The pharmacokinetic profile of fesoterodine 8 mg with daytime or nighttime dosing

Purpose  

Diurnal variation can affect drug pharmacokinetics. Fesoterodine is a new antimuscarinic drug for the treatment of overactive bladder (OAB). We estimated the relative bioavailability of 5-hydroxymethyl tolterodine (5-HMT), the active metabolite of fesoterodine, following nighttime and daytime administration.     

Influence of molecular properties on oral bioavailability of lipophilic drugs – Mapping of bulkiness and different measures of polarity

The biopharmaceutical assessment of new drug candidates based on their chemical structure is important in drug discovery and development. The scope of this study is to focus on lipophilic drugs and to clarify the role of their chemical predictors on oral bioavailability in humans. First their chemical properties were calculated from molecular modeling and the bioavailability data was obtained from the literature. The data was then analyzed by a partial least square method including non-linear terms. Significant coefficients were identified from a group of polarity- and solubility-related properties. Contour plots were constructed mapping molecular weight together with different polarity factors. Depending on the molecular weight a maximal bioavailability was found at solubility parameters of about 31–35 (J/cm³)^1/2 and HLB values of roughly 4–12. The mapping of lipophilic drugs also revealed that a solubility parameter of less than 20 (J/cm³)^1/2 or a HLB of smaller than unity is critical for the drug-likeness of new compounds.     

Preparation and characterization of polymeric pH-sensitive STEALTH® nanoparticles for tumor delivery of a lipophilic prodrug of paclitaxel

Paclitaxel is an effective and widely used anti-cancer agent. However, the drug is difficult to formulate for parenteral administration because of its low water solubility and Cremophor EL, the expient used for its formulation, has been shown to cause serious side effects. The present study reports an alternative administration vehicle involving a lipophilic paclitaxel prodrug, paclitaxel oleate, incorporated in the core of a nanoparticle-based dosage form. A hydrophobic poly (β-amino ester) (PbAE) was used to formulate the nanoparticles, which were stabilized with a mixture of phosphatidylcholine, Synperonic? F 108, and poly(ethylene glycol)-dipalmitoyl phosphatidyl ethanolamine. PbAE undergoes rapid dissolution when the pH of the medium is less than 6.5 and is expected to rapidly release its content within the acidic tumor microenvironment and endo/lysosome compartments of cancer cells. PbAE nanoparticles were prepared by an ultrasonication method and characterized for particle size and physical stability. The nanoparticles obtained had a diameter of about 70 nm and a good physical stability when stored at 4 °C. In vitro cellular uptake and release of paclitaxel oleate PbAE nanoparticles were studied in Jurkat acute lymphoblastic leukemia cells. The results were compared with pclitaxel oleate in poly(?-caprolactone) (PCL) particles, that do not display pH-sensitive release behavior, and paclitaxel in PbAE particles. Both uptake and release of the prodrug were faster when administered in PbAE than in PCL, but much slower than those of the free drug in PbAE. Cytotoxicity assay was performed on the formulations at different doses. Paclitaxel and paclitaxel oleate showed almost identical activity, IC50 123 and 128 nM, respectively, while that of the prodrug in PCL was much lower with IC50 at 2.5 μM. Thus, PbAE nanoparticles with the incorporated paclitaxel prodrug paclitaxel oleate may prove useful for replacement of the toxic Cremophor EL and also by improving the distribution of the drug to the tumor.     

Solid lipid nanoparticles as drug carriers. I. Incorporation and retention of the lipophilic prodrug 3′-azido-3′-deoxythymidine palmitate

Solid lipid nanoparticles (SLN) were prepared with trilaurin (TL) as the SLN solid core and dipalmitoylphosphatidylcholine (DPPC) or a mixture of DPPC and dimyristoylphosphatidylglycerol (DMPG) to produce neutral and negatively charged SLNs. The ester prodrug of 3′-azido-3′-deoxythimidine (Zidovudine®, AZT) with palmitic acid, AZT palmitate (AZT-P), was synthesized and its incorporation and retention in SLNs determined. The incorporation of hydrophilic AZT in SLNs was minimal; however the incorporation of AZT-P increased with increasing phospholipid (PL) content and was independent of the amount of TL used. The incorporation of AZT-P was greater in negatively charged SLNs than in neutral SLNs. The in vitro release of AZT-P from different SLNs formulation was studied at 37°C using a bulk-equilibrium reverse dialysis sac technique. Increased drug release was observed in SLNs formulated with PLs having a transition temperature below 37°C. The results obtained indicate that the highly packed TL core of the SLN is not compatible with lipophilic molecules such as AZT-P. The incorporation and subsequent retention of AZT-P appears to be dependent on the PL coating on the SLNs surface and is independent of the TL solid core.     

Preparation, characterization and pharmacokinetic studies of tacrolimus-dimethyl-β-cyclodextrin inclusion complex-loaded albumin nanoparticles

The purpose of the study is to develop a new formulation for clinically used anti-cancer agent tacrolimus (FK506) to minimize the severe side effects. Toward this end, a new formulation method has been developed by complexation of FK506 with an hydrophilic cyclodextrin derivative, heptakis (2,6-di-O-methyl)-β-cyclodextrin (DM-β-CD) using ultrasonic means. The resulting complex displays dramatically enhanced solubility of FK506. Then bovine serum albumin (BSA) nanoparticles were prepared directly from the preformed FK506/DM-β-CD inclusion complex by the desolvation-chemical crosslinking method, with the size of 148.4-262.9 nm. Stable colloidal dispersions of the nanoparticles were formed with zeta potentials of the range of -24.9 to -38.4 mV. The entrapment efficiency of FK506 was increased as high as 1.57-fold. Moreover, notably FK506 was released from the nanoparticles in a sustained manner. As demonstrated, pharmacokinetic studies reveal that, as compared with FK506-loaded BSA nanoparticles, the FK506/DM-β-CD inclusion complex-loaded BSA nanoparticles have significant increase at T(max), t(1/2), MRT and decrease at C(max). In summary, these results suggest that the drug/DM-β-CD inclusion complex-loaded BSA nanoparticles display significantly improved delivery efficiency for poorly soluble FK506 or its derivatives.     

Prediction of drug–drug interaction potential using physiologically based pharmacokinetic modeling

The occurrence of drug–drug interactions (DDIs) can significantly affect the safety of a patient, and thus assessing DDI risk is important. Recently, physiologically based pharmacokinetic (PBPK) modeling has been increasingly used to predict DDI potential. Here, we present a PBPK modeling concept and strategy. We also surveyed PBPK-related articles about the prediction of DDI potential in humans published up to October 10, 2017. We identified 107 articles, including 105 drugs that fit our criteria, with a gradual increase in the number of articles per year. Studies on antineoplastic and immunomodulatory drugs (26.7%) contributed the most to published PBPK models, followed by cardiovascular (20.0%) and anti-infective (17.1%) drugs. Models for specific products such as herbal products, therapeutic protein drugs, and antibody–drug conjugates were also described. Most PBPK models were used to simulate cytochrome P450 (CYP)-mediated DDIs (74 drugs, of which 85.1% were CYP3A4-mediated), whereas some focused on transporter-mediated DDIs (15 drugs) or a combination of CYP and transporter-mediated DDIs (16 drugs). Full PBPK, first-order absorption modules and Simcyp^® software were predominantly used for modeling. Recently, DDI predictions associated with genetic polymorphisms, special populations, or both have increased. The 107 published articles reasonably predicted the DDI potentials, but further studies of physiological properties and harmonization of in vitro experimental designs are required to extend the application scope, and improvement of DDI predictions using PBPK modeling will be possible in the future.     

Can finger-prick sampling replace venous sampling to determine the pharmacokinetic profile of oral paracetamol?

The drive to increase the availability of paediatric pharmacokinetic data with minimum blood loss has led to the development of micro-sampling techniques. However studies have suggested that pharmacokinetic data from venous or capillary blood samples may not be directly comparable.

AIM

The aim of this study was to determine whether paracetamol demonstrates concentration differences between finger-prick and venous blood samples.

METHODS

Paired finger-prick and venous blood samples were taken at 0, 15, 30 and 60 min following 1 g oral paracetamol, from 12 male adult subjects. Paracetamol concentration was determined using HPLC and UV detection with a LLOQ of 2200 pg on column. Intra-assay coefficient of variation for paracetamol at the LLOQ was 3%.

RESULTS

At 15, 30, and 60 min post dose the median finger-prick paracetamol concentration was 349%, 72%, and 9.3% greater than the equivalent venous concentrations, respectively. Regression analysis confirmed a significant relationship between finger-prick and venous paracetamol concentrations at 15 min (r² = 0.81, P = 0.006), at 30 min (r² = 0.82, P < 0.0001) and at 60 min (r² = 0.87, P < 0.0001) post dose. The regression equation for venous and finger-prick blood concentrations at 15, 30 and 60 min post dose were Venous₁₅ = Finger₁₅ − 3.4, Venous₃₀ = Finger₃₀ − 3.4 and Venous₆₀ = 0.68Finger₆₀ + 3.06, respectively.

CONCLUSIONS

Paracetamol demonstrates an arteriovenous difference in concentration, and the use of finger-prick samples may give rise to results which differ from those obtained with traditional venous sampling especially during the first 1 h following drug ingestion.     

Improved method for autoradiographic localization of ß-adrenoceptors using photoaffinity labelling

Summary Contact autoradiography of tissue sections, using emulsion coated coverslips or X-ray films, is widely used to provide information about the regional distribution of receptors. This easy to perform, standard technique has the disadvantage of an image spread due to the gap between the radioactive source and the film. The present study describes a new technique which combines photoaffinity labeling of ß-adrenoceptors with dipping autoradiography and a modified trichrome stain. Incubation of 16 m cryosections of rat lung tissue with the iodinated, photoaffintiy labeling, non-selective, ß-adrenergic agonist [¹²⁵I]-cyanopindololazide II ([¹²⁵I]-CYPA II) (100 pmol/1) in the absence or presence of 1 mol (±)-propranolol revealed strong, specific ß-adrenoceptor binding to alveolar parenchyma and bronchial epithelium of large and small bronchioles, lesser binding to smooth muscle bundles of large airways and only sparse binding to the smooth muscle of small bronchioles or peripheral branches of pulmonary artery. With standard autoradiographic techniques, a similiar distribution of the label was obtained, although resolution and sensitivity were inferior. Staining of tissue sections through the photo-emulison by means of a modified Mallory's trichrome dye facilitated the discrimination between alveolar and bronchial epithelium, muscular and collagenous tissues. In conclusion, the photoaffinity labeling of ß-adrenoceptors with [¹²⁵I]-CYPA II allows the use of dipping autoradiography. This technique, in combination with trichrome staining through the photoemulsion, results in an improved autoradiograpic image together with a better association of the label with distinct histological structures and the higher sensitivity of the method.Presented, in part, at the Frühjahrstagung der Deutschen Gesellschaft für Pharmakologie and Toxikologie in Mainz 1988 (Hesse and Erdmann, Naunyn Schiedebergs Arch Pharmacol 337 [Suppl]:R 100)     

The Øie-Tozer model of drug distribution and its suitability for drugs with different pharmacokinetic behavior

INTRODUCTION: Drug distribution is a major pharmacokinetic process that affects the time course of drug concentrations in tissues, biological fluids and the resulting pharmacological activities. Drug distribution may follow different pathways and patterns, and is governed by the drug's physicochemical properties and the body's physiology. The classical ?ie-Tozer model is frequently used for predicting volume of drug distribution and for pharmacokinetic calculations. AREAS COVERED: In this review, the suitability of the ?ie-Tozer model for drugs that exhibit different distribution patterns is critically analyzed and illustrated. The method used is a pharmacokinetic modeling and simulation approach. It is demonstrated that the major limitation of the ?ie-Tozer model stems from its focus on the total drug concentrations and not on the active (unbound) concentrations. Moreover, the ?ie-Tozer model may be inappropriate for drugs with nonlinear or complex pharmacokinetic behavior, such as biopharmaceuticals, drug conjugates or for drugs incorporated into drug delivery systems. Distribution mechanisms and alternative distribution models for these drugs are discussed. EXPERT OPINION: The ?ie-Tozer model can serve for predicting unbound volume of drug distribution for 'classical' small molecular mass drugs with linear pharmacokinetics. However, more detailed mechanism-based distribution models should be used in preclinical and clinical settings for drugs that exhibit more complex pharmacokinetic behavior.     

In vivo investigation of thiomer–polyvinylpyrrolidon nanoparticles using magnetic resonance imaging

This study focused on the investigation of the permeation enhancing effects of a stomach targeted, nanoparticulate drug delivery system. The polyacrylic acid–cysteine/polyvinylpyrrolidon nanoparticles were loaded with the magnetic resonance imaging (MRI) contrast agent diethylenetriaminepentaacetic acid gadolinium(III)dihydrogen salt (Gd‐DTPA). Average particle size was determined to be 130 nm and the optimum for stability was found to be below a pH of 4.5. In vitro permeation studies were performed on rat gastric mucosa and revealed an eightfold increase in Gd‐DTPA uptake when incorporated in the nanoparticles compared to evaluation in the presence of unformulated polyacrylic acid–cysteine. In vivo investigations with rats were performed via the noninvasive MRI method in order to track the nanoparticles way through the gastrointestinal tract. When Gd‐DTPA was administered orally as nanoparticulate suspension, an increased MRI signal in the urinary bladder was detected after 34 min, providing evidence for systemic uptake and renal elimination of the contrast agent. As control experiments with Gd‐DTPA only or in combination with unformulated polyacrylic acid–cysteine revealed no MRI signal increase at all, the significant permeation enhancing effect could be identified based on the nanoparticulate formulation. © 2009 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 2008–2017, 2010     

Evaluation of in vivo behavior of controlled and pulsatile release pastilles using pharmacokinetic and γ-scintigraphic techniques

Objective: To evaluate the in vivo behavior of controlled and pulsatile release pastilles for chronic treatment of asthma and chronic obstructive pulmonary disease (COPD) and for the chronotherapeutic management of nocturnal asthma, respectively.

Research design & methods: The prepared immediate release and controlled release pastilles were subjected to in vivo pharmacokinetic studies in rats. Whereas, pulsatile release formulation was subjected to γ-scintigraphic study in rats to study the gastrointestinal transit of the formulations and its results were correlated with the previous pharmacokinetic data.

Results: The in vivo pharmacokinetic study of controlled release pastille formulation showed significant decrease in C_max with increase in t_max, which indicates that the effect of dosage form would last for longer duration. Thus, the prepared formulation can be useful for the chronic treatment of asthma and COPD. The γ-scintigraphic study and pharmacokinetic data indicated that the pastilles coated with the enteric coat and the additional floating coat were effective in significantly delaying the in vivo drug release (by 4–5 h) required for the chronotherapeutic treatment of nocturnal asthma.

Conclusion: This study opens a new alternative to the conventional tablet or capsule dosage form for the development of both immediate and modified release drug delivery systems.     

Development of drugs for Epstein–Barr virus using high-throughput in silico virtual screening

Importance of the field: Epstein–Barr virus (EBV) is a ubiquitous human herpesvirus that is causally associated with endemic forms of Burkitt's lymphoma, nasopharyngeal carcinoma and lymphoproliferative disease in immunosuppressed individuals. On a global scale, EBV infects > 90% of the adult population and is responsible for ～ 1% of all human cancers. To date, there is no efficacious drug or therapy for the treatment of EBV infection and EBV-related diseases.

Areas covered in this review: In this review, we discuss the existing anti-EBV inhibitors and those under development. We discuss the value of different molecular targets, including EBV lytic DNA replication enzymes as well as proteins that are expressed exclusively during latent infection, such as EBV nuclear antigen 1 (EBNA-1) and latent membrane protein 1. As the atomic structure of the EBNA-1 DNA binding domain has been described, it is an attractive target for in silico methods of drug design and small molecule screening. We discuss the use of computational methods that can greatly facilitate the development of novel inhibitors and how in silico screening methods can be applied to target proteins with known structures, such as EBNA-1, to treat EBV infection and disease.

What the reader will gain: The reader is familiarized with the problems in targeting of EBV for inhibition by small molecules and how computational methods can greatly facilitate this process.

Take home message: Despite the impressive efficacy of nucleoside analogs for the treatment of herpesvirus lytic infection, there remain few effective treatments for latent infections. As EBV latent infection persists within and contributes to the formation of EBV-associated cancers, targeting EBV latent proteins is an unmet medical need. High-throughput in silico screening can accelerate the process of drug discovery for novel and selective agents that inhibit EBV latent infection and associated disease.     

Demonstration of the heterogeneity of the κ-opioid receptors in guinea-pig cerebellum using selective and nonselective drugs

In guinea-pig cerebellum, saturation studies reveal that the nonselective opioid [³H]ethylketazocine has a binding capacity (R) of 6.79 pmol/g tissue which is similar to the sum of the individual R values of the μ-, δ- and κ₁-selective opioids. Conversely, the binding parameters of the nonselective opioid [³H]bremazocine are best-fitted to a two-site model (K_d1 = 0.12 nM, R₁ = 11.3 pmol/g tissue; K_d2 = 6.03 nM, R₂ = 9.09 pmol/g tissue) with an R_TOTAL value of 20.3 pmol/g tissue which is statistically different from the R value of [³H]ethylketazocine or the sum of R_μ + R_δ + R_κ1. This suggests that [³H]bremazocine labels additional opioid binding sites. After suppression of the μ-, δ- and κ₁-receptors, [³H]bremazocine binding is then best-fitted to a one-site model with a K_d value of 1.48 nM and an R value of 11.2 pmol/g tissue. Competition studies done against the binding of [³H]U69593 indicate that the opioid receptors labelled with this ligand are related to the κ₁-receptor subtype. However, competition studies performed against the binding of [³H]bremazocine (under suppressed conditions) display a pharmacological profile related to another subtype of κ-receptors previously described in guinea-pig brain as the κ₂-receptors.     

Enhancing mechanism of intestinal absorption of highly lipophilic compounds using microemulsion – Quantitative analysis of the partitioning to the mesenteric lymph in intestinal cells

The purpose of this study was to quantify the effect of the fatty acid alkyl-chain length of a polyethylene glycol (PEG) glyceryl ester, which was used as a microemulsion oil component, on the partitioning of highly lipophilic compounds to the mesenteric lymph after oral administration. Oil blue N, a highly lipophilic anthraquinone derivative, was orally administered to lymph duct-cannulated and untreated rats in two kinds of different microemulsions. Gelucire^® 50/13 and Gelucire^® 44/14 were used as the oil component with long chain and medium chain fatty acid portions, respectively, of PEG glyceryl esters in microemulsions. The cumulative amount of oil blue N in lymph fluid was almost the same between the two microemulsions, although the transferred amount of oil component (triglyceride) in the lymph after administration of the Gelucire^® 50/13 microemulsion was significantly higher than that of the Gelucire^® 44/14 microemulsion. On the other hand, the solubility of oil blue N in Gelucire^® 44/14 was much higher than that in Gelucire^® 50/13. No significant differences were observed between microemulsions in the bioavailability of oil blue N. From these data, the partitioning of oil blue N to the lymph was calculated using a mathematical model, showing that the partitioning ratios of oil blue N to the lymph fluid were almost the same for both microemulsions. The solubility of oil blue N to the oil component of the microemulsions and the transfer of triglycerides to the lymph after administration of the microemulsions counteract each other, leading to similar partitioning ratios of oil blue N to the lymph.     

Using population pharmacokinetic analyses of drugs metabolized by CYP2D6 to study the genotype–phenotype translation

Cytochrome P450 2D6 (CYP2D6) is an important drug-metabolizing enzyme exhibiting extensive interindividual variability predominantly caused by genetic polymorphism. Predicting CYP2D6 function based on genotype may be used to personalize pharmacotherapy, but the process of translating CYP2D6 genotype into predicted phenotype is complex and has suffered from a lack of consensus. The Clinical Pharmacogenetics Implementation Consortium and Dutch Pharmacogenetics Working Group have proposed a standardized translation scheme based on the activity score system aiming to facilitate more consistent CYP2D6 genotype–phenotype translation. However, this system remains suboptimal particularly with regards to decreased function alleles and substrate-specific behaviour. This review summarizes the process and challenges for functional assignment of CYP2D6 alleles. We discuss population pharmacokinetics (popPK) as a tool for estimating CYP2D6 function and present findings from three popPK meta-analyses quantifying the impact of individual CYP2D6 alleles in the metabolism of vortioxetine, tedatioxetine and brexpiprazole. Findings from these analyses indicate that the activity values currently assigned to decreased function alleles CYP2D6*9, *17 and *41 overestimate their function. Moreover, the CYP2D6*2 allele exhibited reduced activity in the metabolism of brexpiprazole, indicating substrate-specific behaviour. Considering the totality of the evidence, the activity score system may be further refined to better reflect the enzyme function associated with these alleles.     

“Subutex is safe”: Perceptions of risk in using illicit drugs during pregnancy

BackgroundThe dominant biomedical discourse stresses the physiological risks to the foetus or newborn posed by the prenatal use of illicit drugs. There is also a strong moral incentive for pregnant women to abstain from drugs. Yet few researchers have explored how pregnant, drug-using women themselves perceive the risks involved. The present paper investigates the reasoning by women about risks involved in prenatal drug use. Theoretically, a socio-cultural approach to risk is taken.MethodsThe paper is based on fourteen ethnographic interviews with women who had used illicit drugs during pregnancy (mainly buprenorphine), had recently given birth and had regularly used prenatal services during pregnancy. The interviews were informal, semi-structured and focused on the women's experiences of pregnancy and service use. Each interview lasted about an hour. The interviews were transcribed and inductively analysed using thematic coding. Risk perceptions were identified in the interviewees’ expressions and understanding of fears, dangers, threats and worries.ResultsThe women were not primarily concerned about health risks: their greatest fears in connection with the prenatal use of illicit drugs were giving birth to a child with withdrawal symptoms, child protection interventions and child removal, encountering negative attitudes in seeking professional help as well as terminating drug use. The interviewees did not see abstaining from drugs as a risk-free option. On the contrary, the prospect of a drug-free life was filled with fears linked to physical and mental pain and disruptions in significant social bonds. The women made use of biomedical and nonprofessional understandings of risks. The women's friends and acquaintances played a central role as providers of knowledge about risks.ConclusionWhen providing health education to pregnant women with drug problems, professionals should take women's perceptions of risk seriously, treat the women respectfully and engage them in dialogue about the risks involved. Further studies on pregnant women's perceptions of risk in using illicit drugs would be highly valuable.     

Silencing of DNA repair sensitizes pediatric brain tumor cells to γ-irradiation using gold nanoparticles

We present a nanoparticle (NP)-mediated delivery vehicle that effectively carries and protects siRNA in pediatric ependymoma (EP) and medulloblastoma (MB) cells. The delivery vehicle consists of gold NPs coated with a polymeric shell comprising polyethylene glycol (PG), chitosan and polyethyleneimine (Au-CP-PEI). NPs loaded with siRNA knocked down Ape1 expression by over 75% in both MB and EP cells. Further, this reduction in Ape1 expression is associated with an increase in DNA damage after irradiation. The results indicate that NP-associated delivery of siApe1 is a feasible approach to circumventing pediatric brain tumor resistance to radiation therapy.     

Stability of drugs of abuse in synthetic oral fluid investigated using a simple “dilute and inject” method of analysis

Human oral fluid is well established as a matrix for drug screening, particularly in the workplace. The need to synthesise synthetic oral fluid (SOF) has been recognised in order to overcome human oral fluid's composition variability. We have used SOF spiked with six common drugs of abuse or their primary metabolites: morphine, amfetamine, benzoylecgonine, cocaine, diazepam, and (−)-Δ⁹-tetrahydrocannabinol (THC) in order to assess the suitability of this matrix for quality assurance purposes. For confirmation of a drug screening test, controls and spiked standards are normally required. All our analytes were detected by LC–MS/MS using a quick and easy “dilute and inject” sample preparation approach as opposed to relatively slower solid-phase extraction. The limit of detection (LOD) was 10 ng/ml for diazepam and THC and 5 ng/ml for morphine, amfetamine, benzoylecgonine and cocaine. Validation results showed good accuracy as well as inter- and intra-assay precision (CV [%] < 5). Our work highlighted the importance of adding Tween® 20 to the SOF and calibrants to reduce losses when handling THC. Furthermore, drug stability was tested at various temperatures (5°C, 20°C and 40°C), for a number of days or after freeze–thaw cycles. Recommendations regarding storage are provided, the spiked SOF being stable at 5°C for up to 1 week without significant drug concentration loss.     

Intranasal delivery of dopamine to the striatum using glycol chitosan/sulfobutylether-β-cyclodextrin based nanoparticles

The aim of this study was to evaluate chitosan (CS)-, glycol chitosan (GCS)- and corresponding thiomer-based nanoparticles (NPs) for delivering dopamine (DA) to the brain by nasal route. Thus, the polyanions tripolyphosphate and sulfobutylether-β-cyclodextrin (SBE-β-CD), respectively, were used as polycation crosslinking agents and SBE-β-CD also in order to enhance the DA stability. The most interesting formulation, containing GCS and SBE-β-CD, was denoted as DA GCS/DA-CD NPs. NMR spectroscopy demonstrated an inclusion complex formation between SBE-β-CD and DA. X-ray photoelectron spectroscopy analysis revealed the presence of DA on the external surface of NPs. DA GCS/DA-CD NPs showed cytotoxic effect toward Olfactory Ensheathing Cells only at higher dosage. Acute administration of DA GCS/DA-CD NPs into the right nostril of rats did not modify the levels of the neurotransmitter in both right and left striatum. Conversely, repeated intranasal administration of DA GCS/DA-CD NPs into the right nostril significantly increased DA in the ipsilateral striatum. Fluorescent microscopy of olfactory bulb after acute administration of DA fluorescent-labeled GCS/DA-CD NPs into the right nostril showed the presence of NPs only in the right olfactory bulb and no morphological tissue damage occurred. Thus, these GCS based NPs could be potentially used as carriers for nose-to-brain DA delivery for the Parkinson’s disease treatment.     

Promoting absorption of drugs in humans using medium-chain fatty acid-based solid dosage forms: GIPET™

One of the most important and challenging goals in drug delivery is overcoming the poor oral absorption of high-value therapeutics that include peptides. Gastrointestinal Permeation Enhancement Technology (GIPET?) attempts to address this question by safely delivering drugs across the small intestine in therapeutically relevant concentrations. GIPET is based primarily on promoting drug absorption through the use of medium-chain fatty acids, medium-chain fatty acid derivatives and microemulsion systems based on medium-chain fatty acid glycerides formulated in enteric-coated tablets or capsules. Importantly, these excipients are generally regarded as safe and the systems are formulated in such a way that there is no change in chemical composition of the active ingredient. More than 300 volunteers have been administered GIPET formulations in 16 Phase I studies of 6 separate drugs comprising both single- and repeat-dosing regimes. Oral bioavailability of alendronate, desmopressin and low-molecular-weight heparin in humans was increased using GIPET formulations compared with unformulated controls. GIPET was well tolerated by human subjects. Using fluxes of markers of epithelial permeability, the effects of GIPET on the human intestine were shown to be rapid, short-lived and reversible in vivo. These data suggest that GIPET formulations have genuine potential as a platform technology for safe and effective oral drug delivery of a wide range of poorly permeable drugs.