Showing papers in "Pharmaceutical Research in 2004"

Solubilizing excipients in oral and injectable formulations.

Abstract: A review of commercially available oral and injectable solution formulations reveals that the solubilizing excipients include water-soluble organic solvents (polyethylene glycol 300, polyethylene glycol 400, ethanol, propylene glycol, glycerin, N-methyl-2-pyrrolidone, dimethylacetamide, and dimethylsulfoxide), non-ionic surfactants (Cremophor EL, Cremophor RH 40, Cremophor RH 60, d-alpha-tocopherol polyethylene glycol 1000 succinate, polysorbate 20, polysorbate 80, Solutol HS 15, sorbitan monooleate, poloxamer 407, Labrafil M-1944CS, Labrafil M-2125CS, Labrasol, Gellucire 44/14, Softigen 767, and mono- and di-fatty acid esters of PEG 300, 400, or 1750), water-insoluble lipids (castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oils, hydrogenated soybean oil, and medium-chain triglycerides of coconut oil and palm seed oil), organic liquids/semi-solids (beeswax, d-alpha-tocopherol, oleic acid, medium-chain mono- and diglycerides), various cyclodextrins (alpha-cyclodextrin, beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, and sulfobutylether-beta-cyclodextrin), and phospholipids (hydrogenated soy phosphatidylcholine, distearoylphosphatidylglycerol, L-alpha-dimyristoylphosphatidylcholine, L-alpha-dimyristoylphosphatidylglycerol). The chemical techniques to solubilize water-insoluble drugs for oral and injection administration include pH adjustment, cosolvents, complexation, microemulsions, self-emulsifying drug delivery systems, micelles, liposomes, and emulsions.

Design of freeze-drying processes for pharmaceuticals: practical advice.

Abstract: Design of freeze-drying processes is often approached with a "trial and error" experimental plan or, worse yet, the protocol used in the first laboratory run is adopted without further attempts at optimization. Consequently, commercial freeze-drying processes are often neither robust nor efficient. It is our thesis that design of an "optimized" freeze-drying process is not particularly difficult for most products, as long as some simple rules based on well-accepted scientific principles are followed. It is the purpose of this review to discuss the scientific foundations of the freeze-drying process design and then to consolidate these principles into a set of guidelines for rational process design and optimization. General advice is given concerning common stability issues with proteins, but unusual and difficult stability issues are beyond the scope of this review. Control of ice nucleation and crystallization during the freezing step is discussed, and the impact of freezing on the rest of the process and final product quality is reviewed. Representative freezing protocols are presented. The significance of the collapse temperature and the thermal transition, denoted Tg', are discussed, and procedures for the selection of the "target product temperature" for primary drying are presented. Furthermore, guidelines are given for selection of the optimal shelf temperature and chamber pressure settings required to achieve the target product temperature without thermal and/or mass transfer overload of the freeze dryer. Finally, guidelines and "rules" for optimization of secondary drying and representative secondary drying protocols are presented.

Uptake and Cytotoxicity of Chitosan Molecules and Nanoparticles: Effects of Molecular Weight and Degree of Deacetylation

Abstract: Purpose. To evaluate the effects of molecular weight (Mw) and degree of deacetylation (DD) on the cellular uptake and in vitro cytotoxicity of chitosan molecules and nanoparticles.

Structure-immunogenicity relationships of therapeutic proteins.

Abstract: As more recombinant human proteins become available on the market, the incidence of immunogenicity problems is rising. The antibodies formed against a therapeutic protein can result in serious clinical effects, such as loss of efficacy and neutralization of the endogenous protein with essential biological functions. Here we review the literature on the relations between the immunogenicity of the therapeutic proteins and their structural properties. The mechanisms by which protein therapeutics can induce antibodies as well as the models used to study immunogenicity are discussed. Examples of how the chemical structure (including amino acid sequence, glycosylation, and pegylation) can influence the incidence and level of antibody formation are given. Moreover, it is shown that physical degradation (especially aggregation) of the proteins as well as chemical decomposition (e.g., oxidation) may enhance the immune response. To what extent the presence of degradation products in protein formulations influences their immunogenicity still needs further investigation. Immunization of transgenic animals, tolerant for the human protein, with well-defined, artificially prepared degradation products of therapeutic proteins may shed more light on the structure-immunogenicity relationships of recombinant human proteins.

Physicochemical Parameters Associated with Nanoparticle Formation in the Salting-Out, Emulsification-Diffusion, and Nanoprecipitation Methods

Abstract: Purpose. The aim of this work was to relate the physicochemical properties of the aqueous and organic phases used for nanoparticle (NP) preparation to the formation of NP produced by salting-out, emulsification-diffusion, and nanoprecipitation. Methods. Methacrylic acid copolymer and poly(vinyl alcohol) (PVAL) were selected as NP polymer and emulsifying agent, respectively. Salting-out and emulsification-diffusion NP batches were prepared modifying the PVAL content in the aqueous phase. For nanoprecipitation, NP were produced with variation of the polymer content and type of solvent in the organic phase. Results. For salting-out and emulsification-diffusion, NP formation was discussed in terms of the emulsification theory. The nanoemulsion obtained during NP preparation was visualized by scanning electron microscopy. Aqueous and organic phases used for NP preparation were characterized by their viscosity and surface tension. NP characteristics such as particle mean size, residual surfactant, suspendability in water after freeze-drying, and morphology were explained in terms of these properties. For nanoprecipitation, NP formation was analyzed considering the diffusion-stranding phenomenon. Conclusions. NP formation by salting-out and emulsification-diffusion was related to PVAL chain interactions at the droplet interface (e.g., reduction in the interfacial tension, mechanical sta- bilization, and steric stabilization) and in the bulk solution (hy- drodynamic stabilization). For nanoprecipitation, χsolvent-water and Δδsolvent-water of the organic phase solvents were well related to the NP characteristics.

Transdermal Delivery of Insulin Using Microneedles in Vivo

Abstract: Purpose. The purpose of this study was to design and fabricate arrays of solid microneedles and insert them into the skin of diabetic hairless rats for transdermal delivery of insulin to lower blood glucose level. Methods. Arrays containing 105 microneedles were laser-cut from stainless steel metal sheets and inserted into the skin of anesthetized hairless rats with streptozotocin-induced diabetes. During and after microneedle treatment, an insulin solution (100 or 500 U/ml) was placed in contact with the skin for 4 h. Microneedles were removed 10 s, 10 min, or 4 h after initiating transdermal insulin delivery. Blood glucose levels were measured electrochemically every 30 min. Plasma insulin concentration was determined by radioimmunoassay at the end of most experiments. Results. Arrays of microneedles were fabricated and demonstrated to insert fully into hairless rat skin in vivo. Microneedles increased skin permeability to insulin, which rapidly and steadily reduced blood glucose levels to an extent similar to 0.05-0.5 U insulin injected subcutaneously. Plasma insulin concentrations were directly measured to be 0.5-7.4 ng/ml. Higher donor solution insulin concentration, shorter insertion time, and fewer repeated insertions resulted in larger drops in blood glucose level and larger plasma insulin concentrations. Conclusions. Solid metal microneedles are capable of increasing transdermal insulin delivery and lowering blood glucose levels by as much as 80% in diabetic hairless rats in vivo.

The mechanism of protraction of insulin detemir, a long-acting, acylated analog of human insulin.

Abstract: Purpose. Insulin detemir has been found in clinical trials to be absorbed with very low variability. A series of experiments were performed to elucidate the underlying mechanisms. Methods. The disappearance from an injected subcutaneous depot and elimination studies in plasma were carried out in pigs. Size-exclusion chromatography was used to assess the self-association and albumin binding states of insulin detemir and analogs. Results. Disappearance T50% from the injection depot was 10.2 ± 1.2 h for insulin detemir and 2.0 ± 0.1 h for a monomeric acylated insulin analog. Self-association of acylated insulin analogs with same albumin affinity in saline correlated with disappearance rate and addition of albumin to saline showed a combination of insulin detemir self association and albumin binding. Intravenous kinetic studies showed that the clearance and volume of distribution decreased with increasing albumin binding affinity of different acylated insulin analogs. Conclusions. The protracted action of detemir is primarily achieved through slow absorption into blood. Dihexamerization and albumin binding of hexameric and dimeric detemir prolongs residence time at the injection depot. Some further retention of detemir occurs in the circulation where albumin binding causes buffering of insulin concentration. Insulin detemir provides a novel principle of protraction, enabling increased predictability of basal insulin.

Effect of chitosan on epithelial cell tight junctions.

Abstract: Purpose Chitosan has been proposed as a novel excipient for transepithelial drug-delivery systems Chitosan is thought to disrupt intercellular tight junctions, thus increasing the permeability of an epithelium The effect of chitosan on tight junction complex was investigated at the molecular level

Chitosan Nanoparticles as New Ocular Drug Delivery Systems: In Vitro Stability, in Vivo Fate, and Cellular Toxicity

Abstract: Purpose. To assess the potential of chitosan (CS) nanoparticles for ocular drug delivery by investigating their interaction with the ocular mucosa in vivo and also their toxicity in conjunctival cell cultures.

Effects of the chemical structure and the surface properties of polymeric biomaterials on their biocompatibility.

Abstract: Polymeric biomaterials have extensively been used in medicinal applications. However, factors that determine their biocompatibility are still not very clear. This article reviews various effects of the chemical structure and the surface properties of polymeric biomaterials on their biocompatibility, including protein adsorption, cell adhesion, cytotoxicity, blood compatibility, and tissue compatibility. Understanding these aspects of biocompatibility is important to the improvement of the biocompatibility of existing polymers and the design of new biocompatible polymers.

Cell penetrating peptides in drug delivery.

Abstract: Protein transduction domains (PTDs) are small cationic peptides that can facilitate the uptake of large, biologically active molecules into mammalian cells. Recent reports have suggested that PTDs may be able to mediate the delivery of cargo to tissues throughout a living organism. Such technology could eliminate the size restrictions on usable drugs, enabling previously unavailable large molecules to modulate in vivo biology and alleviate disease. In this article, we review the evidence that PTDs can be used both to deliver active molecules to pathological tissue in vivo and to treat models of disease such as ischemia, inflammation, and cancer.

Pharmacokinetics and biodistribution of novel aptamer compositions.

Abstract: Purpose. Aptamers are highly selective nucleic acid–based drugs that are currently being developed for numerous therapeutic indications. Here, we determine plasma pharmacokinetics and tissue distribution in rat of several novel aptamer compositions, including fully 2′-O-methylated oligonucleotides and conjugates bearing high-molecular weight polyethylene glycol (PEG) polymers, cell-permeating peptides, and cholesterol.

The “High Solubility” Definition of the Current FDA Guidance on Biopharmaceutical Classification System May Be Too Strict for Acidic Drugs

Abstract: Purpose. The purpose of this study was to assess if the definition of high solubility as proposed in the FDA Guidance on Biopharmaceutical Classification System (BCS) is too strict for highly permeable acidic drugs. Methods. The solubility and permeability values of 20 (18 acidic and 2 non-acidic) nonsteroidal anti-inflammatory drugs (NSAID) were determined. The NSAIDs were grouped into three different sets having acetic acid, propionic acid, or other acidic moieties such as fenamate, oxicam, and salicylate. Two nonacidic NSAIDs (celecoxib and rofecoxib) were also included for comparison purposes. Equilibrium solubility values were determined at pH 1.2, 5.0, 7.4, and in bio-relevant media simulating fed intestinal fluid at pH 5.0. For a select number of acids, we also measured solubility values in media simulating gastric and fasted intestinal fluids. Permeability classification was established relative to that of reference drugs in the Caco-2 cell permeability model. Permeability coefficients for all drugs were measured at concentrations corresponding to the lowest and highest marketed dose strengths dissolved in 250 ml volume, and their potential interaction with cellular efflux pumps was investigated. Results. All NSAIDs with different acidic functional groups were classified as highly permeable based on their Caco-2 cell permeability. Only ketorolac appeared to have a potential for interaction with cellular efflux pumps. Solubility classification was based on comparison of equilibrium solubility at pH 1.2, 5.0, and 7.4 relative to marketed dose strengths in 250 ml. The pK a values for the acidic NSAIDs studied were between 3.5 and 5.1, and, as expected, their solubility increased dramatically at pH 7.4 compared to pH 1.2. Only three NSAIDs, ketorolac, ketoprofen, and acetyl salicylic acid, meet the current criteria for high solubility over the entire pH range. However, with the exception of ibuprofen, oxaprozin, and mefenamic acid, the remaining compounds can be classified as Class I drugs (high solubility-high permeability) relative to solubility at pH 7.4. The use of bio-relevant media simulating gastric and intestinal milieu for solubility measurements or increasing the dose volume to 500 ml did not provide for a better boundary for solubility classification. Conclusions. Based on the current definition of solubility, 15 of the 18 acidic NSAIDs in this study will be classified as Class II compounds as the solubility criteria applies to the entire pH range of 1.2 to 7.4, although the low solubility criteria does not hold true over the entire pH range. Whence, of the 18 acidic drugs, 15 can be classified as Class I based on the pH 7.4 solubility alone. This finding is intriguing because these drugs exhibit Class I behavior as their absorption does not seem to be dissolution or solubility limited. It could then be argued that for acidic drugs, the boundaries for solubility are too restrictive. Solubility at pH > 5 (pH in duodenum) may be more appropriate because most compounds are mainly absorbed in the intestinal region. Consideration for an intermediate solubility classification for highly permeable ionizable compounds that reflects physiological conditions seems warranted.

Modulatory Properties of Various Natural Chemopreventive Agents on the Activation of NF-κB Signaling Pathway

Abstract: Purpose. To study and compare effects of selected natural chemopreventive agents on the transcription activation of nuclear factor-kappa B (NF-κB) in human HT-29 colon cancer cells.

A dynamic artificial gastrointestinal system for studying the behavior of orally administered drug dosage forms under various physiological conditions.

Abstract: Purpose. The purpose of this study was to demonstrate the potential of a dynamic, multicompartmental in vitro system simulating the human stomach and small intestine (TIM-1) for studying the behavior of oral drug dosage forms under various physiological gastrointestinal conditions. Methods. Two model drug compounds were studied in TIM-1: a lyophilized Lactobacillus strain and paracetamol (acctaminophen). The Lactobacillus survival rate was determined by bacterial counting in the gastric and ileal effluents while simulating the conditions of the gastrointestinal tract of infants or adults. The availability for absorption of paracetamol from two oral dosage forms was investigated by measuring the drug concentration in jejunal dialysis fluid. The effect of gastrointestinal passage time and food intake on paracetamol absorption was also studied. Results. The Lactobacillus survival rate in both gastric and ileal effluents was higher during simulation of the infant compared to adult conditions. We also showed that (i) paracetamol absorption was faster when it was administered as a free powder than in sustained-release tablet form, (ii) a slow passage time resulted in a delay in the absorption of paracetamol, and (iii) there was a lower rate of absorption when paracetamol was ingested with a standard breakfast as opposed to water. The in vitro results were consistent with in vivo data, showing the predictive value of TIM-1. Conclusions. TIM-1 is a powerful tool for supplying valuable information about the effects of various gastrointestinal conditions on biopharmaceutical behavior and efficacy of drug delivery systems in the development of oral formulations. Chemicals / CAS: pancreatin, 8049-47-6; paracetamol, 103-90-2; pepsin A, 9001-75-6; starch, 9005-25-8, 9005-84-9; triacylglycerol lipase, 9001-62-1; Acetaminophen, 103-90-2; Dosage Forms

Functional Analysis of SNPs Variants of BCRP/ABCG2

Abstract: Purpose. The aim of the current study was to identify the effect of single nucleotide polymorphisms (SNPs) in breast cancer resistance protein (BCRP/ABCG2) on its localization, expression level, and transport activity.

The complexities of hepatic drug transport: current knowledge and emerging concepts.

Abstract: Recently, hepatic transport processes have been recognized as important determinants of drug disposition. Therefore, it is not surprising that characterization of the hepatic transport and biliary excretion properties of potential drug candidates is an important part of the drug development process. Such information also is useful in understanding alterations in the hepatobiliary disposition of compounds due to drug interactions or disease states. Basolateral transport systems are responsible for translocating molecules across the sinusoidal membrane, whereas active canalicular transport systems are responsible for the biliary excretion of drugs and metabolites. Several transport proteins involved in basolateral transport have been identified including the Na+-taurocholate co-transporting polypeptide [NTCP (SLC10A1)], organic anion transporting polypeptides [OATPs (SLCO family)], multidrug resistance-associated proteins [MRPs (ABCC family)], and organic anion and cation transporters [OATs, OCTs (SLC22A family)]. Canalicular transport is mediated predominantly via P-glycoprotein (ABCB1), MRP2 (ABCC2), the bile salt export pump [BSEP (ABCB11)], and the breast cancer resistance protein [BCRP (ABCG2)]. This review summarizes current knowledge regarding these hepatic basolateral and apical transport proteins in terms of substrate specificity, regulation by nuclear hormone receptors and intracellular signaling pathways, genetic differences, and role in drug interactions. Transport knockout models and other systems available for hepatobiliary transport studies also are discussed. This overview of hepatobiliary drug transport summarizes knowledge to date in this rapidly growing field and emphasizes the importance of understanding these fundamental processes in hepatic drug disposition.

Rheological Characterization of Topical Carbomer Gels Neutralized to Different pH

Abstract: Purpose. The primary objective of this study is to perform detailed and extensive rheological characterization of rheology of carbomer (Carbopol) microgels formulated using a solvent system typically used in topical gel formulations. Solvents like glycerin and propylene glycol can alter rheology and drug delivery characteristics of topical gels owing to their different viscosities and due to the change in solvent-polymer and solvent-solvent interactions. Methods. Aqueous gels with different pH were prepared by dissolving cross-linked Carbopol polymers in a co-solvent system comprising water, propylene glycol, and glycerol and subsequently neutralizing the carboxylic groups of the polymers with triethanolamine (TEA). Oscillatory, steady, and transient shear measurements were performed to measure viscoelastic properties, temperature dependency, yield strength, and thixotropy of carbomer pharmaceutical gels. Results. The topical pharmaceutical gels exhibit remarkable temperature stability. Flow curves obtained at different temperatures indicate Carbopol microgels show much more pseudoplastic behavior (lower power law index) compared to Carbopol gels dissolved only in water. Substantial yield strength is required to break the microgel network of the topical gels. The gel samples exhibit modest thixotropy at higher deformation rates. Conclusions. The rheological behavior of the Carbopol microgels do not change appreciably in the pH range 5.0-8.0, and the gels can be used as effective dermatological base for topical applications.

Strategies to improve DNA polyplexes for in vivo gene transfer: will "artificial viruses" be the answer?

Abstract: For the purpose of introducing nucleic acids into cells, cationic polymers have been steadily improved as gene carriers. This has resulted in improved polymer-based gene transfer formulations, termed polyplexes, which efficiently transfect cell cultures and also have shown encouraging gene transfer potential in in vivo administration. Targeted delivery to liver, lung, tumor, or other tissues has been achieved in experimental animals by localized or systemic application. Therapeutic effect has been demonstrated, although efficiencies are still too low to justify clinical use. The limitations of first-generation polymeric carriers (modest activity and significant toxicity) have been addressed by developments of new biodegradable polycations, incorporation of targeting and intracellular transport functions, and polyplex formulations that avoid unspecific adverse interactions with the host. A key future step will be the development of polyplexes into artificial viruses, with virus-like entry functions presented by smart polymers and polymer conjugates. These polymers have to sense their biologic microenvironment, respond in a more dynamic manner to alterations in pH, ionic or redox environment, undergoing programmed structural changes compatible with the different gene delivery steps.

Partial acetylation of polyethylenimine enhances in vitro gene delivery.

Abstract: Purpose. Polyethylenimine (PEI) is a highly effective gene delivery vector, but because it is an off-the shelf material, its properties may not be optimal. To investigate the effects of the protonation properties of the polymer, we generated PEI derivatives by acetylating varying fractions of the primary and secondary amines to form secondary and tertiary amides, respectively.

The characteristics and mechanisms of uptake of PLGA nanoparticles in rabbit conjunctival epithelial cell layers

Abstract: Purpose. To delineate the characteristics and mechanisms of up- take of biodegradable poly(d,l-lactide-co-glycolide) (PLGA) nanoparticles in primary cultured rabbit conjunctival epithelial cells (RCECs).

Peroxisome Proliferator-Activated Receptor (PPAR)-α: A Pharmacological Target with a Promising Future

Abstract: Peroxisome proliferator-activated receptor (PPAR)-α is a ligand-activated transcriptional factor that belongs to the family of nuclear receptors. PPAR-α regulates the expression of genes involved in fatty acid β-oxidation and is a major regulator of energy homeostasis. Fibrates are PPAR-α agonists and have been used to treat dyslipidemia for several decades because of their triglyceride (TG) lowering and high- density lipoprotein cholesterol (HDL-C) elevating effects. More recent research has demonstrated anti-inflammatory and anti-thrombotic actions of PPAR-α agonists in the vessel wall as well. Thus, PPAR-α agonists decrease the progression of atherosclerosis by modulating metabolic risk factors and by their anti-inflammatory actions on the level of the vascular wall. This is confirmed by several clinical studies, in which fibrates have shown to reduce atherosclerotic plaque formation and the event rate of coronary heart disease (CHD), especially in patients suffering from metabolic syndrome (MS). MS is characterized by a group of metabolic risk factors that include obesity, raised blood pressure, dyslipidemia, insulin resistance or glucose intolerance, and a prothrombotic state, and its incidence in the Western world is rising to epidemic proportions. This review paper will focus on the functions of PPAR-α in fatty acid β-oxidation, lipid metabolism, and vascular inflammation. Furthermore, PPAR-α genetics, the clinical use of PPAR-α activators and their future perspective will be discussed.

Enhancement of topical delivery from biodegradable nanoparticles.

Abstract: Purpose. To determine whether and how encapsulation of lipophilic compounds in polymeric nanoparticles is able to improve topical delivery to the skin.

Susceptibility to lipase-mediated digestion reduces the oral bioavailability of danazol after administration as a medium-chain lipid-based microemulsion formulation.

Abstract: Purpose. To investigate the impact of lipidic formulation type on in vitro dispersion and digestion properties and the relationship to oral bioavailability, using danazol as a model lipophilic poorly water-soluble drug. Methods. Three lipid-based danazol formulations [a long-chain triglyceride solution (LCT-solution) and self-microemulsifying drug delivery systems (SMEDDS) based on long-chain (C18) lipids (LC-SMEDDS) and medium-chain (C8-C10) lipids (MC-SMEDDS)] were adminis- tered to fasted beagle dogs and compared with a micronized danazol formulation administered postprandially and in the fasted state. In vitro dispersion and particle size data for the two SMEDDS were compared, and the distribution/solubilization patterns of danazol across the various phases produced during in vitro digestion quantified. Results. The LCT-solution and LC-SMEDDS formulations significantly enhanced the oral bioavailability of danazol when compared to fasted administration of the powder formulation. In contrast, and despite displaying excellent dispersion properties, the MC-SMEDDS resulted in little enhancement in danazol bioavailability. In support of the in vivo findings, in vitro digestion of the medium-chain formulation resulted in significant drug precipitation when compared with the long-chain lipid formulations. Conclusions. Digestion of microemulsion preconcentrate formulations based on medium-chain lipids may limit in vivo utility when compared with similar formulations based on long chain lipids.

Comparison of the use of liver models for predicting drug clearance using in vitro kinetic data from hepatic microsomes and isolated hepatocytes

Abstract: Purpose. To compare three liver models (well-stirred, parallel tube, and dispersion) for the prediction of in vivo intrinsic clearance (CLint), hepatic clearance (CLh), and hepatic availability (Fh) of a wide range of drugs in the rat using in vitro data from two in vitro sources. Methods. In vitro CLint was obtained from studies using isolated rat hepatocytes (35 drugs) or rat liver microsomes (52 drugs) and used to predict in vivo CLint using reported scaling factors, and subsequently CLh and Fh were predicted based on the three liver models. In addition, in vivo CLint values were calculated from the reported values of CLh based on each of the three models. Results. For all of the parameters, predictions from hepatocyte data were consistently more accurate than those from microsomal data. Comparison of in vitro and in vivo CLint values demonstrated that the dispersion model and the parallel tube model were comparable and more accurate (less bias, more precise) than the well-stirred model. For CLh and Fh prediction, the three models performed similarly. Conclusions. Considering the statistics of the predictions for three liver models, the use of parallel tube model is recommended for the evaluation of in vitro CLint values both from microsomes and hepatocytes. However, for the prediction of the in vivo drug (hepatic) clearance from in vitro data, as there are minimal differences between the models, the use of the well-stirred liver model is recommended.

Stability and solubility of celecoxib-PVP amorphous dispersions: a molecular perspective.

Abstract: Purpose. The purpose of the current study is to evaluate the solubility advantage offered by celecoxib (CEL) amorphous systems and to characterize and correlate the physical and thermodynamic properties of CEL and its amorphous molecular dispersions containing poly(vinylpyrrolidone) (PVP).

The cohesive-adhesive balances in dry powder inhaler formulations I: direct quantification by atomic force microscopy

Abstract: Purpose. To obtain a quantitative assessment of the cohesive and adhesive force balance within dry powder inhaler formulations.

Drug solubilization behavior during in vitro digestion of simple triglyceride lipid solution formulations.

Abstract: Purpose. The purpose of this study was to characterize the solubilization and precipitation characteristics of a range of poorly water-soluble drugs during digestion of either long-chain or medium-chain triglyceride (TG) lipid formulations.

Creatinine transport by basolateral organic cation transporter hOCT2 in the human kidney.

Abstract: Purpose. Creatinine is excreted into urine by tubular secretion in addition to glomerular filtration. The purpose of this study was to clarify molecular mechanisms underlying the tubular secretion of creatinine in the human kidney.

Novel approaches to vaccine delivery.

Abstract: Although the currently available vaccines represent an outstanding success story in modern medicine and have had a dramatic effect on morbidity and mortality worldwide, it is clear that improvements are required in the current vaccine delivery technologies. Improvements are required to enable the successful development of vaccines against infectious diseases that have so far proven difficult to control with conventional approaches. Improvements may include the addition of novel injectable adjuvants or the use of novel routes of delivery, including mucosal immunization. Mucosal delivery may be required to provide protection against pathogens that infect at mucosal sites, including sexually transmitted diseases. Alternatively, novel approaches to delivery, including mucosal administration, may be used to improve compliance for existing vaccines. Of particular interest for safer mass immunization campaigns are needle-free delivery devices, which would avoid problems due to needle re-use in many parts of the world and would avoid needle-stick injuries.