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Pharmaceutical Research
Journal Prestige (SJR): 1.077
Citation Impact (citeScore): 3
Number of Followers: 177  
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 1573-904X - ISSN (Online) 0724-8741
Published by Springer-Verlag Homepage  [2574 journals]
  • E-Jet 3D-Printed Scaffolds as Sustained Multi-Drug Delivery Vehicles in
           Breast Cancer Therapy
    • Abstract: Purpose Combination chemotherapy is gradually receiving more attention because of its potential synergistic effect and reduced drug doses in clinical application. However, how to precisely control drug release dose and time using vehicles remains a challenge. This work developed an efficient drug delivery system to combat breast cancer, which can enhance drug effects despite reducing its concentration. Methods Controlled-release poly-lactic-co-glycolic acid (PLGA) scaffolds were fabricated by E-jet 3D printing to deliver doxorubicin (DOX) and cisplatin (CDDP) simultaneously. Results This drug delivery system allowed the use of a reduced drug dosage resulting in a better effect on the human breast cancer cell apoptosis and inhibiting tumor growth, compared with the effect of each drug and the two drugs administrated without PLGA scaffolds. Our study suggested that DOX-CDDP-PLGA scaffolds could efficiently destroy MDA-MB-231 cells and restrain tumor growth. Conclusions The 3D printed PLGA scaffolds with their time-programmed drug release might be useful as a new multi-drug delivery vehicle in cancer therapy, which has a potential advantage in a long term tumor cure and prevention of tumor recurrence.
      PubDate: 2019-11-18
  • Remote Controlled Autonomous Microgravity Lab Platforms for Drug Research
           in Space
    • Abstract: Research conducted in microgravity conditions has the potential to yield new therapeutics, as advances can be achieved in the absence of phenomena such as sedimentation, hydrostatic pressure and thermally-induced convection. The outcomes of such studies can significantly contribute to many scientific and technological fields, including drug discovery. This article reviews the existing traditional microgravity platforms as well as emerging ideas for enabling microgravity research focusing on SpacePharma’s innovative autonomous remote-controlled microgravity labs that can be launched to space aboard nanosatellites to perform drug research in orbit. The scientific literature is reviewed and examples of life science fields that have benefited from studies in microgravity conditions are given. These include the use of microgravity environment for chemical applications (protein crystallization, drug polymorphism, self-assembly of biomolecules), pharmaceutical studies (microencapsulation, drug delivery systems, behavior and stability of colloidal formulations, antibiotic drug resistance), and biological research, including accelerated models for aging, investigation of bacterial virulence , tissue engineering using organ-on-chips in space, enhanced stem cells proliferation and differentiation.
      PubDate: 2019-11-18
  • Exposure to Docetaxel in the Elderly Patient Population: a Population
           Pharmacokinetic Study
    • Abstract: Background Docetaxel is commonly used in elderly patients, who are frequently diagnosed with prostate cancer. Although previous studies revealed no clinically relevant impact of older age on docetaxel pharmacokinetics (PK), this may be masked by indication. Metastatic castration-resistant prostate cancer (mCRPC) patients were reported to have approximately two-times lower systemic exposure compared to patients with other solid tumors. This study assessed the impact of older age on docetaxel PK, also considering the effect of indication on docetaxel PK. Methods Prospectively collected docetaxel PK data from patients aged ≥70 was pooled with PK data from an earlier published multicenter study. A 3-compartment population PK model, including multiple covariates, was used to describe docetaxel plasma concentration-time data. We added the effect of prostate cancer (mCRPC and metastatic hormone-sensitive prostate cancer (mHSPC)) on clearance to this model. Hereafter, we evaluated the additional impact of older age on docetaxel clearance, using a significance threshold of p < 0.005. Results Docetaxel plasma concentration-time data from 157 patients were analyzed. Median age in the total cohort was 67 years (range 31-87), with 49% of the total cohort aged ≥70. The impact of age on docetaxel clearance was statistically significant (p < 0.005). For a typical patient, a 10-year and 20-year increase of age led to a reduction in clearance of 17% and 34%, respectively. Conclusion In this cohort study, age significantly and independently affected docetaxel clearance, showing lower docetaxel clearance in elderly patients. In our cohort, mCRPC and mHSPC patients both had higher clearance than patients with other solid tumors.
      PubDate: 2019-11-15
  • Stratum Corneum Sampling to Assess Bioequivalence between Topical
           Acyclovir Products
    • Abstract: Purpose To examine the potential of stratum corneum (SC) sampling via tape-stripping in humans to assess bioequivalence of topical acyclovir drug products, and to explore the potential value of alternative metrics of local skin bioavailability calculable from SC sampling experiments. Methods Three acyclovir creams were considered in two separate studies in which drug amounts in the SC after uptake and clearance periods were measured and used to assess bioequivalence. In each study, a “reference” formulation (evaluated twice) was compared to the “test” in 10 subjects. Each application site was replicated to achieve greater statistical power with fewer volunteers. Results SC sampling revealed similarities and differences between products consistent with results from other surrogate bioequivalence measures, including dermal open-flow microperfusion experiments. Further analysis of the tape-stripping data permitted acyclovir flux into the viable skin to be deduced and drug concentration in that ‘compartment’ to be estimated. Conclusions Acyclovir quantities determined in the SC, following a single-time point uptake and clearance protocol, can be judiciously used both to objectively compare product performance in vivo and to assess delivery of the active into skin tissue below the barrier, thereby permitting local concentrations at or near to the site of action to be determined.
      PubDate: 2019-11-14
  • The Duration of Nerve Block from Local Anesthetic Formulations in Male and
           Female Rats
    • Abstract: Purpose It is unknown whether there are sex differences in response to free or encapsulated local anesthetics. Methods We examined nerve block duration and toxicity following peripheral nerve blockade in male and female rats. We studied the local anesthetic bupivacaine (free or encapsulated) as well as tetrodotoxin, which acts on a different site of the same voltage-gated channel. Results Sensory nerve blockade was 158.5 [139–190] minutes (median [interquartile range]) (males) compared to 173 [134–171] minutes (females) (p = 0.702) following bupivacaine injection, N = 8 male, 8 female. Motor nerve blockade was 157 [141–171] minutes (males) compared to 172 [146–320] minutes (females) (p = 0.2786). Micellar bupivacaine (N = 8 male, 8 female) resulted in sensory nerve blockade of 266 [227–320] minutes (males) compared to 285 [239–344] minutes (females) (p = 0.6427). Motor nerve blockade was 264 [251–264] minutes (males) compared to 287 [262–287] minutes (females) (p = 0.3823). Liposomal bupivacaine (N = 8 male, 8 female) resulted in sensory nerve blockade of 240 [207–277] minutes (males) compared to 289 [204–348] minutes (females) (p = 0.1654). Motor nerve blockade was 266 [237–372] minutes (males) compared to 317 [251–356] minutes (females) (p = 0.6671). Following tetrodotoxin injection (N = 12 male,12 female) sensory nerve blockade was 54.8 [5–117] minutes (males) compared to 54 [14–71] minutes (females) (p = 0.6422). Motor nerve blockade was 72 [40–112] minutes (males) compared to 64 [32–143] minutes (females) (p = 0.971). Conclusions We found no statistically significant sex differences associated with the formulations tested. In both sexes, durations of nerve block were similar between micellar and liposomal bupivacaine formulations, despite the micellar formulation containing less drug.
      PubDate: 2019-11-08
  • A Cell-Free Approach Based on Phospholipid Characterization for
           Determination of the Cell Specific Unbound Drug Fraction (f u,cell )
    • Abstract: Purpose The intracellular fraction of unbound compound (fu,cell) is an important parameter for accurate prediction of drug binding to intracellular targets. fu,cell is the result of a passive distribution process of drug molecules partitioning into cellular structures. Initial observations in our laboratory showed an up to 10-fold difference in the fu,cell of a given drug for different cell types. We hypothesized that these differences could be explained by the phospholipid (PL) composition of the cells, since the PL cell membrane is the major sink of unspecific drug binding. Therefore, we determined the fu,cell of 19 drugs in cell types of different origin. Method The cells were characterized for their total PL content and we used mass spectrometric PL profiling to delineate the impact of each of the four major cellular PL subspecies: phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS) and phosphatidylinositol (PI). The cell-based experiments were compared to cell-free experiments that used beads covered by PL bilayers consisting of the most abundant PL subspecies. Results PC was found to give the largest contribution to the drug binding. Improved correlations between the cell-based and cell-free assays were obtained when affinities to all four major PL subspecies were considered. Together, our data indicate that fu,cell is influenced by PL composition of cells. Conclusion We conclude that cellular PL composition varies between cell types and that cell-specific mixtures of PLs can replace cellular assays for determination of fu,cell as a rapid, small-scale assay covering a broad dynamic range. Graphical .
      PubDate: 2019-11-07
  • Functional and Nonclinical Similarity of ABP 980, a Biosimilar of
    • Abstract: Purpose The in vitro and in vivo pharmacologic assessment of ABP 980 similarity to its reference product is intended to compare the activity of ABP 980 and trastuzumab and support the overall conclusion of similarity based on a comprehensive analytical and functional evaluation. Methods This work complements the primary assessment of functional similarity with additional in vitro assays, binding studies, and non-clinical studies including human epidermal growth factor receptor-2 (HER2) kinetic binding, HER2 signaling, HER2 internalization, synergy with docetaxel chemotherapy, FcγR kinetic binding, primary natural killer and monocyte cell binding, antibody-dependent cellular phagocytosis activity, in vivo xenograft studies, and toxicokinetic parameters. Results The results contribute to the totality of evidence with respect to functional similarity and support that ABP 980 is similar to trastuzumab in all primary and secondary mechanisms of action. Conclusions These results also support the scientific justification of extrapolation to all approved indications of trastuzumab given the established functional similarity of the two products and the same mechanisms of action across all conditions of use.
      PubDate: 2019-11-06
  • A Sialylated-Bortezomib Prodrug Strategy Based on a Highly Expressed
           Selectin Target for the Treatment of Leukemia or Solid Tumors
    • Abstract: Purpose This study aimed to explore the potential of sialic acid - related selectin targeting strategy in the treatment of leukemia and some solid tumors. We expected it could “actively” bind tumor cells and kill them, reducing non-specific toxicity to normal cells. Methods BOR-SA prodrug was synthesized by reacting an ortho-dihydroxy group in SA with a boronic acid group in BOR. Two kinds of leukemia cells (RAW264.7 and HL60 cells), one solid sarcoma cell model (S180 cells) and their corresponding normal cells (monocytes (MO), neutrophil (NE) and fibroblast (L929)) were selected for the in vitro cell experiments (cytotoxicity, cellular uptake, cell cycle and apoptosis experiments). The S180 tumor-bearing Kunming mice model was established for anti-tumor pharmacodynamic experiments. Results In vitro cell assay results showed that uptake of BOR-SA by HL60 and S180 cells were increased compared with the control group. BOR-SA induced a lower IC50, higher ratio of apoptosis and cell cycle arrest of tumor cells. In vivo anti-S180 tumor pharmacodynamics experiments showed that mice in the BOR-SA group had higher tumor inhibition rate, higher body weight and lower immune organ toxicity compared with the control group. Conclusions sialic acid-mediated selectin targeting strategy may have great potential in the treatment of related tumors.
      PubDate: 2019-11-04
  • Drug-Polymer Solubility Determination: A New Thermodynamic Model Free from
           Lattice Theory Assumptions
    • Abstract: Purpose Traditional methods for estimating drug-polymer solubility either require fast dissolution in the polymeric matrix, rapid re-crystallization kinetics from supersaturated states or derive from regular solution theories. In this work, we present a new method for determining drug solubility, purely based on thermodynamic considerations, that uses only experimental data from DSC for calculations. Methods The new thermodynamic model presented combines DSC analysis and application of Hess’s law to determine free energies of conversion of binary mixtures to amorphous solid dispersions, free energies of mixing as well as solubility as a function of temperature. The model drug indomethacin and polymers HPMCAS LF, PVP K29/32 and Eudragit EPO were used in these studies. Results Free energies were calculated as a function of temperature, for different drug-polymer compositions and the results show that HPMCAS LF solid dispersion with high drug content are less thermodynamically favorable compared to other polymer systems. Solubility of indomethacin in HPMCAS LF, PVP K29/32 and Eudragit EPO was 24, 55 and 56% w/w, respectively, at 25°C. Conclusions The thermodynamic model presented has great advantages over traditional methods. It does not require estimation of any interaction parameters, it is almost assumption-free and uses only thermal data for calculations.
      PubDate: 2019-11-01
  • Characterization of Phase Transformations for Amorphous Solid Dispersions
           of a Weakly Basic Drug upon Dissolution in Biorelevant Media
    • Abstract: Purpose The overall goal of this study was to investigate the dissolution performance and crystallization kinetics of amorphous solid dispersions (ASDs) of a weakly basic compound, posaconazole, dispersed in a pH-sensitive polymeric matrix consisting of hydroxypropyl methylcellulose acetate succinate (HPMC-AS), using fasted-state simulated media. Methods ASDs with three different drug loadings, 10, 25 and 50 wt.%, and the commercially available tablets were exposed to acidic media (pH 1.6), followed by transfer to, and dissolution in, intestinal media (pH 6.5). Parallel single stage dissolution experiments in only simulated intestinal media were also performed to better understand the impact of the gastric stage. Different analytical methods, including nanoparticle tracking analysis, powder x-ray diffraction, second harmonic generation and two-photon excitation ultraviolet fluorescence microscopy, were used to characterize the phase behavior of these systems at different stages of dissolution. Results Results revealed that all ASDs exhibited some degree of drug release upon suspension in acidic media, and were also vulnerable to matrix crystallization. Upon transfer to intestinal media conditions, supersaturation was observed. This was short-lived for some dispersions due to the release of the crystals formed in the acid immersion stage which acted as seeds for crystal growth. Lower drug loading ASDs also exhibited transient formation of amorphous nanodroplets prior to crystallization. Conclusions This work emphasizes the significance of assessing the impact of pH change on dissolution and provides a fundamental basis of understanding the phase behavior kinetics of ASDs of weakly basic drugs when formulated with pH sensitive polymers.
      PubDate: 2019-10-30
  • Application of Externally Applied Lower Punch Vibration and its Effects on
           Tablet Manufacturing
    • Abstract: Purpose In the present study the influence and application of a newly developed external lower punch vibration system for an improved die filling on a running rotary tablet press was investigated. Methods Tablets were manufactured at different conditions (with and without vibration) and characterized regarding their direct compressibility and mechanical stability. Thus, two typical pharmaceutical binders for direct compression (Parmcel 102 and Tablettose® 80) were compared with two binders unsuitable for direct compression (Ceolus® KG1000 and GranuLac® 200). The powders were characterized by helium pycnometry, laser diffraction, scanning electron microscopy, and by determination of the powder flow. Furthermore, a novel technique to determine the occurrences of segregation within a tablet after manufacturing was introduced. For this purpose, a powder blend containing one spray-colored type of microcrystalline cellulose (Vivapur® 200) were prepared. Results It was shown that under application of externally applied lower punch vibration, the powder flow into the die increased and thus the die filling process was significantly improved. Hence, it was possible to manufacture tablets from powders, which are actually unsuitable for direct compression. In addition, the mechanical stability of the produced tablets was distinctly improved by application of lower punch vibration, whereby the occurrence of segregation was comparatively low. Conclusion In summary, lower punch vibration allows a more efficient die filling, whereby the powder flow as well as mechanical stability of the tablets are improved.
      PubDate: 2019-10-28
  • Thrifty, Rapid Intestinal Monolayers (TRIM) Using Caco-2 Epithelial Cells
           for Oral Drug Delivery Experiments
    • Abstract: Purpose Caco-2 monolayers are the most common model of the intestinal epithelium and are critical to the development of oral drug delivery strategies and gastrointestinal disease treatments. However, current monolayer systems are cost- and/or time-intensive, hampering progress. This study evaluates two separate methods to reduce resource input: FB Essence as a fetal bovine serum (FBS) alternative and a new, 3-day Caco-2 system deemed “thrifty, rapid intestinal monolayers” (TRIM). Methods Caco-2 cells were cultured with FB Essence and compared to cells in 10% FBS for proliferation and monolayer formation. TRIM were compared to commonly-used 21-day and Corning® HTS monolayer systems, as well as mouse intestines, for permeability behavior, epithelial gene expression, and tight junction arrangement. Results No amount of FB Essence maintained Caco-2 cells beyond 10 passages. In contrast, TRIM compared favorably in permeability and gene expression to intestinal tissues. Furthermore, TRIM cost $109 and required 1.3 h of time per 24-well plate, compared to $164 and 3.7 h for 21-day monolayers, and $340 plus 1.0 h for the HTS system. Conclusions TRIM offer a new approach to generating Caco-2 monolayers that resemble the intestinal epithelium. They are anticipated to accelerate the pace of in vitro intestinal experiments while easing financial burden.
      PubDate: 2019-10-28
  • The Effect of Promiscuous Aggregation on in Vitro Drug Metabolism Assays
    • Abstract: Purpose Many bioactive molecules show a type of solution phase behavior, termed promiscuous aggregation, whereby at micromolar concentrations, colloidal drug-rich aggregates are formed in aqueous solution. These aggregates are known to be a major cause of false positives and false negatives in select enzymatic high-throughput screening assays. The goal of this study was to investigate the impact of drug-rich aggregates on in vitro drug screening metabolism assays. Methods Cilnidipine was selected as an aggregate former and its impact on drug metabolism was evaluated against rCYP2D6, rCYP1A2, rCYP2C9 and human liver microsomes. Results The cilnidipine aggregates were shown to non-specifically inhibit multiple cytochrome P450 enzymes with an IC50 comparable with the IC50 of potent model inhibitors. Conclusions This newly demonstrated mode of “promiscuous inhibition” is of great importance as it can lead to false positives during drug metabolism evaluations and thus it needs to be considered in the future to better predict in vivo drug-drug interactions.
      PubDate: 2019-10-25
  • Fit-for-Purpose Validation of a Ligand Binding Assay for Toxicokinetic
           Study Using Mouse Serial Sampling
    • Abstract: Purpose The purpose of this study was to validate a ligand binding assay for the quantitation of a monoclonal antibody-based biotherapeutics (PF-57781346) in samples collected via capillary microsampling to support a regulated mouse toxicity study. Method A quantitative ligand binding assay on the Gyrolab platform was developed to quantify PF-57781346 in blood samples derived from capillary mouse serial sampling. The method validation evaluated assay characteristics including accuracy and precision, influence of sample processing on drug quantitation, whole blood matrix selectivity, dilution linearity and the stability of the drug in the study sample matrix. Results The method validation demonstrated acceptable analytical characteristics. The whole blood selectivity testing demonstrated accuracy between −4.8% and 13.9% in 10 out of 10 individual whole blood samples, suggesting that drug quantitation from whole blood is not impacted by the serial sampling procedure. Short-term and long-term drug stability in study sample matrix were established to cover required stability for sample storage and analysis (accuracy between −7.3% and 6.1%). Conclusion We reported a successful validation of a bioanalytical method that quantifies PF-55781346 in samples collected via capillary microsampling. The experience shared in this study could serve as a model process for bioanalytical method validation when capillary microsampling is used.
      PubDate: 2019-10-25
  • Transferrin Receptor Targeted Cellular Delivery of Doxorubicin Via a
           Reduction-Responsive Peptide-Drug Conjugate
    • Abstract: Purpose Transferrin receptors (TfRs) are overexpressed in tumor cells but are scarce in normal tissues, which makes TfR an attractive target for drug treatment of cancer. The objective of this study was to evaluate the potential of BP9a (CAHLHNRS) as a peptide vector for constructing TfR targeted peptide-drug conjugates and selective drug delivery. Methods Doxorubicin (DOX) was connected to BP9a via a disulfide-intercalating linker to afford a reduction-responsive BP9a-SS-DOX conjugate. By using HepG2 human liver cancer cells and L-O2 normal hepatic cells as TfR over-expressing and low-expressing in vitro models, respectively, TfR mediated cellular uptake of this conjugate was studied by using flow cytometry and confocal laser scanning microscopy. The in vitro cytotoxicities of the conjugate against HepG2 and L-O2 cells were examined by cell counting kit-8 (CCK-8) assay to evaluate its tumorous specificity. Results Cellular uptake and TfR blockage test results showed that the BP9a-SS-DOX conjugate gained entry into HepG2 cells via endocytosis mediated by TfR and mainly accumulated in cytoplasm. The in vitro antiproliferative activity of this conjugate against HepG2 cells (IC50 6.21 ± 1.12 μM) was approximately one-sixth of that of free DOX (IC50 1.03 ± 0.13 μM). However, its cytotoxic effect on L-O2 cells was obviously reduced compared with that of free DOX. Conclusions The BP9a-SS-DOX conjugate showed specific antiproliferative activity against HepG2 liver cancer cells. Our study suggests that BP9a has the potential to target chemotherapeutic agents to tumor cells over-expressing TfR and facilitate selective drug delivery.
      PubDate: 2019-10-25
  • Physiologically Based Pharmacokinetic Modeling of Oxycodone in Children to
           Support Pediatric Dosing Optimization
    • Abstract: Purpose Physiologically-based pharmacokinetic (PBPK) modeling offers a unique modality to predict age-specific pharmacokinetics. The objective of this study was to assess the ability of PBPK model to predict plasma exposure of oxycodone, a widely used opioid for pain management, in adults and children. Methods A full PBPK model of oxycodone following intravenous and oral administration was developed using a ‘bottom-up’ and ‘top-down’ combined strategy. The model was then extrapolated to pediatrics through a reasonable scaling method. The adult and pediatric model was evaluated using data from 17 clinical PK studies by testing predicted/observed goodness of fit. The mean fold error for PK parameters was calculated. Finally, we used the validated PBPK model to visualize adult-children dose conversion for oxycodone. Results The developed PBPK model successfully predicted the oxycodone disposition in adults, wherein the predicted versus observed AUC, Cmax, and tmax were within 0.90 to 1.20-fold difference. After scaling anatomy/physiology, protein binding, and clearance, the model showed satisfactory prediction performance for pediatric populations as predicted AUC were within the 1.50-fold range of the observed values. According to the application of PBPK model, we found that different intravenous doses should be given in children of different ages compared to a standard 0.1 mg/kg in adults, while a progressive increasing dose with age growth following oral administration is recommended for children. Conclusions The current example provides the opportunity for using the PBPK model to guide dose adjustment of oxycodone in the design of future pediatric clinical studies.
      PubDate: 2019-10-25
  • Why Wait' The Case for Treating Tuberculosis with Inhaled Drugs
    • Abstract: The discovery of drugs to treat tuberculosis (TB) was a major medical milestone in the twentieth century. However, from the outset, drug resistance was observed. Currently, of the 10 million people that exhibit TB symptoms each year, 450,000 have multidrug or extensively drug resistant (MDR or XDR) TB. While greater understanding of the host and pathogen (Mycobacterium tuberculosis, Mtb) coupled with scientific ingenuity will lead to new drugs and vaccines, in the meantime 4000 people die daily from TB. Thus, efforts to improve existing TB drugs should also be prioritized. Improved efficacy and decreased dose and associated toxicity of existing drugs would translate to greater compliance, life expectancy and quality of life of Mtb infected individuals. One potential strategy to improve existing drugs is to deliver them by inhalation as aerosols to the lung, the primary site of Mtb infection. Inhaled drugs are used for other pulmonary diseases, but they have yet to be utilized for TB. Inhaled therapies for TB represent an untapped opportunity that the pharmaceutical, clinical and regulatory communities should consider.
      PubDate: 2019-10-24
  • On-Demand Manufacturing of Direct Compressible Tablets: Can Formulation Be
    • Abstract: Purpose Oral direct compressible tablets are the most frequently used drug products. Manufacturing of tablets requires design and development of formulations, which need a number of excipients. The choice of excipients depends on the concentration, manufacturability, stability, and bioavailability of the active pharmaceutical ingredients (APIs). At MIT, we developed a miniature platform for on-demand manufacturing of direct compressible tablets. This study investigated how formulations could be simplified to use a small number of excipients for a number of different API’s in which long term stability is not required. Method Direct compressible tablets of five pharmaceutical drugs, Diazepam, Diphenhydramine HCl, Doxycycline Monohydrate, Ibuprofen, and Ciprofloxacin HCl, with different drug loadings, were made using direct compression in an automated small scale system.. The critical quality attributes (CQA) of the tablets were assessed for the quality standards set by the United States Pharmacopeia (USP). Results This miniature system can manufacture tablets - on-demand from crystalline API using the minimum number of excipients required for drug product performance. All drug tablets met USP quality standards after manufacturing and after 2 weeks of accelerated stability test, except for slightly lower drug release for Ibuprofen. Conclusions On-demand tablets manufacturing where there is no need for long term stability using a flexible, miniature, automated (integrated) system will simplify pharmaceutical formulation design compared to traditional formulations. This advancement will offer substantial economic benefits by decreasing product time-to-market and enhancing quality.
      PubDate: 2019-10-24
  • Chrysin and Docetaxel Loaded Biodegradable Micelle for Combination
           Chemotherapy of Cancer Stem Cell
    • Abstract: Purpose Cancer stem cells (CSCs) have been suggested to represent the main cause of tumour progression, metastasis and drug resistance. Therefore, these cells can be an appropriate target to improve cancer treatment. Methods A novel biodegradable brush copolymeric micelle was synthesized by the ring-opening polymerization (ROP) and reversible addition-fragmentation chain transfer (RAFT) polymerization. The obtained micelle was used for co-delivery of the anticancer drug docetaxel (DTX) and Chrysin (CHS) as an adjuvant on the CSCs originated from Human colon adenocarcinoma cell line. Cancer stem cells were enriched by MACS technique and characterized by flow cytometry analysis against CD133 marker. Results Data demonstrated that the micelles harbouring DTX@CHS had potential to reduce cancer stem cell viability compared to free DTX@CHS, single-drug formulations and the control group (p < 0.05). The combination effect of DTX and CHS formulated in micelle was synergistic in CSCs (CI < 1). The reactive oxygen species content was shown to increase after cell treatment with DTX@CHS loaded on micelles (p < 0.05). DTX@CHS-micelles inhibited cancer stem cell migration rate in vitro (p < 0.05), indicating an impaired metastasis activity. Conclusion In conclusion, the synthesized DOX@CHS-micelles can be applied in the introduction of anticancer agents to resistant cancer population by further investigations.
      PubDate: 2019-10-23
  • Utilization of In Vitro , In Vivo and In Silico Tools to Evaluate the
           pH-Dependent Absorption of a BCS Class II Compound and Identify a
           pH-Effect Mitigating Strategy
    • Abstract: Purpose To describe a stepwise approach to evaluate the pH effect for a weakly basic drug by in vitro, in vivo and in silico techniques and identify a viable mitigation strategy that addresses the risk. Methods Clinical studies included assessment of the pH effect with famotidine. In vitro dissolution was evaluated in various biorelevant media and in a pH-shift test. PK studies in dogs were conducted under pentagastrin or famotidine pre-treatment and GastroPlus was employed to model human and dog PK data and simulate the performance in human. Results Clinical data indicated considerable pH dependent absorption of the drug when dosed in the presence of H2-antagonists. In vitro dissolution and in vivo dog data confirmed that the observed pH effect was due to reduced dissolution rate and lower solubility at increased gastric and intestinal pH. A salt form was identified to overcome the effect by providing fast dissolution and prolonged supersaturation. GastroPlus simulations predicted a mitigation of the pH effect by the salt. Conclusions The drug exhibited a strong pH-effect in humans. The in vitro, in vivo and modeling approach provides a systematic workflow to evaluate the risk of a new drug and identify a strategy able to mitigate the risk.
      PubDate: 2019-10-21
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