Systemic Drug Concentrations Research Articles

Development of long-circulating docetaxel loaded poly (3-hydroxybutyrate-co-3-hydroxyvalerate) nanoparticles: Optimization, pharmacokinetic, cytotoxicity and in vivo assessments

Long-circulating nanoparticles (NPs) are promising drug delivery vehicles which target solid tumors via enhanced permeation and retention effect. Plackett–Burman (PBD) and Box–Behnken (BBD) designs were adopted to study the effects of factors viz. polymer concentration, surfactant concentration, homogenizer speed, homogenization time and ultrasonication time on responses. A graphical and numerical optimization technique was used to obtain predicted value of the response. The drug entrapment efficiency was approximately 39±0.85%. The particle size of the nanoparticles was found to be 260±2.85nm, while the zeta potential was −18±2.12mV, indicating more stable particles. SEM, TEM, and AFM were used for characterization of surface morphology and the physicochemical characters of NPs. A pharmacokinetic evaluation carried out intravenous administration in healthy Charles Foster rats displayed enhanced systemic bioavailability and plasma drug concentration. The in vivo-in silico assessment by GastroPlus™ showed good prediction accuracy and presented best-fit model. Nanoparticles were also studied for stability testing and were found to be stable concerning their drug content and physical characters. In vitro cytotoxicity was assessed using MCF-7 for percentage inhibition of human breast cancer cell line. Anticancer studies of optimized NPs showed a significant increase in efficacy as observed by relative tumor volume up to 30 days.

Is incomplete estradiol suppression during aromatase inhibitor treatment in post-menopausal patients with breast cancer due to insufficient systemic drug concentrations?

1063 Background: Aromatase inhibitors (AI) suppress estrogen biosynthesis and are effective treatments for estrogen receptor (ER)-positive breast cancer. In a prospectively enrolled cohort we observed a subset of post-menopausal women who exhibit high plasma estradiol (E2) concentrations during AI treatment, which could potentially contribute to treatment failure. We tested the hypothesis that incomplete E2 suppression is due to insufficient systemic AI concentrations. Methods: Five hundred post-menopausal women with ER-positive breast cancer were randomized to daily exemestane (Exe) 25 mg or letrozole (Let) 2.5 mg. Plasma E2 was measured using GC/MS/MS (lower limit of quantification (LLOQ) = 1.25 pg/mL) at baseline and after 3 months. Let and Exe plasma concentrations measured after 1 or 3 months were compared with the magnitude of E2 depletion using four complementary statistical procedures to assess associations of drug concentrations with: 1) a binary outcome of E2 suppression below LLOQ (logistic regression), 2) 3-month E2 concentrations (linear regression), 3) absolute change from baseline in E2 concentrations (Spearman correlation), and 4) an ordinal outcome defined by E2: decreased to below LLOQ, decreased but not to LLOQ, stayed the same, or increased from baseline (cumulative logistic regression). Results: 397 patients with E2 and AI concentration measurements were evaluable (Exe n = 199, Let n = 198). Thirty (7.6%) patients (Exe n = 13, Let n = 17) had E2 concentrations above the LLOQ at 3 months (range: 1.42-63.8 pg/mL). Exe and Let concentrations were not associated with achievement of unmeasurable E2 concentrations, on-treatment E2 concentrations, E2 change from baseline, or ordinal groupings of E2 change (all p > 0.05). In a parallel analysis there was no association of estrone-sulfate and drug concentrations (data not shown). Conclusions: Our results suggest that circulating drug concentrations do not explain incomplete E2 suppression in women receiving AI therapy. Additional studies are underway to determine whether age, body mass and genetic variation in the aromatase enzyme influence AI treatment response.

Impact of Chemical Structure on Conjunctival Drug Permeability: Adopting Porcine Conjunctiva and Cassette Dosing for Construction of In Silico Model

Conjunctiva occupies most of the ocular surface area, and conjunctival permeability affects ocular and systemic drug absorption of topical ocular medications. Therefore, the aim of this study was to obtain a computational in silico model for structure-based prediction of conjunctival drug permeability. This was done by employing cassette dosing and quantitative structure-property relationship (QSPR) approach. Permeability studies were performed ex vivo across fresh porcine conjunctiva and simultaneous dosing of a cassette mixture composed of 32 clinically relevant drug molecules with wide chemical space. The apparent permeability values were obtained using drug concentrations that were quantified with liquid chromatography tandem-mass spectrometry. The experimental data were utilized for building a QSPR model for conjunctival permeability predictions. The conjunctival permeability values presented a 17-fold range (0.63-10.74 × 10−6 cm/s). The final QSPR had a Q2 value of 0.62 and predicted the external test set with a mean fold error of 1.34. The polar surface area, hydrogen bond donor, and halogen ratio were the most relevant descriptors for defining conjunctival permeability. This work presents for the first time a predictive QSPR model of conjunctival drug permeability and a comprehensive description on conjunctival isolation from the porcine eye. The model can be used for developing new ocular drugs.

Inhibition of Stat3 by a Small Molecule Inhibitor Slows Vision Loss in a Rat Model of Diabetic Retinopathy.

PurposeDiabetic retinopathy is a leading cause of vision loss. Previous studies have shown signaling pathways mediated by Stat3 (signal transducer and activator of transcription 3) play a primary role in diabetic retinopathy progression. This study tested CLT-005, a small molecule inhibitor of Stat3, for its dose-dependent therapeutic effects on vision loss in a rat model of diabetic retinopathy.MethodsBrown Norway rats were administered streptozotocin (STZ) to induce diabetes. CLT-005 was administered daily by oral gavage for 16 weeks at concentrations of 125, 250, or 500 mg/kg, respectively, beginning 4 days post streptozotocin administration. Systemic and ocular drug concentration was quantified with mass spectrometry. Visual function was monitored at 2-week intervals from 6 to 16 weeks using optokinetic tracking to measure visual acuity and contrast sensitivity. The presence and severity of cataracts was visually monitored and correlated to visual acuity. The transcription and translation of multiple angiogenic factors and inflammatory cytokines were measured by real-time polymerase chain reaction and Multiplex immunoassay.ResultsStreptozotocin-diabetic rats sustain progressive vision loss over 16 weeks, and this loss in visual function is rescued in a dose-dependent manner by CLT-005. This positive therapeutic effect correlates to the positive effects of CLT-005 on vascular leakage and the presence of inflammatory cytokines in the retina.ConclusionsThe present study indicates that Stat3 inhibition has strong therapeutic potential for the treatment of vision loss in diabetic retinopathy.

Novel Treatment with Intraperitoneal MOC31PE Immunotoxin in Colorectal Peritoneal Metastasis: Results From the ImmunoPeCa Phase 1 Trial

MOC31PE immunotoxin was developed to rapidly kill cells expressing the tumor-associated epithelial cell adhesion molecule, which is highly expressed in colorectal cancer. Although cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) may offer long-term survival to patients with peritoneal metastasis from colorectal cancer (PM-CRC), most patients experience disease relapse and novel therapeutic options are needed. On this basis, MOC31PE is being developed as a novel therapeutic principle to target PM-CRC. This was a dose-escalating phase I trial to evaluate the safety and toxicity (primary endpoint), pharmacokinetic profile, and neutralizing antibody response (secondary endpoints) upon intraperitoneal administration of MOC31PE in patients with PM-CRC undergoing CRS-HIPEC with Mitomycin C. Fifteen patients received the study drug at four dose levels (3+3+3+6), administered intraperitoneally as a single dose the day after CRS-HIPEC. No dose-limiting toxicity was observed, and the maximum tolerated dose was not reached. There was negligible systemic absorption of the study drug. Drug concentrations in peritoneal fluid samples were in the cytotoxic range and increased in a dose-dependent manner. MOC31PE recovered from peritoneal cavity retained its cytotoxic activity in cell-based assays. All patients developed neutralizing antibodies. Intraperitoneal administration of MOC31PE was safe and well tolerated, and combined with low systemic uptake, MOC31PE seems ideal for local intraperitoneal treatment. The drug will be further evaluated in an ongoing phase II expansion cohort.

Pharmacokinetic Assessment of Continuous Infusion Ceftolozane/Tazobactam for Drug-Resistant Pseudomonas aeruginosa Left Ventricular Assist Device Driveline Infection

Background Pseudomonas aeruginosa is a common pathogen in left ventricular assist device (LVAD) infections. Ceftolozane/tazobactam (C/T) is a β-lactam/β-lactamase inhibitor with activity against P. Aeruginosa, including multi-drug-resistant (MDR) isolates. We describe the novel use of continuous infusion (CI) C/T with therapeutic drug monitoring in a 70-year-old man who developed a MDR P. Aeruginosa LVAD driveline infection.MethodsThe patient received CI C/T 6g IV over 24 hours to facilitate long-term outpatient therapy after receipt of five days of intermittent infusion (3g IV every 8 hours over 1 hour). Blood samples were collected in heparinized tubes immediately prior to and at 6, 12, 18, 24, and 48 hours after initiating CI. The samples were centrifuged at 2,500 rpm for 10 minute and stored at -80°C until assayed. Ceftolozane and tazobactam concentrations were quantified using previously validated high-performance liquid chromatography (HPLC) methods.ResultsCeftolozane and tazobactam concentrations are shown in Table 1. The susceptibility profile (VITEK® 2) demonstrated the following minimum inhibitory concentrations (MICs): gentamicin ≤ 1 mcg/mL, cefepime = 32 mcg/mL, ciprofloxacin ≥ 4 mcg/mL, meropenem = 8 mcg/mL. Colistin, polymyxin B, and C/T MICs were confirmed via E-test (2 mcg/mL, 2 mcg/mL, and 1.5 mcg/mL, respectively). The patient clinically improved with resolution of signs and symptoms of infection after 6 weeks with CI C/T. Suppressive therapy was continued indefinitely in lieu of source control. A subjective increase in gout pain was reported, but no other major adverse events were noted during therapy.ConclusionAdequate systemic drug concentrations of C/T well above the MIC were achieved when administered as a CI of 6g over 24 hours. Based on serum ceftolozane concentrations, dose modification of CI may be possible with future evaluation. Continuous infusion represents a potentially well-tolerated delivery for C/T and warrants further study.Table 1. Ceftolozane and tazobactam drug concentrations.Collection TimeCeftolozane Concentration (µg/ml)Tazobactam Concentration (µg/ml) Intermittent Infusion Trough, steady state97.8325.62 Continuous Infusion 6 hour55.1216.9112 hour47.4913.3218 hour39.369.3124 hour39.9010.9248 hour40.6419.64Disclosures D. P. Nicolau, Merck: Investigator and Speaker’s Bureau, Research support. P. B. Bookstaver, Rock Pointe: Content Developer, Consulting fee

ALGINATE BASED GASTRO-RETENTIVE RAFT FORMING TABLETS FOR ENHANCED BIOAVAILABILITY OF TINIDAZOLE

Objective: Tinidazole, a nitroimidazole derivative is having low aqueous solubility which is a major barrier for systemic drug absorption. The aim of the present research was to develop gastro retentive raft forming tablets of tinidazole to achieve prolonged gastric residence time and thus higher bioavailability.Methods: Solid dispersion of tinidazole was prepared by kneading method by using methanol and polyvinylpyrrolidone (PVP). Different concentration of sodium alginate and hydroxypropyl methylcellulose (HPMC) was used to formulate a suitable raft forming tablets and then evaluated for drug content, floating lag time, raft strength, raft volume, raft weight, drug release and release kinetics.Results: Fourier transform infra-red (FT-IR) study confirms compatibility between drug and polymer. The floating lag time was found in the range of 40±4 to 60±5 s for all the formulation. Raft strength for all the formulations was within the range from 3.03±0.12 to 5.92±0.06 g. The raft volume for all the formulation was found within the range of 7.37±1.86 to 9.84±2.76 ml. Raft weight was measured after completion of raft formation for each formulation and was found in the range of 5.21±1.17 to 7.88±1.95 g. In vitro dissolution was carried up to 8 h and percentage of drug release was found to vary between 79.71±2.18 to 94.32±1.79 %.Conclusion: It can be concluded that the combination of solid dispersion and raft formation increases the bioavailability of tinidazole in tablet formulation.

Preclinical Modeling of ACVR1-Dependent Hepcidin Production and Anemia By Momelotinib

▪Patients with myelofibrosis (MF) often develop anemia and frequently become dependent on red blood cell transfusions. Elevated levels of hepcidin in MF patients suggest that deregulated iron homeostasis is a driver of anemia in MF (Pardanani et al., Am J Hematol, 2013). A phase 2 study in MF patients demonstrated that momelotinib (MMB) treatment resulted in improvement of anemia (Pardanani et al., Blood, 2013, ASH Suppl). We have demonstrated that in addition to inhibiting JAK1/2, MMB also inhibits the bone morphogenetic protein receptor kinase, activin A receptor type 1 (ACVR1), a key regulator of hepcidin production in hepatocytes (Asshoff et al., Blood, 2015, ASH Suppl). This work supports a model by which the improvement of anemia observed in MF patients with MMB treatment results from the inhibition of ACVR1-mediated hepcidin expression in the liver, increased mobilization of sequestered iron from cellular stores and subsequent stimulation of erythropoiesis.Here we demonstrate that MMB treatment in anemic rats resulted in a reduction of hepcidin and amelioration of anemia; whereas ruxolitinib dosing affected neither hepcidin nor anemia. Short-term MMB oral treatment in anemic rats resulted in a dose responsive inhibition of serum hepcidin induction with complete suppression at 25 mg/kg QD, 82% inhibition at 10 mg/kg QD, and 55% inhibition at 5 mg/kg QD (Table 1). Interestingly, only the two higher doses show significant time above EC50 levels, whereas the 5 mg/kg dose (which most closely approximates MMB human clinical exposures) only shows significant time above EC20. This suggests that systemic drug concentrations alone may not accurately predict activity in the model as 5 mg/kg demonstrated a 55% reduction in serum hepcidin. In a rat quantitative whole body autoradiography tissue distribution study, MMB levels have been demonstrated to be 3-4 fold higher in the liver relative to blood (Figure 1). Thus, the significant inhibiton of hepcidin levels in animals dosed with 5 mg/kg MMB may be due to higher concentrations in the liver. MMB concentrations would be expected to be higher in the liver relative to blood in humans as well.Our results provide preclinical evidence for a direct role of MMB in regulating iron homeostasis through the ACVR1/hepcidin axis. Evaluation of the activity of MMB on the ACVR1/hepcidin axis is being done in ongoing MMB clinical studies in patients with MF. [Display omitted] [Display omitted] DisclosuresWarr:Gilead Sciences: Employment, Equity Ownership. Zheng:Gilead Sciences: Employment, Equity Ownership. Sharma:Gilead Sciences: Employment, Equity Ownership. Maciejewski:Gilead Sciences: Employment, Equity Ownership. Theurl:Gilead Sciences: Research Funding. Whitney:Gilead Sciences: Employment, Equity Ownership.

A comprehensive insight on ocular pharmacokinetics.

The eye is a distinctive organ with protective anatomy and physiology. Several pharmacokinetics compartment models of ocular drug delivery have been developed for describing the absorption, distribution, and elimination of ocular drugs in the eye. Determining pharmacokinetics parameters in ocular tissues is a major challenge because of the complex anatomy and dynamic physiological barrier of the eye. In this review, pharmacokinetics of these compartments exploring different drugs, delivery systems, and routes of administration is discussed including factors affecting intraocular bioavailability. Factors such as precorneal fluid drainage, drug binding to tear proteins, systemic drug absorption, corneal factors, melanin binding, and drug metabolism render ocular delivery challenging and are elaborated in this manuscript. Several compartment models are discussed; these are developed in ocular drug delivery to study the pharmacokinetics parameters. There are several transporters present in both anterior and posterior segments of the eye which play a significant role in ocular pharmacokinetics and are summarized briefly. Moreover, several ocular pharmacokinetics animal models and relevant studies are reviewed and discussed in addition to the pharmacokinetics of various ocular formulations.

Cellulosic on Transdermal Drug Delivery System: A Review

Transdermal patch is a medicated adhesive patch that is placed on the skin to deliver the drug through the skin in order to achieve systemic absorption of drug at a predetermined rate over a prolonged period of time. The amalgamation of polymer and pharmaceutical sciences led to the introduction of polymer in the design and development of drug delivery systems. Polymeric delivery systems are mainly intended to achieve controlled or sustained drug delivery. Polysaccharides fabricated into hydrophilic matrices remain popular biomaterials for controlled-release dosage forms and the most abundant naturally occurring biopolymer is cellulose; thus, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), microcrystalline cellulose (MCC) and ethyl cellulose (EC) can be used for production of controlled transdermal drug delivery systems (TDDS). This paper assembles the current knowledge on the structure and chemistry of cellulose, and in the development of innovative cellulose esters and ethers for controlled release TDDS. In addition, bacterial cellulose applications through chemical modification as a new TDDS will be discussed. Key words: Cellulosic, Transdermal Drug Delivery System, Bacterial Cellulose, Adhesive Patch

Development and validation of a liquid chromatographic-tandem mass spectrometric method for the multiplexed quantification of etravirine, maraviroc, raltegravir, and rilpivirine in human plasma and tissue

BackgroundAnalytical methodologies for antiretroviral (ARV) quantification are important in determining both systemic and localized drug concentrations. The CCR5-antagonist maraviroc (MVC), the non-nucleoside reverse transcriptase inhibitors (NNRTIs) etravirine (ETV) and rilpivirine (RPV), as well as the integrase strand transfer inhibitor (INSTI) raltegravir (RAL), have all been evaluated using both oral and non-oral dosing regimens, demonstrating a need for dynamic and sensitive bioanalytical tools for drug quantification in plasma and tissue. MethodsK2EDTA plasma or blank luminal tissue lysate were spiked with ETV, MVC, RAL, and RPV. Following the addition of isotopically-labeled internal standards and sample extraction via protein precipitation or solid phase extraction, respectively, samples were subjected to liquid chromatographic-tandem mass spectrometric (LC–MS/MS) analysis. Chromatographic separation was performed using a Waters BEH C8, 50×2.1mm, 1.7μm particle size column, and detected on an API 5000 mass analyzer operated in selective reaction monitoring mode. The method was validated according to FDA Bioanalytical Method Validation guidelines. ResultsAnalytical methods were optimized for the multiplexed monitoring of ETV, MVC, RAL, and RPV in plasma and homogenized tissue lysate. The lower limits of quantification (LLOQs) for ETV, RAL, and RPV were 1ng/mL and the LLOQ for MVC was 0.1ng/mL in plasma; the LLOQs for all ARVs in homogenized tissue lysate was 0.05ng/sample. Standard curves were generated via weighted quadratic (plasma) or linear (tissue) regression of calibrators. Intra- and inter-assay precision and accuracy studies demonstrated %CVs≤15.93% and %DEVs ≤±13.52%, respectively. Stability and matrix effects studies, as well as external proficiency testing assessment, were also performed. All results were acceptable and in accordance with the guidelines recommended by the FDA, Guidance for Industry: Bioanalytical Method Validation document. ConclusionsLC–MS/MS assays that are sensitive, specific, and dynamic have been developed and validated for the multiplexed quantification of ETV, MVC, RAL, and RPV in plasma and homogenized tissue lysate. The described methods meet sufficient throughput criteria to support large research trials.

The Importance of Reporting Unexpected Drug Failure

Unexpected drug failure is a lack of therapeutic effect, which is not expected based on the characteristics of the drug and patient. Essentially, it may occur either for interactions (with other drugs or foods) or for biopharmaceutical issues. The risk arising from interactions is generally well characterised and physicians are well aware of it, and the importance of reporting cases of failure due to interactions is obvious. Less is known about the mechanisms and potential risk deriving from biopharmaceutical problems, and we will therefore focus on this issue. Biopharmaceutics describes the influence of the physical/chemical properties of the drug and drug product on the rate and extent of systemic drug absorption. Because after oral administration of solid pharmaceutical forms drugs must dissolve in gastrointestinal fluids before being absorbed through the intestinal epithelium, biopharmaceutical problems essentially arise from an insufficient dissolution performance. A typical situation where an insufficient dissolution may cause unexpected drug failure is when a patient is switched from one drug product to a different product. Different drug products with the same active substance may differ in manufacture and excipient composition.

Mucoadhesive, nanostructured microparticles for their prolonged retention in gastrointestinal tract

Event Abstract Back to Event Mucoadhesive, nanostructured microparticles for their prolonged retention in gastrointestinal tract Chun Gwon Park1, Beom Kang Huh2, Se Na Kim2, Seung Ho Lee2, Min Park2, Hye Rim Hong2, Ka Ryeong Kim2, Hyein Won2 and Young Bin Choy1, 2, 3 1 Seoul National University, Institute of Medical & Biological Engineering, Korea 2 Seoul National University, Interdisciplinary Program for Bioengineering, Korea 3 Seoul National University, Department of Biomedical Engineering, Korea Introduction: Oral drug of poor bioavailability often needs multiple daily administrations to maintain a therapeutically effective level of systemic drug concentration, which is limited in an inconvenient regimen of drug therapy. In this sense, the carriers, which could stay in the gastrointestinal (GI) tract and also release drug in a sustained manner, would be useful. For this, we propose mucoadhesive, nanostructured microparticles as a potential oral-drug carrier in this work. Those functional microparticles herein possessed a high specific surface area originated from their nanostructure, hence improved mucoadhesion through a gastrointestinal (GI) tract [1]. We examined the in vivo retention time of the microparticles in the GI tract after their oral administration in living rats in this study. Methods: Four different types of the microparticles were prepared to examine the effect of particle morphology (i.e., spherical or nanostructured) and mucoadhesiveness on their residence time in GI tract: spherical microparticles (MS) of PLGA only (PLGA MS), MS of PLGA and PEG (PLGA/PEG MS), nanostructured microparticles (NM) of PLGA only (PLGA NM) and NM of PLGA and PEG (PLGA/PEG NM) [1]. The microparticles were composed mainly of PLGA, where PEG was used as additive to give a mucoadhesion property. The MS was prepared by the conventional emulsion method. The NM was prepared by freeze-milling the nanofibrous sheets prepared via electrospinning. All microparticles were labeled with near-infrared fluorescent dye, 3,3′-Diethylthiatricarbocyanine iodide (DTTCI) and orally administered to living rat to monitor their retention property in the GI tract (IVIS (Lumina II); excitation and emission wavelengths of 745 and 840 nm, respectively). The suspensions containing the DTTCI only was also evaluated for comparison. Results and Conclusion: The MS prepared by the emulsion method exhibited a spherical shape with a smooth surface (Fig. 1(a-b)). The NM showed the morphology with randomly entangled nanofibers to give a rough surface (Fig. 1(c-d)). The presence of PEG in microparticles did not seem to influence their own purposed surface morphology (Fig. 1) Figure 1(e) shows the in vivo fluorescence images of the whole rats at scheduled times after oral administration of the microparticle formulations. For all control groups (i.e., the dye suspension, PLGA MS, PLGA/PEG MS and PLGA NM groups), fluorescence signal was observed through the GI tract for up to 12 h, which, however, became not detectable afterwards. On the other hand, the PLGA/PEG NM showed the best retention in GI tract as their fluorescence signal was detectable until 36 h. This could be ascribed to the fact that mucoadhesiveness was synergistically improved by the enlarged specific surface area originated from the nanostructure of the PLGA/PEG NM. This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF- 2013R1A1A2A10011055); This research was supported by BK21 Plus Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (grant numbers 22A20130011025)

Prediction of Ocular Drug Distribution from Systemic Blood Circulation.

Systemically circulating drugs may distribute to ocular tissues across the blood-ocular barriers. Ocular distribution is utilized in the treatment of ocular diseases with systemic medications, but ocular delivery of systemic drugs and xenobiotics may also lead to adverse ocular effects. Ocular distribution after systemic drug administration has not been predicted or modeled. In this study, distribution clearance between vitreous and plasma was obtained from a previous QSPR model for clearance of intravitreal drugs. These values were used in a pharmacokinetic simulation model to describe entry of unbound drug from plasma to vitreous. The simulation models predicted ocular distribution of 10 systemic drugs in rabbit eyes within 1.96 mean fold error and the distribution of cefepime from plasma to vitreous in humans. This is the first attempt to predict ocular distribution of systemic drugs. Reliable predictions were obtained using systemic concentrations of unbound drug, computational value of ocular distribution clearance, and a simple pharmacokinetic model. This approach can be used in drug discovery to estimate ocular drug exposure at an early stage.

Comparison of Simple Eudragit Microparticles Loaded with Prednisolone and Eudragit-Coated Chitosan-Succinyl-Prednisolone Conjugate Microparticles: Part II. In Vivo Evaluation of Efficacy, Toxicity, and Biodisposition Characteristics.

We previously prepared and evaluated simple Eudragit S100 microparticles loaded with prednisolone (ES-MP) and Eudragit S100-coated chitosan-succinyl-prednisolone conjugate microparticles (Ch-MP/ES) in vitro. In this work, the effectiveness, toxic side effects (5 mg prednisolone (PD) eq/kg × 3 d, 10 mg PD eq/kg × 3 d), and pharmacokinetic characteristics (5 mg PD eq/kg) were examined using rats with colitis induced through 2,4,6-trinitrobenzenesulfonic acid. ES-MP did not change the efficacy or toxic side effects of PD, and this was attributed to incomplete delivery to the target site and prolonged systemic drug absorption by ES-MP. On the other hand, Ch-MP/ES promoted the efficacy of PD and ameliorated its toxic side effects due to better delivery to the target site, very slow drug release and the strong suppression of drug absorption. Only Ch-MP/ES, which markedly changed drug release characteristics, improved the in vivo features of PD.

Preparation and evaluation of a timolol maleate drug–resin ophthalmic suspension as a sustained-release formulation in vitro and in vivo

The aim of this work was to assess the performance of resin as an ocular delivery system. Timolol maleate (TM) was chosen as the model drug and an ion exchange resin (IER) as the carrier. The drug–resin complex was prepared using an oscillation method and then characterized regarding particle size, zeta potential, morphology, and drug content. After in vitro drug release study and corneal permeation study were performed, in vivo studies were performed in New Zealand albino rabbits using a suspension with particles sized 4.8 ± 1.2 μm and drug loading at 43.00 ± 0.09 %. The results indicate that drug released from the drug–resin ophthalmic suspension permeated the cornea and displayed a sustained-release behavior. Drug levels in the ocular tissues after administration of the drug–resin ophthalmic suspension were significantly higher than after treatment with an eye drop formulation but were lower in body tissues and in the plasma. In conclusion, resins have great potential as effective ocular drug delivery carriers to increase ocular bioavailability of timolol while simultaneously reducing systemic drug absorption.

Dimethadione embryotoxicity in the rat is neither correlated with maternal systemic drug concentrations nor embryonic tissue levels

Pregnant rats treated with dimethadione (DMO), the N-demethylated metabolite of the anticonvulsant trimethadione, produce offspring having a 74% incidence of congenital heart defects (CHD); however, the incidence of CHD has high inter-litter variability (40–100%) that presents a challenge when studying the initiating events prior to the presentation of an abnormal phenotype. We hypothesized that the variability in CHD incidence was the result of differences in maternal systemic concentrations or embryonic tissue concentrations of DMO. To test this hypothesis, dams were administered 300mg/kg DMO every 12h from the evening of gestational day (GD) 8 until the morning of GD 11 (six total doses). Maternal serum levels of DMO were assessed on GD 11, 12, 13, 14, 15, 18 and 21. Embryonic tissue concentrations of DMO were assessed on GD 11, 12, 13 and 14. In a separate cohort of GD 12 embryos, DMO concentrations and parameters of growth and development were assessed to determine if tissue levels of DMO were correlated with these endpoints. Embryos were exposed directly to different concentrations of DMO with whole embryo culture (WEC) and their growth and development assessed. Key findings were that neither maternal systemic concentrations nor tissue concentrations of DMO identified embryos that were sensitive or resistant to DMO in vivo. Direct exposure of embryos to DMO via WEC also failed to show correlations between embryonic concentrations of DMO with developmental outcomes in vitro. We conclude that neither maternal serum nor embryonic tissue concentrations of DMO predict embryonic outcome.

Abstract 5146: Establishment of an orthotopic bladder cancer model to evaluate continuous intravesical delivery of small molecule inhibitors in the nude rat

Abstract Bladder cancer is a disease with high unmet need, with no new treatments being registered in the last two decades. Intravesical delivery is an attractive option for organ-confined bladder cancer; indeed, non-muscle invasive disease is currently treated by intravesical administration of agents such as bacillus Calmette-Guerin (BCG) and mitomycin C, and neoadjuvant intravesical therapy has the potential to preserve the bladder and improve survival in M0 muscle invasive disease. Intravesical delivery has the potential to increase the therapeutic index compared with systemic dosing routes, particularly if the duration of exposure can be extended. In order to explore this concept, we have developed an orthotopic model of bladder cancer and a drug delivery method to administer gemcitabine into the nude rat bladder for one week. An orthotopic model of bladder cancer was established by serial passaging of MGH-U3 human bladder cancer cells into the muscle wall. Tumor take-rate and growth was monitored by ultrasound imaging. Serial ex vivo - in vivo passaging increased growth and take rate of the tumors in both orthotopic and subcutaneous locations. Orthotopic implantation of cells following two previous passages in vivo resulted in reproducible tumor growth and take rates of >90%. Immunohistochemistry analysis showed that the orthotopic tumors were stably epithelial in phenotype after three serial in vivo passages. Principal component analysis of gene expression (GE) data from RNA sequencing of the parental cell line, sequentially passaged cells growing ex vivo, and both subcutaneous and orthotopically implanted tumours after various numbers of passages revealed three clusters; two distinct but closely related clusters representing the orthotopic and subcutaneously growing tumors, and another distinct cluster representing the various cell lines. This analysis showed that in vitro/in vivo location of growth is a more important determinant of global GE than the process of serial passaging in vivo. We have used the iPRECIO programmable infusion pump system to continuously infuse gemcitabine into the bladders of rats with orthotopic bladder tumors. Infusion of 2.5 mg/day at a flow rate of 5 ul/h for 7 days resulted in urine concentrations in the range of 1- 10 mM (∼ 1000-fold greater than systemic plasma drug concentrations), a 4-fold increase of γH2AX and induction of both necrosis and apoptosis (10-fold induction of cleaved casapse 3) in the orthotopic tumors. This model system holds considerable potential for evaluation of intravesical small molecule therapies that are potentially translatable to patients. Citation Format: Leigh J. Williams, Stephanie K. Klein, Danielle Greenawalt, Dawn Trueman, Helen Musgrove, Helen Jones, Linette Ruston, Barry R. Davies. Establishment of an orthotopic bladder cancer model to evaluate continuous intravesical delivery of small molecule inhibitors in the nude rat. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5146. doi:10.1158/1538-7445.AM2015-5146

Niosomal drug delivery for transdermal targeting: recent advances

Niosomes are vesicular nanocarriers and are receiving much attention as potential transdermal drug delivery systems due to properties such as enhanced drug penetration, local depot for sustained drug release, and a rate-limiting membrane for modulation of systemic absorption of drugs via the skin. Several mechanisms have been proposed to explain the ability of niosomes to increase drug transfer through the skin. Niosomal carriers are suitable for the transdermal delivery of numerous pharmacological agents, including antioxidant, anticancer, anti-inflammatory, antimicrobial, and antibacterial molecules, and this review attempts to provide an exhaustive collection of recent investigations in this interesting field, with special emphasis on the strategies used to enhance the potential of niosomes.

Colon-targeted oral drug delivery systems: design trends and approaches.

Colon-specific drug delivery systems (CDDS) are desirable for the treatment of a range of local diseases such as ulcerative colitis, Crohn's disease, irritable bowel syndrome, chronic pancreatitis, and colonic cancer. In addition, the colon can be a potential site for the systemic absorption of several drugs to treat non-colonic conditions. Drugs such as proteins and peptides that are known to degrade in the extreme gastric pH, if delivered to the colon intact, can be systemically absorbed by colonic mucosa. In order to achieve effective therapeutic outcomes, it is imperative that the designed delivery system specifically targets the drugs into the colon. Several formulation approaches have been explored in the development colon-targeted drug delivery systems. These approaches involve the use of formulation components that interact with one or more aspects of gastrointestinal (GI) physiology, such as the difference in the pH along the GI tract, the presence of colonic microflora, and enzymes, to achieve colon targeting. This article highlights the factors influencing colon-specific drug delivery and colonic bioavailability, and the limitations associated with CDDS. Further, the review provides a systematic discussion of various conventional, as well as relatively newer formulation approaches/technologies currently being utilized for the development of CDDS.