Differential Surface Adsorption Phenomena for Conventional and Novel Surfactants Correlates with Changes in Interfacial mAb Stabilization.

Protein adsorption on surfaces can result in loss of drug product stability and efficacy during the production, storage, and administration of protein-based therapeutics. Surface-active agents (excipients) are typically added in protein formulations to prevent undesired interactions of proteins on surfaces and protein particle formation/aggregation in solution. The objective of this work is to understand the molecular-level competitive adsorption mechanism between the monoclonal antibody (mAb) and a commercially used excipient, polysorbate 80 (PS80), and a novel excipient, N-myristoyl phenylalanine-N-polyetheramine diamide (FM1000). The relative rate of adsorption of PS80 and FM1000 was studied by pendant bubble tensiometry. We find that FM1000 saturates the interface faster than PS80. Additionally, the surface-adsorbed amounts from X-ray reflectivity (XRR) measurements show that FM1000 blocks a larger percentage of interfacial area than PS80, indicating that a lower bulk FM1000 surface concentration is sufficient to prevent protein adsorption onto the air/water interface. XRR models reveal that with an increase in mAb concentration (0.5-2.5 mg/mL: IV based formulations), an increased amount of PS80 concentration (below critical micelle concentration, CMC) is required, whereas a fixed value of FM1000 concentration (above its relatively lower CMC) is sufficient to inhibit mAb adsorption, preventing mAb from co-existing with surfactants on the surface layer. With this observation, we show that the CMC of the surfactant is not the critical factor to indicate its ability to inhibit protein adsorption, especially for chemically different surfactants, PS80 and FM1000. Additionally, interface-induced aggregation studies indicate that at minimum surfactant concentration levels in protein formulations, fewer protein particles form in the presence of FM1000. Our results provide a mechanistic link between the adsorption of mAbs at the air/water interface and the aggregation induced by agitation in the presence of surfactants.

Application of Combinatorial Methods for the Identifi cation of Synthetic Hair-Conditioning Polymers.

Cationic conditioning polymers have a role as deposition aids for depositing benefit agents such as silicone polymers and are used in shampoo formulations to provide improved combing properties, feel, and look. The objective of this work was to develop synthetic high-performance polymeric conditioning agents that exhibit conditioning performance as good as, or better than, the current commercially available polymers. We describe the application of high throughput methods to identify high-performance synthetic hair-conditioning polymers through using high throughput combinatorial methods for polymer synthesis and screening to prepare several hundred cationic polymer candidates. Shampoo formulations were then formulated with these polymers; hair tresses were treated with these formulations and tested via a parallel automated wet combing method. Three high-performing polymer candidates were selected for further evaluation, prepared on a larger scale and evaluated via a panel study. A (3-acrylamidopropyl)trimethylammonium chloride-vinyl monomer-based cationic copolymer is shown to exhibit hair conditioning efficiency equal to or greater than that of a high-performance cellulose ether-based polymer, SOFTCAT™ SL-5 (Polyquaternium-67) in a shampoo formulation.

Dynamic Properties of Novel Excipient Suggest Mechanism for Improved Performance in Liquid Stabilization of Protein Biologics.

To improve liquid formulation stability, formulators employ various excipients designed to stabilize protein drugs, including buffers, salts, sugars, and surfactants. One of the roles of surfactants is to protect the protein drug from surface interactions that can destabilize the protein. Protein drug products formulated with surfactants usually contain either a polysorbate or poloxamer. Even in the presence of these surfactants, protein drug stability is often insufficient, particularly because of agitation-induced aggregation. FM1000 is one of a series of surfactants containing an alkyl chain, an amino acid, and a polyetheramine. The characterization of the dynamics of FM1000 at various water/hydrophobic interfaces was compared to Polysorbate 20, Polysorbate 80, and Poloxamer 188. FM1000 stabilizes an interface 1-2 orders of magnitude faster than all three of these surfactants, even in the presence of protein. The faster dynamics leads to improved stabilization of model protein biologic drugs IgG and abatacept against agitation-induced aggregation. These results provide mechanistic understanding of the key causes and drivers of protein aggregation.

Feasibility Investigation of Cellulose Polymers for Mucoadhesive Nasal Drug Delivery Applications.

The feasibility of various cellulose polymer derivatives, including methylcellulose (MC), hydroxypropyl methylcellulose (HPMC), sodium-carboxymethylcellulose (sodium-CMC), and cationic-hydroxyethylcellulose (cationic-HEC), for use as an excipient to enhance drug delivery in nasal spray formulations was investigated. Three main parameters for evaluating the polymers in nasal drug delivery applications include rheology, ciliary beat frequency (CBF), and permeation across nasal tissue. Reversible thermally induced viscosity enhancement was observed at near nasal physiological temperature when cellulose derivatives were combined with an additional excipient, poly(vinyl caprolactam)-poly(vinyl acetate)-poly(ethylene glycol) graft copolymer (PVCL-PVA-PEG). Cationic-HEC was shown to enhance acyclovir permeation across the nasal mucosa. None of the tested cellulosic polymers caused any adverse effects on porcine nasal tissues and cells, as assessed by alterations in CBF. Upon an increase in polymer concentration, a reduction in CBF was observed when ciliated cells were immersed in the polymer solution, and this decrease returned to baseline when the polymer was removed. While each cellulose derivative exhibited unique advantages for nasal drug delivery applications, none stood out on their own to improve more than one of the performance characteristics examined. Hence, these data may be useful for the development of new cellulose derivatives in nasal drug formulations.

Novel Surfactant Compatibility with Downstream Protein Bioprocesses.

Downstream processing of antibodies consists of a series of steps aimed at purifying the product and ensuring it is delivered to formulators structurally and functionally intact. The process can be complex and time-consuming, involving multiple filtrations, chromatography, and buffer exchange steps that can interfere with product integrity. This study explores the possibility and benefits of adding N-myristoyl phenylalanine polyether amine diamide (FM1000) as a process aid. FM1000 is a nonionic surfactant that is highly effective at stabilizing proteins against aggregation and particle formation and has been extensively explored as a novel excipient for antibody formulations. In this work, FM1000 is shown to stabilize proteins against pumping-induced aggregation which can occur while transporting them between process units and within certain processes. It is also shown to prevent antibody fouling of multiple polymeric surfaces. Furthermore, FM1000 can be removed after some steps and during buffer exchange in ultrafiltration/diafiltration, if needed. Additionally, FM1000 was compared to polysorbates in studies focusing on surfactant retention on filters and columns. While the different molecular entities of polysorbates elute at different rates, FM1000 flows through purification units as a single molecule and at a faster rate. Overall, this work defines new areas of application for FM1000 within downstream processing and presents it as a versatile process aid, where its addition and removal are tunable depending on the needs of each product.

International Phase IV Field Study for the Reliability and Validity of the European Organisation for Research and Treatment of Cancer Thyroid Cancer Module EORTC QLQ-THY34.

Purpose: The aim of this study was to validate the new European Organisation for Research and Treatment of Cancer Quality of Life Thyroid Cancer Module (EORTC QLQ-THY34). Methods: We enrolled 437 thyroid cancer patients from 17 countries. One group (n = 303), undergoing treatment or best supportive care, completed the questionnaires at three time points (before therapy [t1], 6 weeks later [t2], and 6 months after t2 [t3]). A second group (survivors ≥2 years after diagnosis, n = 134) completed it at a random baseline time point and a second time 1 week later. We determined internal consistency (using Cronbach's alpha), the scale structure (with confirmatory factor analysis), and discriminant validity (using known-group comparisons). Group 1 data were used to assess responsiveness and group 2 data to determine test-retest reliability using intra-class correlations (ICC). Results: All 34 items fulfilled the criteria to be kept in the questionnaire. Cronbach's alpha was >0.70 in 8 of the 9 multi-item scales. All standardized factor loadings exceeded 0.40, confirming the proposed scale structure. The ICC was >0.70 in all scales expressing good test-retest reliability. Differences in scale scores between patients with different histology were >5 points in all scales. In all but one of the pre-specified scales (Dry Mouth), changes over time were ≥|4| points between at least two time points. Conclusion: The EORTC QLQ-THY34 with its 9 multi-item and 8 single-item scales is a reliable and valid tool to measure quality of life in thyroid cancer patients and can be used in future trials and studies.

Stress Factors in Primary Packaging, Transportation and Handling of Protein Drug Products and Their Impact on Product Quality.

Protein-based biologic drugs encounter a variety of stress factors during drug substance (DS) and drug product (DP) manufacturing, and the subsequent steps that result in clinical administration by the end user. This article is the third in a series of commentaries on these stress factors and their effects on biotherapeutics. It focuses on assessing the potential negative impact from primary packaging, transportation, and handling on the quality of the DP. The risk factors include ingress of hazardous materials such as oxidizing residuals from the sterilization process, delamination- or rubber stopper-derived particles, silicone oil droplets, and leachables into the formulation, as well as surface interactions between the protein and packaging materials, all of which may cause protein degradation. The type of primary packaging container used (such as vials and prefilled syringes) may substantially influence the impact of transportation and handling stresses on DP Critical Quality Attributes (CQAs). Mitigations via process development and robustness studies as well as control strategies for DP CQAs are discussed, along with current industry best practices for scale-down and in-use stability studies. We conclude that more research is needed on postproduction transportation and handling practices and their implications for protein DP quality.

Nurse-Led Medicines' Monitoring for Patients with Dementia in Care Homes: A Pragmatic Cohort Stepped Wedge Cluster Randomised Trial.

BACKGROUND: People with dementia are susceptible to adverse drug reactions (ADRs). However, they are not always closely monitored for potential problems relating to their medicines: structured nurse-led ADR Profiles have the potential to address this care gap. We aimed to assess the number and nature of clinical problems identified and addressed and changes in prescribing following introduction of nurse-led medicines' monitoring. DESIGN: Pragmatic cohort stepped-wedge cluster Randomised Controlled Trial (RCT) of structured nurse-led medicines' monitoring versus usual care. SETTING: Five UK private sector care homes. PARTICIPANTS: 41 service users, taking at least one antipsychotic, antidepressant or anti-epileptic medicine. INTERVENTION: Nurses completed the West Wales ADR (WWADR) Profile for Mental Health Medicines with each participant according to trial step. OUTCOMES: Problems addressed and changes in medicines prescribed. DATA COLLECTION AND ANALYSIS: Information was collected from participants' notes before randomisation and after each of five monthly trial steps. The impact of the Profile on problems found, actions taken and reduction in mental health medicines was explored in multivariate analyses, accounting for data collection step and site. RESULTS: Five of 10 sites and 43 of 49 service users approached participated. Profile administration increased the number of problems addressed from a mean of 6.02 [SD 2.92] to 9.86 [4.48], effect size 3.84, 95% CI 2.57-4.11, P <0.001. For example, pain was more likely to be treated (adjusted Odds Ratio [aOR] 3.84, 1.78-8.30), and more patients attended dentists and opticians (aOR 52.76 [11.80-235.90] and 5.12 [1.45-18.03] respectively). Profile use was associated with reduction in mental health medicines (aOR 4.45, 1.15-17.22). CONCLUSION: The WWADR Profile for Mental Health Medicines can improve the quality and safety of care, and warrants further investigation as a strategy to mitigate the known adverse effects of prescribed medicines. TRIAL REGISTRATION: ISRCTN 48133332.

Synergistic effects of high molecular weight polyethylene oxide (PEO) and cationic cellulosic polymers on conditioning properties of hair care products [corrected].

A hair cleansing composition containing both high molecular weight PEO and cationic hydroxyethyl cellulose (HEC) was found to provide superior conditioning performance. Hair treated with a formulation containing both cationic HEC and high molecular weight PEO showed 30% better wet combing reduction than the formulation containing cationic HEC only. In conjunction with PEO, cationic HEC-dependent deposition of silicone oil and octyl methoxycinnamate (OMC) onto hair was enhanced 27% and 25%, respectively. When examined with a polarized microscope, the appearance of the polymer-surfactant complex (coacervate) of the diluted formation differed in the presence of PEO. In particular, the particle size of the coacervate in the formulation containing both PEO and cationic HEC was smaller. This result indicates PEO reduces the size of the deposition precipitate by preventing the coacervate from agglomerating. Surface analysis also showed that the presence of PEO in formulations containing cationic HEC deposited insoluble actives more evenly on the hair surface.

Practice patterns for subacromial decompression and rotator cuff repair: an analysis of the American Board of Orthopaedic Surgery database.

BACKGROUND: Recently there have been several evolving trends in the practice of shoulder surgery. Arthroscopic subacromial decompression has been performed with greater frequency by orthopaedic surgeons, and there has been considerable recent interest in arthroscopic rotator cuff repair. The purpose of this study was to identify trends in practice patterns for subacromial decompression and rotator cuff repair over time and in relation to the location of practice, fellowship training, and declared subspecialty of the surgeon. METHODS: We reviewed the American Board of Orthopaedic Surgery Part II database to identify patterns in the utilization of open and arthroscopic subacromial decompression and rotator cuff repair among candidates for board certification. All procedures involving only arthroscopic or open subacromial decompression and/or rotator cuff repair from 2004 to 2009 were identified. The rates of arthroscopic and open subacromial decompression and/or rotator cuff repair were compared in terms of year, geographic region, fellowship training, and declared subspecialty of the surgeon. RESULTS: Between 2004 and 2009, 12,136 surgical procedures involving only arthroscopic or open subacromial decompression and/or rotator cuff repair were performed. There were significant differences in treatment with respect to year, geographic region of practice, declared subspecialty, and fellowship training (p < 0.001). There was a significant increase over time in the utilization of arthroscopy among all candidates (p < 0.001). Surgeons with sports medicine fellowship training or a sports-medicine-declared subspecialty performed significantly more subacromial decompressions and rotator cuff repairs arthroscopically than all other candidates (p < 0.001). During this time period, there was a significant decrease in the rate of arthroscopic subacromial decompression, both as an isolated procedure and combined with arthroscopic rotator cuff repair (p < 0.001). CONCLUSIONS: From 2004 to 2009, there was a significant shift throughout the United States toward arthroscopic rotator cuff repair and subacromial decompression among young orthopaedic surgeons, with sports medicine fellowship-trained surgeons performing more of their procedures arthroscopically than surgeons with other training. However, there was an increasing frequency of arthroscopic rotator cuff repair performed without subacromial decompression, and, overall, there was a decrease in the frequency of isolated arthroscopic subacromial decompression over time.

Posterior cruciate ligament reconstruction using a new arthroscopic tibial inlay double-bundle technique.

The treatment of posterior cruciate ligament injuries sparks debate in the field of sports medicine. Surgeons argue about the ideal technique for reconstruction (tibial inlay or transtibial) and the optimal graft design (single-bundle or double-bundle). We present a novel all-arthroscopic tibial inlay technique using a bifid bone-patellar tendon-bone allograft. Advantages of our technique include avoidance of the killer turn associated with the transtibial technique and restoration of biomechanical stability through bony fixation of the tibial inlay. In addition, our technique can be performed arthrosopically without the need for a posterior incision and capsulotomy. Our graft also restores the double-bundle anatomy of the native posterior cruciate ligament, which may improve stability more effectively than single-bundle techniques. With cadaveric studies, we have demonstrated that our technique restores stability as effectively as the traditional open tibial inlay technique. Results from our early experience are encouraging, and longer-term follow-up is in progress.