Assessment of subcutaneously administered insulins using in vitro release cartridge: Medium composition and albumin binding.

Biotherapeutics is the fastest growing class of drugs administered by subcutaneous injection. In vitro release testing mimicking physiological conditions at the injection site may guide formulation development and improve biopredictive capabilities. Here, anin vitrorelease cartridge (IVR cartridge) comprising a porous agarose matrix emulating subcutaneous tissue was explored. The objective was to assess effects of medium composition and incorporation of human serum albumin into the matrix. Drug disappearance was assessed for solution, suspension and in situ precipitating insulin products (Actrapid, Levemir, Tresiba, Mixtard 30, Insulatard, Lantus) using the flow-based cartridge. UV-Vis imaging and light microscopy visualized dissolution, precipitation and albumin binding phenomena at the injection site. Divalent cations present in the release medium resulted in slower insulin disappearance for suspension-based and in situ precipitating insulins. Albumin-binding acylated insulin analogs exhibited rapid disappearance from the cartridge; however, sustained retention was achieved by coupling albumin to the matrix. An in vitro-in vivorelation was established for the non-albumin-binding insulins.The IVR cartridge is flexible with potential in formulation development as shown by the ability to accommodate solutions, suspensions, and in situ forming formulations while tailoring of the system to probe in vivo relevant medium effects and tissue constituent interactions.

Lyophilised protein formulations as a patient-centric dosage form: A contribution toward sustainability paradigm.

At present, society has embraced the fact apropos population aging and climate changes, that demand, amongst others, innovative pharmaceutical technologies, emphasising the development of patient-specific delivery systems and thus the provision of efficient and sustainable drugs. Protein drugs for subcutaneous administration, by allowing less frequent application, represent one of the most important parts of the pharmaceutical field, but their development is inevitably faced with obstacles in providing protein stability and suitable formulation viscosity. To gain further knowledge and fill the gaps in the already constructed data platform for the development of monoclonal antibody formulations, we designed a study that examines small model proteins, i.e., bovine serum albumin. The main aim of the presented work is to evaluate the effect of protein concentrations on critical quality attributes of both, pre-lyophilised liquid formulations, and lyophilised products. Through the study, the hypothesis that increasing protein concentration leads to higher viscosity and higher reconstitution time without affecting the stability of the protein was confirmed. The most important finding is that sucrose plays a key role in the lyophilisation of investigated protein, nevertheless, it can be predicted that, to ensure the beneficial effect of mannitol, its amount has to prevail over the amount of sucrose.

The search for novel proline analogs for viscosity reduction and stabilization of highly concentrated monoclonal antibody solutions.

Administration of monoclonal antibodies (mAbs) is currently focused on subcutaneous injection associated with increased patient adherence and reduced treatment cost, leading to sustainable healthcare. The main bottleneck is low volume that can be injected, requiring highly concentrated mAb solutions. The latter results in increased solution viscosity with pronounced mAb aggregation propensity because of intensive protein-protein interactions. Small molecule excipients have been proposed to restrict the protein-protein interactions, contributing to reduced viscosity. The aim of the study was to discover novel compounds that reduce the viscosity of highly concentrated mAb solution. First, the chemical space of proline analogs was explored and 35 compounds were determined. Viscosity measurements revealed that 18 proline analogs reduced the mAb solution viscosity similar to or more than proline. The compounds forming both electrostatic and hydrophobic interactions with mAb reduced the viscosity of the formulation more efficiently without detrimentally effecting mAb physical stability. A correlation between the level of interaction and viscosity-reducing effect was confirmed with molecular dynamic simulations. Structure rigidity of the compounds and aromaticity contributed to their viscosity-reducing effect, dependent on molecule size. The study results highlight the novel proline analogs as an effective approach in viscosity reduction in development of biopharmaceuticals for subcutaneous administration.

[Administration of anti-HER2 and satisfaction of patients treated for breast cancer]. / Administration des anti-HER2 et satisfaction des patients avec un cancer du sein.

INTRODUCTION: Quality of life (QoL) and patient satisfaction are major concerns in oncology. METHODS: The aim of this prospective observational study was to evaluate these parameters according to the mode of administration of anti-HER2 (subcutaneous [SC] versus intravenous [IV]), the place of administration (Home Hospitalization or HOD versus hospital) for patients supervised by an advanced practice nurse (APN). RESULTS: Between January 2022 and June 2023, 32 patients were included. They were statistically more satisfied with subcutaneous management (P=0.0004), a result explained by the speed of administration (43.5%), comfort during administration (26%) even though some expressed pain on injection and felt less anxiety (26%). Management by the APN seems more appropriate when anti-HER2 drugs were administered in HOD. In HOD, patients perceived an overall improvement in their quality of life, appetite and cognitive abilities, with a reduction in fatigue, pain and depression (P<0.05). However, the rate of outsourcing to HOD remained too low (30.4%), as 56.3% of patients would have liked to be cared for in HOD if they had had the opportunity. CONCLUSION: SC administration of anti-HER2 under the supervision of an APN has advantages for the patient, resulting in greatest satisfaction and improved patient QOL, preferably in HOD.

Assessing Physicochemical Stability of Monoclonal Antibodies in a Simulated Subcutaneous Environment.

Monoclonal antibodies (mAbs) are being increasingly administered by the subcutaneous (SC) route compared to the traditional intravenous route. Despite the growing popularity of the subcutaneous route, our current knowledge regarding the intricate mechanistic changes happening in the formulation after injection in the subcutaneous space, as well as the in vivo stability of administered mAbs, remains quite limited. Changes in the protein environment as it transitions from a stabilized, formulated drug product in an appropriate container closure to the SC tissue environment can drastically impact the structural stability and integrity of the injected protein. Interactions of the protein with components of the extracellular matrix can lead to changes in its structure, potentially impacting both safety and efficacy. Investigating protein stability in the SC space can enable early assessment of risk and performance of subcutaneously administered proteins influencing clinical decisions and formulation development strategies. The Subcutaneous Injection Site Simulator (SCISSOR) is a novel in vitro system that mimics the subcutaneous injection site and models the events that a protein goes through as it transitions from a stabilized formulation environment to the dynamic physiological space. In this paper, we utilize the SCISSOR to probe for biophysical and chemical changes in seven mAbs post SC injection using a variety of analytical techniques. After 24 h, all mAbs demonstrated a relative decrease in conformational stability, an increase in fragmentation, and elevated acidic species. Higher order structure analysis revealed a deviation in the secondary structure from the standard and an increase in the number of unordered species. Our findings suggest an overall reduced stability of mAbs after subcutaneous administration. This reduced stability could have a potential impact on safety and efficacy. In vitro systems such as the SCISSOR combined with downstream analyses have potential to provide valuable information for assessing the suitability of lead molecules and aid in formulation design optimized for administration in the intended body compartment, thus improving chances of clinical success.

Subcutaneous Bolus Infusions of Undiluted Levetiracetam for End-of-Life Patients: Two Cases.

We present two cases, in which end-of-life patients were inadvertently treated with bolus infusions of undiluted subcutaneous levetiracetam. The patients were treated for three and four days respectively. In both cases, the course of treatment was uneventful. Especially, no seizures, nor local irritation was observed. Administration of undiluted subcutaneous levetiracetam as intermittent bolus infusions by hand holds alluring properties for end-of-life patients. Amongst others reducing patient discomfort, increasing freedom of movement, and accessibility to essential seizure prophylaxis by eliminating the need for a syringe driver, thereby helping accommodate many patients wish to die in their own home. However, pharmacokinetics, efficacy, and safety, including the optimum dilution and administration time of the subcutaneous preparation remains to be determined in clinically controlled trials.

The Subcutaneous Administration of Beta-Lactams: A Case Report and Literary Review-To Do Small Things in a Great Way.

The subcutaneous (s.c.) route is a commonly used method for delivering various drugs, although its application in the administration of antibiotics is relatively uncommon. In this case, we report a successful treatment of nosocomial pneumonia using piperacillin/tazobactam via continuous subcutaneous administration. Furthermore, this article provides an overview of the current literature regarding the s.c. administration of beta-lactam antibiotics. Based on our analysis, we identified only 15 studies that described the s.c. use of beta-lactam antibiotics in human subjects. Among these studies, cephalosporins were the most extensively investigated antibiotic class, with 10 available studies. According to the study findings, all three antibiotic classes (cephalosporins, penicillins, and carbapenems) demonstrated a similar pharmacokinetic profile when administered via the subcutaneous route. The subcutaneous route appears to be associated with a lower peak serum concentration (Cmax) but a comparable minimum blood concentration (Cmin) and an extended half-life (t1/2) when compared to conventional routes of antibiotic administration. Further research is necessary to determine whether subcutaneously administered beta-lactam antibiotics in human subjects achieve pharmacodynamic targets and demonstrate clinical efficacy.

Long-Term Constant Subcutaneous Drug Administration.

In this chapter, a long-term drug delivery system for preclinical therapeutic research is introduced. By using a subcutaneously implanted ALZET® Osmotic Pumps osmotic pump, continuous zero-order delivery of drugs under investigation that need repeated oral or intravenous dosing is realizable. Compared to traditional delivery systems, implanted osmotic pumps present several advantages, such as that no external connections or researcher intervention is required during infusion and that it is possible to save time by eliminating the need for frequent animal handling and repetitive injection schedules. Most importantly, a stable peripheral concentration of a drug can be obtained using this constant drug delivery system, which would benefit researchers in verifying the efficiency of anti-rheumatoid drugs and establishing safety profiles in preclinical studies.

Intravenous or subcutaneous natalizumab in patients with relapsing-remitting multiple sclerosis: investigation on efficiency and savings-the EASIER study.

INTRODUCTION: EASIER is a multicenter, observational, cross-sectional study investigating the consumption of healthcare resources, including healthcare professional (HCP) active working time, the costs associated with the current natalizumab intravenous (IV) administration, and the potential impact of the adoption of subcutaneous (SC) route. METHODS: The EASIER study has three parts: (1) time and motion study to measure healthcare resources and working time needed for natalizumab IV administration using a digital data collection tool operated directly by HCPs; (2) HCP structured questionnaire-based estimation of the potential impact of natalizumab SC vs. IV administration; and (3) patient survey on the burden of natalizumab administration. RESULTS: Nine Italian multiple sclerosis (MS) centers measured 404 IV natalizumab administration procedures and administered 26 HCP questionnaires and 297 patient questionnaires. Patients had a mean of 52 (range 1-176) previous IV administrations and spent a mean (median, IQR) of 152 (130, 94-184) minutes in the center per each IV procedure, with IV infusion covering 50% of the total. Including patient travel time, an average of 5 h was dedicated to each IV administration. Active working time by HCP amounted to 29 min per IV administration procedure, 70% of which by nursing staff. With adoption of the SC route, HCPs estimated a 50% reduction in patient procedure time and 55% lower HCP active working time. This translated into a 63% cost reduction for the MS center per natalizumab administration procedure. CONCLUSIONS: SC natalizumab administration will consistently reduce consumption of patient and HCP times per procedure and associated costs.

Polycaprolactone microparticles for the subcutaneous administration of cannabidiol: in vitro and in vivo release.

Cannabidiol (CBD) has become a highly attractive entity in therapeutics. However, its low aqueous solubility, instability and handling problems limit the development of effective CBD formulations. Subcutaneously administered CBD-loaded polycaprolactone microparticles (MP) represent an interesting strategy to overcome these challenges. This work focuses on evaluating the pharmacokinetics of CBD formulated in polymer microparticles for subcutaneous administration and characterising its release. The mean release time (MRLT) parameter is used to compare the release of CBD from two microparticle formulations in vitro and in a mouse model. After the administration of CBD in solution, a bicompartmental distribution is observed due to the extensive diffusion to the brain, being the brain/blood AUC ratio 1.29. The blood and brain mean residence time (MRT) are 0.507 ± 0.04 and 0.257 ± 0.0004 days, respectively. MP prepared with two drug/polymer ratios (15/150-MP and 30/150-MP) are designed, showing similar in vitro dissolution profiles (similarity factor (f2) is 63.21), without statistically significant differences between MRLTin vitro values (4.68 ± 0.63 and 4.32 ± 0.05 days). However, considerable differences in blood and brain profiles between both formulations are detected. The blood and brain MRT values of 15/150-MP are 6.44 ± 0.3 days and 6.15 ± 0.25 days, respectively, whereas significantly lower values 3.91 ± 0.29 days and 2.24 ± 0.64 days are obtained with 30/150-MP. The extended release of CBD during 10 days after a single subcutaneous administration is achieved.

Subcutaneous administration of drugs and hydration in acute palliative care units: Physician attitudes and beliefs in the United States and Canada.

OBJECTIVES: The objective of this study was to compare the attitudes and beliefs of PCU physicians leaders in the United States versus Canada regarding the subcutaneous method in the administration of medications and hydration in order to gain a better understanding as to why variations in practice exist. METHODS: This survey trial took place from November 2022 to May 2023. The MD Anderson Cancer Center institutional review board in Houston, Texas, approved this study. The participants were the physician leaders of the acute palliative care units (PCUs) in the United States and Canada. The survey comprised questions formulated by the study investigators regarding the perceived comfort, efficiency, and preference of using the subcutaneous versus the intravenous method. The consent form and survey links were emailed to the participants. RESULTS: Sixteen PCUs were identified in the United States and 15 PCUs in Canada. Nine US and 8 Canadian physicians completed the survey. Physicians in Canada were more likely to use the subcutaneous route for administering opioids, antiemetics, neuroleptics, and hydration. They preferred subcutaneous over intravenous or intramuscular routes (p = 0.017). Canadian physicians felt their nursing staff was more comfortable with subcutaneous administration (p = 0.022) and that it was easier to administer (p = 0.02). US physicians felt the intravenous route was more efficient (p = 0.013). SIGNIFICANCE OF RESULTS: The study results suggest that exposure to the subcutaneous route influences a physician's perception. Further research is needed to explore ways to incorporate its use to a greater degree in the US healthcare system.

Subcutaneous Administration of a Zwitterionic Chitosan-Based Hydrogel for Controlled Spatiotemporal Release of Monoclonal Antibodies.

Subcutaneous (SC) administration of monoclonal antibodies (mAbs) is a proven strategy for improving therapeutic outcomes and patient compliance. The current FDA-/EMA-approved enzymatic approach, utilizing recombinant human hyaluronidase (rHuPH20) to enhance mAbs SC delivery, involves degrading the extracellular matrix's hyaluronate to increase tissue permeability. However, this method lacks tunable release properties, requiring individual optimization for each mAb. Seeking alternatives, physical polysaccharide hydrogels emerge as promising candidates due to their tunable physicochemical and biodegradability features. Unfortunately, none have demonstrated simultaneous biocompatibility, biodegradability, and controlled release properties for large proteins (≥150 kDa) after SC delivery in clinical settings. Here, a novel two-component hydrogel comprising chitosan and chitosan@DOTAGA is introduced that can be seamlessly mixed with sterile mAbs formulations initially designed for intravenous (IV) administration, repurposing them as novel tunable SC formulations. Validated in mice and nonhuman primates (NHPs) with various mAbs, including trastuzumab and rituximab, the hydrogel exhibited biodegradability and biocompatibility features. Pharmacokinetic studies in both species demonstrated tunable controlled release, surpassing the capabilities of rHuPH20, with comparable parameters to the rHuPH20+mAbs formulation. These findings signify the potential for rapid translation to human applications, opening avenues for the clinical development of this novel SC biosimilar formulation.

Supramolecular approaches for insulin stabilization without prolonged duration of action.

Aggregation represents a significant challenge for the long-term formulation stability of insulin therapeutics. The supramolecular PEGylation of insulin with conjugates of cucurbit[7]uril and polyethylene glycol (CB[7]‒PEG) has been shown to stabilize insulin formulations by reducing aggregation propensity. Yet prolonged in vivo duration of action, arising from sustained complex formation in the subcutaneous depot, limits the application scope for meal-time insulin uses and could increase hypoglycemic risk several hours after a meal. Supramolecular affinity of CB[7] in binding the B1-Phe residue on insulin is central to supramolecular PEGylation using this approach. Accordingly, here we synthesized N-terminal acid-modified insulin analogs to reduce CB[7] interaction affinity at physiological pH and reduce the duration of action by decreasing the subcutaneous depot effect of the formulation. These insulin analogs show weak to no interaction with CB[7]‒PEG at physiological pH but demonstrate high formulation stability at reduced pH. Accordingly, N-terminal modified analogs have in vitro and in vivo bioactivity comparable to native insulin. Furthermore, in a rat model of diabetes, the acid-modified insulin formulated with CB[7]‒PEG offers a reduced duration of action compared to native insulin formulated with CB[7]‒PEG. This work extends the application of supramolecular PEGylation of insulin to achieve enhanced stability while reducing the risks arising from a subcutaneous depot effect prolonging in vivo duration of action.

High concentration formulation developability approaches and considerations.

The growing need for biologics to be administered subcutaneously and ocularly, coupled with certain indications requiring high doses, has resulted in an increase in drug substance (DS) and drug product (DP) protein concentrations. With this increase, more emphasis must be placed on identifying critical physico-chemical liabilities during drug development, including protein aggregation, precipitation, opalescence, particle formation, and high viscosity. Depending on the molecule, liabilities, and administration route, different formulation strategies can be used to overcome these challenges. However, due to the high material requirements, identifying optimal conditions can be slow, costly, and often prevent therapeutics from moving rapidly into the clinic/market. In order to accelerate and derisk development, new experimental and in-silico methods have emerged that can predict high concentration liabilities. Here, we review the challenges in developing high concentration formulations, the advances that have been made in establishing low mass and high-throughput predictive analytics, and advances in in-silico tools and algorithms aimed at identifying risks and understanding high concentration protein behavior.

Pharmacokinetics and Pharmacodynamics of Antibody-Drug Conjugates Administered via Subcutaneous and Intratumoral Routes.

We hypothesize that different routes of administration may lead to altered pharmacokinetics/pharmacodynamics (PK/PD) behavior of antibody-drug conjugates (ADCs) and may help to improve their therapeutic index. To evaluate this hypothesis, here we performed PK/PD evaluation for an ADC administered via subcutaneous (SC) and intratumoral (IT) routes. Trastuzumab-vc-MMAE was used as the model ADC, and NCI-N87 tumor-bearing xenografts were used as the animal model. The PK of multiple ADC analytes in plasma and tumors, and the in vivo efficacy of ADC, after IV, SC, and IT administration were evaluated. A semi-mechanistic PK/PD model was developed to characterize all the PK/PD data simultaneously. In addition, local toxicity of SC-administered ADC was investigated in immunocompetent and immunodeficient mice. Intratumoral administration was found to significantly increase tumor exposure and anti-tumor activity of ADC. The PK/PD model suggested that the IT route may provide the same efficacy as the IV route at an increased dosing interval and reduced dose level. SC administration of ADC led to local toxicity and reduced efficacy, suggesting difficulty in switching from IV to SC route for some ADCs. As such, this manuscript provides unprecedented insight into the PK/PD behavior of ADCs after IT and SC administration and paves the way for clinical evaluation of these routes.

In-line warming reduces in-line pressure of subcutaneous infusion of concentrated immunoglobulins.

Immunoglobulin replacement therapy is a life-saving treatment in patients with immunodeficiency and effective in the management of autoimmune disorders. Immunoglobulins are administered intravenously or subcutaneously, with the latter route reducing systemic reactions and providing an option for self-infusion, increasing patient convenience, while decreasing patient burden, healthcare utilization, and costs. A major limitation with subcutaneous administrations is the frequency of infusion due to limited volumes administrable into subcutaneous space, necessitating increased drug concentration, absorption, and dispersion. Increasing the concentration of immunoglobulins from 10 to 20% halves the required volume, but leads to higher dynamic viscosity, limiting infusion rate. Recombinant human hyaluronidase increases dispersion and absorption of immunoglobulins allowing administration of ≤ 600 mL per site, but does not change viscosity. Since the viscosity of fluids depends on temperature, we tested the feasibility of in-line warming of immunoglobulin formulations to physiological temperatures. In vitro analysis showed no negative impact of in-line warming to 38 °C on product quality. Subcutaneous infusion studies in pigs confirmed the feasibility of infusion rates of up to 7.5 mL/min with in-line warmed TAK-881, an immunoglobulin 20% facilitated with recombinant human hyaluronidase. In-line pressures were reduced compared with conventional immunoglobulin 20%, and local tolerance was not altered. Reduction of in-line pressures was more pronounced with thinner needle sets, indicating a potential benefit for patients. In summary, an in in-line warming device can circumvent the limitation of high viscosity, while product quality and local tolerance are maintained. The results of the presented studies warrant further testing in a phase 1 clinical study.

Microphysiological endothelial models to characterize subcutaneous drug absorption.

The high variability in subcutaneous bioavailability of protein therapeutics is poorly understood, contributing to critical delays in patient access to new therapies. Preclinical animal and in vitro models fail to provide a physiologically relevant testbed to parse potential contributors to human bioavailability, therefore new strategies are necessary. Here, we present a microphysiological model of the human hypodermal vasculature at the injection site to study the interactions of administered protein therapeutics within the microenvironment that influence subcutaneous bioavailability. Our model combines human dermal endothelial cells, fibroblasts, and adipocytes, self-assembled into three-dimensional, perfusable microvessels that express relevant extracellular matrix. We demonstrate the utility of the model for measurement of biophysical parameters within the hypodermal microenvironment that putatively impact protein kinetics and distribution at the injection site. We propose that microphysiological models of the subcutaneous space have applications in preclinical development of protein therapeutics intended for subcutaneous administration with optimal bioavailability.

Subcutaneous immunoglobulin 16.5% for the treatment of pediatric patients with primary antibody immunodeficiency.

INTRODUCTION: Human immunoglobulin (IG) administered intravenously (IVIG) or subcutaneously (SCIG) is used to prevent infections in patients with primary immunodeficiency diseases (PIDDs) such as primary antibody immunodeficiencies. AREAS COVERED: This review provides an overview of PIDD with a focus on SCIG treatment, including the properties and clinical trial results of a new SCIG 16.5% (Cutaquig, Octapharma) in pediatric patients. We also discuss the various benefits of SCIG including stable serum immunoglobulin G levels, high tolerability with fewer systemic side effects, and the flexibility of self-administration. EXPERT OPINION: Individualized treatment for PIDD in children is necessary given the different factors that affect administration of SCIG. Variables such as the dose, dosing interval, administration sites, and ancillary equipment can be adjusted to impact the long-term satisfaction with SCIG administration in pediatric patients. The successful work that has been conducted by both professional and patient organizations to increase awareness of PIDD, especially in pediatric patients, is substantial and ongoing. The importance of early diagnosis and treatment in the pediatric patient population cannot be overstated. The safety, efficacy, and tolerability of SCIG 16.5% have been demonstrated in pediatric patients with PIDDs providing an additional therapeutic option in this vulnerable population.

Human immunoglobulin (IG) is extracted from the plasma of donors as a sterile, purified blood product that is administered intravenously (via a vein [IVIG]) or subcutaneously (under the skin [SCIG]) and is used for a variety of disorders, including the prevention of infections in patients with primary immunodeficiency diseases (PIDDs) such as primary antibody immunodeficiencies. This review provides an overview of PIDD with a focus on SCIG treatment, including the properties and clinical trial results of a new SCIG 16.5% (Cutaquig, Octapharma) in pediatric patients. We also discuss the various benefits of SCIG including stable serum immunoglobulin G levels, high tolerability with fewer systemic side effects, and the flexibility of self-administration. The importance of early identification of PIDD, especially in pediatric patients, cannot be overstated to ensure prompt treatment. The safety, efficacy, and tolerability of SCIG 16.5% have been demonstrated in pediatric patients with PIDDs providing an additional therapeutic option in this vulnerable population.

Pharmacokinetic characterization, benefits and barriers of subcutaneous administration of monoclonal antibodies in oncology.

OBJECTIVE: Therapeutic monoclonal antibodies in oncology are slowly becoming the dominant treatment option for many different cancer types. The main route of administration, infusion, requires extensive product preparations, patient hospitalization and close monitoring. Patient comfort improvement, staff workload reduction and cost savings dictated the development of subcutaneous formulations. The aim of this review is to present pharmacokinetic characteristics of subcutaneous products, discuss the differences between intravenous and subcutaneous routes and to point out the advantages as well as challenges of administration route shift from the formulation development and pharmacometric angle. DATA SOURCES: Food and Drug administration's Purple book database and electronic medicines compendium were used to identify monoclonal antibodies in oncology approved as subcutaneous forms. Using keywords subcutaneous, monoclonal antibodies, pharmacokinetics, model, as well as specific drugs previously identified, both PubMed and ScienceDirect databases were researched. DATA SUMMARY: There are currently six approved subcutaneous onco-monoclonal antibodies on the market. For each of them, exposure to the drug was similar in relation to infusion, treatment effectiveness was the same, administration was well tolerated by the patients and costs of the medical service were reduced. CONCLUSION: Development of subcutaneous forms for existing and emerging new monoclonal antibodies for cancer treatment as well as shifting from administration via infusion should be encouraged due to patient preference, lower costs and overall lack of substantial differences in efficacy and safety between the two routes.

Promotion of cutaneous diabetic wound healing by subcutaneous administration of Wharton's jelly mesenchymal stem cells derived from umbilical cord.

Wound healing is a major problem in diabetic patients, and current treatments have been confronted with limited success. The present study examined the benefit of Wharton's jelly mesenchymal stem cells (WJ-MSCs) derived from the human umbilical cord (UC) in wound healing in diabetic rats. Thirty days after inducing diabetes, a circular excision was created in the skin of rats, and the treatments were performed for 21 days. Two groups were studied, which included the Control group and WJ-MSCs group. The studied groups were sampled on the 7th, 14th, and 21st days after wounding. Histological ultrasound imaging of dermis and epidermis in the wound area for thickness and density measurement and skin elasticity were evaluated. Our results on post-wounding days 7, 14, and 21 showed that the wound closure, thickness, and density of new epidermis and dermis, as well as skin elasticity in the healed wound, were significantly higher in the WJ-MSCs group compared to the Control group. Subcutaneous administration of WJ-MSCs in diabetic wounds can effectively accelerate healing. Based on this, these cells can be used along with other treatment methods in the healing of different types of chronic wounds.