Purpose
The purpose of this study was to identify and optimize spray drying parameters of importance for the design of an inhalable powder formulation of a cationic liposomal adjuvant composed of dimethyldioctadecylammonium (DDA) bromide and trehalose-6,6′-dibehenate (TDB).Methods
A quality by design (QbD) approach was applied to identify and link critical process parameters (CPPs) of the spray drying process to critical quality attributes (CQAs) using risk assessment and design of experiments (DoE), followed by identification of an optimal operating space (OOS). A central composite face-centered design was carried out followed by multiple linear regression analysis.Results
Four CQAs were identified; the mass median aerodynamic diameter (MMAD), the liposome stability (size) during processing, the moisture content and the yield. Five CPPs (drying airflow, feed flow rate, feedstock concentration, atomizing airflow and outlet temperature) were identified and tested in a systematic way. The MMAD and the yield were successfully modeled. For the liposome size stability, the ratio between the size after and before spray drying was modeled successfully. The model for the residual moisture content was poor, although, the moisture content was below 3% in the entire design space. Finally, the OOS was drafted from the constructed models for the spray drying of trehalose stabilized DDA/TDB liposomes.Conclusions
The QbD approach for the spray drying process should include a careful consideration of the quality target product profile. This approach implementing risk assessment and DoE was successfully applied to optimize the spray drying of an inhalable DDA/TDB liposomal adjuvant designed for pulmonary vaccination.Purpose
In designing pharmaceutical manufacturing alongside the principles of quality by design (QbD) and process analytical technology (PAT), unit operations process development and corporate decision-making processes such as business profits and environmental impact assessments are often undertaken separately. This paper presents a strategic three-tier framework linking the process, operations, and business/enterprise levels for process development and improvement alongside an in silico optimization approach.Methods
At the process level, first principles reaction kinetics and semi-batch process parameters are used for process simulations. Data exchanges between the process and operations levels were achieved through the OLE for process control (OPC) protocol with real-time chemometrics modeling of in situ spectroscopic measurements. At the operations level, multivariate statistical models were utilized for continuous process improvement in conjunction with profit maximization and environmental waste considerations at the business/enterprise level.Results
In silico optimization of consecutive semi-batch epoxidation reactions was performed using MATLAB/Simulink. Pareto-optimal operating parameters within the design space that considers product quality and process efficiency, profitability, and environmental impact were arrived through systematic simulations conducted using design of experiments (DoE) and partial least squares (PLS) modeling.Conclusions
A simple three-tier methodological framework was proposed to bridge process development, profitability, and environmental assessment. Through such a framework, the links between process, operations, and business/enterprise levels toward sustainable development and product value chain become more transparent. The Pareto-optimal solutions generated demonstrate how process development choices could impact business/enterprise decision-making.Purpose
Current in vitro disintegration methods for polymeric films are qualitative and introduce significant user bias. The goal of these studies is to develop a novel, quantitative disintegration technique which can be used to characterize polymeric films in vitro.Methods
A method was developed using a Texture Analyzer instrument to evaluate film disintegration. Solvent-casted, clinically advanced, anti-HIV, vaginal films as well as marketed vaginal films were used throughout these studies. Method development followed a quality by design (QbD) process and was used to evaluate film products.Results
The current method developed provided reproducible, quantitative disintegration times for the commercially available vaginal contraceptive film (57.88?±?5.98 s). It distinguished between two clinically advanced antiretroviral containing films based on disintegration time (p value <?0.001): the tenofovir film (41.28?±?3.35 s) and the dapivirine film (88.36?±?10.61 s). This method could also distinguish between tenofovir and dapivirine films which had been altered in terms of volume (p?<?0.0001) and formulation (p?<?0.0001) based on disintegration time.Conclusions
This method can be applied for pharmaceutical films for ranging indications as part of vigorous in vitro characterization. Parameters of the test can be altered based on site of application or indication.Introduction
Continuous manufacturing can be benefited by the use of the Quality by Design (QbD) strategy for robust process development and by the use of Process Analytical Technology (PAT) for real-time process monitoring and control. A successful implementation of QbD and PAT for continuous processes relies on a robust and information-rich process model as a basis for process understanding, monitoring, and control. Compared to first principles and other empirical models, a latent variables-based process model is capable of decomposing multidimensional process data into a few orthogonal latent variables and of providing accessible process understanding/visualization and control within the latent variable space. This study is an extension of our group’s earlier effort (Liu et al., J Pharm Innov 6:170–180, 2011) to explore the utility of latent variables-based process modeling in pharmaceutical manufacturing processes.Methods
The case presented here is the first application of latent variables-based modeling to a reaction process in small-molecule active pharmaceutical ingredient route synthesis, i.e., a continuous-flow hydrogenation. A particular reactor configuration and operation was used in this proof-of-concept study.Results
It was found that time-variant profiles of pressure in the flow tube reactor served as an effective indicator of gas–liquid interaction within the reactor, thus determining process outcomes, i.e., the extent of reaction and enantiomeric excess (ee), given the importance of process set points. In addition, a design space of process parameters predicted to produce optimal outcomes, i.e., extent of reaction greater than 98 % and ee higher than 93 %, was established in order to provide a flexible operation space for performing the reaction with desired process outcomes.Conclusions
The capabilities of latent variables-based process modeling have been well demonstrated as applied to a continuous-flow hydrogenation reaction, regarding its improved process understanding and the potential for process optimization & control as well. Future efforts will be focused on continuing understanding of the capabilities and limitations of such a methodology on a fully-automated control scheme for continuous flow reaction. 相似文献Purpose
Physiological changes during pregnancy can effect pharmacokinetic (PK) parameters, which may lead to altered dose requirements. We aimed to leverage literature-based physiological changes during pregnancy into a PK model and compare its performance to a published reference model in pregnant women and to use the literature-based model to determine informative PK sampling times for a clinical study that aims to quantify the PK of enoxaparin throughout pregnancy.Methods
Changes in total body water (BW) and creatinine clearance (CRCL) during pregnancy were described using regression models. BW and CRCL were linked to a PK model of enoxaparin in non-pregnant women. Performance of the literature-based PK model was compared to a previously published empirical reference model. D-optimal sampling times were determined and evaluated for literature-based and reference models.Results
The literature-based model adequately predicted anti-Xa plasma concentrations when compared to reference model predictions. An informative sampling design was succesfully developed, with parameters expected with good precision (RSE?36.4%).Conclusion
A literature-based model describing enoxaparin PK during pregnancy was developed and evaluated. The modelling framework could be used to support development of informative designs in pregnancy when prior models are unavailable. 相似文献Purpose
Metal-catalyzed oxidation (MCO) of proteins is of primary concern in the development of biotherapeutics as it represents a prominent degradation pathway with potential undesired biological and biotherapeutic consequences.Methods
We developed a fluorogenic derivatization methodology to study the MCO of IgG1 using a model oxidation system, CuCl2/L-ascorbic acid.Results
Besides the oxidation of Met, Trp and His residues, we detected significant oxidation of Phe and Tyr in IgG1.Conclusion
The fluorogenic derivatization method provides an alternative approach for the rapid detection of oxidized Tyr and Phe as their benzoxazole derivatives by fluorescence spectrometry and size exclusion chromatography coupled to fluorescence detection. 相似文献Purpose
Guidelines discourage chronic benzodiazepines and related Z drugs (BZD/Zs) for sleep problems. However, prevalence among nursing home residents remains high. Discontinuing these drugs is widely recommended but seems difficult to implement. The aim of our study was to evaluate the overall feasibility in the nursing home, in terms of willingness towards discontinuation and success rate at 8 months, together with the impact on withdrawal symptoms, change in sleep quality, quality of life and medication use.Methods
In a convenience sample of five nursing homes (823 residents), we included cognitively competent residents with chronic BZD/Z use for insomnia. We investigated sleep quality [with Pittsburgh Sleep Quality Index (PSQI)], quality of life (EQ-5D) and withdrawal symptoms [Benzodiazepine Withdrawal Symptom Questionnaire (BWSQ)]. Success rate was analysed with survival analysis.Results
Of the 135 eligible residents, both general physician (GP) and resident were willing to initiate discontinuation in 38 residents. Reasons for refusing to initiate discontinuation among GPs was the unmotivated patient and among residents the reluctance towards change. At 8 months, 66.0 % were successful discontinuers, with the subjective PSQI component evolving favourably (p?=?0.013) and a decreasing number of midnight awakenings (p?=?0.041). In the relapse group (n?=?13), the quality of life decreased (p?=?0.012), with mainly an increase of problems with activities and pain/discomfort. In both groups, the withdrawal symptoms, functionality and medication use did not change.Conclusion
Discontinuation of chronic BZD/Z use is feasible in the nursing home setting without noticeable withdrawal symptoms, without a switch in medication use, without detrimental effect on quality of life and with a positive effect on the self-perceived sleep quality. 相似文献Rationale
The loudness dependence of the auditory evoked potential (LDAEP) is considered a noninvasive in vivo marker of central serotonergic functioning in humans. Nevertheless, results of genetic association studies point towards a modulation of this biomarker by dopaminergic neurotransmission.Objective
We examined the effect of dopaminergic modulation on the LDAEP using L-3,4-dihydroxyphenylalanine (levodopa)/benserazide (Madopar?) as a challenge agent in healthy volunteers.Methods
A double-blind placebo-controlled challenge design was chosen. Forty-two healthy participants (21 females and 21 males) underwent two LDAEP measurements, following a baseline LDAEP measurement either placebo or levodopa (levodopa 200?mg/benserazide 50?mg) were given orally. Changes in the amplitude and dipole source activity of the N1/P2 intensities (60, 70, 80, 90, and 100?dB) were analyzed.Results
The participants of neither the levodopa nor the placebo group showed any significant LDAEP alterations compared to the baseline measurement. The test?Cretest reliability (Cronbachs Alpha) between baseline and intervention was 0.966 in the verum group and 0.759 in the placebo group, respectively.Conclusions
The administration of levodopa showed no effect on the LDAEP. These findings are in line with other trials using dopamine receptor agonists. 相似文献Electronic supplementary material
The online version of this article (doi:10.1208/s12248-010-9206-0) contains supplementary material, which is available to authorized users.KEY WORDS: biopharmaceutics, dissolution, product performance, quality by design, quality target product profile 相似文献Purpose
Targeted delivery of aerosols could not only improve efficacy of inhaled drugs but also reduce side effects resulting from their accumulation in healthy tissue. Here we investigated the impact of magnetized aerosols on model drug accumulation and transgene expression in magnetically targeted lung regions of unanesthetized mice.Methods
Solutions containing superparamagnetic iron oxide nanoparticles (SPIONs) and model drugs (fluorescein or complexed plasmid DNA) were nebulized to unanesthetized mice under the influence of an external magnetic gradient directed to the lungs. Drug accumulation and transgene expression was subsequently measured at different time points.Results
We could demonstrate 2?C3 fold higher accumulation of the model drug fluorescein and specific transgene expression in lung regions of mice which had been exposed to an external magnetic gradient during nebulization compared to the control mice without any exposure to magnetic gradient.Conclusions
Magnetized aerosols present themselves as an efficient approach for targeted pulmonary delivery of drugs and gene therapeutic agents in order to treat localized diseases of the deeper airways. 相似文献Purpose
An optimized methodology for the development of a new generation of lipid nanoparticles, the multiple lipid nanoparticles (MLN) is described. MLN have characteristics between nanostructured lipid carriers (NLC) and multiple emulsions (W/O/W), but without the outer aqueous phase.Methods
The production is based on a hot homogenization method combined with high shear and ultrasonication. The antiretroviral agent lamivudine (3TC), was loaded in the MLN. For comparison purposes, NLC-3TC formulation was also developed and physico-chemically characterized by the same parameters as MLN-3TC. The development and optimization of MLN and NLC formulations were supported by a Quality by Design (QbD) approach.Results
The MLN-3TC formulation exhibited a size of about 450 nm, polydispersity <0.3 and negative zeta potential > ?20 mV. Furthermore, the morphology assessed by TEM showed a structure with multiples aqueous vacuoles. MLN-3TC was physically stable for at least 45 days, had low cytotoxicity and drug release studies showed a sustained and controlled release of 3TC under gastric and plasma-simulated conditions (at pH 7.4 for about 45 h).Conclusions
The optimized formulations present suitable profiles for oral administration. Overall, the results reveal that MLN present higher loading capacity and storage stability than NLC.Purpose
To prepare acylated exenatide analogues and investigate their biological properties for guiding the development of PLGA formulations of exenatide.Methods
The acylated exenatide analogues were prepared by reaction with glycolic acid (GA), one constitutional unit of PLGA, and characterized by HPLC-MS/MS and Circular Dichroism (CD). The pharmacokinetic properties and anti-diabetic activities were studied in SD rats and db/db mice, respectively.Results
Structural characterizations of the acylated products showed that one to four glycolic acids (GAs) were connected to the primary amine groups of exenatide, and there was a conversion of α-helix to β-sheet to some extent. Pharmacokinetic studies in SD rats revealed that acylated exenatides had a similar Tmax with that of the prototype drug, whereas the Cmax and the AUC values of the adducts were significantly decreased. Biological activity tests demonstrated that exenatide and acylated exenatide analogues had similar in vivo antidiabetic activities in terms of controlling blood glucose concentration, HbA1c level, body weight and food intake.Conclusions
These findings suggest that GA conjugated exenatide had no influence on the peptide efficacy, therefore it’s not necessary to inhibit exenatide acylation in PLGA formulations during the peptide release process. 相似文献Introduction
Atypical antipsychotics have significantly improved the quality of life for schizophrenic patients. Despite their beneficial effects, these antipsychotics induce weight gain, diabetes, and dyslipidemia. The aims of this study were to investigate the antioxidative activity of paraoxonase and assess lipid profile as a cardiovascular risk factor in patients with schizophrenia under long-term clozapine or risperidone treatment.Methods
The study included 66 patients with schizophrenia under clozapine or risperidone treatment and 19 healthy control subjects. Serum paraoxonase activities against paraoxon (PON(PO)), phenylacetate (PON(PA)), dihydrocoumarin (PON(DHC)), serum Trolox equivalent antioxidant activity (TEAC), antioxidant gap (GAP), and lipid profile were determined.Results
PON(DHC) activity was reduced in both antipsychotic drug-treated groups (clozapine 43.46?±?1.06 U/ml, p?0.001; risperidone 50.57?±?1.54 U/ml, p?0.01; control 52.27?±?1.34 U/ml). A similar pattern was observed for the PON(DHC)/HDL-cholesterol (HDLC) ratio. On the contrary, PON(PO) and PON(PA) were increased in the treated group, but the corresponding paraoxonase/HDLC ratios were not significantly different from controls, except for PON/HDLC in the clozapine group. TEAC and GAP were only decreased in the clozapine-treated group.Conclusions
In patients with schizophrenia, clozapine or risperidone treatment had different effects on various paraoxonase activities. The results of the present study suggest that patients with schizophrenia might be at increased risk for metabolic and cardiovascular disease related to reduced PON(DHC), TEAC, and GAP. 相似文献Rationale
Methylphenidate (MPH), the most widely prescribed psychostimulant to treat many neuropsychiatric conditions, is reported to improve attention and speed of processing in survivors of traumatic brain injury (TBI). The neural correlate of this efficacy, however, remains unclear.Objective
Using perfusion functional magnetic resonance imaging (fMRI) as a biomarker of regional neural activity, the current study aimed to examine the neural correlates of single-dose (0.3?mg/kg) MPH administration in a randomized double-blind placebo-controlled crossover study design.Methods
Twenty-three individuals with moderate to severe TBI were tested on two occasions approximately 1?week apart. Perfusion fMRI scanning was carried out at rest and while participants performed cognitive tasks requiring sustained attention and working memory.Results
Behaviorally, MPH significantly improved both accuracy and reaction time (RT) in the sustained attention task but only RT in the working memory task. A trend of global reduction of cerebral blood flow by MPH was observed in all task conditions including resting. Voxel-wise whole-brain analysis revealed an interaction effect of drug by condition (MPH?Cplacebo X task?Crest) for the sustained attention task in the left posterior superior parietal cortex and parieto?Coccipital junction (BA 7/19). The magnitude of drug-related deactivation of this area during task performance was correlated with improvement in RT.Conclusion
Suppression of activity in this area during task performance may reflect a compensatory mechanism by which MPH ameliorates attention impairments in TBI. 相似文献Areas covered: This review describes the elements, different design and tools of QbD as well as multidimensional applications of QbD ranging from dosage form and method development to meeting latest regulatory requirements.
Expert opinion: The understanding of a process is facilitated by proper identification of sources of variation, management of variability by process design, and prediction of product quality attributes using design space. The pharmaceutical industry is rapidly adopting the QbD principles for fabrication of safe, effective and quality products; however, we are still on a journey and the process of gathering all experience and metrics required for connecting and demonstrating QbD benefits to all stakeholders is still in progress. Understanding the formulation and process parameters with the philosophy of QbD will be useful for the optimization of complex drug delivery systems in the near future. 相似文献