Subcutaneous Delivery System Research Articles

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.

In Situ Imaging of Subcutaneous Drug Delivery Systems Using Microspatially Offset Low-Frequency Raman Spectroscopy.

The noninvasive in situ monitoring of the status of drug retention and implant integrity of subcutaneous implants would allow optimization of therapy and avoid periods of subtherapeutic delivery kinetics. A proof-of principle study was conducted to determine the use of microspatially offset low-frequency Raman spectroscopy (micro-SOLFRS) for nonintrusive in situ analysis of subcutaneous drug delivery systems. Caffeine was used as the model drug, and it was embedded in a circular-shape Soluplus matrix via vacuum compression molding. For the exploratory analysis, prototype implants were positioned underneath skin tissue samples, and various caffeine concentrations (1-50% w/w) and micro-SOLFRS displacement settings (Δz = 0-8 mm) were tested from the pseudo three-dimensional (3D)-imaging perspective. This format allowed the optimization of real-time micro-SOLFRS analysis of implants through skin tissue that was embedded in an agarose hydrogel. Notably, this analytical approach allowed the temporal and spatial erosion of the implant and solid-state transformations of caffeine to be distinguished. The spectrometric results correlated with complementary high-performance liquid chromatography (HPLC) determination of changes in drug concentration, illustrating drug dissipation/diffusion characteristics. The discovered capability of micro-SOLFRS for in situ measurements of drugs and implants makes it attractive for biomedical diagnostics that, ultimately, could result in development of a new point-of-care technology.

From Poly(glycerol itaconate) Gels to Novel Nonwoven Materials for Biomedical Applications.

Electrospinning is a process that has attracted significant interest in recent years. It provides the opportunity to produce nanofibers that mimic the extracellular matrix. As a result, it is possible to use the nonwovens as scaffolds characterized by high cellular adhesion. This work focused on the synthesis of poly(glycerol itaconate) (PGItc) and preparation of nonwovens based on PGItc gels and polylactide. PGItc gels were synthesized by a reaction between itaconic anhydride and glycerol. The use of a mixture of PGItc and PLA allowed us to obtain a material with different properties than with stand-alone polymers. In this study, we present the influence of the chosen ratios of polymers and the OH/COOH ratio in the synthesized PGItc on the properties of the obtained materials. The addition of PGItc results in hydrophilization of the nonwovens' surface without disrupting the high porosity of the fibrous structure. Spectral and thermal analyzes are presented, along with SEM imagining. The preliminary cytotoxicity research showed that nonwovens were non-cytotoxic materials. It also helped to pre-determine the potential application of PGItc + PLA nonwovens as subcutaneous tissue fillers or drug delivery systems.

Comprehensive Assessment of Pharmacokinetics, Pharmacodynamics, and Tolerability of Ligelizumab in Healthy Volunteers and Patients with Chronic Spontaneous Urticaria to Optimize Its Subcutaneous Delivery System.

Ligelizumab is a highly potent, humanized IgG1, anti-IgE monoclonal antibody. To explore its optimal subcutaneous delivery, the pharmacokinetics (PK), pharmacodynamics (PD), and tolerability of ligelizumab from two Phase 1 studies in healthy volunteers (HVs) and four Phase 2 and 3 studies in patients with chronic spontaneous urticaria (CSU) were assessed. Using different injection volumes or durations of a liquid-in-vial (LIVI) formulation or different formulations (LIVI vs. prefilled syringe (PFS)), single-dose ligelizumab showed comparable PK exposure in HVs. Steady-state exposure of ligelizumab was also comparable between LIVI and PFS following multiple dosing in CSU patients. The total IgE level (a PD marker) and tolerability were similar between the two formulations in both HVs and patients. Furthermore, the PK, total IgE, and tolerability were comparable for PFS administered either by patients or healthcare providers (HCPs). Collective evidence demonstrated that the injection duration or volume, formulation, or administrator had no apparent impact on the PK, PD, and tolerability of ligelizumab, supporting no clinically relevant difference between LIVI and PFS, and that PFS can be administered by patients or HCPs. This report provides a comprehensive assessment based on data of multiple clinical endpoints from both HVs and patients to inform formulation development and commercial use of a monoclonal antibody.

Functional anatomy of the worker honeybee stinger (Apis mellifera)

The honeybee stinger is a powerful defense mechanism that combines painful venom, a subcutaneous delivery system, and the ability to autotomize. It is a complex organ and to function autonomously it must carry with it all the anatomical components required to operate. In this study, we combined high-speed filming, SEM imagery, and micro-CT for volumetric rendering of the stinger with a synthesis of existing literature. We present a comprehensive description of all components, including cuticular elements, musculature, nervous and glandular tissue using updated imagery. We draw from the Hymenoptera literature to make interspecific comparisons where relevant. The use of 3D reconstruction allows us to separate stinger components and present the first 3D renders of the bee stinger including the terminal abdominal ganglion and its projections. It also clarifies the in-situ geometry of the valves within the bulb and the spatial relationships among the accessory plates and accompanying musculature.

Autoinjector Design Parameters: A Human Factors Perspective

Subcutaneous drug delivery systems have evolved to include patient-operated devices such as pen injectors, autoinjectors, and on-body injectors. This evolution is driven by a rising need for devices that enable users across chronic disease states to routinely self-administer medications at home instead of going to a clinic. Convenient and easy-to-use autoinjectors are a primary target of interest due to its simplicity to operate. There is an anticipated substantial growth in the autoinjectors market, which is driven by many factors, such as the growing demand for home care due to the increased chronic diseases rate. Autoinjectors that are easy to operate may reduce users’ anxiety related to needle-related phobia, accidents, and errors. Human factors development work is critical since enhanced usability can increase patient acceptability, safety, and compliance. Human factors methodologies can be applied to not only evaluate the safe and effectiveness of a user interface, but also to optimize the design of user interface by considering the user population characteristics including physical, cognitive, and sensory abilities. In this investigation, we focus our efforts on user interface attributes relating to critical tasks in operating the autoinjector device, by consolidating information from successful autoinjector design published in literature and different anthropometric and ergonomic parameters, that could inform the user interface requirements that drive design specifications for autoinjectors.

Hypoglycemia and glycemic variability of people with type 1 diabetes with lower and higher physical activity loads in free-living conditions using continuous subcutaneous insulin infusion with predictive low-glucose suspend system

IntroductionMaintaining glycemic control during and after physical activity (PA) is a major challenge in type 1 diabetes (T1D). This study compared the glycemic variability and exercise-related diabetic management strategies of...

Promising biomedical subcutaneous delivery system in opioid disaccustom process: In vitro/in vivo evaluation of naloxone microparticles on antagonist effect of morphine

The addiction induced by the misuse of opioids, is not only a public health emergency but also a social and economic welfare. The main therapy is based on opioid antagonists. Oral and injectable naltrexone administration is the most widely used, presenting some inconveniences: poor patient adherence to the oral daily dosing schedule, cases of hepatitis and clinically significant liver dysfunction.This study proposes the in vitro e in vivo evaluation of anti-opioid properties of naloxone loaded-poly(lactic-co-glycolic) acid microparticles (NX-MP). In previous studies, NX-MP showed in vitro sustained naloxone release for one week at least.Our results demonstrate the in vitro efficacy of the NX-MP antagonizing for 7 days the morphine effect in SH-SY5Y cells and myenteric plexus-longitudinal muscle preparations isolated from guinea-pig ileum.The in vivo evaluation of the NX-MP was carried out in mice testing the antagonism of the antinociceptive effect of morphine. Results showed that subcutaneous administration of NX-MP blocked the morphine effect.The results of this work suggest that the subcutaneous administration of NX-MP enhances naloxone therapeutic efficacy as non-addictive medication and could be a promising alternative to naltrexone. Furthermore, the dose of NX-MP can be adapted to the patient necessities. It would be an interesting advantage to treat opioid-addiction.

Model-based Glycemic Control Using Subcutaneous Insulin for Infants in Critical Care

Neonatal hyperglycaemia is common for infants in critical care, and can lead to increases in mortality and morbidity. Subcutaneous insulin delivery systems offer an easy way to control blood glucose (BG) to more normal levels. However, research on subcutaneous insulin models are lacking in this cohort. This paper presents a model combining validated NICU models with adult subcutaneous models for glycaemic control. Clinical data from 12 very/extremely pre-mature infants was collected for an average study duration of 10.1 days. Glucose, interstitial and plasma insulin, as well as subcutaneous and local insulin were modelled, and insulin sensitivity profiles were identified for each patient. Modelling error was low, where the cohort median [IQR] for mean percentage error was 0.8 [0.3-3.4] %. The model was able to capture glucose and insulin activity accurately, but further research should be undertaken to validate the model and its parameters, to explore the potential of subcutaneous insulin delivery under a model-based protocol.

Subcutaneous injection of a bortezomib-loaded thermosensitive hydrogel for the treatment of multiple myeloma

Multiple myeloma (MM) is incurable as one of the most common hematologic malignancies. Bortezomib (BTZ) is a first-in-class reversible proteasome inhibitor in the clinic for the treatment of MM. BTZ was initially approved for the administrator by only the intravenous injection route in 2003. Then, subcutaneous administration was approved in the US and EU in 2012 in addition to the intravenous injection route. The rates and severity of peripheral neuropathy were significantly lower than those of intravenous injection administration. Injectable thermosensitive hydrogels are a potential drug delivery system for controlled release. But it is difficult to achieve the aim of local therapy of MM. A subcutaneous delivery system for a long time may be a potential therapy method due to the subcutaneous administration of BTZ. Here, we designed a BTZ-loaded injectable hydrogel system to sustain drug release for a period of days. It could lower the side effects, enhance the therapeutic effect, and reduce the injection time.

The pharmacokinetics of continuous subcutaneous levodopa/carbidopa infusion: Findings from the ND0612 clinical development program.

While treatment with levodopa remains the cornerstone of Parkinson's disease (PD) management, chronic oral therapy is often associated with the development of motor complications, that correlate to fluctuating levodopa plasma concentrations, limiting its clinical utility. Continuous infusion is considered to be the optimal delivery route for treating PD patients with motor fluctuations, but current infusion systems require invasive surgery. Subcutaneous infusion of (SC) levodopa has the potential to provide a better tolerated and more convenient route of continuous levodopa delivery. ND0612 is in development as a combination product providing continuous levodopa/carbidopa via a minimally invasive, subcutaneous delivery system for PD patients experiencing motor response fluctuations. We present pharmacokinetic results from a series of studies that analyzed plasma concentrations after SC levodopa delivery with ND0612 to inform the clinical development program. We performed a series of six Phase I and II studies to characterize the pharmacokinetics of levodopa and carbidopa derived from ND0612 infusion with/without adjunct oral therapy of the same ingredients. These studies were conducted in healthy volunteers and in PD patients experiencing motor response fluctuations while on their current levodopa therapy regimen. Taken together, the results demonstrate dose-proportionality dependent on rate of subcutaneous levodopa infusion leading to stable and sustained plasma concentrations of levodopa. Subcutaneous infusion of ND0612 administered with oral levodopa/carbidopa maintained near-constant, therapeutic levodopa plasma concentrations, thereby avoiding the troughs in levodopa plasma concentrations that are associated with OFF time in PD. The data generated in this series of studies also confirmed that a levodopa/carbidopa dose ratio of 8:1 would be the most reasonable choice for ND0612 development. This series of clinical pharmacokinetic studies have demonstrated that ND0612, administered continuously with a levodopa concentration of 60 mg/ml combined with carbidopa 7.5 mg/ml, and complemented with oral levodopa/carbidopa, is suitable for 24 h continuous administration in patients with PD. The stable plasma concentrations of levodopa achieved predict utility of ND0612 as a parenteral formulation for achieving clinically useful delivery of levodopa for PD patients.

Electrospun Poly(acrylic acid-co-4-styrene sulfonate) as Potential Drug-Eluting Scaffolds for Targeted Chemotherapeutic Delivery Systems on Gastric (AGS) and Breast (MDA-Mb-231) Cancer Cell Lines.

Potential drug-eluting scaffolds of electrospun poly(acrylic acid-co-styrene sulfonate) P(AA-co-SS) in clonogenic assays using tumorigenic gastric and ovarian cancer cells were tested in vitro. Electrospun polymer nanofiber (EPnF) meshes of PAA and PSSNa homo- and P(AA-co-SS) copolymer composed of 30:70, 50:50, 70:30 acrylic acid (AA) and sodium 4-styrene sulfonate (SSNa) units were performed by electrospinning (ES). The synthesis, structural and morphological characterization of all EPnF meshes were analyzed by optical and electron microscopy (SEM-EDS), infrared spectroscopy (FTIR), contact angle, and X-ray diffraction (XRD) measurements. This study shows that different ratio of AA and SSNa of monomers in P(AA-co-SS) EPnF play a crucial role in clonogenic in vitro assays. We found that 50:50 P(AA-co-SS) EPnF mesh loaded with antineoplastic drugs can be an excellent suppressor of growth-independent anchored capacities in vitro assays and a good subcutaneous drug delivery system for chemotherapeutic medication in vivo model for surgical resection procedures in cancer research.

Pharmacokinetic comparison of three delivery systems for subcutaneous testosterone administration in female mice

Transmasculine individuals are often prescribed testosterone (T) for masculinizing hormone therapy. Mouse models mimicking transmasculine T therapy require reliable long-term T administration. The objectives of this study were three-fold, namely, to compare: 1) the release dynamics of three different subcutaneous delivery systems of T enanthate administration (subcutaneous injections, commercially available pellets, and silastic implants) over a 6-week period in postpubertal C57BL/6N mice, 2) to compare the timing for T levels in plasma to return to baseline and cyclicity to resume after cessation of T between injections and pellets, 3) to utilize silastic implants to achieve sustainable increase in T levels utilizing T enanthate and crystalline T. All three modes of T administration resulted in an increase in T levels in plasma. Pharmacokinetic analyses showed a similar overall exposure to T enanthate over 6 weeks (integrated area) for, subcutaneous injection (0.45 mg two times per week and 0.90 mg one time per week), pellet (5 mg 60-day release), and silastic implant (5 mg 21 week) groups. Crystalline T had lower solubility and a decreased integrated area compared to T enanthate, even when implanted at a higher dosage, indicating different pharmacokinetic profiles based on type of T formulation when utilizing the same silastic delivery method. Surgical removal of pellets and silastic tubing led to a quick drop in T levels and resumption of estrous cyclicity, while cessation of injections required a long washout period for T levels to drop and estrous cycles to resume. Sustained elevation in T levels was achieved for at least 21 weeks with silastic implants. As all three delivery methods are able to elevate T levels in female mice for at least 6 weeks, choice of T administration method should be based on outcomes of interest and study design.

Effects of Ultramicronized Palmitoylethanolamide on Mitochondrial Bioenergetics, Cerebral Metabolism, and Glutamatergic Transmission: An Integrated Approach in a Triple Transgenic Mouse Model of Alzheimer's Disease.

The therapeutic potential of ultramicronized palmitoylethanolamide (um-PEA) was investigated in young (6-month-old) and adult (12-month-old) 3 × Tg-AD mice, which received um-PEA for 3 months via a subcutaneous delivery system. Mitochondrial bioenergetics, ATP homeostasis, and magnetic resonance imaging/magnetic resonance spectroscopy were evaluated in the frontal cortex (FC) and hippocampus (HIPP) at the end of um-PEA treatment. Glutamate release was investigated by in vivo microdialysis in the ventral HIPP (vHIPP). We demonstrated that chronic um-PEA treatment ameliorates the decrease in the complex-I respiration rate and the FoF1-ATPase (complex V) activity, as well as ATP content depletion in the cortical mitochondria. Otherwise, the impairment in mitochondrial bioenergetics and the release of glutamate after depolarization was not ameliorated by um-PEA treatment in the HIPP of both young and adult 3 × Tg-AD mice. Moreover, progressive age- and pathology-related changes were observed in the cortical and hippocampal metabolism that closely mimic the alterations observed in the human AD brain; these metabolic alterations were not affected by chronic um-PEA treatment. These findings confirm that the HIPP is the most affected area by AD-like pathology and demonstrate that um-PEA counteracts mitochondrial dysfunctions and helps rescue brain energy metabolism in the FC, but not in the HIPP.

Enhancing adoptive CD8 T cell therapy by systemic delivery of tumor associated antigens

Adoptive T-cell transfer (ACT) offers a curative therapeutic option for subsets of melanoma and hematological cancer patients. To increase response rates and broaden the applicability of ACT, it is necessary to improve the post-infusion performance of the transferred T cells. The design of improved treatment strategies includes transfer of cells with a less differentiated phenotype. Such T cell subsets have high proliferative potential but require stimulatory signals in vivo to differentiate into tumor-reactive effector T cells. Thus, combination strategies are needed to support the therapeutic implementation of less differentiated T cells. Here we show that systemic delivery of tumor-associated antigens (TAAs) facilitates in vivo priming and expansion of previously non-activated T cells and enhance the cytotoxicity of activated T cells. To achieve this in vivo priming, we use flexible delivery vehicles of TAAs and a TLR7/8 agonist. Contrasting subcutaneous delivery systems, these vehicles accumulate TAAs in the spleen, thereby achieving close proximity to both cross-presenting dendritic cells and transferred T cells, resulting in robust T-cell expansion and anti-tumor reactivity. This TAA delivery platform offers a strategy to safely potentiate the post-infusion performance of T cells using low doses of antigen and TLR7/8 agonist, and thereby enhance the effect of ACT.

Sustained release of PKR inhibitor C16 from mesoporous silica nanoparticles significantly enhances mRNA translation and anti-tumor vaccination

In this study, we developed a mesoporous silica nanoparticles - mRNA (MSN-mRNA) subcutaneous delivery system composed of naked mRNA and a subcutaneous depot of imidazolo-oxindole RNA-activated protein kinase (PKR) inhibitor C16. We show that C16 treatment during mRNA transfection is a potent immune evasion approach that non-linearly enhances translation of unmodified mRNA in both mouse fibroblasts and dendritic cells in vitro exceeding that of nucleoside-modified mRNA. Notably, C16 further enhances translation of nucleoside-modified mRNA and HPLC purified mRNA. However, translation enhancement is dependent on and potentiated by C16′s continuous presence. C16 mediated translation enhancement is extended in vivo by employing MSN as an interface to sustain-release C16. Subcutaneously administered MSN-mRNA significantly enhanced in vivo translation and expression kinetics of naked mRNA in unmodified, nucleoside-modified, and HPLC purified formats. We applied a MSN-mRNA vaccine formulation composed of naked mRNA encoding ovalbumin and granulocyte macrophage colony stimulating factor, and C16@MSNs on a xenograft E.G7-OVA prophylactic tumor model, resulting in very potent tumor inhibition. The MSN-mRNA delivery system bears great translational potential in mRNA therapeutics.

Advances in Subcutaneous Delivery Systems of Biomacromolecular Agents for Diabetes Treatment.

Diabetes mellitus is a major threat to human health. Both its incidence and prevalence have been rising steadily over the past few decades. Biomacromolecular agents such as insulin and glucagon-like peptide 1 receptor agonists are commonly used hypoglycemic drugs that play important roles in the treatment of diabetes. However, their traditional frequent administration may cause numerous side effects, such as pain, infection or local tissue necrosis. To address these issues, many novel subcutaneous delivery systems have been developed in recent years. In this review, we survey recent developments in subcutaneous delivery systems of biomacromolecular hypoglycemic drugs, including sustained-release delivery systems and stimuli-responsive delivery systems, and summarize the advantages and limitations of these systems. Future opportunities and challenges are discussed as well.

Outpatient Subcutaneous Antimicrobial Therapy (OSCAT) as a Measure to Improve the Quality and Efficiency of Healthcare Delivery for Patients With Serious Bacterial Infections.

Since the 1970s, outpatient parenteral antimicrobial therapy (OPAT) has been a viable option for patients who require intravenous antibiotics when hospitalization is not warranted. While the benefits of OPAT as a measure to improve the efficiency of healthcare delivery (i.e., reduced hospital days) and patient satisfaction are well-documented, OPAT is associated with a number of challenges, including line complications and reliance on daily healthcare interactions in some cases at home or in a clinic. To minimize the continued need for intensive healthcare services in the outpatient setting, there is trend toward patients self-administering antibiotics at home without the presence of healthcare workers, after adequate training. In most cases, patients administer the antibiotics through an established intravenous catheter. While this OPAT practice is becoming more accepted as a standard of care, the potential for line complications still exists. Outpatient subcutaneous antimicrobial therapy (OSCAT) has become an increasingly accepted alternative route of administration of antibiotics to IV by French infectious diseases physicians and geriatricians; however, currently, no antibiotics are approved to be administered subcutaneously. Antibiotics with longer half-lives that are completely absorbed and have a favorable local tolerability profile are ideal candidates for OSCAT and have the potential to maximize the quality and efficiency of parenteral antibiotic delivery in the outpatient setting. The increasing development of wearable, on-body subcutaneous delivery systems make OSCAT even more viable as they increase patient independence while avoiding line complications and potentially removing the need for direct healthcare professional observation.

Vegetable oil-based hybrid microparticles as a green and biocompatible system for subcutaneous drug delivery

The aim of this study was to evidence the ability of vegetable oil-based hybrid microparticles (HMP) to be an efficient and safe drug delivery system after subcutaneous administration. The HMP resulted from combination of a thermostabilized emulsification process and a sol–gel chemistry. First of all, castor oil was successfully silylated by means of (3-Isocyanatopropyl)trimethoxysilane in solvent-free and catalyst-free conditions. Estradiol, as a model drug, was dissolved in silylated castor oil (ICOm) prior to emulsification, and then an optimal sol–gel crosslinking was achieved inside the ICOm microdroplets. The resulting estradiol-loaded microparticles were around 80 µm in size and allowed to entrap 4 wt% estradiol. Their release kinetics in a PBS/octanol biphasic system exhibited a one-week release profile, and the released estradiol was fully active on HeLa ERE-luciferase ERα cells. The hybrid microparticles were cytocompatible during preliminary tests on NIH 3T3 fibroblasts (ISO 10993-5 standard) and they were fully biocompatible after subcutaneous injection on mice (ISO 10993-6 standard) underlining their high potential as a safe and long-acting subcutaneous drug delivery system.

Vegetable Oil-based Hybrid Submicron Particles Loaded with JMV5038: A Promising Formulation against Melanoma.

The aim of this work was to carry out a preformulation study on JMV5038 as a new potent cytotoxic agent, and to develop its formulation within vegetable oil-based hybrid submicron particles (HNP) in order to obtain a versatile dosage form against melanoma. JMV5038 was first characterized through physico-chemical tests and it exhibited high melting point and logP value, an important pH-sensitivity that led to the formation of well-identified degradation products at low pH, as well as a substantial solubility value in silylated castor oil (ICO). Then, JMV5038-loaded HNP were formulated through a thermostabilized emulsion process based on the sol-gel cross-linking of ICO. They showed high loading efficiency and their invitro release kinetic assessed in a biorelevant PBS/octanol biphasic system showed a constant sustained release over one month. The cytotoxic activity and cytocompatibility of HNP were evaluated on A375 melanoma cells and NIH 3T3 cells, respectively. JMV5038-loaded HNP exhibited a slightly enhanced cytotoxic activity of JMV5038 on melanoma cells while demonstrating their safety on NIH 3T3 cells. In conclusion, JMV5038-loaded HNP proved to be an efficient and safe drug subcutaneous delivery system that will be interesting to evaluate through preclinical studies.