Role of PLGA Variability in Controlled Drug Release from Dexamethasone Intravitreal Implants.

Long-acting injectable formulations based on poly(lactide-co-glycolide) (PLGA) have been commercialized for over 30 years in at least 20 FDA-approved products. These formulations offer several advantages, including reduced dosing frequency, improved patient compliance, and maintenance of therapeutic levels of drug. Despite extensive studies, the inherent complexity of the PLGA copolymer still poses significant challenges associated with the development of generic formulations having drug release profiles equivalent to those of the reference listed drugs. In addition, small changes to PLGA physicochemical properties or the drug product manufacturing process can have a major impact on the drug release profile of these long-acting formulations. This work seeks to better understand how variability in the physicochemical properties of similar PLGAs affects drug release from PLGA solid implants using Ozurdex (dexamethasone intravitreal implant) as the model system. Four 50:50, acid-terminated PLGAs of similar molecular weights were used to prepare four dexamethasone intravitreal implants structurally equivalent to Ozurdex. The PLGAs were extensively characterized by using a variety of analytical techniques prior to implant manufacture using a continuous, hot-melt extrusion process. In vitro release testing of the four structurally equivalent implants was performed in both normal saline and phosphate-buffered saline (PBS), yielding drastically different results between the two methods. In normal saline, no differences in the release profiles were observed. In PBS, the drug release profiles were sensitive to small changes in the residual monomer content, carboxylic acid end group content, and blockiness of the polymers. This finding further underscores the need for a physiologically relevant in vitro release testing method as part of a robust quality control strategy for PLGA-based solid implant formulations.

Bony Ingrowth of Coil-Type Open-Architecture Anchors Compared With Screw-Type PEEK Anchors for the Medial Row in Rotator Cuff Repair: A Randomized Controlled Trial.

PURPOSE: To evaluate outcomes of screw-type and coil-type open-architecture suture anchors with respect to bony ingrowth, release of biological markers, and patient-reported outcome measures when used in rotator cuff repair (RCR). METHODS: Forty patients undergoing arthroscopic RCR for full-thickness rotator cuff tears were enrolled and prospectively randomized to receive a screw-type (19 patients) or coil-type (21 patients) suture anchor for the medial row during repair. All repairs used a transosseous-equivalent configuration with footprint anchors laterally. Marrow elements released during surgery were evaluated for 9 cytokine markers (insulin-like growth factor 1, fibroblast growth factor 2, bone morphogenetic proteins 7 and 2, platelet-derived growth factors AA and BB, epidermal growth factor, transforming growth factor beta1, and vascular endothelial growth factor). Postoperative computed tomography scans were performed at 6 months. Range of motion, strength, and validated patient-reported outcome measures (Simple Shoulder Test, Single Assessment Numeric Evaluation, visual analog scale, and American Shoulder and Elbow Surgeons scores) were gathered before the operation and at 6 months and 1 year postoperatively. RESULTS: Bone mineral density surrounding the coil-type anchor was significantly greater than that surrounding the screw-type anchor (P = .005). Bone mineral density values within the coil-type and screw-type anchors were comparable (P = .527); however, a larger amount of total bone mineral mass (in milligrams) was shown within the coil-type anchor owing to its larger volume (P < .01). Marrow elements released at the repair site were similar between groups (P > .05). Postoperatively, no statistically significant difference was found between groups for clinical outcome measures at 6 months or 1 year. Retear and complication rates were similar between groups (P > .05). CONCLUSIONS: Both the coil-type and screw-type anchors can be reliably used for RCR and produce similar clinical outcomes. The coil-type anchor resulted in superior bony growth surrounding the anchor and a larger total bone mineral mass within the anchor owing to its larger volume. LEVEL OF EVIDENCE: Level II, randomized prospective comparative study.

Diagnostic tests for oral cancer and potentially malignant disorders in patients presenting with clinically evident lesions.

BACKGROUND: Oral squamous cell carcinoma is the most common form of malignancy of the lip and oral cavity, often being proceeded by potentially malignant disorders (PMD). Early detection can reduce the malignant transformation of PMD and can improve the survival rate for oral cancer. The current standard of scalpel biopsy with histology is painful for patients and involves a delay whilst histology is completed; other tests are available that are unobtrusive and provide immediate results. PRIMARY OBJECTIVE: To estimate the diagnostic accuracy of index tests for the detection of oral cancer and PMD of the lip and oral cavity, in people presenting with clinically evident lesions. SECONDARY OBJECTIVE: To estimate the relative accuracy of the different index tests. SEARCH METHODS: The electronic databases were searched on 30 April 2013. We searched MEDLINE (OVID) (1946 to April 2013) and four other electronic databases (the Cochrane Diagnostic Test Accuracy Studies Register, the Cochrane Oral Health Group's Trials Register, EMBASE (OVID) and MEDION (Ovid)). There were no restrictions on language in the searches of the electronic databases. We conducted citation searches and screened reference lists of included studies for additional references. SELECTION CRITERIA: We selected studies that reported the diagnostic test accuracy of the following index tests when used as an adjunct to conventional oral examination in detecting PMD or oral squamous cell carcinoma of the lip or oral cavity: vital staining, oral cytology, light-based detection and oral spectroscopy, blood or saliva analysis (which test for the presence of biomarkers in blood or saliva). DATA COLLECTION AND ANALYSIS: Two review authors independently screened titles and abstracts for relevance. Eligibility, data extraction and quality assessment were carried out by at least two authors, independently and in duplicate. Studies were assessed for methodological quality using QUADAS-2. Meta-analysis was used to combine the results of studies for each index test using the bivariate approach to estimate the expected values of sensitivity and specificity. MAIN RESULTS: We included 41 studies, recruiting 4002 participants, in this review. These studies evaluated the diagnostic accuracy of conventional oral examination with: vital staining (14 studies), oral cytology (13 studies), light-based detection or oral spectroscopy (13 studies). Six studies assessed two combined index tests. There were no eligible diagnostic accuracy studies evaluating blood or salivary sample analysis.The summary estimates for vital staining obtained from the meta-analysis were sensitivity of 0.84 (95% CI 0.74 to 0.90) with specificity of 0.70 (0.59 to 0.79), with 14 studies were included in the meta-analysis. For cytology, sensitivity was 0.91 (0.81 to 0.96) and specificity was 0.91 (0.81 to 0.95) with 12 studies included in the meta-analysis. For light-based detection, sensitivity was 0.91 (0.77 to 0.97) and specificity was 0.58 (0.22 to 0.87) with 11 studies included in the meta-analysis. The relative test accuracy was assessed by adding covariates to the bivariate analysis, no difference in model fit was observed. AUTHORS' CONCLUSIONS: The overall quality of the included studies was poor. None of the adjunctive tests can be recommended as a replacement for the currently used standard of a scalpel biopsy and histological assessment. Given the relatively high values of the summary estimates of sensitivity and specificity for cytology, this would appear to offer the most potential. Combined adjunctive tests involving cytology warrant further investigation.

Clinical assessment to screen for the detection of oral cavity cancer and potentially malignant disorders in apparently healthy adults.

BACKGROUND: The early detection and excision of potentially malignant disorders (PMD) of the lip and oral cavity that require intervention may reduce malignant transformations (though will not totally eliminate malignancy occurring), or if malignancy is detected during surveillance, there is some evidence that appropriate treatment may improve survival rates. OBJECTIVES: To estimate the diagnostic accuracy of conventional oral examination (COE), vital rinsing, light-based detection, biomarkers and mouth self examination (MSE), used singly or in combination, for the early detection of PMD or cancer of the lip and oral cavity in apparently healthy adults. SEARCH METHODS: We searched MEDLINE (OVID) (1946 to April 2013) and four other electronic databases (the Cochrane Diagnostic Test Accuracy Studies Register, the Cochrane Oral Health Group's Trials Register, EMBASE (OVID), and MEDION) from inception to April 2013. The electronic databases were searched on 30 April 2013. There were no restrictions on language in the searches of the electronic databases. We conducted citation searches, and screened reference lists of included studies for additional references. SELECTION CRITERIA: We selected studies that reported the diagnostic test accuracy of any of the aforementioned tests in detecting PMD or cancer of the lip or oral cavity. Diagnosis of PMD or cancer was made by specialist clinicians or pathologists, or alternatively through follow-up. DATA COLLECTION AND ANALYSIS: Two review authors independently screened titles and abstracts for relevance. Eligibility, data extraction and quality assessment were carried out by at least two authors independently and in duplicate. Studies were assessed for methodological quality using QUADAS-2. We reported the sensitivity and specificity of the included studies. MAIN RESULTS: Thirteen studies, recruiting 68,362 participants, were included. These studies evaluated the diagnostic accuracy of COE (10 studies), MSE (two studies). One randomised controlled of test accuracy trial directly evaluated COE and vital rinsing. There were no eligible diagnostic accuracy studies evaluating light-based detection or blood or salivary sample analysis (which tests for the presence of bio-markers of PMD and oral cancer). Given the clinical heterogeneity of the included studies in terms of the participants recruited, setting, prevalence of target condition, the application of the index test and reference standard and the flow and timing of the process, the data could not be pooled. For COE (10 studies, 25,568 participants), prevalence in the diagnostic test accuracy sample ranged from 1% to 51%. For the eight studies with prevalence of 10% or lower, the sensitivity estimates were highly variable, and ranged from 0.50 (95% confidence interval (CI) 0.07 to 0.93) to 0.99 (95% CI 0.97 to 1.00) with uniform specificity estimates around 0.98 (95% CI 0.97 to 1.00). Estimates of sensitivity and specificity were 0.95 (95% CI 0.92 to 0.97) and 0.81 (95% CI 0.79 to 0.83) for one study with prevalence of 22% and 0.97 (95% CI 0.96 to 0.98) and 0.75 (95% CI 0.73 to 0.77) for one study with prevalence of 51%. Three studies were judged to be at low risk of bias overall; two were judged to be at high risk of bias resulting from the flow and timing domain; and for five studies the overall risk of bias was judged as unclear resulting from insufficient information to form a judgement for at least one of the four quality assessment domains. Applicability was of low concern overall for two studies; high concern overall for three studies due to high risk population, and unclear overall applicability for five studies. Estimates of sensitivity for MSE (two studies, 34,819 participants) were 0.18 (95% CI 0.13 to 0.24) and 0.33 (95% CI 0.10 to 0.65); specificity for MSE was 1.00 (95% CI 1.00 to 1.00) and 0.54 (95% CI 0.37 to 0.69). One study (7975 participants) directly compared COE with COE plus vital rinsing in a randomised controlled trial. This study found a higher detection rate for oral cavity cancer in the conventional oral examination plus vital rinsing adjunct trial arm. AUTHORS' CONCLUSIONS: The prevalence of the target condition both between and within index tests varied considerably. For COE estimates of sensitivity over the range of prevalence levels varied widely. Observed estimates of specificity were more homogeneous. Index tests at a prevalence reported in the population (between 1% and 5%) were better at correctly classifying the absence of PMD or oral cavity cancer in disease-free individuals that classifying the presence in diseased individuals. Incorrectly classifying disease-free individuals as having the disease would have clinical and financial implications following inappropriate referral; incorrectly classifying individuals with the disease as disease-free will mean PMD or oral cavity cancer will only be diagnosed later when the disease will be more severe. General dental practitioners and dental care professionals should remain vigilant for signs of PMD and oral cancer whilst performing routine oral examinations in practice.

Manufacturing dexamethasone intravitreal implants: Process control and critical quality attributes.

Over 20 long-acting injectable formulations based on poly(lactide-co-glycolide) (PLGA) have been approved by the FDA to date. PLGA is a biodegradable polymer that can extend drug release from these dosage forms for up to six months after administration. Despite the commercial success of several of these formulations, there are still a limited number of products that utilize PLGA, and there are currently no generic counterparts of these products on the market. Significant technical challenges are associated with preparation of chemically and structurally equivalent formulations that yield an equivalent drug release profile to the reference listed drug (RLD) both in vitro and in vivo. In this work, Ozurdex (dexamethasone intravitreal implant) was used as a model system to explore how the manufacturing process of PLGA-based solid implants impacts the quality and performance of the dosage form. Control of implant structural characteristics, including diameter, internal porosity, and surface roughness, was required to maintain accurate unit dose potency. Implants were prepared by a continuous hot-melt extrusion process that was thoroughly characterized to show the importance of precise feeding control to meet dimensional specifications. Five extruder die designs were evaluated using the same hot-melt extrusion process to produce five structurally-distinct implants. The structural differences did not alter the in vitro drug release profile when tested in both normal saline and phosphate-buffered saline (pH 7.4); however, implant porosity was shown to impact the mechanical strength of the implants. This work seeks to provide insight into the manufacturing process of PLGA-based solid implants to support development of future novel and generic drug products.

Drug release mechanisms of high-drug-load, melt-extruded dexamethasone intravitreal implants.

Ozurdex is an FDA-approved sustained-release, biodegradable implant formulated to deliver the corticosteroid dexamethasone to the posterior segment of the eye for up to 6 months. Hot-melt extrusion is used to prepare the 0.46 mm × 6 mm, rod-shaped implant by embedding the drug in a matrix of poly(lactic-co-glycolic acid) (PLGA) in a 60:40 drug:polymer ratio by weight. In our previous work, the Ozurdex implant was carefully studied and reverse engineered to produce a compositionally and structurally equivalent implant for further analysis. In this work, the reverse-engineered implant was thoroughly characterized throughout the in vitro dissolution process to elucidate the mechanisms of controlled drug release. The implant exhibited a triphasic release profile in 37 °C normal saline with a small burst release (1-2 %), a one-week lag phase with limited release (less than 10 %), and a final phase where the remainder of the dose was released over 3-4 weeks. The limited intermolecular interaction between dexamethasone and PLGA rendered the breakdown of the polymer the dominating mechanism of controlled release. A close relationship between drug release and total implant mass loss was observed. Unique chemical and structural differences were seen between the core of the implant and the implant surface driven by diffusional limitations, autocatalytic hydrolysis, and osmotic effects.

Effect of polysorbate 80 quality on photostability of a monoclonal antibody.

Polysorbate 80 is one of the key components of protein formulations. It primarily inhibits interfacial damage of the protein molecule due to mechanical stress during shipping and handling. However, polysorbate 80 also affects the formulation photostability. Exposure to light of polysorbate 80 aqueous solution results in peroxide generation, which in turn may result in oxidation of the susceptible amino acid residues in the protein molecule. The purpose of this study was to determine if the photostability of our proprietary IgG(1) monoclonal antibody formulation containing polysorbate 80 is affected by the quality (grade/vendor) of polysorbate 80. Following four types of polysorbate 80 were tested: (1) Polysorbate 80 Super-Refined, Mallinckrodt Baker, (2) Polysorbate 80 NF, Mallinckrodt Baker, (3) Polysorbate 80 NF, EMD Chemicals, and (4) Ultra-pure Polysorbate 80 (HX), NOF Corporation. The samples were exposed to light as per ICH guidelines Q1B. The results of the study show that photostability of the antibody formulation is indeed affected by the quality of polysorbate 80. This study underscores the importance of carefully choosing the quality of polysorbate 80 to ensure the robustness of formulation.

Liposomial Bupivacaine for Postoperative Pain Control in Fragility Intertrochanteric Hip Fractures.

OBJECTIVES: To determine whether intraoperative liposomal bupivacaine reduces postoperative opioid requirements, pain scores, and length of stay (LOS) in patients with fragility intertrochanteric femur fractures in comparison with a group of patients who did not receive liposomal bupivacaine. DESIGN: Retrospective observational study. SETTING: Two academic medical centers. PATIENTS: One hundred two patients with intertrochanteric hip fracture treated with a cephalomedullary nail implant. INTERVENTION: Nonrandomized administration of liposomal bupivacaine in 2 cohorts of patients with similar injuries and treatment. MAIN OUTCOME MEASUREMENTS: Postoperative oral average morphine equivalents (MME) and average numerical pain rating score (NRS). Secondary endpoints included postoperative LOS, operative time, and home discharge. RESULTS: Forty-six patients received intraoperative liposomal bupivacaine and 56 patients did not. There was no significant difference between age, sex, and American Society of Anesthesiologist level between groups (P > 0.05). The liposomal bupivacaine group received significantly less MME (0.34 vs. 0.92 mg/h/kg, P = 0.04) and had significantly lower NRS (2.89 vs. 5.13, P = 0.04) in the first 24 hours after surgery. MME (1.18 vs. 1.37 mg/h/kg, P = 0.27) and NRS (3.61 vs. 5.51, P = 0.34) were similar at the 36-hour mark. The liposomal bupivacaine group had similar LOS (3.2 days vs. 3.8, P = 0.08), more home discharges (7 vs. 2, P = 0.001), and longer operative time (73.4 vs. 67.2 minutes, P = 0.004). CONCLUSIONS: Intraoperative liposomal bupivacaine use reduced opioid use and postoperative pain for the first 24 hours after fixation of intertrochanteric femur fractures. Significant increases in likelihood of discharge to home may present an opportunity for cost savings. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.