Showing papers in "Pharmaceutical Research in 1995"
TL;DR: A biopharmaceutics drug classification scheme for correlating in vitro drug product dissolution and in vivo bioavailability is proposed based on recognizing that drug dissolution and gastrointestinal permeability are the fundamental parameters controlling rate and extent of drug absorption.
Abstract: A biopharmaceutics drug classification scheme for correlating in vitro drug product dissolution and in vivo bioavailability is proposed based on recognizing that drug dissolution and gastrointestinal permeability are the fundamental parameters controlling rate and extent of drug absorption. This analysis uses a transport model and human permeability results for estimating in
vivo drug absorption to illustrate the primary importance of solubility and permeability on drug absorption. The fundamental parameters which define oral drug absorption in humans resulting from this analysis are discussed and used as a basis for this classification scheme. These Biopharmaceutic Drug Classes are defined as: Case 1. High solubility-high permeability drugs, Case 2. Low solubility-high permeability drugs, Case 3. High solubility-low permeability drugs, and Case 4. Low solubility-low permeability drugs. Based on this classification scheme, suggestions are made for setting standards for in vitro drug dissolution testing methodology which will correlate with the in vivo process. This methodology must be based on the physiological and physical chemical properties controlling drug absorption. This analysis points out conditions under which no
in vitro-in vivo correlation may be expected e.g. rapidly dissolving low permeability drugs. Furthermore, it is suggested for example that for very rapidly dissolving high solubility drugs, e.g. 85% dissolution in less than 15 minutes, a simple one point dissolution test, is all that may be needed to insure bioavailability. For slowly dissolving drugs a dissolution profile is required with multiple time points in systems which would include low pH, physiological pH, and surfactants and the in vitro conditions should mimic the in vivo processes. This classification scheme provides a basis for establishing in vitro-in vivo correlations and for estimating the absorption of drugs based on the fundamental dissolution and permeability properties of physiologic importance.
5,049 citations
TL;DR: It is hoped that this review will lead to a more direct approach to the characterization of pharmaceuticalsolids and ultimately to faster approval of regulatory documents containing information on pharmaceutical solids.
Abstract: Purpose. This review describes a conceptual approach to the characterization of pharmaceutical solids.
Methods. Four flow charts are presented: (1) polymorphs, (2) hydrates, (3) desolvated solvates, and (4) amorphous forms.
Results. These flow charts (decision trees) are suggested as tools to develop information on pharmaceutical solids for both scientific and regulatory purposes.
Conclusions. It is hoped that this review will lead to a more direct approach to the characterization of pharmaceutical solids and ultimately to faster approval of regulatory documents containing information on pharmaceutical solids.
966 citations
TL;DR: In the temperature range studied the model amorphous solids were in a transition zone between regions of very high molecular mobility above Tg and very low molecular mobility much further below Tg, which should be expected to experience significant molecular mobility at temperatures up to fifty degrees below their glass transition temperature.
Abstract: Purpose. To measure the molecular mobility of amorphous pharmaceutical solids below their glass transition temperatures (Tg), using indomethacin, poly (vinyl pyrrolidone) (PVP) and sucrose as model compounds.
Methods. Differential scanning calorimetry (DSC) was used to measure enthalpic relaxation of the amorphous samples after storage at temperatures 16-47 K below Tg for various time periods. The measured enthalpy changes were used to calculate molecular relaxation time parameters. Analogous changes in specimen dimensions were measured for PVP films using thermomechanical analysis.
Results. For all the model materials it was necessary to cool to at least 50 K below the experimental Tg before the molecular motions detected by DSC could be considered to be negligible over the lifetime of a typical pharmaceutical product. In each case the temperature dependence of the molecular motions below Tg was less than that typically reported above Tg and was rapidly changing.
Conclusions. In the temperature range studied the model amorphous solids were in a transition zone between regions of very high molecular mobility above Tg and very low molecular mobility much further below Tg. In general glassy pharmaceutical solids should be expected to experience significant molecular mobility at temperatures up to fifty degrees below their glass transition temperature.
926 citations
TL;DR: This review highlights the state-of-the-art in pharmaceutical microemulsions with emphasis on self-emulsifying systems, from both a physical and biopharmaceutical perspective, primarily focused on their potential for oral drug delivery and intestinal absorption improvement.
Abstract: Purpose This review highlights the state-of-the-art in pharmaceutical microemulsions with emphasis on self-emulsifying systems, from both a physical and biopharmaceutical perspective Although these systems have several pharmaceutical applications, this review is primarily focused on their potential for oral drug delivery and intestinal absorption improvement
769 citations
TL;DR: Findings indicate that pCAT is taken up by the liver via scavenger receptors on the non-parenchymal cells, which provides useful information for the development of delivery systems for in vivo gene therapy.
Abstract: Purpose. We examined the stability and disposition characteristics of a naked plasmid DNA pCAT as a model gene after intravenous injection in mice to construct the strategy of in vivo gene delivery systems.
Methods. After the injection of pCAT to the mice, stability, tissue distribution, hepatic cellular localization, and effect of some polyanions on the hepatic uptake were studied.
Results. The in vitro study demonstrated that the pCAT was rapidly degraded in mouse whole blood with a half-life of approximately 10 min at a concentration of 100 µg/ml. After intravenous injection, pCAT was degraded at a significantly faster rate than that observed in the whole blood, suggesting that pCAT in vivo was also degraded in other compartments. Following intravenous injection of [32P] pCAT, radioactivity was rapidly eliminated from the plasma due to extensive uptake by the liver. Hepatic accumulation occurred preferentially in the non-parenchymal cells. The hepatic uptake of radioactivity derived from [32P] pCAT was inhibited by preceding administration of polyanions such as polyinosinic acid, dextran sulfate, maleylated and succinylated bovine serum albumin but not by polycytidylic acid. These findings indicate that pCAT is taken up by the liver via scavenger receptors on the non-parenchymal cells. Pharmacokinetic analysis revealed that the apparent hepatic uptake clearance was fairly close to the liver plasma flow.
Conclusions. These findings provide useful information for the development of delivery systems for in vivo gene therapy.
463 citations
TL;DR: In this article, a method for simultaneous application of ultrasound and protein on the skin surface in order to deliver therapeutic doses of proteins across the skin was proposed, which can enhance transdermal transport of high-molecular weight proteins.
Abstract: Applications of low-frequency (20 KHz) ultrasound enhances transdermal transport of high-molecular weight proteins. This method includes a simultaneous application of ultrasound and protein on the skin surface in order to deliver therapeutic doses of proteins across the skin. Examples demonstrate in vitro and in vivo administration of insulin (molecular weight 6,000 D), and in vitro administration of gamma interferon (molecular weight 17,000 D), and erythropoeitin (molecular weight 48,000 D).
431 citations
TL;DR: A general review of the methods available for the physical characterization of pharmaceutical solids is presented in this article, which is classified as being on the molecular level, the particulate level, and the bulk level.
Abstract: A general review of the methods available for the physical characterization of pharmaceutical solids is presented. The techniques are classified as being on the molecular level (properties capable of being detected in an ensemble of individual molecules), the particulate level (properties which can be detected through the analysis of an ensemble of particles), and the bulk level (properties which can be measured only using a relatively large amount of material). The molecular-level properties discussed are infrared spectroscopy and nuclear magnetic resonance spectrometry, the particulate-level properties discussed are particle morphology, particle size distribution, powder X-ray diffraction, and thermal methods of analysis, and the bulk-level properties discussed are surface area, porosity and pore size distribution, and powder flow characteristics. Full physical characterization of three modifications of lactose (hydrous, anhydrous, and Fast-Flo) is presented to illustrate the type of information which can be obtained using each of the techniques discussed.
366 citations
TL;DR: An unexpected high degree of transcytosis of a monoclonal antibody through the primate BBB in vivo is demonstrated in vivo in anesthetized Rhesus monkeys.
Abstract: Purpose. The ability of monoclonal antibodies against the human insulin receptor to undergo transcytosis through the blood-brain barrier (BBB) was examined in the present studies.
311 citations
TL;DR: Three types of nucleic acid drugs are discussed in this review: aptamers, compounds which bind specific proteins; triplex forming (antigene) compounds; which bind double stranded DNA; and ribozymes (catalytic RNA), which bind and cleave RNA targets.
Abstract: Nucleic acids are increasingly being considered for therapeutic uses, either to interfere with the function of specific nucleic acids or to bind specific proteins. Three types of nucleic acid drugs are discussed in this review: aptamers, compounds which bind specific proteins; triplex forming (antigene) compounds; which bind double stranded DNA; and ribozymes (catalytic RNA), which bind and cleave RNA targets. The binding of aptamers to protein may involve specific sequence recognition, although this is not always the case. The interaction of triplex forming oligonucleotides or ribozymes with their targets always involves specific sequence recognition and hybridization. Early optimism concerning the possibility of designing drugs without a priori knowledge of the structure of the target (except a nucleotide sequence) has been tempered by the finding that target structure has a dramatic effect upon the hybridization potential of the nucleic acid drug. Other obstacles to the creation of effective nucleic acid drugs are their relative high molecular weight (>3300) and their sensitivity to degradation. The molecular weight of these compounds has created a significant delivery problem which needs to be solved if nucleic acid drugs are to become effective therapies.
310 citations
TL;DR: ADR entrapment in polymeric micelles is expected to affect markedly the pharmacokinetics of ADR, and the findings suggest that ADR is stably entrapped in PEO-PBLA micells.
Abstract: The entrapment of Adriamycin (ADR) in micelles composed of AB block copolymers (poly(ethylene oxide-co-β-benzyl L-aspartate) (PEO-PBLA)) was investigated. The loading process involved transfer of ADR and PEO-PBLA into an aqueous milieu from dimethyl-formamide (DMF) through a dialysis procedure. Evidence for the physical entrapment of ADR in the polymeric micelles was derived from fluorescence spectroscopy and gel permeation chromatography (GPC). The total fluorescence intensity of ADR was low, suggesting that the drug was self-associated in the micelles. In addition, quenching experiments, using a water-soluble quencher (iodide (I–)), showed that the fluorescence of ADR present in micellar solutions was largely unaffected by I–, whereas the fluorescence of free ADR was readily quenched. From Stern-Volmer plots, quenching constants (KSV) of 2.2 and 17 M−l were determined for ADR in micellar solutions and free ADR, respectively. As a result of the entrapment of ADR in the micelles, ADR binds only slightly serum albumin as evidenced by GPC. In contrast, ADR readily binds serum albumin in aqueous solutions. The findings suggest that ADR is stably entrapped in PEO-PBLA micelles. ADR entrapment in polymeric micelles is expected to affect markedly the pharmacokinetics of ADR.
283 citations
TL;DR: A biophysically relevant model of drug transport through human skin is derived based solely on the physical properties of the drug, which provides an algorithm to predict permeability from the drug's structure and/or physical properties.
Abstract: Purpose. To develop a predictive algorithm of nonelectrolyte transport through skin based upon a partitioning-diffusion model.
Methods. Drug permeability is described by a partitioning-diffusion equation. Through free-energy relationships, partitioning is related to the drug's molecular volume (MV), and hydrogen bond donor (Hd) and acceptor (Ha) activity. Diffusion is related to the drug's MV using a theory of diffusion through lipid lamellae based on free-volume fluctuations within the lipid domain. These two explicit descriptions are combined to give an equation describing permeability in terms of the permeant's physical properties. The aqueous permeability coefficients of 37 nonelectrolytes through human epidermis were evaluated as a function of these physical properties using a multiple regression analysis.
Results. The results of the regression analysis show that 94% of the variability in the data can be explained by a model which includes only the permeant's MV, Hd and Ha. These results further provide an algorithm to predict skin permeability based upon the values of these parameters. In addition, the relative contribution of various chemical functional groups (e.g., -COOH) is derived, and can be used to predict skin transport from drug structure alone.
Conclusions. A biophysically relevant model of drug transport through human skin is derived based solely on the physical properties of the drug. The model provides an algorithm to predict permeability from the drug's structure and/or physical properties. Moreover, the model is applicable to a number of lipid barrier membranes, suggesting a common transport mechanism in all.
TL;DR: The experiments show the dynamic nature of micronized albuterol sulfate and aid in the determination of the actual physical state of this pharmaceutical powder.
Abstract: Pharmaceutical powders are often milled to achieve the optimum particle size. These size reduction processes can introduce dislocations and/or defects onto particle surfaces affecting the overall crystallinity of the powder. If enough energy is imparted, amorphous regions on the particle surfaces may be produced. These amorphous regions have the propensity to absorb significant quantities of water. In this study the effect of sorbed water on the physical characteristics of albuterol sulfate is investigated. Physical properties of this compound are studied in both micronized and unmicronized states using scanning electron microscopy, differential scanning calorimetry, powder x-ray diffraction, solution microcalorimetry, laser diffraction particle size analysis and water vapor sorption analysis. Subtle differences in crystallinity induced by air jet micronization are detected by several analytical methods. Amorphous to crystalline conversions are observed, the kinetics of which are found to be both temperature and relative humidity dependent. These experiments show the dynamic nature of micronized albuterol sulfate and aid in the determination of the actual physical state of this pharmaceutical powder.
TL;DR: It was shown that it was possible to establish a tight intestinal segment which behaved as a well-mixed compartment and the low perfusion rate of 3 ml/min was preferred, since it resulted in the lowest variability in absorption.
Abstract: Recently a new in vivo approach in man, using a regional intestinal perfusion technique, has been developed. The perfusion tube consists of a multichannel tube with two inflatable balloons, which are placed 10 cm apart. The tube is introduced orally and the time required for insertion and positioning of the tube is approximately 1 hr. In the present study eight healthy subjects were perfused in the proximal jejunum on three separate occasions. The first two perfusion experiments used the same flow rate, 3 ml/min, and the third experiment used 6 ml/min. Phenazone (antipyrine) was chosen as the model drug. The recovery of PEG 4000 in the outlet intestinal perfusate was complete in experiments 1 and 2, but slightly lower (90%) when the higher flow rate was used. The mean (+/- SD) fraction of phenazone absorbed calculated from perfusion data was 51 +/- 12% (3 ml/min), 64 +/- 19% (3 ml/min), and 42 +/- 27% (6 ml/min) for the three experiments, respectively. The mean fraction absorbed estimated by deconvolution of the plasma data was 47 +/- 16%, 51 +/- 19%, and 38 +/- 26%, respectively. The effective permeability of phenazone was 5.3 +/- 2.5, 11 +/- 6.8, and 11 +/- 12 (x 10(4) cm/sec, respectively. We have shown that it was possible to establish a tight intestinal segment which behaved as a well-mixed compartment. The low perfusion rate of 3 ml/min was preferred, since it resulted in the lowest variability in absorption.(ABSTRACT TRUNCATED AT 250 WORDS)
TL;DR: A formulation of sterically stabilized liposomes with the proper thermal sensitivity in human plasma has been obtained and the results suggest that complement may play an important role in the interaction of rigid but not fluid liposome with bovine serum.
Abstract: Purpose. To formulate thermosensitive sterically stabilized liposomes and to study the effects of plasma and serum components in vitro.
Methods. The rate of release of encapsulated doxorubicin (Dox) from liposomes of various compositions was followed by fluorometric assay at 37°, 42° and 45°C, in buffer and also in both calf serum and human plasma up to 50% by volume.
Results. The optimal composition for the maximal differential release of doxorubicin between 37°C and 42°C in human plasma was a mixture of dipalmitoylphosphatidylcholine/hydrogenated soy phosphatidylcholine/cholesterol and distearoylphosphatidylethanolamine derivatized with polyethylene glycol at a molar ratio of 100:50:30:6. In experiments designed to study the mechanism causing increased permeability of liposomes in bovine serum, we found two different distinct release patterns: a slow linear rise of rate of Dox release for fluid liposomes and fast exponential rise reaching plateau within 5 minutes for solid phase (rigid) liposomes. This release of Dox from rigid but not fluid liposomes was inhibited by pre-heating serum at 55°C for 30 minutes or by addition of EDTA (but not EGTA) or antiserum to the C3 component of complement.
Conclusions. A formulation of sterically stabilized liposomes with the proper thermal sensitivity in human plasma has been obtained. In addition, the results suggest that complement may play an important role in the interaction of rigid but not fluid liposomes with bovine serum. Human plasma did not show this effect.
TL;DR: The results support caution in extrapolating correlations based on findings with small organic molecules to the behavior of complex peptidomimetics, and suggest that CACO-2 cell monolayers and rat single-pass intestinal perfusion combine the highest correlation between systems, most defined relationship with fraction absorbed in humans, and experimental logistics in-line with discovery candidates.
Abstract: In vitro and in situ experimental models that are descriptive of drug absorption in vivo are valuable tools in the discovery of new chemical entities that are bioavailable after oral administration. The specific objective of the study was to compare the intestinal permeabilities obtained in the three absorption models for consistency, and to assess the utility of the models in predicting the fraction of dose absorbed in human studies. The intestinal absorption models that were compared are widely used: the rat in situ single-pass intestinal perfusion system, the rat everted intestinal ring method, and monolayers of human colon adenocarcinoma cell line (CACO-2). The models were compared using small molecular reference compounds, as well as a series of peptidomimetic (PM) analogs. Each model had strong potential for estimating the fraction absorbed. For small organic molecules, excellent correlation was observed when permeabilities from CACO-2 cells and perfusions, or everted rings and perfusions, were compared. Weaker correlation was observed between everted rings and CACO-2 cells. Permeabilities for the set of reference compounds and PMs were positively correlated between any two of the three systems. Variance between correlations for reference compounds and PMs are likely due to structural features and physicochemical properties that are unique to the latter class of compounds. The results support caution in extrapolating correlations based on findings with small organic molecules to the behavior of complex peptidomimetics. Corroboration of permeabilities with two methods of determination is a useful cross-validation of experimental systems, as well as producing a reliable permeability assessment. CACO-2 cell monolayers and rat single-pass intestinal perfusion combine the highest correlation between systems, most defined relationship with fraction absorbed in humans, and experimental logistics in-line with discovery candidates.
TL;DR: The non-cytotoxic cytokine inhibition by liposome encapsulated clodronate could be beneficial in local inflammatory diseases, where the inflammation is sustained by the excessive amounts of inflammatory cytokines produced by activated macrophages.
Abstract: Purpose. In order to evaluate the possible antiinflammatory action of bisphosphonates, the effect of the drugs on the secretion of proinflammatory cytokines (IL-lβ, IL-6 and TNFα) from macrophages was studied. Liposomes or high concentration of extracellular calcium was used to enhance the intracellular delivery of bisphosphonates.
TL;DR: The PCA method is a promising technique for the preparation of drug-containing microparticles with potential advantages including the flexibility of preparingmicroparticles of different size and morphology, the elimination of surfactants, the minimization of residual organic solvents, low to moderate processing temperatures and the potential for scale-up.
Abstract: Purpose The objective was to prepare polymeric microparticles by atomizing organic polymer solutions into a spray chamber containing compressed CO2 (PCA-process) and to study the influence of various process parameters on their morphological characteristics
TL;DR: This technique offers a new method for estimating the protein:surfactant binding stoichiometries by using the partitioning behavior of a spin label to study the interaction of these formulation additives with proteins.
Abstract: Surfactants are known to stabilize proteins and are often employed as additives in protein formulations. We have developed a method to study the interaction of these formulation additives with proteins by using the partitioning behavior of a spin label. In protein-free formulations, 16-doxyl stearic acid partitions into micelles above the critical micelle concentration (CMC) of the surfactant and gives rise to composite electron paramagnetic resonance (EPR) spectra composed of spectra from “free” label and “rotationally hindered” label. We compute the fraction of micelle-associated label by factor analysis and generate a label partition curve. When protein is added to the formulation, surfactant-protein aggregates form at concentrations below the surfactant's CMC. Partitioning of the label into these aggregates causes the EPR spectrum to reflect hindered rotation of the label at lower surfactant concentrations than in the protein-free solutions. A simple model of label partitioning shows that these partitioning shifts can be correlated to the surfactant:protein binding stoichiometry. We have studied the interactions of various non-ionic surfactants like Brij and Tween with recombinant human growth hormone and recombinant human interferon-γ and obtained corresponding binding stoichiometries. These binding stoichiometries match those obtained by other techniques. This technique offers a new method for estimating the protein:surfactant binding stoichiometries.
TL;DR: The findings suggest that using informative graphical and statistical techniques enhance the understanding of the data structure and lead to an efficient analysis of theData.
Abstract: Purpose. The usefulness of several modelling methods were examined in the development of a population pharmacokinetics model for cefepime.
TL;DR: Examination of the dried-state conformation of interleukin-2 was used to determine the pH conditions and stabilizers that provide optimal storage stability for the lyophilized product and a strong direct correlation between the retention of the native (aqueous) structure during freeze-drying and enhanced stability is demonstrated.
Abstract: Purpose. Examination of the dried-state conformation of interleukin-2 (IL-2) was used to determine the pH conditions and stabilizers that provide optimal storage stability for the lyophilized product.
Methods. Fourier-transform infrared spectroscopy and accelerated stability studies which examined solubility, aggregate formation, and covalent cross-linking were used.
Results. Varying the pH in the absence of excipients resulted in dramatic differences in the dried state conformation of IL-2. At pH 7, IL-2 unfolds extensively upon lyophilization while at pH below 5 it remains essentially native. Additional unfolding was observed upon incubation at elevated temperatures. A strong direct correlation between the retention of the native (aqueous) structure during freeze-drying and enhanced stability is demonstrated. IL-2 prepared at pH 5 is approximately an order of magnitude more stable than at pH 7 with regard to formation of soluble and insoluble aggregates. A similar pH profile was observed in the presence of excipients, although the excipients alter the overall stability profile. Additional accelerated stability studies examined the stabilizers necessary for optimal stability.
Conclusions. Excipients with the capacity to substitute for water upon dehydration better preserve the native structure resulting in enhanced stability. Those that have high glass transition temperatures provide the highest level of stability during storage, although they do not prevent dehydration induced unfolding.
TL;DR: The poly(acrylates) investigated may have potential to protect peptides from tryptic degradation and may be used to master the peroral delivery of peptide drugs.
Abstract: Purpose. The evaluation of the inhibitory action of two mucoadhesive poly(acrylates), polycarbophil and carbomer, registered by the Food and Drug Administration (FDA), on the intestinal proteolytic enzyme trypsin.
TL;DR: The results suggest that these cationic compounds are transported by plural P-glycoprotein-mediated efflux systems with different substrate specificities depending on the intestinal site.
Abstract: Purpose. We investigated the intestinal transport of verapamil, chlorpromazine, and propantheline, particularly their P-glycoprotein-mediated secretion.
TL;DR: A review of follicular drug delivery and a discussion of the feasibility of the pilosebaceous unit as a target site are presented.
Abstract: The hair follicle, hair shaft, and sebaceous gland collectively form what is recognized as the pilosebaceous unit. This complex, three-dimensional structure within the skin possesses a unique biochemistry, metabolism and immunology. Recent studies have focused on the hair follicle as a potential pathway for both localized and systemic drug delivery. Greater understanding of the structure and function of the hair follicle may facilitate rational design of drug formulations to target follicular delivery. Targeted drug delivery may enhance current therapeutic approaches to treating diseases of follicular origin. Presented here is a review of follicular drug delivery and a discussion of the feasibility of the pilosebaceous unit as a target site.
TL;DR: It has been shown that iontophoretic sampling of glucose is feasible, and the shorter periods (15 minutes or less) of extraction considered yield results which are “contaminated” by glucose that is a product of lipid metabolism within the skin.
Abstract: Purpose. To demonstrate that “reverse iontophoresis” can be used to noninvasively obtain information about systemic glucose levels in vivo in humans.
TL;DR: There are cut-off values for viscosity and/or surface tension above or below which ultrasonic devices fail to operate, and jet nebulizers generated an aerosol with an optimum respirable output from median-viscosity fluids.
Abstract: Purpose. Empirical formulae relate the mean size of primary droplets from jet and ultrasonic nebulizers to a fluid's physicochemical properties. Although the size selective “filtering” effects of baffling and evaporation may modify the secondary aerosol produced, this research sought to evaluate whether viscosity and surface tension of nebulized fluids influenced the aerosol's size and output characteristics.
TL;DR: There is a fairly strong case that peptides can be differentially transported at the blood-brain barrier, and future directions should be directed towards development of molecular strategies to up-regulate specific BBB peptide transporters to enhance brain delivery of peptide neuropharmaceuticals, or to down- Regulate transport of peptides with potential role in cerebral pathogenesis.
Abstract: The study of peptide transport across the blood-brain barrier (BBB) is a field fraught with conflicting interpretations. This review presents a fairly strong case that peptides can be differentially transported at the BBB. However, minimal transport of peptides could have important impact on central nervous system (CNS) functions since only small amounts are needed for physiologic, pharmacologic and/or pathologic effects. Several BBB peptide transport mechanisms (i.e., receptor-mediated, absorptive-mediated, carrier-mediated and non-specific passive diffusion), as well as non-transport processes (i.e., endocytosis without transcytosis, aborption and metabolism) are discussed. It is emphasized that peptide transport systems at the BBB could be important targets for both therapeutic delivery of peptides and the development of certain brain pathologies. Strategies to manipulate peptide BBB transport processes have been discussed including lipidization, chemical modifications of the N-terminal end, coupling of transport with post-BBB metabolism and formation of potent neuroactive peptides, up-regulation of putative peptide transporters, use of chimeric peptides in which non-transportable peptide is chemically linked to a transportable peptide, use of monoclonal antibodies against peptide receptors, and binding of circulating peptides to apolipoproteins. It is suggested that future directions should be directed towards development of molecular strategies to up-regulate specific BBB peptide transporters to enhance brain delivery of peptide neuropharmaceuticals, or to down-regulate transport of peptides with potential role in cerebral pathogenesis.
TL;DR: Poloxamer gel proved to be the most promising carrier for lidocaine in the use of low-viscosity gels in prolonging the release of lidocane in rats.
Abstract: Purpose. Methods of delaying the action of local anesthetics are important, since short duration of action limits their use in the treatment of postoperative and chronic pain. The present study evaluated the use of low-viscosity gels in prolonging the release of lidocaine.
Methods. Release of lidocaine from 2% lidocaine-HC1 containing methylcellulose (MC), hydroxypropylmethylcellulose (HPMC), sodiumcarboxymethyl cellulose (CMC), and poloxamer 407 (PO) gels was studied in phosphate buffer, pH 7.4, at 37°C. Commercial metylcellulose gel (MCcom) served as control. The in vivo efficacy of the respective gel formulations were evaluated in rats. The gel was injected into the vicinity of the sciatic nerve and nociception and motor function were tested.
Results. The cumulative amount of lidocaine released during 8 hr was slowest from the PO gel, followed by the CMC, HPMC and MC gels. The antinociceptive effect was not prevented by the motor block and lasted longest with the PO gel. Good linear and rank order correlation was obtained between in vitro and in vivoresults. The microscopic examination of the tissue samples revealed only mild or no irritation of the skeletal muscle tissue by the PO, HPMC, and CMC gels.
Conclusions. Based on these results poloxamer gel proved to be the most promising carrier for lidocaine.
TL;DR: Two types of polyglycerol ester of fatty acid (PGEF)-based microspheres were prepared and they adhered strongly to mucosa prepared from rat stomach and small intestine because each CP particle in the CPD-microsphere was hydrated and swelled with part of it remaining within the microsphere and part extending to the surface serving to anchor the micro Spheres to the mucus layer.
Abstract: Two types of polyglycerol ester of fatty acid (PGEF)-based microspheres were prepared: Carbopol 934P (CP)-coated microspheres (CPC-microspheres) and CP-dispersion microspheres (CPD-microspheres). Comparative studies on mucoadhesion were done with these microspheres and PGEF-based microspheres without CP (PGEF-microspheres). In an in vitro adhesion test, the CPD-microspheres adhered strongly to mucosa prepared from rat stomach and small intestine because each CP particle in the CPD-microsphere was hydrated and swelled with part of it remaining within the microsphere and part extending to the surface serving to anchor the microsphere to the mucus layer. The gastrointestinal transit patterns after administration of the CPD-microspheres and PGEF-microspheres to fasted rats were fitted to a model in which the microspheres are emptied from the stomach monoexponentially with a lag time and then transit through the small intestine at zero-order. Parameters obtained by curve fitting confirmed that the gastrointestinal transit time of the CPD-microspheres was prolonged compared with that of the PGEF-microspheres. MRT in the gastrointestinal tract was also prolonged after administration of the CPD-microspheres compared with that following the administration of the PGEF-microspheres.
TL;DR: A phase diagram was constructed for the TBA-water system and it was found that TBA altered the crystal habit of ice and the rate of sublimation of the TBA and water molecules was found to be concentration dependent.
Abstract: Utilizing differential scanning calorimetry (DSC) for tertiary butyl alcohol (TBA) solutions a phase diagram was constructed for the TBA-water system. By utilizing thermal treatment during the DSC measurements the metastable states were eliminated. The phase diagram fit that for a congruently melting compound in which compound formation occurred with a maximum at 70% TBA representing pure TBA hydrate. Two eutectics occurred at 20% (Eutectic A) and 90% (Eutectic B). A freeze-drying microscope revealed that TBA altered the crystal habit of ice. A concentration of 3% TBA was required before large needle-shaped ice crystals became evident. The addition of 10% TBA to the system resulted in even finer needle-shaped ice crystals. At the eutectic compositions (20% and 90% TBA), the frozen eutectic mixture could not be resolved with the microscope because eutectic crystals are very small. The 70% TBA solution, which corresponds to the melting of pure TBA hydrate, formed very large hydrate crystals. The rate of sublimation of the TBA and water molecules was found to be concentration dependent. At concentrations below 20% TBA (water rich portion of the phase diagram) water molecules sublimed faster while at concentrations above 20% TBA (TBA rich portion of the phase diagram) TBA molecules sublimed faster. At the eutectic A composition, both TBA and water molecules sublimed at the same rate. This may be because all of the TBA molecules are strongly associated with each other in the form of a clathrate hydrate.
TL;DR: These mechanical property data are consistent with the hypothesis that water acts as a plasticizer and influences the mechanical properties of microcrystalline cellulose.
Abstract: Purpose. This study determined the effects of moisture on the mechanical and powder flow properties of microcrystalline cellulose.