Excipient Solutions Research Articles

Stability evaluation from hydrogen peroxide spiking studies

The ability to detect traces of hydrogen peroxide (H2O2) in water is an important prerequisite to ensure a safe and reliable use of H2O2 for isolator or cleanroom sanitization. While the residual airborne H2O2 concentration can be easily monitored, detection of trace H2O2 residues in aseptically filled drug products is challenging. In an industrial setting, samples must be pulled, handled, stored, and transported before analysis takes place. Therefore, knowledge about the analyte stability in the relevant matrix is crucial to ensure correct results.The objective of this study was to provide stability data for the analyte at low concentrations and in aqueous solutions. For this, H2O2 was spiked into four different aqueous matrices at two different concentrations and stored up to 60 days at four different storage temperatures. The tested matrices included water, buffer, and an exemplary excipient solution with and without additional protein.A developmental quantitative, fluorometric Amplex UltraRed assay was applied for analysis. The results show clearly, that of the four storage temperatures investigated, only -80 °C resulted in reasonably good recovery of the spiked H2O2 content within two weeks or even up to two months of storage.

Curcumin amorphous solid dispersions benefit from hydroxypropyl methylcellulose E50 to perform enhanced anti-inflammatory effects

The solubility and permeability enhancement of curcumin (Cur) is crucial for its manufacture and application in medical field. Herein, Cur amorphous solid dispersions (ASDs) with enhanced drug solubility and permeability was formulated by Eudragit EPO (EuD) and biological macromolecules of hydroxypropyl methylcellulose E50 (HPMC), and significant functions of HPMC for Cur ASDs were mainly studied. The results showed that the mean particle size of Cur decreased from more than 300 nm to less than 200 nm with the addition of HPMC in excipient aqueous solution evidenced by dynamic light scattering result, confirming that HPMC had the ability to inhibit crystallization by lowering drug-rich droplets in the initial mixing process. Innovatively for molecular dynamic modeling study, crystalline Cur molecules in EuD medium trended to aggregate while not for EuD/HPMC 1:1 and EuD/HPMC 3:1 medium. HPMC functioned as surfactant converted the arrangement of phospholipid bilayers to un-ordered, and un-ordered state of phospholipids lead to the enhancement of Cur transmembrane using HPMC as auxiliary excipient. Cur-EuD/HPMC 3:1 contributed greatly to the Cur permeability, leading to obtain superior relative oral bioavailability and anti-inflammatory effect. Cur ASDs with proper amount of HPMC can be rendered as outstanding therapeutic strategy for medical application.

Inhalation powder development without carrier: How to engineer ultra-flying microparticles?

Particle engineering technologies have led to the commercialization of new inhaled powders like PulmoSolTM or PulmoSphereTM. Such platforms are produced by spray drying, a well-known process popular for its versatility, thanks to wide-ranging working parameters. Whereas these powders contain a high drug-loading, we have studied a low-dose case, in optimizing the production of powders with two anti-asthmatic drugs, budesonide and formoterol. Using a Design of Experiments approach, 27 powders were produced, with varying excipient mixes (cyclodextrins, raffinose and maltodextrins), solution concentrations, and spray drying parameters in order to maximize deep lung deposition, measured through fine particle fraction (next generation impactor). Based on statistical analysis, two powders made of hydropropyl-β-cyclodextrin alone or mixed with raffinose and L-leucine were selected. Indeed, the two powders demonstrated very high fine particle fraction (>55%), considerably better than commercially available products. Deep lung deposition has been correlated to very fine particle size and lower microparticles interactions shown by laser diffraction assays at different working pressures, and particle morphometry. Moreover, the two drugs would be predicted to deposit homogeneously into the lung according to impaction studies. Uniform delivery is fundamental to control symptoms of asthma. In this study, we develop carrier-free inhalation powders promoting very efficient lung deposition and demonstrate the high impact of inter-particular interactions intensity on their aerosolization behaviour.

Sorbitol-coated indomethacin and naproxen particles produced by supercritical CO2-assisted spray drying

Co-spraying active pharmaceutical ingredients (APIs) with excipients is a strategy to create excipient matrices containing API particles to address formulation challenges such as the reconstitution of powders into homogeneous suspensions. In this work, indomethacin and naproxen were co-sprayed with/without sorbitol using supercritical CO2-assisted spray drying (SASD), followed by particle collection in a filter paper, and resuspension in an aqueous excipient solution. SASD yielded particles in the range of 0.4–7.6 µm, naproxen crystalline Form 1 particles in an amorphous sorbitol matrix, and a partially crystalline indomethacin-sorbitol mixture. Most naproxen-sorbitol mixtures successfully constituted homogenous microparticle suspensions where sorbitol matrix dissolved upon contact with water releasing naproxen particles, while indomethacin-sorbitol mixtures were not reconstitutable and not studied further. The API-sorbitol interactions were studied in detail by thermal analysis and COSMO-RS modelling. Overall, the work presented herein provides a better understanding of co-spraying of APIs with excipients for the formulation of reconstitutable dried microparticles.

Surface and mechanical properties of polyurethane central venous catheters after repeated contact with chemotherapy excipient solutions.

This article investigates the impact of the interactions between polyurethane central venous catheters and solutions containing excipients used in cisplatin and paclitaxel formulations. Changes to the properties of catheters and the leaching of catheter additives into the infused solutions were studied while these solutions were infused cyclically for several months. Chemotherapy treatment was mimicked in vitro in compliance with hospital practices. The treatment cycle was repeated 10 times, using solutions containing only the excipients. After 10 treatment cycles, no physical or chemical degradation of the catheter was observed. Mechanical performances were stable, but surface modifications occurred, causing the surface to become more hydrophobic. A loss in polyurethane antioxidant amount was observed in part due to a leaching phenomenon.

Spray drying siRNA-lipid nanoparticles for dry powder pulmonary delivery.

While all the siRNA drugs on the market target the liver, the lungs offer a variety of currently undruggable targets which could potentially be treated with RNA therapeutics. Hence, local, pulmonary delivery of RNA nanoparticles could finally enable delivery beyond the liver. The administration of RNA drugs via dry powder inhalers offers many advantages related to physical, chemical and microbial stability of RNA and nanosuspensions. The present study was therefore designed to test the feasibility of engineering spray dried lipid nanoparticle (LNP) powders. Spray drying was performed using 5% lactose solution (m/V), and the targets were set to obtain nanoparticle sizes after redispersion of spray-dried powders around 150 nm, a residual moisture level below 5%, and RNA loss below 15% at maintained RNA bioactivity. The LNPs consisted of an ionizable cationic lipid which is a sulfur-containing analog of DLin-MC3-DMA, a helper lipid, cholesterol, and PEG-DMG encapsulating siRNA. Prior to the spray drying, the latter process was simulated with a novel dual emission fluorescence spectroscopy method to preselect the highest possible drying temperature and excipient solution maintaining LNP integrity and stability. Through characterization of physicochemical and aerodynamic properties of the spray dried powders, administration criteria for delivery to the lower respiratory tract were fulfilled. Spray dried LNPs penetrated the lung mucus layer and maintained bioactivity for >90% protein downregulation with a confirmed safety profile in a lung adenocarcinoma cell line. Additionally, the spray dried LNPs successfully achieved up to 50% gene silencing of the house keeping gene GAPDH in ex vivo human precision-cut lung slices at without increasing cytokine levels. This study verifies the successful spray drying procedure of LNP-siRNA systems maintaining their integrity and mediating strong gene silencing efficiency on mRNA and protein levels both in vitro and ex vivo. The successful spray drying procedure of LNP-siRNA formulations in 5% lactose solution creates a novel siRNA-based therapy option to target respiratory diseases such as lung cancer, asthma, COPD, cystic fibrosis and viral infections.

Polysorbate identity and quantity dictate the extensional flow properties of protein‐excipient solutions

AbstractWhile protein medications are promising for treatment of cancer and autoimmune diseases, challenges persist in terms of development and injection stability of high‐concentration formulations. Here, the extensional flow properties of protein‐excipient solutions are examined via dripping‐onto‐substrate extensional rheology, using a model ovalbumin (OVA) protein and biocompatible excipients polysorbate 20 (PS20) and 80 (PS80). Despite similar PS structures, differences in extensional flow are observed based on PS identity in two regimes: at moderate total concentrations where surface tension differences drive changes in extensional flow behavior, and at small PS:OVA ratios, which impact the onset of weakly elastic flow behavior. Undesirable elasticity is observed in ultra‐concentrated formulations, independent of PS identity; higher PS contents are required to observe these effects than in analogous polymeric excipient solutions. These studies reveal novel extensional flow behaviors in protein‐excipient solutions, and provide a straightforward methodology for assessing the extensional flow stability of new protein‐excipient formulations.

Virucidal Activity of Different Mouthwashes Using a Novel Biochemical Assay.

Background: Saliva of patients with COVID-19 has a high SARS-CoV-2 viral load. The risk of spreading the virus is not insignificant, and procedures for reducing viral loads in the oral cavity have been proposed. Little research to date has been performed on the effect of mouthwashes on the SARS-CoV-2 virus, and some of their mechanisms of action remain unknown. Methods: SARS-CoV-2 positive nasopharyngeal swabs measured by RT-PCR were used for virucidal activity in a 1:1 ratio, with an incubation time of 1 min. The solutions used in this study were: iodopovidone (8 mg); * D-limonene, a terpene extracted from citrus peels (0.3%); † cetylpyridinium chloride (0.1%) (CPC); ‡ chlorhexidine gluconate (10%) (CHX); § a CPC (0.12%) and CHX (0.05%) containing formula; ** a formula containing essential oils; †† a CPC containing formula (0.07%); ‡‡ a D-limonene (0.2%) and CPC (0.05%) containing formula; §§ a solution containing sodium fluoride (0.05%) and CPC (0.075%); *** a solution containing CHX (0.12%) and; ††† a CHX (0.2%) containing formula. ‡‡‡ As a control reaction, saline solution or excipient solution (water, glycerin, citric acid, colorant, sodium citrate) was used. Conclusion: Within the limitations of this study, we can conclude that a mouthwash containing both D-limonene and CPC reduced the virucidal activity in about 6 logs (>99.999% reduction). Hence, establishing a clinical protocol for dentists is suggested, where all patients to be treated rinse pre-operatively with a mouthwash containing both D-limonene and CPC to reduce the likelihood of infection with SARS-CoV-2 for dentists. This is a relatively inexpensive way to reduce viral transmission of SARS-CoV-2 from infected individuals within the community. It is also a simple way to decrease infections from asymptomatic and pre-symptomatic patients.

Near Infrared Spectroscopy as a PAT tool for monitoring and control of protein and excipient concentration in ultrafiltration of highly concentrated antibody formulations

Excipient concentrations are critical quality attributes of monoclonal antibody (mAb) drug products and affect their safety and efficacy. In manufacturing processes, mAb products are formulated into the buffer containing the desired excipients using ultrafiltration (UF) and diafiltration (DF). Control of excipient concentrations is a challenge during high concentration UF due to electrostatic interactions which lead to excipient concentration drifts. This challenge is of increasing importance due to the growing preference towards high concentration subcutaneous drug formulations over conventional intravenous formulations in the biotherapeutic industry. Excipient concentrations are currently measured using offline RP-HPLC which is time-consuming and not suited for real time control. We propose a novel process analytical technology (PAT) tool for monitoring and control of mAb and excipients in high concentration UF using Near Infrared Spectroscopy (NIRS). The NIRS is able to monitor concentrations within ±1% for mAb and ±2% for two common excipients, L-histidine and acetate. A Python-based controller uses real time concentration data to deliver concentrated excipient stock solutions to the UF reservoir whenever the excipient concentrations drift out of range. The PAT control system is able to achieve the target formulation without manual intervention or at-line analysis and is well-suited for implementation in mAb manufacturing platforms.

Validation of a green spectrophotometric method for the determination of dropropizine in commercial oral solutions

The present work describes a first-order derivative spectrophotometric (1D-UV) method for determination of dropropizine in commercial oral solutions. The method was developed using ecologically correct solvents and validated according to International Conference on Harmonization (ICH) recommendations. The response was linear in the concentration range of 6–24 μg/mL (r = 0.9997, n = 7) at wavelength 249 nm, which was the zero crossing point of excipient solutions. The detection and quantitation limits were 0.36 and 1.18 μg/mL, respectively. The method showed adequate precision, with a relative standard deviation values lower than 1.41%. Excellent values of accuracy were obtained, with a mean value of 99.44%. The method proved to be robust by a full factorial design evaluation. It is simple, it has low cost, and it has low use of polluting reagents. Minimum environmental hazards observed and the results obtained attest to the reliability of the proposed green method, showing to be specific, linear, precise, accurate and robust. Thus, the validated 1D-UV spectrophotometric method was successfully applied to the quantitative analysis of dropropizine in oral solutions dosage forms, helping to improve quality control and to assure therapeutic efficacy.

Effect of Shear Stresses on Adenovirus Activity and Aggregation during Atomization To Produce Thermally Stable Vaccines by Spray Drying.

Considering the substantive potential benefits of thermally stable dry powder vaccines to public health, causes for inactivation of their sensitive viral vectors during preparation require intensive study. The focus of this work was atomization of suspensions containing encapsulating excipients and a human type 5 adenovirus, involving a detailed investigation of shear stresses in the nozzle of a spray dryer. Samples were sprayed at 25 °C into falcon tubes and immediately evaluated for viral activity by in vitro testing, minimizing the confounding of thermal effects on the deactivation of the virus, although interfacial stresses could not be decoupled from shear stresses. Despite the expectations of only virus deactivation with ever-increasing shear stresses in the spray nozzle, some conditions were found to show better activity than the positive control, leading to investigations of viral aggregation. It was found that the adenovirus experienced minor aggregation when mixed with the excipient solutions, which was reversed by subjecting samples to moderate shear conditions in the spray nozzle. At very high shear rates, the activity diminished again because of damage to the viral capsid fibers, which also led to the production of new aggregates after atomization. Despite these findings, activity losses caused by shear were small compared to the overall spray drying process loss. However, formulation composition, solution viscosity, and process conditions should be considered carefully for optimization because of their impact on aggregation. This is the first known report comparing shear, aggregation, and biological activity loss during the atomization step of spray drying viral vaccines.

Sex Differences in Medicine Acceptability: A New Factor to Be Considered in Medicine Formulation.

Palatability is a recognized driver of medicine acceptability in pediatrics but deemed less relevant in older populations due to sensory decline. Preliminary findings from an observational study implicated palatability problems with one Alzheimer’s medicine. Among 1517 observer reports combining multiple measures on medicines uses in patients aged over 64, we focused on two original formulations of memantine (Ebixa®, tablets (n = 25) and oral solution (n = 60)). Evaluations were scored with an acceptability reference framework (CAST), the rodent Brief Access Taste Aversion (BATA) model tested aversiveness. Focusing on women treated with Ebixa® (n = 54), the oral formulation sub-group was classified as “negatively accepted”, while the coated tablet was associated with the “positively accepted” cluster. In men, both formulations belonged to the “positively accepted” profile. Using BATA, the original oral solution was categorized as highly aversive/untolerated while solutions of excipients only were well tolerated. Furthermore, the number of licks was significantly lower in female than in male rats. These results revealed that medicine palatability remains important for acceptability in older populations. Moreover, converging results from humans and animal models highlighted that palatability profiles can significantly vary between the sexes. These drivers should be closely considered during drug development to enhance acceptability in this population.

NTG-101: A Novel Molecular Therapy that Halts the Progression of Degenerative Disc Disease

The tremendous cost, pain and disability associated with degenerative disc disease (DDD) makes the development of a biological agent that can mitigate the course of DDD, a critical unmet need. We have identified and reported that a single injection of a combination of recombinant human (rh) Transforming growth factor beta 1 (TGF-β1) and Connective tissue growth factor (CTGF) proteins into the injured intervertebral disc (IVD) nucleus pulposus (NP) can mediate DDD in a pre-clinical rodent model. In this study, we developed and evaluated the efficacy of a novel molecular therapy (NTG-101) containing rhTGF-β1 and rhCTGF proteins suspended in an excipient solution using in vivo models of DDD including rat-tail and chondrodystrophic (CD) canines. Needle puncture injury in CD-canine NPs resulted in loss of hydration, disc height and showed radiographic evidence of DDD like humans. However, NTG-101-injected IVDs maintained disc height and demonstrated retention of viscoelastic properties as compared to IVDs injected with phosphate buffer saline (PBS, 1X, pH = 7.2). In addition, a single intra-discal injection of NTG-101 into the injured IVD-NPs resulted in sustained expression of healthy extra-cellular matrix (ECM) proteins (aggrecan, collagen 2A1) and reduced expression of inflammation associated proteins and molecules (IL-1β, IL-6, IL-8, MMP-13, Cox-2 and PGE2) as compared to vehicle controls. In conclusion, we demonstrated that a single intra-discal injection of the novel formulation, NTG-101 confers a robust anti-inflammatory, anti-catabolic and pro-anabolic effects in pre-clinical models of DDD thereby restoring homeostasis. These findings suggest the therapeutic potential of NTG-101 for clinical use.

SECOND-ORDER DERIVATIVE UV SPECTROPHOTOMETRIC AND RP-HPLC METHODS FOR THE ANALYSIS OF VILDAGLIPTIN AND APPLICATION FOR DISSOLUTION STUDY

This study describes two analytical methods, by second-order derivative UV spectrophotometric by HPLC, for determination of vildagliptin, a drug used for treatment of type 2 Diabetes Mellitus that belongs to a therapeutic class called inhibitors of dipeptidyl peptidase 4. The methods were validated in accordance with ICH and USP requirements. Analyses by UV derivative method were performed at 220 nm, which was the zero crossing point of excipient solutions. HPLC was optimized and the analysis was carried out using a Zorbax Eclipse Plus RP-C8 column (150 mm × 4.6 mm, 5 μm), detection at 207 nm, and potassium phosphate buffer solution pH 7.0 : acetonitrile (85:15, v/v) as mobile phase. In dissolution test, the conditions used were 0.01 mol L-1 hydrochloric acid in 900 mL of dissolution medium, USP apparatus 2 (paddle) and 50 rpm stirring speed. Both methods were successfully applied for analysis of dissolution samples from marketed vildagliptin tablets.

Development of Adjuvanted Solid Fat Nanoemulsions for Pulmonary Hepatitis B Vaccination

Pulmonary vaccination is one of the most promising routes for immunization owing to its noninvasive nature and induction of strong mucosal immunity and systemic response. In the present study, recombinant hepatitis B surface antigen loaded solid fat nanoemulsions (SFNs) as carrier system and monophosphoryl lipid A as an adjuvant-carrier system was prepared and evaluated as multiadjuvanted vaccine system for deep pulmonary vaccination. Deposition and clearance from the deep lung of rats were determined by gamma scintigraphy. Biodistribution of SFNs was determined by the live animal imaging system. SFNs dispersion showed slower clearance as compared with sodium pertechnetate control solution (∗∗∗p <0.001) from the pulmonary region due to the virtue of particulate and hydrophobic nature of formulations. Humoral (sIgA and IgG) and cellular (IL-2 and IF-γ) immune responses were found to be significant (∗∗∗p <0.001) when compared with naïve antigen (recombinant surface antigen without any excipient) solution. Data indicate that deep pulmonary immunization offers a stronger immune response with balanced humoral, mucosal, and cellular immunization, which further needs to be tested in higher animals to support this hypothesis for clinical translation of this so far neglected yet potential target tissue for immunization.

Mixing of Stratified Miscible Liquids in an Unbaffled Tank with Application in High Concentration Protein Drug Product Manufacturing

During high-concentration protein drug product compounding, the property difference between the drug substance solution and the buffer excipient solution can potentially cause the formation of stratified layers, which may prohibit effective mixing. In this study, mixing of two stratified liquids in an unbaffled tank with an angle-mounted impeller was investigated using both experiments and computational fluid dynamics (CFD) simulations. The results revealed that the mixing time under the stratified conditions could be over an order of magnitude longer than that predicted by a commonly used blend time correlation. Further analysis showed that the observed long mixing time occurred when the buoyancy force due to density difference between the liquids was dominant over the impeller stir and was correlated with high Richardson number. The study also looked into the impact of factors such as liquid height and impeller size, and a new correlation was proposed based on the experimental data.

Bilateral Effects of Excipients on Protein Stability: Preferential Interaction Type of Excipient and Surface Aromatic Hydrophobicity of Protein.

Understanding the mechanism of protein-excipient interaction and illuminating the influencing factors on protein stability are key steps in the rational design of protein formulations. The objective of this study was to assess effects of preferential interaction type of excipient and surface aromatic hydrophobicity of protein on protein solution stability. The preferential interaction between excipient and aromatic hydrophobic area of protein was investigated by solubility and fluorescence studies of amino acid derivatives in excipient solutions. We examined conformational, colloidal and mechanical stabilities of model proteins with different surface aromatic hydrophobicities, including bovine serum albumin (BSA) and ovalbumin (OVA), and then stability data were visualized by three-index empirical phase diagram. The result showed that preferentially excluded excipients (trehalose, sucrose and sorbitol) protected protein conformation against damage, but they could accelerate mechanical stress-induced aggregation. Preferentially bound excipients (propanediol and arginine) suppressed BSA aggregation, but arginine failed to inhibit OVA aggregation, which might be attributed to the disparate conformational perturbing effects of arginine on aromatic hydrophobic regions of BSA and OVA. These findings provided strong evidence that excipient possessed bilateral effects, and its application should be determined on different preferential interaction behaviors of excipients with protein, especially with the aromatic hydrophobic region.

Viscoelastic interactions between polydeoxyribonucleotide and ophthalmic excipients

This study investigated the interaction between polydeoxyribonucleotide (PDRN) and several ionic and nonionic isotonic agents, thickeners and a preservative that were employed as excipients in ophthalmic preparations. Interaction of each individual excipient and PDRN aqueous solution was evaluated by analyzing their rheological properties. Rheological properties of PDRN solutions were evaluated by dynamic oscillatory shear tests and values of elastic modulus (G′), viscous modulus (G″) and loss tangent (tan δ) were used to assess the relative changes in viscoelastic properties. At given concentrations, sodium chloride was found to show alteration in viscoelastic properties of PDRN solution while nonionic isotonic agents like d-glucose and d-sorbitol did not alter them. Similarly, nonionic water soluble polymers like polyvinylpyrrolidone (PVP) and hydroxypropyl methylcellulose (HPMC) also did not interact with PDRN to alter the viscoelastic properties. However, there were changes observed when carbopol 940 was used as a thickener. Therefore, PDRN was found to interact with ionic excipients and the interactions were negligible when nonionic materials were examined, which suggests that nonionic excipients are suitable to be formulated with PDRN.

5-HT denervation of the adult rat prefrontal cortex induces changes in the expression of α4 and α7 nicotinic acetylcholine receptor subtypes

IntroductionNicotinic acetylcholine receptors (nAChRs) are widely expressed throughout several brain regions. Formation of the α4β2 and α7 subtypes in particular is involved in the organisation of different types of memory. Furthermore, due to their location, these receptors can control the release of various types of neurotransmitters and contribute to synaptic plasticity. MethodsRats were divided into three groups, an experimental group (E), sham-operated group (S) and an intact group (T). In group E, stereotactic guidance was used to induce a chemical lesion with 1μg/μL of 5,7-dihydroxytryptamine (5,7-DHT) in the anteroventral part of the dorsal raphe nucleus (DRN). In the sham-operated group (S), animals underwent surgery including delivery of the same excipient solution to the same site. The intact group (T) received no treatment whatsoever. Twenty days after surgery, animals in all groups were euthanised by decapitation to evaluate the expression of α4 and α7 nAChRs by means of molecular biology techniques. Results5-HT denervation of the rat prefrontal cortex (PFC) differentially modified the expression of α4 and α7 receptors: while α4 receptor expression increased, α7 expression decreased. ConclusionExpression differences observed between the two subtypes may be due to their separate locations. The α4 subtype is found in postsynaptic locations and may be related to adaptive changes in postsynaptic cells, while the location of α7 is presynaptic. This explains why the lesion and the elimination of 5-HT fibres in the CPF would cause a decrease in α7 expression.

Usefulness of applying lidocaine in esophagogastroduodenoscopy performed under sedation with propofol

To determine whether topical lidocaine benefits esophagogastroduoduenoscopy (EGD) by decreasing propofol dose necessary for sedation or procedure-related complications. The study was designed as a prospective, single centre, double blind, randomised clinical trial and was conducted in 2012 between January and May (NCT01489891). Consecutive patients undergoing EGD were randomly assigned to receive supplemental topical lidocaine (L; 50 mg in an excipient solution which was applied as a spray to the oropharynx) or placebo (P; taste excipients solution without active substance, similarly delivered) prior to the standard propofol sedation procedure. The propofol was administered as a bolus intravenous (iv) dose, with patients in the L and P groups receiving initial doses based on the patient's American Society of Anaesthesiologists (ASA) classification (ASA I-II: 0.50-0.60 mg/kg; ASA III-IV: 0.25-0.35 mg/kg), followed by 10-20 mg iv dose every 30-60 s at the anaesthetist's discretion. Vital signs, anthropometric measurements, amount of propofol administered, sedation level reached, examination time, and the subjective assessments of the endoscopist's and anaesthetist's satisfaction (based upon a four point Likert scale) were recorded. All statistical tests were performed by the Stata statistical software suite (Release 11, 2009; StataCorp, LP, College Station, TX, United States). No significant differences were found between the groups treated with lidocaine or placebo in terms of total propofol dose (310.7 ± 139.2 mg/kg per minute vs 280.1 ± 87.7 mg/kg per minute, P = 0.15) or intraprocedural propofol dose (135.3 ± 151.7 mg/kg per minute vs 122.7 ± 96.5 mg/kg per minute, P = 0.58). Only when the L and P groups were analysed with the particular subgroups of female, < 65-year-old, and lower anaesthetic risk level (ASA I-II) was a statistically significant difference found (L: 336.5 ± 141.2 mg/kg per minute vs P: 284.6 ± 91.2 mg/kg per minute, P = 0.03) for greater total propofol requirements). The total incidence of complications was also similar between the two groups, with the L group showing a complication rate of 32.2% (95%CI: 21.6-45.0) and the P group showing a complication rate of 26.7% (95%CI: 17.0-39.0). In addition, the use of lidocaine had no effect on the anaesthetist's or endoscopist's satisfaction with the procedure. Thus, the endoscopist's satisfaction Likert assessments were equally distributed among the L and P groups: unsatisfactory, [L: 6.8% (95%CI: 2.2-15.5) vs P: 0% (95%CI: 0-4.8); neutral, L: 10.1% (95%CI: 4.2-19.9) vs P: 15% (95%CI: 7.6-25.7)]; satisfactory, [L: 25.4% (95%CI: 10-29.6) vs P: 18.3% (95%CI: 15.5-37.6); and very satisfactory, L: 57.6% (95%CI: 54-77.7) vs P: 66.6% (95%CI: 44.8-69.7)]. Likewise, the anaesthetist's satisfaction Likert assessments regarding the ease of maintaining a patient at an optimum sedation level without agitation or modification of the projected sedation protocol were not affected by the application of lidocaine, as evidenced by the lack of significant differences between the scores for the placebo group: unsatisfactory, L: 5.8% (95%CI: 1.3-13.2) vs P: 0% (95%CI: 0-4.8); neutral, L: 16.9% (95%CI: 8.9-28.4) vs P: 16.7% (95%CI: 8.8-27.7); satisfactory, L: 15.2% (95%CI: 7.7-26.1) vs P: 20.3% (95%CI: 11.3-31.6); and very satisfactory, L: 62.7% (95%CI: 49.9-74.3) vs P: 63.3% (95%CI: 50.6-74.7). Topical pharyngeal anaesthesia is safe in EGD but does not reduce the necessary dose of propofol or improve the anaesthetist's or endoscopist's satisfaction with the procedure.