Subcutaneous Delivery System Research Articles

Thiol–ene addition enables tailored synthesis of poly(2‐oxazoline)‐graft‐poly(vinyl pyrrolidone) copolymers for binder jetting 3D printing

AbstractThe continued interest in graft copolymer architectures arises from their unique solution properties and potential for a myriad of applications ranging from drug delivery to adhesives. Poly(vinyl pyrrolidone) (PVP) represents a popular amorphous, water‐soluble polymer used as a polymeric binder in binder jetting additive manufacturing, as fillers in cosmetic products, and for subcutaneous drug delivery systems. This report describes the synthesis of poly(2‐oxazoline) and PVP graft copolymers using a ‘grafting to’ methodology with an efficient thiol–ene ‘click’ reaction. Copolymerization of 2‐methyl‐2‐oxazoline and 2‐(3‐butenyl)‐2‐oxazoline introduced pendent vinyl grafting sites with a predictable absolute number‐average molecular weight. In parallel, reversible addition‐fragmentation chain‐transfer polymerization and subsequent aminolysis yielded well‐defined, oligomeric, thiol‐terminated PVP. Thiol–ene click chemistry enabled the formation of poly(2‐oxazoline)‐graft‐poly(vinyl pyrrolidone) (PMeOx‐g‐PVP) copolymers with varying mole percent grafting sites and PVP graft length. 1H NMR spectroscopy, aqueous SEC with multiangle light scattering (SEC‐MALS), and bromine titrations confirmed chemical structure, and DSC with TGA elucidated thermal transitions. Aqueous SEC‐MALS and 1H NMR spectroscopy also determined absolute number‐ and weight‐average molecular weights and average grafting levels, which revealed optimal reaction conditions. Zero‐shear viscosities of 5 and 10 wt% solutions in deionized water for each graft copolymer compared to their linear analogs demonstrated a significant (ca 31%) decrease in viscosity at the same number‐average molecular weight. This decrease in solution viscosity suggested PMeOx‐g‐PVP copolymers as exceptional alternatives to linear analogs for aqueous‐based, binder jetting additive manufacturing.

Subcutaneous Furosemide in the Treatment of Patients with Decompensated Heart Failure: Data from the Sub-Q Pilot Studies

Introduction IV furosemide is used in most patients hospitalized with HF. A buffered formulation of furosemide delivered via an on-body subcutaneous delivery system (scPharmacauticals) that potentially would allow for treatment to be shifted to the outpatient setting was evaluated in 2 pilot studies in patients hospitalized for HF with signs and symptoms of congestion. Hypothesis Treatment with sc furosemide is a safe and feasible approach to treatment of patients with HF and congestion. Methods Patients hospitalized for HF with and congestion regardless of EF were enrolled in 2 sequential pilot studies at 5 centers. Patients requiring high doses of iv loop diuretics (> 200 mg furosemide/day) or clinical instability were excluded. The Sub-Q inpatient pilot (IP) enrolled 20 patients and treated them for 48 hours with sc furosemide (80mg sc over 5 hours given QD or BID based on need) in place of iv loop diuretics while they remained hospitalized. The Sub-Q outpatient pilot (OP) enrolled 20 patients with transition (within 24 hours) to the OP setting where they continued sc furosemide (80mg sc over 5 hours given QD or BID based on need) for up to 7 days. Data were collected on feasibility, urine output, weights, symptoms, and safety. Results In the IP, median age was 70, median EF was 39, and median Cr was 1.4 mg/dL. Patients received a mean of 2.9 treatments over 48 hours and urine output over the 2 days of treatment was 5.3 L (figure). There were 8 device issues observed. There were 4 AEs in the IP, 3 were injection site discomfort. In the OP, median age was 61, median EF was 35, and median cr was 1.4 mg/dL. Patients received a mean of 6.9 treatments over 7 days. Signs and symptoms of congestion improved in most patients, although weight did not change significantly from baseline to day 7. There were 21 device issues in 10 unique patients (mostly difficulty the filling the delivery system). There were 18 AE's (mostly mild and related to injection site discomfort). There was 1 SAE that was unrelated to study treatment. There were 2 rehospitalizations for HF over 14 days from randomization in the OP. Conclusions Treatment of selected HF patients with sc furosemide provided the anticipated effects on decongestion in both the inpatient and outpatient settings, although there were issues with the drug delivery system that limited feasibility. Ongoing developments of the delivery system for sc furosemide may make this a safe and feasible approach for treatment of congestion in the outpatient setting in selected patients.

Ultramicronized palmitoylethanolamide rescues learning and memory impairments in a triple transgenic mouse model of Alzheimer\u2019s disease by exerting anti-inflammatory and neuroprotective effects

In an aging society, Alzheimer’s disease (AD) exerts an increasingly serious health and economic burden. Current treatments provide inadequate symptomatic relief as several distinct pathological processes are thought to underlie the decline of cognitive and neural function seen in AD. This suggests that the efficacy of treatment requires a multitargeted approach. In this context, palmitoylethanolamide (PEA) provides a novel potential adjunct therapy that can be incorporated into a multitargeted treatment strategy. We used young (6-month-old) and adult (12-month-old) 3×Tg-AD mice that received ultramicronized PEA (um-PEA) for 3 months via a subcutaneous delivery system. Mice were tested with a range of cognitive and noncognitive tasks, scanned with magnetic resonance imaging/magnetic resonance spectroscopy (MRI/MRS), and neurochemical release was assessed by microdialysis. Potential neuropathological mechanisms were assessed postmortem by western blot, reverse transcription–polymerase chain reaction (RT-PCR), and immunofluorescence. Our data demonstrate that um-PEA improves learning and memory, and ameliorates both the depressive and anhedonia-like phenotype of 3×Tg-AD mice. Moreover, it reduces Aβ formation, the phosphorylation of tau proteins, and promotes neuronal survival in the CA1 subregion of the hippocampus. Finally, um-PEA normalizes astrocytic function, rebalances glutamatergic transmission, and restrains neuroinflammation. The efficacy of um-PEA is particularly potent in younger mice, suggesting its potential as an early treatment. These data demonstrate that um-PEA is a novel and effective promising treatment for AD with the potential to be integrated into a multitargeted treatment strategy in combination with other drugs. Um-PEA is already registered for human use. This, in combination with our data, suggests the potential to rapidly proceed to clinical use.

Improving long-term subcutaneous drug delivery by regulating material-bioenvironment interaction.

Subcutaneous long-acting release (LAR) formulations have been extensively developed in the clinic to increase patient compliance and reduce treatment cost. Despite preliminary success for some LAR systems, a major obstacle limiting the therapeutic effect remains on their interaction with surrounding tissues. In this review, we summarize how living bodies respond to injected or implanted materials, and highlight some typical strategies based on smart material design, which may significantly improve long-term subcutaneous drug delivery. Moreover, possible strategies to achieve ultra-long (months, years) subcutaneous drug delivery systems are proposed. Based on these discussions, we believe the well-designed subcutaneous long-acting formulations will hold great promise to improve patient quality of life in the clinic.

Targeting postprandial glycaemia in children with diabetes: Opportunities and challenges.

Postprandial glycaemia makes a substantial contribution to overall glycaemic control in diabetes, particularly in patients whose preprandial glycaemia is relatively well controlled and glycated haemoglobin (HbA1c) only modestly elevated. Our review addresses the determinants of postprandial glycaemia and how it may be targeted therapeutically in children with diabetes. Postprandial glycaemia is influenced by preprandial glycaemia, macronutrients and their absorption, insulin delivery and sensitivity, the action of the enteroendocrine system, and the rate of gastric emptying. Contemporary continuous glucose monitoring systems reveal patterns of post prandial glycaemia and allow management to be guided more precisely. Delays in blood glucose determination, insulin delivery and its absorption remain challenges in the rapidly evolving closed loop continuous subcutaneous insulin and glucagon delivery systems developed for children with type 1 diabetes. Augmentation of the incretin system through nutritional preloads or incretin mimetics targets postprandial glycaemia by slowing gastric emptying as well as insulinotropic and glucagonostatic effects. These treatments are of particular relevance to children with type 2 diabetes. Following the development of targeted therapies in adults, postprandial blood glucose control will now be increasingly targeted in the treatment of diabetes in children.

Arrowhead sheds programs, staff

In a surprise move, Arrowhead Pharmaceuticals is discontinuing development of multiple RNAi drug candidates that use the same delivery technology. The decision comes just weeks after FDA placed a hold on a clinical trial of ARC-520, a hepatitis B treatment, following the death of several non-human primates in a preclinical toxicology study of the drug. Arrowhead is abandoning three programs—ARC-520, ARC-521, and ARC-AAT—that use the same liver-targeted, intravenously administered delivery vehicle. Arrowhead will refocus its R&D on subcutaneous and non-hepatic delivery systems. As a consequence of the changes, the biotech is laying off 30% of its workforce.

Novel intrathecal and subcutaneous catheter delivery systems in the mouse

BackgroundCatheter systems that permit targeted delivery of genes, molecules, ligands, and other agents represent an investigative tool critical to the development of clinically relevant animal models that facilitate the study of neurological health and disease. The development of new sustained catheter delivery systems to spinal and peripheral sites will reduce the need for repeated injections, while ensuring constant levels of drug in plasma and tissues. New methodHere, we introduce two novel catheter delivery systems in the mouse: the O’Buckley intrathecal catheter system for sustained delivery to the spinal region and a subcutaneous bifurcated catheter system for sustained drug delivery to both hindpaws. ResultsThe O’Buckley intrathecal catheter system consistently distributed Evans Blue throughout the spinal cord, with the greatest concentration at the thoracic region, and with an 85% surgery success rate. The subcutaneous catheter system consistently distributed Evans Blue to the hindlimbs, with a 100% surgery success rate. Comparison to existing methodThe O’Buckley intrathecal catheter system accomplishes sustained drug delivery to the spinal region, with a 2-fold increase in surgery success rate, as compared to the traditional method. Our subcutaneous bifurcated catheter system accomplishes sustained drug delivery to both hindpaws, eliminating the need for repeated intraplantar injections. ConclusionsWe have developed catheter systems that improve upon traditional methods in order to achieve sustained localized drug delivery to spinal tissues and to hindpaw tissues surrounding peripheral sciatic nerve terminals. These methods have a broad reach, and can be used to enhance behavioral, physiologic and mechanistic studies in mice.

Novel intrathecal and subcutaneous catheter delivery systems in the mouse

Novel intrathecal and subcutaneous catheter delivery systems in the mouse

Long-acting hormonal contraception.

Today, a new category of fertility-regulating agents has been created: long-acting, reversible hormonal contraceptives; they minimize compliance, while maximize effectiveness. They comprise subdermal implants and intrauterine devices. Other long-acting agents exist, such as Depo Provera and Noristerat. Use of Depo Provera and Noristerat carries great effectiveness, good clinical safety and usefulness in developing countries. They cause no significant increase in breast cancer risk, but they may carry an increased risk of HIV. Subcutaneous delivery systems have two common features: prolongation of effect is obtained by a drug reservoir and for most of their duration of action they provide a continuous, sustained release of the active hormone. Finally, the intrauterine system Mirena represents both a very effective contraceptive and a specific treatment for menorrhagia.

Novel delivery systems for improving the clinical use of peptides.

Peptides have long been recognized as a promising group of therapeutic substances to treat various diseases. Delivery systems for peptides have been under development since the discovery of insulin for the treatment of diabetes. The challenge of using peptides as drugs arises from their poor bioavailability resulting from the low permeability of biological membranes and their instability. Currently, subcutaneous injection is clinically the most common administration route for peptides. This route is cost-effective and suitable for self-administration, and the development of appropriate dosing equipment has made performing the repeated injections relatively easy; however, only few clinical subcutaneous peptide delivery systems provide sustained peptide release. As a result, frequent injections are needed, which may cause discomfort and additional risks resulting from a poor administration technique. Controlled peptide delivery systems, able to provide required therapeutic plasma concentrations over an extended period, are needed to increase peptide safety and patient compliancy. In this review, we summarize the current peptidergic drugs, future developments, and parenteral peptide delivery systems. Special emphasis is given to porous silicon, a novel material in peptide delivery. Biodegradable and biocompatible porous silicon possesses some unique properties, such as the ability to carry exceptional high peptide payloads and to modify peptide release extensively. We have successfully developed porous silicon as a carrier material for improved parenteral peptide delivery. Nanotechnology, with its different delivery systems, will enable better use of peptides in several therapeutic applications in the near future.

The development and evaluation of a subcutaneous infusion delivery system based on osmotic pump control and gas drive

A novel, self-administration drug delivery system for subcutaneous infusion was developed and evaluated. The device includes two main components: an osmotic tablet controlled gas actuator and a syringe catheter system. The sodium carbonate in the osmotic pump tablet will release into the surround citric acid solution and produce CO2 gas, which will drive the drug solution into subcutaneous tissue. The key formulation factors of the osmotic tablet that would influence the infusion profiles of the device were investigated by single factor exploration. The formulation was optimized via a response surface methodology. With an 18 ± 4 min of lag time, the delivery system was able to infuse at an approximate zero-order up to 5.90 ± 0.37 h with a precision of 9.0% RSD (n = 6). A linear correlation was found for the infusion profile and the fitting equation was Y = 0.014X − 0.004 (r = 0.998). A temperature change of 4 °C was found to modify the flow rate by about 12.0%. In vivo results demonstrated that the present subcutaneous infusion device was similar to the commercial infusion pump, and it could bring a long and constant ampicillin plasma level with minimized fluctuations.

A novel subcutaneous infusion delivery system based on osmotic pump: in vitro and in vivo evaluation

An economical, convenient portable drug delivery system combining osmotic pump with subcutaneous infusion was developed, which was composed of three primary components: water chamber, osmotic pump chamber and support base. Ceftriaxone sodium (CRO) was selected as the model drug and osmotic pump tablets were prepared. The influence of osmotic agents on drug release profiles was evaluated. As the adjustment made by the osmotic agents was limited, the compositions of semipermeable membrane were investigated to determine significant associations of factors based on orthogonal design. The in vitro release profiles of the optimum formulation achieved to the predetermined value (15 ± 3 min for the initial release time Ti and 5.75 ± 0.25 h for the extent release time Te). The pharmacokinetic profiles of this drug delivery system were evaluated in Beagle dogs. In vivo results demonstrated that the osmotic pump subcutaneous infusion administration was equivalent to intravenous injection administration in terms of bioavailability. Moreover, constant drug plasma levels with minimized fluctuations could be achieved with this osmotic pump subcutaneous infusion system, compared with intravenous injection.

Lymphatic Function and Immune Regulation in Health and Disease

Lymphatic vessels are present throughout the body, except in the central nervous system and bone marrow. The lymph nodes (LNs), spleen, and other secondary lymphoid organs (e.g., Peyer's patches) are strategically located in anatomical sites where they collect foreign antigen and antigen presenting cells to activate antigen-specific lymphocytes efficiently.1 In the peripheral tissues, specialized lymphatic capillaries—called initial lymphatic vessels—allow soluble materials and cells to enter the lymphatic system easily. The collected fluid and cells form lymph, which is transported by smooth muscle-invested collecting lymphatic vessels to the draining lymph node. The lymph node provides a highly organized microarchitecture that supports optimal immune surveillance. The “filtered” lymph fluid, as well as naive and activated lymphocytes, exit the lymph node via efferent lymphatic vessels. Lymphatic capillaries, collecting lymphatic vessels, and lymph nodes together provide protective immunity for the body. Disruptions of lymphatic function compromise immune function and result in lymphedema. In this review, we will summarize the current knowledge of how lymphatic function is altered in inflammatory states, cancer, and infection.

Development and evaluation of pluronic- and methylcellulose-based thermoreversible drug delivery system for insulin

The objective of the current work was to develop and evaluate thermoreversible subcutaneous drug delivery system for Insulin. Thermoreversible in-situ gel system was developed and evaluated both in-vitro and in-vivo comprising of pluronic F-127 alone or in combination with methylcellulose in different ratios. The drug release kinetics and mechanism was predicted by applying various mathematical models to the in-vitro dissolution data. Rabbits were used as animal model following subcutaneous injection to predict various pharmacokinetic parameters by applying Pk-Summit® software. The in-vitro and in-vivo data revealed that the formulation IPM 15/3 consisting of the pluronic F-127 (15% w/v) and methylcellulose (3% w/v) was the most robust and capable formulation for extending the drug release and maintaining basal plasma insulin level between 10 and 40 µU/ml for 240 h (10 d).

Randomized Trial of Continuous Subcutaneous Delivery of Exenatide by ITCA 650 Versus Twice-Daily Exenatide Injections in Metformin-Treated Type 2 Diabetes

OBJECTIVETo evaluate ITCA 650, a continuous subcutaneous miniature osmotic pump delivery system of exenatide versus twice-daily exenatide injections (Ex-BID) in subjects with type 2 diabetes.RESEARCH DESIGN AND METHODSWe conducted a randomized, two-stage, 24-week, open-label, phase 2 study in type 2 diabetes inadequately controlled with metformin. Stage I: 155 subjects were randomized to 20 or 40 μg/day of ITCA 650 or Ex-BID 5→10 μg. Stage II: 131 subjects were rerandomized to 20, 40, 60, or 80 μg/day of ITCA 650. Change from baseline for HbA1c, weight, and fasting plasma glucose were evaluated at weeks 12 and 24.RESULTSHbA1c was significantly lower in all groups after 12 and 24 weeks. Stage I: mean change in HbA1c from a mean baseline of 7.9–8.0% was −0.98, −0.95, and −0.72% for the 20 and 40 μg/day ITCA 650 and Ex-BID groups, respectively, with 63, 65, and 50% of subjects achieving HbA1c levels ≤7% (P < 0.05). Stage II: significant (P < 0.05) reductions in HbA1c (∼1.4% from baseline) were achieved with 60 and 80 μg/day ITCA 650, and 86 and 78% of subjects achieved HbA1c ≤7% at 24 weeks; respectively. Weight was reduced by 2.8–3.7 kg (P < 0.05) at 24 weeks in all except the 20→20 μg/day group. ITCA 650 was well tolerated; nausea was lower and transient with 20 μg/day relative to Ex-BID; and 60 μg/day had the best profile of tolerability and HbA1c lowering.CONCLUSIONSITCA 650 significantly reduced HbA1c and weight and was well tolerated. The 20→60 μg/day regimen was considered the best dose for further examination in phase 3.

Exenatide-loaded PLGA microspheres with improved glycemic control: In vitro bioactivity and in vivo pharmacokinetic profiles after subcutaneous administration to SD rats

A subcutaneous exenatide delivery system was developed and characterized in vitro and in vivo. The results clearly showed that the exenatide loaded PLGA microspheres prepared by using a non-aqueous processing medium had low burst release and high drug encapsulation efficiency. Exenatide loaded in the microspheres preserved its bioactivity. The pharmacokinetics parameters were determined after subcutaneous administration of microspheres to SD rats. The plasma concentration of the single dose of the sustained-release microspheres attained Cmax of 108.19±14.92ng/ml at tmax of 1.33±0.58h and the t1/2 was 120.65±44.18h. There was a linear correlation between the in vitro and in vivo release behavior (R2=0.888). Exenatide loaded microspheres may prove to have great potential for clinical use.

Comprehensive Treatment Based on Intra-arterial Chemotherapy for Distal Femur Neoplasms

To investigate the clinical efficacy of intra-arterial chemotherapy by subcutaneous implantable delivery system (SIDS) in the treatment of distal femur neoplasm. From March 2002 to December 2009, 51 patients were treated with SIDS intra-femoral artery chemotherapy, followed by customized prosthetic reconstruction, including 45 patients of osteosarcoma and 6 malignant fibrous histiocytoma in distal femur. The average follow-up period was 64months (ranging between 24 and 116months) to track on the efficacy of chemotherapy, which shows that 96.1% of patients got pain relief, 70.6% of patients had significant radiological change, and 82.4% of paitents with medium to severe pathological variation responded to the chemotherapy. Local recurrence happened in 4 cases, 3 cases are alive with disease, 4 cases died because of pulmonary metastases and other 40 patients are free of local recurrence or distant metastasis. SIDS intra-femur artery chemotherapy can improve clinical outcome of DFN, and provide effective method for treatment of DFN when combined with customized prosthetic reconstruction.

Silicone-Acyclovir Controlled Release Devices Suppress Primary Herpes Simplex Virus-2 and Varicella Zoster Virus InfectionsIn Vitro

Following initial infection, herpesviruses retreat into a permanent latent state with periodic reactivation resulting in an enhanced likelihood of transmission and clinical disease. The nucleoside analogue acyclovir reduces clinical symptoms of the three human alpha herpesviruses, HSV-1, HSV-2, and VZV. Long-term administration of acyclovir (ACV) can reduce the frequency and severity of reactivation, but its low bioavailability and short half-life require a daily drug regimen. Our lab is working to develop a subcutaneous delivery system to provide long-lasting, sustained release of ACV. Previously, we demonstrated that an implantable silicone (MED-4050) device, impregnated with ACV protected against HSV-1 both in vitro and in vivo. Here, we extend our in vitro observations to include protection against both HSV-2 and VZV. We also demonstrate protection against HSV-2 in vitro using MED-4750, a silicone polymer designed for long-term use in humans. When release of ACV from MED-4750 is quantitated on a daily basis, an initial burst of 5 days is observed, followed by a long period of slow release with near-zero-order kinetics, with an average daily release of 1.3923 ± 0.5908 μg ACV over days 20–60. Development of a slow-release implant has the potential to significantly impact the treatment of human alpha herpesvirus infections.

Development and evaluation of diclofenac sodium thermorevesible subcutaneous drug delivery system

The objective of current work was to develop and evaluate thermoreversible subcutaneous drug delivery system for diclofenac sodium. The poloxamer 407, methyl cellulose, hydroxypropyl methyl cellulose and polyethylene glycol were used alone and in combination in different ratios to design the delivery system. The physical properties like Tsol-gel, viscosity, clarity of solution and gel were evaluated. The in vitro release of the drug delivery system was evaluated using membrane less method and the drug release kinetics and mechanism was predicted by applying various mathematical models to the in vitro dissolution data. Rabbits were used as in vivo model following subcutaneous injection to predict various pharmacokinetics parameters by applying Pk-Summit software. The in vitro and in vivo data revealed that the system consisting of the poloxamer 407 in concentration of 20% (DP20) was the most capable formulation for extending the drug release and maintaining therapeutic blood level of DS for longer duration (144 h). The data obtained for drug content after autoclaving the solutions indicate that autoclaving results in 6% degradation of DS. The data also suggested that the studied polymers poloxamer, MC and PG are good candidate to extend the drug release possessing a unique thermoreversible property.

Subcutaneous Implantable Cardioverter Defibrillator

Implantable cardioverter-defibrillators (ICDs) represent a very effective therapy for primary and secondary prevention of sudden cardiac death (SCD). However, implantation of endocardial leads using a transvenous approach is associated with significant procedural and long term complications. An entirely subcutaneous ICD (S-ICD) has been developed, potentially eliminating many of the complications associated with traditional transvenous ICDs. This novel approach has been demonstrated to be a reliable and effective system for detection and termination of ventricular arrhythmias. The available therapeutic interventions are a result of the unique characteristics of a high energy subcutaneous delivery system, and therefore require appropriate patient selection to optimize therapeutic benefit and minimize the limitations of the first generation S-ICD. By maintaining the effectiveness of conventional ICDs while limiting the associated complications, the S-ICD provides an alternative therapy for clinicians treating many patients at risk for SCD. This review will examine the development of the subcutaneous ICD, its advantages, limitations, and potential clinical role in the treatment of ventricular tachyarrhythmias and prevention of SCD. Despite advances in cardiovascular care, SCD remains a significant public health issue.1 A variety of nonpharmacologic therapies for primary and secondary prevention of SCD exist, including ICDs by endovascular lead implantation or placement of epicardial defibrillation patches. Nonimplantable strategies for SCD protection in high risk patients have also been attempted, including a wearable defibrillator vest,2,3 as well as automated external defibrillator use at home in selected cohorts.4 The subcutaneous ICD provides an alternative device for treatment of SCD.5 The development of an entirely subcutaneous ICD was motivated initially by special circumstances where a traditional endovascular system was not practical. It was first applied in the pediatric population, where congenital anatomic variation often precludes safe endocardial lead placement; the technique was extended to other patient populations in whom venous …