Effect of VIPS fabrication parameters on the removal of acetic acid by supported liquid membrane using a PES-graphene membrane support.

In this study, the removal of acetic acid by supported liquid membrane (SLM) using hybrid polyethersulfone (PES)-graphene membrane prepared by vapor induced phase separation (VIPS) was investigated. The effects of graphene loading, coagulation bath temperature, air exposure time, and air humidity on the morphology, mechanical strength, porosity, and contact angle of the membrane were analyzed. The performance and stability of the hybrid membrane as a SLM support for acetic acid removal were studied. The best PES-graphene membrane support was produced at a coagulation bath temperature of 50 °C, an air exposure time of 30 s and air humidity of 80%. The fabricated membrane has a symmetrical micropore cellular structure, high porosity and high contact angle. Under specific SLM conditions, almost 95% of acetic acid was successfully removed from 10 g L-1 aqueous acetic acid solution. The hybrid membrane remains stable for more than 116 h without suffering any membrane breakage during the continuous SLM process.

Allergic rhinitis, rather than asthma, is a risk factor for dental caries.

OBJECTIVES: The association between AS (asthma) and dental caries is controversial, while that between allergic rhinitis (AR) and caries has not been established. This study aimed to verify the relationship among AR, AS and dental caries. DESIGN: Retrospective cohort study. SETTING: Data from Health Insurance Database of the Taiwan's National Health Insurance Research Database. PARTICIPANTS: Nine thousand and thirty-eight children born in 2004 were obtained. Their claims data were evaluated from birth to the age of 9 years. MAIN OUTCOME MEASURES: The frequencies of clinical visits for dental caries were calculated for primary teeth (age 1-5) and for dental transitional period (age 6-9). Differences in the frequencies of clinical visits for caries in AR vs non-AR and AS vs non-AS children were compared. Correlation between AR, AS and caries frequencies was studied, and the influences of AR drugs on the development of caries were evaluated. RESULTS: After adjusting for confounding factors and AS case, the frequencies of clinical visits for caries were higher in AR (increased by 13%-25% and P<.001 at different age periods). The AR frequencies significantly correlated with caries frequencies in children with AR. Different AR drugs also correlated with caries formation. After adjusting for confounding factors and AR case, there was no relationship between AS and caries in children. CONCLUSION: Asthma is not associated with dental caries, but AR can increase the frequency of clinical visits for caries. Medications for AR may also play a role in caries formation. Thus, AR may be a risk factor for childhood dental caries.

Clinical presentations and outcomes of patients with Ebola virus disease in Freetown, Sierra Leone.

BACKGROUND: Clinical and laboratory data were collected and analysed from patients with Ebola virus disease (EVD) in Jui Government Hospital in Freetown, Sierra Leone, where patients with EVD were received and/or treated from October 1, 2014 to March 21, 2015 during the West Africa EVD outbreak. METHODS: The study admitted 285 patients with confirmed EVD and followed them up till the endpoint (recovery or death). EVD was confirmed by quantitative RT-PCR assays detecting blood Ebola virus (EBOV). RESULTS: Among the 285 lab-confirmed EVD cases in Jui Government Hospital, 146 recovered and 139 died, with an overall survival rate of 51.23 %. Patients under the age of 6 years had a lower survival rate (37.50 %). Most non-survivors (79.86 %) died within 7 days after admission and the mean hospitalization time for non-survivors was 5.56 ± 6.11 days. More than half survivors (63.69 %) turned blood EBOV negative within 3 weeks after admission and the mean hospitalization time for survivors was 20.38 ± 7.58 days. High blood viral load (≥106 copies/ml) was found to be predictive of the non-survival outcome as indicated by the Receiver Operating Characteristic (ROC) curve analysis. The probability of patients' survival was less than 15 % when blood viral load was greater than 106 copies/ml. Multivariate analyses showed that blood viral load (P = 0.005), confusion (P = 0.010), abdominal pain (P = 0.003), conjunctivitis (P = 0.035), and vomiting (P = 0.004) were factors independently associated with the outcomes of EVD patients. CONCLUSIONS: Most death occurred within 1 week after admission, and patients at the age of 6 or younger had a lower survival rate. Most surviving patients turned blood EBOV negative within 1-4 weeks after admission. Factors such as high blood viral load, confusion, abdominal pain, vomiting and conjunctivitis were associated with poor prognosis for EVD patients.

Metabolic stress induces a Wnt-dependent cancer stem cell-like state transition.

Reciprocal interactions between cancer cells and the tumor microenvironment drive multiple clinically significant behaviors including dormancy, invasion, and metastasis as well as therapy resistance. These microenvironment-dependent phenotypes share typical characteristics with cancer stem cells (CSC). However, it is poorly understood how metabolic stress in the confined tumor microenvironment contributes to the emergence and maintenance of CSC-like phenotypes. Here, we demonstrate that chronic metabolic stress (CMS) in a long-term nutrient deprivation induces a Wnt-dependent phenoconversion of non-stem cancer cells toward stem-like state and this is reflected in the transcriptome analysis. Addition of Wnt3a as well as transfection of dominant-negative Tcf4 establishes an obligatory role for the Wnt pathway in the acquisition of CSC-like characteristics in response to metabolic stress. Furthermore, systematic characterization for multiple single cell-derived clones and negative enrichment of CD44+/ESA+ stem-like cancer cells, all of which recapitulate stem-like cancer characteristics, suggest stochastic adaptation rather than selection of pre-existing subclones. Finally, CMS in the tumor microenvironment can drive a CSC-like phenoconversion of non-stem cancer cells through stochastic state transition dependent on the Wnt pathway. These findings contribute to an understanding of the metabolic stress-driven dynamic transition of non-stem cancer cells to a stem-like state in the tumor metabolic microenvironment.

The effective dose assessment of C-arm CT in hepatic arterial embolisation therapy.

OBJECTIVE: To assess the effective dose of the liver C-arm computed tomography (CT) scan during hepatic arterial embolisation surgery with clinical dose-area product (DAP) data from Taiwan. METHODS: The experiment used two kinds of phantoms: RANDO® Man and RANDO Woman (The Phantom Laboratory, Salem, NY), embedded with thermoluminescent dosemeters at locations according to the International Commission on Radiological Protection 103 report. The conversion factors of DAP to effective doses for males and females, respectively, were obtained. The clinical DAP data of liver C-arm CT scan during hepatic arterial embolisation surgery were collected in a hospital in Taiwan. RESULTS: There were 125 liver transarterial embolisation therapy cases, including 94 males and 31 females, from February 2009 to June 2010. C-arm CT was used 38 times for males and 17 times for females. The corresponding average and standard deviation of clinical DAP were 61.0±6.6 Gy cm(2) and 52.2±8.3 Gy cm(2), respectively. CONCLUSION: The DAP of RANDO Man and RANDO Woman phantoms simply scanned by C-arm CT are much lower than that of patients. After consideration of the clinical DAP of patients, the effective doses of a liver C-arm CT scan recommended for males and females in Taiwan are 11.5±2.3 mSv and 11.3±3.0 mSv, respectively. ADVANCES IN KNOWLEDGE: The conversion factors of DAP to effective doses for males and females are 0.19±0.03 mSv Gy(-1) cm(-2) and 0.22±0.05 mSv Gy(-1) cm(-2). Only if the actual DAP value of a patient scan is multiplied by the conversion factor can the correct effective dose be determined.

Effect of Oral Administration of Intact Casein on Gastrointestinal Hormone Secretion and Pancreatic α-Amylase Activity in Korean Native Steer.

Three Korean native steers (779±24 kg) fitted with duodenal cannulas were used in a 3×3 Latin square design to investigate the influence of oral administration of soluble proteins, intact casein (IC) and acid hydrolyzed casein (AHC), on gastrointestinal hormone (GIH) secretion in the blood and pancreatic α-amylase activity in the duodenum. Oral treatment consisted of a basic diet (control), IC (C+100% protein), or AHC (C+80% amino acid, 20% peptide) for 21 d. Blood and duodenum samples were collected for measurement of serum GI hormones, and pancreatic α-amylase activity was determined at 900, 1030, 1330, 1630, and 1930 h after feeding on d 21 of treatment. The levels of serum cholecystokinin (CCK) and secretin in the IC treatment group were higher compared to the other treatment groups (p<0.05). In addition to the changes in CCK and secretin levels upon IC treatment, the pancreatic α-amylase activity in the duodenum was higher in the IC group compared to the control diet group (p<0.05). The response of serum ghrelin to IC and AHC treatment was in accordance with the response of serum secretin. The level of peptide fragments flowing in the duodenum was higher in the IC treatment group than the other treatment groups (p<0.05). In conclusion, this study demonstrated that an increase in duodenal CCK and secretin upon IC oral administration increased pancreatic α-amylase secretion. In addition, ghrelin may be associated with GI hormone secretion in Korean native steers.

A biopharmaceutical classification-based Right-First-Time formulation approach to reduce human pharmacokinetic variability and project cycle time from First-In-Human to clinical Proof-Of-Concept.

A Right-First-Time approach is described for developing bona fide formulations for First-In-Human (FIH) to Proof-Of-Concept (POC) studies to meet an overarching goal of reduced project cycle time from IND to NDA (as short as four years). Bona fide formulations are tailor-made according to the drug's biopharmaceutical properties including solubility, permeability and stability. Solubilization techniques are used extensively to reduce oral absorption variability for most compounds. Bona fide formulations contain all necessary functional excipients such as diluent, solubilizer, stabilizer, pH adjuster, disintegrant and lubricant so formulation changes are minimized to avoid significant PK bridging studies. Cycle time of FIH formulation development is aligned with IND-enabling toxicology studies, generally 4-6 months. Resources range from 0.5 full time equivalents (FTE) for a BCS-1 compound to 3 FTE for a BCS-4 compound with high drug delivery hurdles. We have achieved our goal by taking the same formulation from FIH to POC 90% of the time and maintaining the same formulation platform from POC to commercial manufacturing 80% of the time in the past eight years. This strategy enables cycle time reduction from 7 to 4 years for IND to NDA by overlapping clinical study phases and eliminating clinical downtime due to PK bridging studies.

PHRMA CPCDC initiative on predictive models of human pharmacokinetics, part 5: prediction of plasma concentration-time profiles in human by using the physiologically-based pharmacokinetic modeling approach.

The objective of this study is to assess the effectiveness of physiologically based pharmacokinetic (PBPK) models for simulating human plasma concentration-time profiles for the unique drug dataset of blinded data that has been assembled as part of a Pharmaceutical Research and Manufacturers of America initiative. Combinations of absorption, distribution, and clearance models were tested with a PBPK approach that has been developed from published equations. An assessment of the quality of the model predictions was made on the basis of the shape of the plasma time courses and related parameters. Up to 69% of the simulations of plasma time courses made in human demonstrated a medium to high degree of accuracy for intravenous pharmacokinetics, whereas this number decreased to 23% after oral administration based on the selected criteria. The simulations resulted in a general underestimation of drug exposure (Cmax and AUC0- t ). The explanations for this underestimation are diverse. Therefore, in general it may be due to underprediction of absorption parameters and/or overprediction of distribution or oral first-pass. The implications of compound properties are demonstrated. The PBPK approach based on in vitro-input data was as accurate as the approach based on in vivo data. Overall, the scientific benefit of this modeling study was to obtain more extensive characterization of predictions of human PK from PBPK methods.

PhRMA CPCDC initiative on predictive models of human pharmacokinetics, part 3: comparative assessement of prediction methods of human clearance.

The objective of this study was to evaluate the performance of various allometric and in vitro-in vivo extrapolation (IVIVE) methodologies with and without plasma protein binding corrections for the prediction of human intravenous (i.v.) clearance (CL). The objective was also to evaluate the IVIVE prediction methods with animal data. Methodologies were selected from the literature. Pharmaceutical Research and Manufacturers of America member companies contributed blinded datasets from preclinical and clinical studies for 108 compounds, among which 19 drugs had i.v. clinical pharmacokinetics data and were used in the analysis. In vivo and in vitro preclinical data were used to predict CL by 29 different methods. For many compounds, in vivo data from only two species (generally rat and dog) were available and/or the required in vitro data were missing, which meant some methods could not be properly evaluated. In addition, 66 methods of predicting oral (p.o.) area under the curve (AUCp.o. ) were evaluated for 107 compounds using rational combinations of i.v. CL and bioavailability (F), and direct scaling of observed p.o. CL from preclinical species. Various statistical and outlier techniques were employed to assess the predictability of each method. Across methods, the maximum success rate in predicting human CL for the 19 drugs was 100%, 94%, and 78% of the compounds with predictions falling within 10-fold, threefold, and twofold error, respectively, of the observed CL. In general, in vivo methods performed slightly better than IVIVE methods (at least in terms of measures of correlation and global concordance), with the fu intercept method and two-species-based allometry (rat-dog) being the best performing methods. IVIVE methods using microsomes (incorporating both plasma and microsomal binding) and hepatocytes (not incorporating binding) resulted in 75% and 78%, respectively, of the predictions falling within twofold error. IVIVE methods using other combinations of binding assumptions were much less accurate. The results for prediction of AUCp.o. were consistent with i.v. CL. However, the greatest challenge to successful prediction of human p.o. CL is the estimate of F in human. Overall, the results of this initiative confirmed predictive performance of common methodologies used to predict human CL.

PhRMA CPCDC initiative on predictive models of human pharmacokinetics, part 1: goals, properties of the PhRMA dataset, and comparison with literature datasets.

This study is part of the Pharmaceutical Research and Manufacturers of America (PhRMA) initiative on predictive models of efficacy, safety, and compound properties. The overall goal of this part was to assess the predictability of human pharmacokinetics (PK) from preclinical data and to provide comparisons of available prediction methods from the literature, as appropriate, using a representative blinded dataset of drug candidates. The key objectives were to (i) appropriately assemble and blind a diverse dataset of in vitro, preclinical in vivo, and clinical data for multiple drug candidates, (ii) evaluate the dataset with empirical and physiological methodologies from the literature used to predict human PK properties and plasma concentration-time profiles, (iii) compare the predicted properties with the observed clinical data to assess the prediction accuracy using routine statistical techniques and to evaluate prediction method(s) based on the degree of accuracy of each prediction method, and (iv) compile and summarize results for publication. Another objective was to provide a mechanistic understanding as to why one methodology provided better predictions than another, after analyzing the poor predictions. A total of 108 clinical lead compounds were collected from 12 PhRMA member companies. This dataset contains intravenous (n = 19) and oral pharmacokinetic data (n = 107) in humans as well as the corresponding preclinical in vitro, in vivo, and physicochemical data. All data were blinded to protect the anonymity of both the data and the company submitting the data. This manuscript, which is the first of a series of manuscripts, summarizes the PhRMA initiative and the 108 compound dataset. More details on the predictability of each method are reported in companion manuscripts.

PhRMA CPCDC initiative on predictive models of human pharmacokinetics, part 2: comparative assessment of prediction methods of human volume of distribution.

The objective of this study was to evaluate the performance of various empirical, semimechanistic and mechanistic methodologies with and without protein binding corrections for the prediction of human volume of distribution at steady state (Vss ). PhRMA member companies contributed a set of blinded data from preclinical and clinical studies, and 18 drugs with intravenous clinical pharmacokinetics (PK) data were available for the analysis. In vivo and in vitro preclinical data were used to predict Vss by 24 different methods. Various statistical and outlier techniques were employed to assess the predictability of each method. There was not simply one method that predicts Vss accurately for all compounds. Across methods, the maximum success rate in predicting human Vss was 100%, 94%, and 78% of the compounds with predictions falling within tenfold, threefold, and twofold error, respectively, of the observed Vss . Generally, the methods that made use of in vivo preclinical data were more predictive than those methods that relied solely on in vitro data. However, for many compounds, in vivo data from only two species (generally rat and dog) were available and/or the required in vitro data were missing, which meant some methods could not be properly evaluated. It is recommended to initially use the in vitro tissue composition-based equations to predict Vss in preclinical species and humans, putting the assumptions and compound properties into context. As in vivo data become available, these predictions should be reassessed and rationalized to indicate the level of confidence (uncertainty) in the human Vss prediction. The top three methods that perform strongly at integrating in vivo data in this way were the Øie-Tozer, the rat -dog-human proportionality equation, and the lumped-PBPK approach. Overall, the scientific benefit of this study was to obtain greater characterization of predictions of human Vss from several methods available in the literature.

PhRMA CPCDC initiative on predictive models of human pharmacokinetics, part 4: prediction of plasma concentration-time profiles in human from in vivo preclinical data by using the Wajima approach.

The objective of this study was to evaluate the performance of the Wajima allometry (Css -MRT) approach published in the literature, which is used to predict the human plasma concentration-time profiles from a scaling of preclinical species data. A diverse and blinded dataset of 108 compounds from PhRMA member companies was used in this evaluation. The human intravenous (i.v.) and oral (p.o.) pharmacokinetics (PK) data were available for 18 and 107 drugs, respectively. Three different scenarios were adopted for prediction of human PK profiles. In the first scenario, human clearance (CL) and steady-state volume of distribution (Vss ) were predicted by unbound fraction corrected intercept method (FCIM) and Øie-Tozer (OT) approaches, respectively. Quantitative structure activity relationship (QSAR)-based approaches (TSrat-dog ) based on compound descriptors together with rat and dog data were utilized in the second scenario. Finally, in the third scenario, CL and Vss were predicted using the FCIM and Jansson approaches, respectively. For the prediction of oral pharmacokinetics, the human bioavailability and absorption rate constant were assumed as the average of preclinical species. Various statistical techniques were used for assessing the accuracy of the simulation scenarios. The human CL and Vss were predicted within a threefold error range for about 75% of the i.v. drugs. However, the accuracy in predicting key p.o. PK parameters appeared to be lower with only 58% of simulations falling within threefold of observed parameters. The overall ability of the Css -MRT approach to predict the curve shape of the profile was in general poor and ranged between low to medium level of confidence for most of the predictions based on the selected criteria.

Performance qualification of a new hypromellose capsule: Part II. Disintegration and dissolution comparison between two types of hypromellose capsules.

This Part II paper describes the disintegration and dissolution aspects of the qualification of a new hypromellose capsule (HPMC Shell 2). This new capsule does not contain any gelling agent, and is manufactured by a thermal gelation process. Rupture time of the carrageenan-containing capsule (HPMC Shell 1) and HPMC Shell 2, as measured by an improved real-time detection method, showed only slight differences that did not manifest in vivo. The absence of a gelling agent appeared to give HPMC Shell 2 advantages in dissolution in acidic media and in buffers containing potassium ions. Slow drug release of HPMC Shell 1 in 0.1M HCl was attributed to the interaction of carrageenan with drug compounds; whereas the presence of potassium ions, a gelling promoter for carrageenan, caused delay in capsule opening and larger capsule-to-capsule variation. Disintegration and dissolution performances of both hypromellose capsules are comparable in other dissolution media tested. Based on the superior dissolution performances and quality attributes in terms of physical, mechanical and processability that were detailed in Paper I, the new hypromellose capsule was satisfactorily qualified and has since been used in nearly 20 investigational new drug (IND) compounds.

The CC16 A38G polymorphism is associated with the development of asthma in children with allergic rhinitis.

BACKGROUND: Although asthma and allergic rhinitis (AR) are considered to be one syndrome, many questions remain unanswered. Why do some AR patients develop asthma but others do not, and which factors play a role in the development of asthma that have so far not been clearly elucidated. OBJECTIVE: We hypothesize that children with AR who have the Clara cell secretory protein (CC16, secretoglobin 1A1) 38A/38A genotype (rs3741240) have an increased likelihood of developing asthma. METHODS: The study sample included 117 children, with AR, but no asthma diagnosed within the following 5 years, as the control group. Cases group (n=202) included age- and gender-matched children with AR first, and asthma developed 3-5 years later, as the study group. The CC16 genotype was determined by PCR and Sau96I restriction digestion of PCR products. The serum CC16 levels were measured by ELISA. Total serum IgE, allergen specific IgE, eosinophil count and pulmonary function were also measured. RESULTS: In children with rhinitis who develop asthma, the frequencies of the AA genotype were significantly higher than those who did not develop asthma [odds ratio (OR)=2.527; 95% confidence interval (CI)=1.571-4.065; P<0.01]. Serum CC16 levels in the children with rhinitis who develop asthma and carry the AA genotype were significantly lower than those who carry the non-AA genotype and those who did not develop asthma. CONCLUSIONS AND CLINICAL RELEVANCE: Results of this study suggest that CC16 38A/38A genotype plays a role in the development of early asthma in children with AR. Early identification of rhinitis children at risk may assist in designing preventative approach to asthma development.

WITHDRAWN: NaS1 sulfate transporter is linked to hyposulfatemia and longevity.

This article has been withdrawn at the request of the editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy.

Asymmetry effect of particle size distribution on content uniformity and over-potency risk in low-dose solid drugs.

Most active pharmaceutical ingredients (API) exhibit particle size distributions with some degrees of asymmetry deviating from log-normality. A new log-skew-normal (L-S-N) distribution model is proposed for a systematic comparison of the asymmetry effect on content uniformity. The new model originated from the S-N model used by Azzalini gives a close approximation to real API particle size distribution. Monte-Carlo method was employed to simulate the dosage potency distribution. A high risk of over potency is uncovered when either the dose is low or API particle size distribution is positively skewed. This is due to the formation of pseudo heavy tail in potency distribution that decays slower than exponentially. Nomographs of API particle size versus dosage strength were constructed with a range of geometric standard deviations and asymmetry parameters with and without particle size cut-off (sieving) for a combined 99% pass rate against USP <905> Uniformity of Dosage Units. It was found that for a given specification of volume median and 90% diameters (d(50) and d(90)), the dosage strength must increase by 10 times if the API asymmetry parameter changes from 1 (log-normal) to 1.1.

Solid dispersion of acetaminophen and poly(ethylene oxide) prepared by hot-melt mixing.

In this study, a model drug, acetaminophen (APAP), was melt mixed with poly(ethylene oxide) (PEO) using a Brabender mixer. APAP was found to recrystallize upon cooling to room temperature for all the drug loadings investigated. Higher drug loading leads to faster recrystallization rate. However, the morphology of the recrystallized drug crystals is identical in samples with different drug loadings and does not change with the storage time. To adjust the drug's dissolution rate, nanoclay Cloisite 15A and 30B were added into the binary mixture. The presence of either of the nanoclay dramatically accelerates the drug's recrystallization rate and slows down the drug's releasing rate. The drop of the releasing rate is mainly due to the decrease of wettability, as supported by the contact angle data. Data analysis of the dissolution results suggests that the addition of nanoclays changes the drug's release mechanism from erosion dominant to diffusion dominant. This study suggests that nanoclays may be utilized to tailor the drug's releasing rate and to improve the dosage form's stability by dramatically shortening the lengthy recrystallization process.

Prediction of drug particle size and content uniformity in low-dose solid dosage forms.

Drug particle size distribution has a profound impact to the content uniformity in low-dose solid drug products. We derived theoretically the skewness of potency distribution as a function of particle size distribution and target dose. It was demonstrated that both skewness and coefficient of variation diverge simultaneously with inverse square root of the target dose. This scaling relation was observed in recent experiment and was verified by Monte Carlo (MC) simulation, which was employed for the first time to solve for the full potency distribution from a random retrieving model. When tested against the criteria from USP 905 uniformity of dosage units, MC simulation showed a striking anisotropic distribution of the data. This suggests a full-scale consideration of the potency distribution is necessary for evaluating the impacts from particle size distribution and the dose, as compared against the normality assumption used before. A nomograph of the median particle size and the dose that meets a 99% pass rate was constructed for the specification of particle size or the lowest dose limit. Furthermore, we showed quantitatively the lowest dose limit can be drastically reduced if a cut-off size is imposed by removing oversized particles.

Performance qualification of a new hypromellose capsule: part I. Comparative evaluation of physical, mechanical and processability quality attributes of Vcaps Plus, Quali-V and gelatin capsules.

This Part I paper describes the qualification of a new high performance hypromellose (hydroxypropyl methylcellulose, HPMC) capsule shell which contains no gelling agent and is dissolution friendly. The development history and the test results for a series of quality attributes including scanning electron microscopy, hygroscopicity, machineability, weight variation, powder leakage, mechanical strength, stability, cross-linking, animal and human pharmacokinetic results are reported. Comparisons to gelatin and HPMC capsule containing carrageenan showed the new HPMC capsule is superior in terms of mechanical strength, hygroscopicity and compatibility with a wide range of drugs. Specifically, the new HPMC capsule demonstrated improved weight variation, machineability and powder leakage than the HPMC capsule containing carrageenan. And the new capsule demonstrated a broader applicability than gelatin capsule for new drug development due to its inertness and compatibility for a wide range of excipients including those used for liquid fill formulations. In the second phase of qualification, disintegration and dissolution properties of the new HPMC were evaluated and reported in a Part II paper for 10 new clinical compounds with a variety of formulations optimized based on the biopharmaceutical classification system of solubility and permeability. Based on the superior performance, the new HPMC capsule is satisfactorily qualified and has since been used successfully for nearly 20 investigational new drug (IND) compounds.

Hybrid molecularly imprinted membranes for targeted tocopherol: uses of cross-linked copolymer particles prepared by surfactant-free dispersion technique.

Alpha-tocopherol (alpha-Toc) targeted membrane adsorbents were prepared by mixing alpha-Toc imprinted particles in polysulfone (PSf) scaffold. The alpha-Toc imprinted particles were prepared with high-shear dispersion copolymerization of alpha-Toc methacrylate (alpha-TMA) and divinylbenzene (DVB) in toluene and water in the agitation range of 300-13,500 rpm. The alpha-Toc groups in resultant imprinted particles were hydrolyzed with 2 M HCl and then the polymers were embedded in PSf membranes by phase inversion technique. The membrane exhibited good selective binding of alpha-Toc with high separation factors to its analogs.