoprotein (P-gp) by Pluronic P85 (P85) block copolymer increases apical (AP) to basolateral (BL) transport of rhodamine 123 (R123) in the polarized monolayers of bovine brain microvessel endothelial cells (BBMEC) and Caco-2 cells. The present work examines the effects of P85 on the transport of fluorescein (Flu), doxorubicin (Dox), etoposide (Et), taxol (Tax), 3′-azido-3′-deoxythymidine (AZT), valproic acid (VPA) and loperamide (Lo) using BBMEC and Caco-2 monolayers as in vitro models of the blood brain barrier and intestinal epithelium respectively.
TL;DR: A non specific permeabilization of the BBB, probably related to the toxicity of the carrier, may account for the CNS penetration of dalargin associated with PBCA NP and polysorbate 80.
Abstract: Purpose. To investigate the mechanism underlying the entry of the analgesic peptide dalargin into brain using biodegradable polybutylcyanoacrylate (PBCA) nanoparticles (NP) overcoated with polysorbate 80.
TL;DR: DSC and EPR are useful techniques to characterize the chemical microenvironment inside eroding microspheres and could allow in the future to predict the stability of such compounds within degradable polymers.
Abstract: Purpose. To measure changes in pH as well as osmotic pressure in aqueous pores and cavities inside biodegradable microspheres made from polymers such as poly(D,L-lactic acid) (PLA) and poly(D,L-lactic acid -co- glycolic acid) (PLGA).
Methods. The internal osmotic pressure inside eroding PLA microspheres was analyzed with differential scanning calorimetry (DSC) in a temperature range of 10 to −25°C. The osmotic pressure was calculated from the melting peaks of the aqueous phase using purity analysis. For pH determination, PLGA microspheres were loaded with a pH-sensitive spin probe which allowed the determination of pH by electron paramagnetic resonance (EPR).
Results. The osmotic pressure in PLA microspheres increased to 600 mOsm within four days and decreased to 400 mOsm after two weeks. The pH in PLGA microspheres in this study was ≤4.7. Basic drugs such as gentamicin free base or buffering additives led to a pH increase. In no case, however, did the internal pH exceed a value of 6 within 13 hours.
Conclusions. DSC and EPR are useful techniques to characterize the chemical microenvironment inside eroding microspheres. This data in combination with detailed information on peptide and protein stability could allow in the future to predict the stability of such compounds within degradable polymers.
TL;DR: Liposome distribution coefficients of ionizable drugs derived by a pH-metric titration were successfully used to calculate a parameter that correlates with the percentage of passive intestinal absorption in humans.
Abstract: Purpose Appropriate physicochemical parameters are desired for the prediction of passive intestinal drug absorption during lead compound selection and drug development
TL;DR: The probability of oral bioavailability for β-lactam antibiotics is mainly determined by their affinity to PEPT1, and the uptake into the cells and the transepithelial flux was highest for those β-biotics, which showed the strongest inhibition of [14C]Gly-Sar transport.
Abstract: Purpose. This study on the intestinal transport of β-lactam antibiotics was undertaken to investigate the correlation between cellular transport parameters and the bioavailability.
TL;DR: GJ significantly activates P-gp-mediated efflux of drugs that are substrates of P- gp, potentially partially counteracting the CYP3A-inhibitory effects of GJ.
Abstract: Purpose. Grapefruit juice (GJ) is known to increase the oral bioavailability of many CYP3A-substrates by inhibiting intestinal phase-I metabolism. However, the magnitude of AUC increase is often insignificant and highly variable. Since we earlier suggested that CYP3A and P-glycoprotein (P-gp) form a concerted barrier to drug absorption, we investigated the role of P-gp in GJ-drug interactions.
TL;DR: Protein stability was improved by formulation with carbohydrate, however, a balance must be achieved between the addition of enough stabilizer to improve protein biochemical stability without compromising blended powder aerosol performance.
Abstract: Purpose. To study the effect of trehalose, lactose, and mannitol on the biochemical stability and aerosol performance of spray-dried powders of an anti-IgE humanized monoclonal antibody.
TL;DR: This review addresses the pharmaceutical potential of the intestinal peptide transport system and summarizes several studies on the mechanism and substrate structure-affinity relationship for this transport system.
Abstract: The intestinal peptide transport system has broad substrate specificities. In addition to its physiological function of absorbing di- and tripeptides resulting from the digestion of dietary proteins, this transport system also absorbs some orally administered peptidomimetic drugs, including β-lactam antibiotics, angiotensin converting enzyme inhibitors, renin inhibitors, bestatin, thrombin inhibitors, and thyrotropin-releasing hormone and its analogues. There have been several studies on the mechanism and substrate structure-affinity relationship for this transport system. Rapid progress has been made recently in studies on the molecular basis of the intestinal peptide transport system. A protein apparently involved in peptide transport has been isolated from rabbit small intestines, and genes for human intestinal peptide transporters have been cloned, sequenced and functionally expressed. This review summarizes these studies and addresses the pharmaceutical potential of the intestinal peptide transport system.
TL;DR: These low cost, and adjustable, controlled DNA delivery systems, using FDA-approved biocompatible/biodegradable and implantable/injectable materials, could be useful for in vivo gene delivery, such as DNA vaccination and gene therapy.
Abstract: Purpose. Genes are of increasing interest as pharmaceuticals, but current methods for long-term gene delivery are inadequate. Controlled release systems using biocompatible and/or biodegradable polymers offer many advantages over conventional gene delivery approaches. We have characterized systems for controlled delivery of DNA from implantable polymer matrices (EVAc: poly (ethylene-co-vinyl acetate)) and injectable microspheres (PLGA and PLA: poly (D, L-lactide-co-glycolide) copolymer and poly (L-lactide), respectively).
TL;DR: The integrated absorption model was successfully applied to digoxin, griseofulvin, and panadiplon to estimate the fraction dose absorbed and to roughly determine the causes of poor oral drug absorption.
Abstract: Purpose. To develop an integrated absorption model for estimating the fraction of dose absorbed and determining the causes of poor oral drug absorption.