Subcutaneous Delivery Research Articles

Emicizumab as a Promising Form of Therapy for Type A Hemophilia - A Review of Current Knowledge from Clinical Trials.

Hemophilia is a plasma bleeding disorder characterized by a deficiency of certain blood clotting factors. The most common forms of this disease, i.e., type A and type B, affect approximately 400,000 people worldwide. Without appropriate treatment ensuring the proper coagulation cascade, this disease may lead to serious disability. Minimizing patient discomfort is possible via replacement therapy, consisting of the substitution of a missing coagulation factor via intravenous administration. Frequent medication and the risk related to factor inhibitors are significant disadvantages, necessitating the improvement of current therapies or the development of novel ones. This review examines the humanized bispecific antibody Emicizumab which ensures hemostasis by mimicking the action of the coagulation factor VIII, a deficiency of which causes type A hemophilia. The paper outlines the topic and then summarizes available clinical trials on Emicizumab in type A hemophilia. Several interventional clinical trials have found Emicizumab to be effective in decreasing bleeding episodes and raising patient satisfaction among various hemophilia A populations. Current Emicizumab-related trials are forecast to be completed between 2024 and 2030, and in addition to congenital hemophilia A, the trials cover acquired hemophilia A and patients playing sports. Providing a more comprehensive understanding of Emicizumab may revolutionize the management of hemophilia type A and improve quality of life. Conclusively, Emicizumab is a gentler therapy owing to subcutaneous delivery and fewer injections, which reduces injection-site reactions and makes therapy less burdensome, ultimately decreasing hospital visits and indirect costs.

Clinical assessment of the potential use of a novel single-dose prefilled injection device for the administration of Acthar Gel in children: a narrative review.

Acthar® Gel (repository corticotropin injection; Mallinckrodt Pharmaceuticals, NJ, USA) is indicated for the treatment of myriad inflammatory disorders and is currently administered manually via a vial and syringe. The administration of Acthar via a single-dose prefilled injector (SelfJect™) is intended to simplify its subcutaneous (SC) delivery. The purpose of this review was to determine whether SelfJect is suitable for use in pediatric patients through a literature assessment of various factors, including skin depth, needle length and gauge, dosage, force required for injection, and potential harms. Infants and young children, who commonly have skin-to-muscle distances less than the minimum depth of SelfJect administration, may have risk of unintentional intramuscular (IM) injection; however, an inadvertent IM injection poses no additional risk to children because of the bioequivalence between SC and IM administration of Acthar. The needle gauge of SelfJect is acceptable for pediatric patients and aligns with the Centers for Disease Control and Prevention recommendations for SC injections. The dosage delivered by SelfJect is only appropriate for children over 2years of age. Although adolescents would likely be able to achieve the minimum force required to remove the protective cap and deliver a full dose of Acthar with SelfJect, an adult (18years of age and older) should administer SelfJect to pediatric patients. In addition to the commonly reported postmarketing adverse events (AEs) from Acthar administration (e.g., asthenic conditions, fluid retention, insomnia, headache and increased blood glucose), injection site-related AEs common to injection devices may occur with SelfJect use. The risk of needlestick injury from SelfJect is mitigated by a needle guard. In summary, this review of injection device considerations demonstrates that SelfJect is appropriate for use in the pediatric population.

Novel Pharmaceutical Interventions for Drug Targeting in Parkinson’s Disease

Parkinson's Disease (PD) presents as a neurodegenerative disorder characterized by a gradual decline in brain function, typically advancing slowly over time in most individuals. However, as the disease evolves and impacts the Gastrointestinal Tract (GIT), the window for effective treatment response often becomes narrower for many patients. Recent advancements in medical science have spurred improvements in drug delivery, primarily through the development of enhanced oral formulations or the exploration of alternative administration routes, such as intestinal infusion, transcutaneous delivery, and inhaled levodopa. Among the recent oral formulation breakthroughs is IPX066, a novel formulation combining immediate and extended-release Carbidopa-Levodopa (CD/LD). Another notable example is levodopa-carbidopa intestinal gel, an authorized treatment involving the direct infusion of LD/CD suspension into the brain. Concurrent investigations are assessing the effectiveness of the 'accordion pill' (AP09004), an Extended-release (ER) LD/CD mixture designed to retain within the GIT for an extended period. Additionally, other formulations in various stages of clinical trials include ND0612, a proprietary liquid formulation intended for the purpose of subcutaneous delivery using a compact patch-pump apparatus, and CVT-301, a levodopa aerosol solution distinguished by its prompt initiation of therapeutic effects. However, several other promising formulations, such as DM-1992 and XP21279, have been terminated. This study aimed to thoroughly examine the pharmacokinetics, clinical effectiveness, and possible adverse reactions linked to innovative medication formulations that are now accessible or being developed for treating PD.

Human-factors validation study for a wearable, single-use injector for patients with paroxysmal nocturnal hemoglobinuria

Pegcetacoplan is a complement component 3 inhibitor approved to treat adults with paroxysmal nocturnal hemoglobinuria, a rare disease characterized by life-threatening complement-mediated hemolysis (often leading to anemia) and thrombosis. Pegcetacoplan is self-administered as a subcutaneous (SC) injection with an at-home infusion pump. A newly approved, more convenient, wearable, single-use automatic injector was evaluated in a human factors study for the safe and effective SC delivery of pegcetacoplan in the abdominal area. Adult patients with anemia (representative of PNH) and caregivers (n=15 each) received formal injector use training (2-hour session followed by 1-hour decay) and reviewed the instructions for use (IFU), whereas health care providers (HCPs; n=15) only received the IFU. Participants completed a use test, knowledge-based assessment (KBA), and interviews. Forty-four of 45 participants (98%) passed the use test. Residual risks from observed errors (17 critical use and 6 KBA errors) were deemed acceptable. This study validated the injector for ease of use and safe and effective SC delivery of pegcetacoplan at home, which may potentially reduce treatment burden for patients with PNH.

Jet injection through microneedles for large volume subcutaneous delivery

Subcutaneous (SC) drug delivery offers several advantages over intravenous (IV) delivery including: self-administration, improved patient experience, and reduced treatment costs. Unfortunately, each SC delivery is currently limited to ∼ 2.25 mL with IV administration required when the delivery volume exceeds this value. In this work, we explore a new technique for large volume subcutaneous drug delivery that uses microneedles to break through the epidermis then forms the liquid drug into many small jets that penetrate past the ends of the microneedles and into the subcutaneous (or muscle) tissue. By performing multiple simultaneous injections, this delivery approach avoids the volume limitations of SC delivery, and thus may be able to greatly increase the volume we can deliver to this space. Here, we present a novel multi-jet prototype that forms seven simultaneous jets through 30G needles that have been shortened to have an exposed length of just ∼ 1mm. The jet speed, shape, and volume of jets formed through these microneedles are measured to assess the consistency of jet production through the microneedles. We then perform jet injections of volumes up to 3.9 mL into ex vivo porcine tissue. The results demonstrate the successful delivery (>95 %) of 3.9 mL in just 0.3 s using jet injection performed through microneedles. This volume is almost double the maximum volume of current autoinjectors and the perceived limit for subcutaneous injection (2.25 mL). We also find that jet speeds of 70 m/s and below do not achieve complete delivery of 3.9 mL with our prototype system, and that the addition of microneedles leads to more consistent large volume delivery than equivalent needle-free injections. These results demonstrate the promise of multi-jet injection through microneedles to accommodate volumes much greater than current autoinjectors, and thus potentially allow patient self-administration in many more delivery applications.

An alternative filament fabrication method as the basis for 3D-printing personalized implants from elastic ethylene vinyl acetate copolymer

In this work, a novel tool for small-scale filament production is presented. Unlike traditional methods such as hot melt extrusion (HME), the device (i) allows filament manufacturing from small material amounts as low as three grams, (ii) ensures high diameter stability almost independent of the viscoelastic behavior of the polymer melt, and (iii) enables processing of materials with rheological profiles specifically tailored toward fused filament fabrication (FFF). Hence, novel materials, previously difficult to process due to HME limitations, become easily accessible for FFF for the first time. Here, we showcase the production of highly flexible drug-free, and drug-loaded filaments based on ethylene-vinyl acetate polymers with a vinyl acetate content of 28 w% (EVA28) and unprecedented high melt flow rates of up to 400 g/10 min. Owing to their low viscosity, FFF with low print nozzle sizes of 250 μm was achieved for the first time for EVA28. These small nozzle diameters facilitate 3D-printing of high-resolution structures in small-dimensional dosage forms such as subcutaneous implantable drug delivery systems, which can later be used for personalization. Consequently, the material portfolio for FFF is tremendously broadened, allowing material and formulation optimization toward FFF, independent of a preliminary extrusion process.

Palliative Radiation Treatment in Patients Managed With Advanced/Interventional Pain Therapy such as Pump-delivered Continuous Opioids.

The study aim was to analyze the feasibility and efficacy of palliative radiotherapy in patients receiving advanced/interventional pain therapy, such as epidural or spinal anesthesia or subcutaneous pump delivery of opioids. Endpoints such as pain relief, treatment in the last month of life and survival were evaluated. Different baseline parameters including but not limited to age and Eastern Cooperative Oncology Group performance status (ECOG PS) were assessed. Outcomes were abstracted from electronic health records. The Edmonton Symptom Assessment System (ESAS) was utilized to score pain intensity. The study included 48 patients, 44 of whom completed radiotherapy as prescribed. Device malfunction was not observed. Overall, 31 patients (65%) had journal notes available allowing for evaluation of pain relief. Twenty-six of 31 experienced pain relief (54% in the intention-to-treat population of 48 study patients). Twelve patients (25%) stopped interventional pain therapy and were converted to transdermal or oral drugs. Median survival was 1.6 months. Forty-four percent had received radiotherapy during the last month of life. Sixty-four percent of patients with ECOG PS 3-4 had received radiotherapy during the last month of life, compared to 22% of those with ECOG PS <3, p=0.004. Palliative radiotherapy was feasible in this setting, but given the short median survival and high likelihood of treatment during the last month of life, patient selection and choice of fractionation regimen should be optimized. The record review identified several patients who experienced worthwhile pain relief, sometimes leading to conversion of pain therapy back to non-invasive oral or transdermal application.

Skin Cancer Treatment with Subcutaneous Delivery of Doxorubicin-Loaded Gelatin Nanoparticles and NIR Activation.

Subcutaneous (SC) administration of chemotherapeutics combined with near-infrared (NIR) light activation can effectively target skin tumors by triggering localized drug release and enhancing cytotoxic effects. In this study, we developed NIR-responsive indocyanine green (ICG) and the chemotherapeutic agent doxorubicin (Dox) loaded into gelatin nanoparticles (NPs) for SC delivery in a skin tumor-bearing mouse model. Histological examination (hematoxylin and eosin staining) confirmed the successful delivery and swelling behavior of the Dox/ICG-loaded gelatin NPs at the SC site. In vitro and in vivo experiments demonstrated that NIR activation of the Dox/ICG-loaded gelatin NPs generated significant photothermal heat (48 and 46 °C), leading to targeted drug release and a substantial reduction in skin tumor size (from 15 to 3 mm3). Our findings suggest that this dual-modality approach of SC chemotherapeutic administration and NIR-triggered photothermal therapy can concentrate cytotoxic drugs at the tumor site, offering a promising strategy for improving skin cancer treatment.

Predicting Human Subcutaneous Bioavailability of Therapeutic Monoclonal Antibodies from Systemic Clearance and Volume of Distribution.

Subcutaneous delivery of monoclonal antibody therapeutics is often preferred to intravenous delivery due to better patient compliance and overall lower cost to the healthcare system. However, the systemic absorption of biologics dosed subcutaneously is often incomplete. The aim of this work was to describe a human bioavailability prediction method for monoclonal antibodies delivered subcutaneously that utilizes intravenous pharmacokinetic parameters as input. A two-compartment pharmacokinetic model featuring a parallel-competitive absorption pathway and a presystemic metabolism pathway was employed. A training data set comprised 19 monoclonal antibodies (geometric mean bioavailability of 68%), with previously reported human pharmacokinetic parameters, while a validation set included data compiled from 5 commercial drug products (geometric mean bioavailability of 69%). A single fitted absorption rate constant, paired with compound-specific estimates of presystemic metabolism rate proportional to compound-specific systemic clearance parameters, resulted in calculations of human subcutaneous bioavailability closely mimicking clinical data in the training data set with a root-mean-square error of 5.5%. Application of the same approach to the validation data set resulted in predictions characterized by 12.6% root-mean-square error. Factors that may have impacted the prediction accuracy include a limited number of validation data set compounds and an uncertainty in the absorption rate, which were subsequently discussed. The predictive method described herein provides an initial estimate of the subcutaneous bioavailability based exclusively on pharmacokinetic parameters available from intravenous dosing.

Pain Reduction With Oral Methotrexate in Knee Osteoarthritis : A Randomized, Placebo-Controlled Clinical Trial.

Treatments for osteoarthritis (OA) are limited. Previous small studies suggest that the antirheumatic drug methotrexate may be a potential treatment for OA pain. To assess symptomatic benefits of methotrexate in knee OA (KOA). A multicenter, randomized, double-blind, placebo-controlled trial done between 13 June 2014 and 13 October 2017. (ISRCTN77854383; EudraCT: 2013-001689-41). 15 secondary care musculoskeletal clinics in the United Kingdom. A total of 207 participants with symptomatic, radiographic KOA and knee pain (severity ≥4 out of 10) on most days in the past 3 months with inadequate response to current medication were approached for inclusion. Participants were randomly assigned 1:1 to oral methotrexate once weekly (6-week escalation 10 to 25 mg) or matched placebo over 12 months and continued usual analgesia. The primary end point was average knee pain (numerical rating scale [NRS] 0 to 10) at 6 months, with 12-month follow-up to assess longer-term response. Secondary end points included knee stiffness and function outcomes and adverse events (AEs). A total of 155 participants (64% women; mean age, 60.9 years; 50% Kellgren-Lawrence grade 3 to 4) were randomly assigned to methotrexate (n = 77) or placebo (n = 78). Follow-up was 86% (n = 134; methotrexate: 66, placebo: 68) at 6 months. Mean knee pain decreased from 6.4 (SD, 1.80) at baseline to 5.1 (SD, 2.32) at 6 months in the methotrexate group and from 6.8 (SD, 1.62) to 6.2 (SD, 2.30) in the placebo group. The primary intention-to-treat analysis showed a statistically significant pain reduction of 0.79 NRS points in favor of methotrexate (95% CI, 0.08 to 1.51; P = 0.030). There were also statistically significant treatment group differences in favor of methotrexate at 6 months for Western Ontario and McMaster Universities Osteoarthritis Index stiffness (0.60 points [CI, 0.01 to 1.18]; P = 0.045) and function (5.01 points [CI, 1.29 to 8.74]; P = 0.008). Treatment adherence analysis supported a dose-response effect. Four unrelated serious AEs were reported (methotrexate: 2, placebo: 2). Not permitting oral methotrexate to be changed to subcutaneous delivery for intolerance. Oral methotrexate added to usual medications demonstrated statistically significant reduction in KOA pain, stiffness, and function at 6 months. Versus Arthritis.

Reversible protein complexes: Advancing subcutaneous delivery with controlled and sustained release of high concentration biologics

High concentration formulations are crucial in developing biological drugs, especially for subcutaneous (SC) administration where the administered dose is adversely impacted by the limited injection volume. In this study, we evaluated the fate and behavior of high concentration formulations of biologics, using the previously described reversible protein complex (RPC) approach and a novel in vitro tool called Subcutaneous Injection Site Simulator (Scissor). The Scissor simulates the changes that a biological drug could encounter as it transitions from a drug product formulation to the homeostatic state of the hypodermis following SC injection. The RPC formulation was injected in a cartridge filled with synthetic extracellular matrix, which was immersed in a release chamber filled with a bicarbonate-based physiological buffer that mimicked the SC injection site and the infinite sink conditions of the body. The system enabled continuous monitoring of the RPC formulation within the cartridge and could be used to characterize physicochemical changes of the drug. The dissociation of RPC and the release of the therapeutic protein from the cartridge to the infinite sink compartment simulated the drug migration from the injection site and uptake to the systemic circulation. Here, we present the evaluation of high concentration RPC formulations using five therapeutic proteins of different formats. Our findings suggest that the Scissor can provide a suitable tool to predict the stability of biological drugs in the subcutaneous environment. Also, the in vitro drug release data obtained from the Scissor highlighted a sustained and controlled release of RPC formulations and a surface erosion-based release mechanism was elucidated thanks to in vitro release models.

Evaluating Unmet Needs in Large-Volume Subcutaneous Drug Delivery: US Payer Perspectives on a Novel, Large-Volume On-Body Delivery System.

This research sought to evaluate payer perspectives around OBDS's through semi-structured interviews with 17 US payers representing approximately 227 million covered lives. When asked about the perceived advantages of the novel on-body delivery system (OBDS), 70.6% of payers independently cited simplicity, ease-of-use, and convenience as the most beneficial features, with the potential to replace IV infusion by facilitating at-home HCP- or self-administration being the second most frequent response. Most payers (88.2%) believed that the novel OBDS could fulfill unmet needs such as cost of IV infusion, convenient administration, and improved patient compliance in large-volume SC delivery by enabling safe, easy, self-administration. Nearly all payers (88.2%) stated they would consider covering and managing pharmaceutical products packaged with the novel OBDS, with the remaining payers considering the total cost compared to other routes. A significant proportion of payers (82.4%) acknowledged that a drug delivered via the novel OBDS could warrant a price premium above the cost of the standalone SC drug vial, with half stating the premium would range from 5% to 20% and the other half citing an unspecified premium dependent on the individual drug situation.Conclusions: Given the ability to help address critical unmet needs for the patient and healthcare system, a large proportion of the payers stated that the novel OBDS would fulfill unmet needs and warrant a price premium versus the cost of the standalone SC vial and certainly over the IV counterpart. Future research to quantify the value that OBDS efficiencies could bring to healthcare delivery is warranted.

Development and Evaluation of Reconstructed Nanovesicles from Turmeric for Multifaceted Obesity Intervention.

The escalating prevalence of obesity poses significant health challenges due to its direct association with various diseases. Most existing medications, such as appetite suppressants and fat absorption inhibitors, suffer from limited effectiveness and undesirable side effects. Here, inspired by the versatile metabolic effects of turmeric, we developed a naturally derived nanoformulation of "Reconstructed Turmeric-derived Nanovesicles (Rec-tNVs)" for obesity treatment. Employing quantitative nanoflow cytometry, a four-orders-of-magnitude increase in curcumin content (∼108 molecules per particle) was identified in individual Rec-tNVs compared to their ultracentrifugation-isolated counterparts. Rec-tNVs, featuring highly aggregated curcumin arrangements and other coencapsulated bioactive compounds, demonstrated a dose-dependent lipid-lowering effect in mature 3T3-L1 cells by promoting lipolysis, suppressing lipogenesis, inducing adipocyte browning, and triggering apoptosis after internalization via multiple pathways. In vivo experiments revealed that Rec-tNVs alleviated obesity more effectively than free curcumin and achieved weight reductions of 18.68 and 14.56% through intragastric and subcutaneous delivery, respectively, in high-fat-diet mouse models over a four-week treatment period. These effects were attributed to targeted actions on adipose tissues and systemic impacts on metabolism and gut microbiota composition. Overall, this study underscores the multifaceted antiobesity efficacy of Rec-tNVs, and offers a promising paradigm for developing plant-derived nanovesicle-based therapeutics.

Formative and validation human factors studies of a new disposable prefilled injection device for subcutaneous delivery of acthar gel (repository corticotropin injection)

ABSTRACT Background The administration of repository corticotropin injection (Acthar Gel) via a single-dose prefilled injector (SelfJect) is intended to provide a simple, ergonomic alternative to traditional injection. Iterative human factors (HF) studies were conducted to identify potential use deviations and ensure appropriate device use. Research design and methods This article presents seven formative studies, a validation study (with prior pilot validation studies), and a supplemental validation study with participants including lay users, patients, caregivers, and healthcare providers. Participant interactions with SelfJect and the user interface were assessed. Use deviations, user preferences, and participants’ ability to successfully complete tasks were evaluated to generate modifications to the device and user interface. Results In the validation study, 91% of participants successfully administered their first injection. Use errors were rare with simulated-use (6.9%) and knowledge-based (1.6%) testing. Use deviations were commonly attributed to experimental artifact or information oversight, and device warming had the most use errors (49% of participants), even with extensive testing and adjustments to the user interface. Conclusions SelfJect was able to be used in a safe and effective manner by the intended users. Iterative HF studies informed the mitigation of use-related risks to reduce the occurrence of use deviations during simulated use.

Dihydrothiazolo ring-fused 2-pyridone antimicrobial compounds treat Streptococcus pyogenes skin and soft tissue infection.

We have developed GmPcides from a peptidomimetic dihydrothiazolo ring-fused 2-pyridone scaffold that has antimicrobial activities against a broad spectrum of Gram-positive pathogens. Here, we examine the treatment efficacy of GmPcides using skin and soft tissue infection (SSTI) and biofilm formation models by Streptococcus pyogenes. Screening our compound library for minimal inhibitory (MIC) and minimal bactericidal (MBC) concentrations identified GmPcide PS757 as highly active against S. pyogenes. Treatment of S. pyogenes biofilm with PS757 revealed robust efficacy against all phases of biofilm formation by preventing initial biofilm development, ceasing biofilm maturation and eradicating mature biofilm. In a murine model of S. pyogenes SSTI, subcutaneous delivery of PS757 resulted in reduced levels of tissue damage, decreased bacterial burdens, and accelerated rates of wound healing, which were associated with down-regulation of key virulence factors, including M protein and the SpeB cysteine protease. These data demonstrate that GmPcides show considerable promise for treating S. pyogenes infections.

HSPiP, Computational, and Thermodynamic Model-Based Optimized Solvents for Subcutaneous Delivery of Tolterodine Tartrate and GastroPlus‑Based In Vivo Prediction in Humans: Part II.

In part I, we reported Hansen solubility parameters (HSP, HSPiP program), experimental solubility at varied temperatures for TOTA delivery. Here, we studied dose volume selection, stability, pH, osmolality, dispersion, clarity, and viscosity of the explored combinations (I-VI). Ex vivo permeation and deposition studies were performed to observe relative diffusion rate from the injected site in rat skin. Confocal laser scanning microscopy (CLSM) study was conducted to support ex vivo findings. Moreover, GastroPlus predicted in vivo parameters in humans and the impact of various critical factors on pharmacokinetic parameters (PK). Immediate release product (IR) contained 60% of PEG400 whereas controlled release formulation (CR) contained PEG400 (60%), water (10%) and d-limonene (30%) to deliver 2mg of TOTA. GastroPlus predicted the plasma drug concentration of weakly basic TOTA as function of pH (from pH 2.0 to 9). The cumulative drug permeation and drug deposition were found to be in the order as B-VI˃ C-VI˃A-VI across rat skin. This finding was further supported with CLSM. Moreover, IR and CR were predicted to achieve Cmax of 0.0038µg/ mL and 0.00023µg/mL, respectively, after sub-Q delivery. Added limonene in CR extended the plasma drug concentration over period of 12h as predicted in GastroPlus. Parameters sensitivity analysis (PSA) assessment predicted that sub-Q blood flow rate is the only factor affecting PK parameters in IR formulation whereas this was insignificant for CR. Thus, sub-Q delivery CR would be promising alternative with ease of delivery to children and aged patient.

Small-Angle X-ray Scattering as a Powerful Tool for Phase and Crystallinity Assessment of Monoclonal Antibody Crystallites in Support of Batch Crystallization.

Crystalline suspensions of monoclonal antibodies (mAbs) have great potential to improve drug substance isolation and purification on a large scale and to be used for drug delivery via high-concentration formulations. Crystalline mAb suspensions are expected to have enhanced chemical and physical properties relative to mAb solutions delivered intravenously, making them attractive candidates for subcutaneous delivery. In contrast to small molecules, the development of protein crystalline suspensions is not a widely used approach in the pharmaceutical industry. This is mainly due to the challenges in finding crystalline hits and the suboptimal physical properties of the resulting crystallites when hits are found. Modern advances in instrumentation and increased knowledge of mAb crystallization have, however, resulted in higher probabilities of discovering crystal forms and improving their particle properties and characterization. In this regard, physical, analytical characterization plays a central role in the initial steps of understanding and later optimizing the crystallization of mAbs and requires careful selection of the appropriate tools. This contribution describes a novel crystal structure of the antibody pembrolizumab and demonstrates the usefulness of small-angle X-ray scattering (SAXS) for characterizing its crystalline suspensions. It illustrates the advantages of SAXS when used to (i) confirm crystallinity and crystal phase of crystallites produced in batch mode; (ii) confirm crystallinity under various conditions and detect variations in crystal phases, enabling fine-tuning of the crystallizations for phase control across multiple batches; (iii) monitor the physical response and stability of the crystallites in suspension with regard to filtration and washing; and (iv) monitor the physical stability of the crystallites upon drying. Overall, this work highlights how SAXS is an essential tool for mAb crystallization characterization.

Anti-Nociceptive Effect of Sufentanil Polymeric Dissolving Microneedle on Male Mice by Hot Plate Technique

Despite the widespread use of opioids to manage severe pain, its systemic administration results in side effects. Among the subcutaneous and transdermal drug delivery systems developed to deal with adverse effects, microneedles have drawn attention due to their rapid action, high drug bioavailability, and improved permeability. Sufentanil (SUF) is an effective injectable opioid for treating severe pain. In this study, we investigated the analgesic effects of SUF using dissolvable microneedles. SUF polymeric dissolvable microneedles were constructed through the mold casting method and characterized by SEM and FTIR analysis. Its mechanical strength was also investigated using a texture analyzer. Fluorescence microscopy was applied in vitro to measure the penetration depth of microneedle arrays. Irritation and microchannel closure time, drug release profile, and hemocompatibility test were conducted for the validation of microneedle efficiency. Hot plate test was also used to investigate the analgesic effect of microneedle in an animal model. Local administration of SUF via dissolving microneedles had an effective analgesic impact. One hour after administration, there was no significant difference between the subcutaneous and the microneedle groups, and the mechanical properties were within acceptable limits. Microneedling is an effective strategy in immediate pain relief compared to the traditional methods.

Perioperative Care of Patients Using Wearable Diabetes Devices.

The increasing prevalence of diabetes mellitus has been accompanied by a rapid expansion in wearable continuous glucose monitoring (CGM) devices and insulin pumps. Systems combining these components in a "closed loop," where interstitial glucose measurement guides automated insulin delivery (AID, or closed loop) based on sophisticated algorithms, are increasingly common. While these devices' efficacy in achieving near-normoglycemia is contributing to increasing usage among patients with diabetes, the management of these patients in operative and procedural environments remains understudied with limited published guidance available, particularly regarding AID systems. With their growing prevalence, practical management advice is needed for their utilization, or for the rational temporary substitution of alternative diabetes monitoring and treatments, during surgical care. CGM devices monitor interstitial glucose in real time; however, there are potential limitations to use and accuracy in the perioperative period, and, at the present time, their use should not replace regular point-of-care glucose monitoring. Avoiding perioperative removal of CGMs when possible is important, as removal of these prescribed devices can result in prolonged interruptions in CGM-informed treatments during and after procedures, particularly AID system use. Standalone insulin pumps provide continuous subcutaneous insulin delivery without automated adjustments for glucose concentrations and can be continued during some procedures. The safe intraoperative use of AID devices in their hybrid closed-loop mode (AID mode) requires the CGM component of the system to continue to communicate valid blood glucose data, and thus introduces the additional need to ensure this portion of the system is functioning appropriately to enable intraprocedural use. AID devices revert to non-AID insulin therapy modes when paired CGMs are disconnected or when the closed-loop mode is intentionally disabled. For patients using insulin pumps, we describe procedural factors that may compromise CGM, insulin pump, and AID use, necessitating a proactive transition to an alternative insulin regimen. Procedure duration and invasiveness is an important factor as longer procedures increase the risk of stress hyperglycemia, tissue malperfusion, and device malfunction. Whether insulin pumps should be continued through procedures, or substituted by alternative insulin delivery methods, is a complex decision that requires all parties to understand potential risks and contingency plans relating to patient and procedural factors. Currently available CGMs and insulin pumps are reviewed, and practical recommendations for safe glycemic management during the phases of perioperative care are provided.

3D bioprinted mesenchymal stem cell laden scaffold enhances subcutaneous vascularization for delivery of cell therapy

Subcutaneous delivery of cell therapy is an appealing minimally-invasive strategy for the treatment of various diseases. However, the subdermal site is poorly vascularized making it inadequate for supporting engraftment, viability, and function of exogenous cells. In this study, we developed a 3D bioprinted scaffold composed of alginate/gelatin (Alg/Gel) embedded with mesenchymal stem cells (MSCs) to enhance vascularization and tissue ingrowth in a subcutaneous microenvironment. We identified bio-ink crosslinking conditions that optimally recapitulated the mechanical properties of subcutaneous tissue. We achieved controlled degradation of the Alg/Gel scaffold synchronous with host tissue ingrowth and remodeling. Further, in a rat model, the Alg/Gel scaffold was superior to MSC-embedded Pluronic hydrogel in supporting tissue development and vascularization of a subcutaneous site. While the scaffold alone promoted vascular tissue formation, the inclusion of MSCs in the bio-ink further enhanced angiogenesis. Our findings highlight the use of simple cell-laden degradable bioprinted structures to generate a supportive microenvironment for cell delivery.Graphical