Implantable Drug Delivery Systems Research Articles

The Advances in Phospholipids-Based Phase Separation Gels for the Sustained Release of Peptides, Proteins, and Chemotherapeutics

Implantable drug delivery systems formed upon injection offer a host of advantages, including localized drug administration, sustained release, minimized side effects, and enhanced patient compliance. Among the various techniques utilized for the development of in situ forming drug implants, solvent-induced phase inversion emerges as a particularly promising approach. However, synthetic polymer-based implants have been associated with undesirable effects arising from polymer degradation. In response to this challenge, a novel category of drug delivery systems, known as phospholipids-based phase separation gels (PPSGs), has emerged. These gels, characterized by their low initial viscosity, exhibit injectability and undergo rapid transformation into in situ implants when exposed to an aqueous environment. A typical PPSG formulation comprises biodegradable components, such as phospholipids, pharmaceutical oil, and a minimal amount of ethanol. The minimized organic solvents in the composition show good biocompatibility. And the relatively simple composition holds promise for industrial-scale manufacturing. This comprehensive review provides an overview of the principles and advancements in PPSG systems, with specific emphasis on their suitability as drug delivery systems for a wide range of active pharmaceutical ingredients (APIs), spanning from small molecules to peptides and proteins. Additionally, we explore the critical parameters and underlying principles governing the formulation of PPSG-based drug delivery strategies, offering valuable insights on optimization strategies.

Fabrication and Optimisation of Alumina Nanoporous Membranes for Drug Delivery Applications: A Comparative Study.

Neurodegenerative disorders cause most physical and mental disabilities, and therefore require effective treatment. The blood-brain barrier (BBB) prevents drug molecules from crossing from the blood to the brain, making brain drug delivery difficult. Implantable devices could provide sustained and regulated medication to solve this problem. Two electrolytes (0.3 M oxalic acid and 0.3 M sulphuric acid) were used to anodise Al2O3 nanoporous membranes, followed by a third anodisation in concentrated H2SO4 to separate the through-hole membranes from the aluminium substrate. FTIR, AFM, and SEM/EDX were used to characterise the membranes' structure and morphology. The effects of the anodisation time and electrolyte type on the AAO layer pore density, diameter, interpore distance, and thickness were examined. As a model drug for neurodegenerative disorders, donepezil hydrochloride (DHC) was loaded onto thin alumina nanoporous membranes. The DHC release profiles were characterised at two concentrations using a UV-Vis spectrophotometer. Oxalic acid membranes demonstrated an average pore diameter of 39.6-32.5 nm, which was two times larger than sulphuric acid membranes (22.6-19.7 nm). After increasing the anodisation time from 3 to 5 h, all of the membranes showed a reduction in pore diameter that was stable regardless of the electrolyte type or period. Drug release from oxalic acid-fabricated membranes was controlled and sustained for over 2 weeks. Thus, nanoporous membranes as implantable drug delivery systems could improve neurodegenerative disease treatment.

Epidural and Intrathecal Drug Delivery Systems for Chronic Pain Management: Progress, Promises, and Challenges

Millions of people worldwide suffer from chronic pain, which significantly impacts their quality of life. Managing chronic pain is often complex and time-consuming. In this narrative review, we explore the use of epidural and intrathecal drug delivery systems (EIDDS) as a solution for chronic pain management. The purpose of this review is to provide an overview of recent approaches in targeted implantable drug delivery systems for chronic pain management, including their long-term safety, efficacy, cost-effectiveness, risks, and future opportunities and challenges. The data was gathered through extensive research using MEDLINE, PubMed, and Google Scholar databases, including studies published until June 13, 2023. The visual analogue scale, Karnofsky Performance Status (KPS), respiration, and oxygen saturation in the group receiving drugs through a targeted implantable drug delivery system were significantly better than those in the group receiving conventionally administered analgesia in a study on patients with advanced cancer. Whereas in comparison to conventional treatment alone, the targeted implantable drug delivery system alone or in combination therapy exhibited some advantages or similar effects in reducing chronic pain during a 1-year follow-up in patients with chronic non-cancer pain. Implantable drug delivery systems are a promising new treatment option for chronic pain treatment. All forms of pain, including those that are still challenging to treat with traditional methods, can now be targeted with devices and treatments.

Facile in situ synthesis of CuO nanoparticles through the copper-crosslinked carboxymethylcellulose hydrogel bead: a potential implantable anticancer drug delivery system

Facile in situ synthesis of CuO nanoparticles through the copper-crosslinked carboxymethylcellulose hydrogel bead: a potential implantable anticancer drug delivery system

Implantable celecoxib nanofibers made by electrospinning: fabrication and characterization.

Background: Osteoarthritis causes tremendous damage to the joints, reducing the quality of life and imposing significant financial burden. An implantable drug-delivery system can improve the symptomatic manifestations with low doses and frequencies. However, the free drug has short retention in the joint cavity. Materials & methods: This study used electrostatic spinning technology to create an implantable drug-delivery system loaded with celecoxib (celecoxib nanofibers [Cel-NFs]) to improve retention and bioavailability. Results: Cel-NFs exhibited good formability, hydrophilicity and tensile properties. Cel-NFs were able to continuously release drugs for 2 weeks and increase the uptake capacity of Raw 264.7 cells, ultimately ameliorating symptoms in osteoarthritis rats. Conclusion: These results suggest that Cel-NFs can effectively ameliorate cartilage damage, reduce joint pain and alleviate osteoarthritis progression.

Recent Progress in Implantable Drug Delivery Systems.

In recent years, tremendous effort is devoted to developing platforms, such as implantable drug delivery systems (IDDSs), with temporally and spatially controlled drug release capabilities and improved adherence. IDDSs have multiple advantages: i) the timing and location of drug delivery can be controlled by patients using specific stimuli (light, sound, electricity, magnetism, etc.). Some intelligent "closed-loop" IDDS can even realize self-management without human participation. ii) IDDSs enable continuous and stable delivery of drugs over a long period (months to years) and iii) to administer drugs directly to the lesion, thereby helping reduce dosage and side effects. iv) IDDSs enable personalized drug delivery according to patient needs. The high demand for such systems has prompted scientists to make efforts to develop intelligent IDDS. In this review, several common stimulus-responsive mechanisms including endogenous (e.g., pH, reactive oxygen species, proteins, etc.) and exogenous stimuli (e.g., light, sound, electricity, magnetism, etc.), are given in detail. Besides, several types of IDDS reported in recent years are reviewed, including various stimulus-responsive systems based on the above mechanisms, radio frequency-controlled IDDS, "closed-loop" IDDS, self-powered IDDS, etc. Finally, the advantages and disadvantages of various IDDS, bottleneck problems, and possible solutions are analyzed to provide directions for subsequent research.

Intratumoral implantable drug delivery system for targeted localized chemotherapy in breast cancer

Breast cancer is a significant concern for many women, and local chemotherapy has emerged as a promising approach to address this issue. This study focuses on simulating the performance of chemotherapy using Doxorubicin, Cisplatin, Fluorouracil, and Methotrexate loaded in a dual release implantable system within a mathematical framework. The drugs are loaded in the implant as two forms: as free agents and encapsulated in nanoparticles. The results demonstrate that the elimination rate through blood microvessels and the diffusion mechanism play a crucial role in determining the bioavailability and effective penetration depth of the therapeutic agents. Drugs with high elimination rates, such as Doxorubicin, Cisplatin, and Fluorouracil, exhibit improved penetration depth by approximately 4, 3.75, and 2.25 times when encapsulated in small nanoparticles that release their content in the extracellular space. On the other hand, Methotrexate, with its weak removal rate, maintains a sufficient penetration depth and effective concentration level even as a free drug in the extracellular space. Therefore, encapsulating Methotrexate does not significantly impact on tumor penetration. This study emphasizes the potential of the dual implantable system as an effective approach for chemotherapy, particularly when considering the specific chemotherapy drug and the method of loading the therapeutic agent. The system proves to be particularly beneficial in tumors with low microvascular density. These findings provide valuable insights for future research in the development of local drug delivery systems for breast cancer treatment.

Mesoporous silica nanoparticles accommodating electrospun nanofibers as implantable local drug delivery system processed by cold atmospheric plasma and spin coating approaches

Nanofibers (NF) and nanoparticles are attractive for drug delivery to improve the drug bioavailability and administration. Easy manipulation of NF as macroscopic bulk material give rise to potential usages as implantable local drug delivery systems (LLDS) to overcome the failures of systemic drug delivery systems such as unmet personalized needs, side effects, suboptimal dosage. In this study, poly(ethylene glycol) polyethyleneimine (mPEG:PEI) copolymer blended poly ϵ-caprolactone NFs, NFblend accommodating mesoporous silica nanoparticles (MSN) as the implantable LLDS was achieved by employing spin coating and cold atmospheric plasma (CAP) as the post-process for accommodation on NFblend. The macroporous morphology, mechanical properties, wettability, and in vitro cytocompatibility of NFblend ensured their potential as an implantable LLDS and superior features compared to neat NF. The electron microscopy images affirmed of NFblend random fiber (average diameter 832 ± 321 nm) alignments and accessible macropores before and after MSN@Cur accommodation. The blending of polymers improved the elongation of NF and the tensile strength which is attributed as beneficial for implantable LLDS. CAP treatment could significantly improve the wettability of NF observed by the contact angle changes from ∼126° to ∼50° which is critical for the accommodation of curcumin-loaded MSN (MSN@Cur) and in vitro cytocompatibility of NF. The combined CAP and spin coating as the post-processes was employed for accommodating MSN@Cur on NFblend without interfering with the electrospinning process. The post-processing aided fine-tuning of curcumin dosing (∼3 µg to ∼15 µg) per dose unit and sustained zero-order drug release profile could be achieved. Introducing of MSN@Cur to cells via LLDS promoted the cell proliferation compared to MSN@Cur suspension treatments and assigned as the elimination of adverse effects by nanocarriers by the dosage form integration. All in all, NFblend-MSN@Cur was shown to have high potential to be employed as an implantable LLDS. To the best of our knowledge, this is the first study in which mPEG:PEI copolymer blend NF are united with CAP and spin coating for accommodating nano-drug carriers, which allows for NF both tissue engineering and drug delivery applications.

A Review on Innovative Drug Delivery Platforms

In recent years, the field of drug delivery has undergone a transformative shift with the introduction of innovative platforms that transcend conventional methods, providing accurate and efficient means for delivering therapeutic agents. This exploration delves into the distinctive features and potential impacts of these pioneering platforms, charting a course for the future of pharmaceutical interventions. In this review article, the advancements regarding the nanotechnology-enabled delivery, lipid-based drug delivery systems, targeted drug delivery, implantable drug delivery systems, 3D printing in drug delivery, stimuli-responsive delivery systems, mRNA and gene delivery platforms and microfluidic - based delivery systems were discussed. These innovative drug delivery platforms represent a dynamic frontier in pharmaceutical research and development. They afford unprecedented control over drug properties, release kinetics and targeting strategies. As research continues to push the boundaries of drug delivery science, these innovations hold the potential to revolutionize the treatment of various diseases, ushering in safer, more effective and patient-centric therapeutic solutions.

Opioid withdrawal following refilling of an implantable drug delivery system for intrathecal infusion

Opioid withdrawal following refilling of an implantable drug delivery system for intrathecal infusion

Exploring the vast potentials and probable limitations of novel and nanostructured implantable drug delivery systems for cancer treatment.

Conventional cancer chemotherapy regimens, albeit successful to some extent, suffer from some significant drawbacks, such as high-dose requirements, limited bioavailability, low therapeutic indices, emergence of multiple drug resistance, off-target distribution, and adverse effects. The main goal of developing implantable drug delivery systems (IDDS) is to address these challenges and maintain anti-cancer drugs directly at the intended sites of therapeutic action while minimizing inevitable side effects. IDDS possess numerous advantages over conventional drug delivery, including controlled drug release patterns, one-time drug administration, as well as loading and stabilizing poorly water-soluble chemotherapy drugs. Here, we summarized conventional and novel (three-dimensional (3D) printing and microfluidic) preparation techniques of different IDDS, including nanofibers, films, hydrogels, wafers, sponges, and osmotic pumps. These systems could be designed with high biocompatibility and biodegradability features using a wide variety of natural and synthetic polymers. We also reviewed the published data on these systems in cancer therapy with a particular focus on their release behavior. Various release profiles could be attained in IDDS, which enable predictable, adjustable, and sustained drug releases. Furthermore, multi-step or stimuli-responsive drug release could be obtained in these systems. The studies mentioned in this article have proven the effectiveness of IDDS for treating different cancer types with high prevalence, including breast cancer, and aggressive cancer types, such as glioblastoma and liver cancer. Additionally, the challenges in applying IDDS for efficacious cancer therapy and their potential future developments are also discussed. Considering the high potential of IDDS for further advancements, such as programmable release and degradation features, further clinical trials are needed to ensure their efficiency. The overall goal of this review is to expand our understanding of the behavior of commonly investigated IDDS and to identify the barriers that should be addressed in the pursuit of more efficient therapies for cancer. See also the graphical abstract(Fig. 1).

Long-Acting Drug Delivery Technologies for Meloxicam as a Pain Medicine.

Meloxicam, a selective COX-2 inhibitor, has demonstrated clinical effectiveness in managing inflammation and acute pain. Although available in oral and parenteral formulations such as capsule, tablet, suspension, and solution, frequent administration is necessary to maintain therapeutic efficacy, which can increase adverse effects and patient non-compliance. To address these issues, several sustained drug delivery strategies such as oral, transdermal, transmucosal, injectable, and implantable drug delivery systems have been developed for meloxicam. These sustained drug delivery strategies have the potential to improve the therapeutic efficacy and safety profile of meloxicam, thereby reducing the frequency of dosing and associated gastrointestinal side effects. The choice of drug delivery system will depend on the desired release profile, the target site of inflammation, and the mode of administration. Overall, meloxicam sustained delivery systems offer better patient compliance, and reduce the side effects, thereby improving the clinical applications of this drug. Herein, we discuss in detail different strategies for sustained delivery of meloxicam.

Enhanced Postsurgical Cancer Treatment Using Methacrylated Glycol Chitosan Hydrogel for Sustained DNA/Doxorubicin Delivery and Immunotherapy.

Background: Cancer recurrence and metastasis are major contributors to treatment failure following tumor resection surgery. We developed a novel implantable drug delivery system utilizing glycol chitosan to address these issues. Glycol chitosan is a natural adjuvant, inducing dendritic cell activation to promote T helper 1 cell immune responses, macrophage activation, and cytokine production. Effective antigen production by dendritic cells initiates T-cell-mediated immune responses, aiding tumor growth control. Methods: In this study, we fabricated multifunctional methacrylated glycol chitosan (MGC) hydrogels with extended release of DNA/doxorubicin (DOX) complex for cancer immunotherapy. We constructed the resection model of breast cancer to verify the anticancer effects of MGC hydrogel with DNA/DOX complex. Results: This study demonstrated the potential of MGC hydrogel with extended release of DNA/DOX complex for local and efficient cancer therapy. The MGC hydrogel was implanted directly into the surgical site after tumor resection, activating tumor-related immune cells both locally and over a prolonged period of time through immune-reactive molecules. Conclusions: The MGC hydrogel effectively suppressed tumor recurrence and metastasis while enhancing immunotherapeutic efficacy and minimizing side effects. This biomaterial-based drug delivery system, combined with cancer immunotherapy, can substantial improve treatment outcomes and patient prognosis.

Sustainable Routed Mxene-Based Aminolyzed PU/PCL Film for Increased Oxidative Stress and a pH-Sensitive Drug Delivery System for Anticancer Therapy.

A remarkable challenge in the anticancer drug delivery system is developing an implantable system that can improve the chemotherapeutic effect. Polyurethane is an excellent implantable substrate, with flaws in hydrophobicity. We modified polyurethane via the chemical aminolysis technique to enhance the wettability and protein interaction. The created pores can release the rutin complex incorporated in the polyurethane matrix. In this work, the hybrid polymer matrix consists of Mxene synthesized via a sustainable and simple method by introducing a toxic-free MAX phase and etchants. The incorporation of Mxene and PCL can enhance physicochemical and biological compatibility. Sustainable Mxene increases oxidative stress, cell death, and antibacterial activity, which also resulted in the Mxene@APU/PCL film. Meanwhile, the drug release with respect to pH sensitivity was demonstrated in which Mxene and Mxene@APU/PCL films showed the highest release at pH 5.2; this indicates that the prepared Mxene and aminolyzed polyurethane can function according to the biological system and release the drug from the polymer matrix on slow degradation and swellability. The Mxene and Mxene@APU/PCL films showed 93.2% drug release with oxidative stress on THP-1 cells, which causes rupturing and apoptosis of cancerous cells. The Mxene@APU/PCL film can show great potential in future implantable anticancer drug delivery systems.

A Review on Implantable Drug Delivery System

Implantable drug delivery system are being developed to release a drug to the bloodstream continuously as well as free patient from being hospitalized to receive intravenous infusion or frequent injectuion. one technique is implantation of a pellet in the subcutaneous tissue so the pellet may be release by erosion. Drug are also diffused through silicon rubber capsule but only polyacrylamide is able to release large molecule. Contraceptive ring containing large molecules.

Development of implantable drug delivery system of embelin for the treatment of breast cancer

Embelin is a traditional herbal medicine that exhibits anti-cancer effects in human breast cancer cells. However, the therapeutic effect of Embelin as Implantable Drug Delivery System is not yet determined. Embelin is having drawbacks like poor bioavailability and toxicity in systemic circulation, so we opt for Implantable Drug Delivery System. In this study, we optimised, developed and evaluated the Implantable Drug Delivery System of Embelin as pellets. The prime objective of the study is to prolong the drug release as much as possible using a combination of naturally occurring biodegradable polymer such as Guar gum, Chitosan, Xanthan gum, Locust bean gum. In this study, integration of Embelin and Chitosan was achieved via Granulation, with the aid of Guar gum as an excipient, followed by Extrusion /spheronisation. In vitro drug release study revealed the chitosan blended Embelin loaded implant possesses a longer, yet steadier, sustained drug release behaviour than the other three bio polymeric implants. It exhibits prolonged drug release of up to nine days and Korsmeyer’s-peppas plot were exhibited.

Use of a polymeric implant system to assess the neurotoxicity of subacute exposure to 2,2′,5,5′-tetrachlorobiphenyl-4-ol, a human metabolite of PCB 52, in male adolescent rats

Polychlorinated biphenyls (PCBs) are persistent organic pollutants (POPs) that ubiquitously exist in the environment. PCB exposure has been linked to cancer and multi-system toxicity, including endocrine disruption, immune inhibition, and reproductive and neurotoxicity. 2,2′,5,5′-Tetrachlorobiphenyl (PCB 52) is one of the most frequently detected congeners in the environment and human blood. The hydroxylated metabolites of PCB 52 may also be neurotoxic, especially for children whose brains are still developing. However, it is challenging to discern the contribution of these metabolites to PCB neurotoxicity because the metabolism of PCB is species-dependent. In this study, we evaluated the subacute neurotoxicity of a human-relevant metabolite, 2,2′,5,5′-tetrachlorobiphenyl-4-ol (4−52), on male adolescent Sprague Dawley rats, via a novel polymeric implant drug delivery system grafted subcutaneously, at total loading concentrations ranging from 0%, 1%, 5%, and 10% of the implant (w/w) for 28 days. Y-maze, hole board test, open field test, and elevated plus maze were performed on exposure days 24–28 to assess their locomotor activity, and exploratory and anxiety-like behavior. 4–52 and other possible hydroxylated metabolites in serum and vital tissues were quantified using gas chromatography with tandem mass spectrometry (GC-MS/MS). Our results demonstrate the sustained release of 4–52 from the polymeric implants into the systemic circulation in serum and tissues. Dihydroxylated and dechlorinated metabolites were detected in serum and tissues, depending on the dose and tissue type. No statistically significant changes were observed in the neurobehavioral tasks across all exposure groups. The results demonstrate that subcutaneous polymeric implants provide a straightforward method to expose rats to phenolic PCB metabolites to study neurotoxic outcomes, e.g., in memory, anxiety, and exploratory behaviors.

Implantable magnetically-actuated capsule for on-demand delivery

Many implantable drug delivery systems (IDDS) have been developed for long-term, pulsatile drug release. However, they are often limited by bulky size, complex electronic components, unpredictable drug delivery, as well as the need for battery replacement and consequent replacement surgery. Here, we develop an implantable magnetically-actuated capsule (IMAC) and its portable magnetic actuator (MA) for on-demand and robust drug delivery in a tether-free and battery-free manner. IMAC utilizes the bistable mechanism of two magnetic balls inside IMAC to trigger drug delivery under a strong magnetic field (|Ba| > 90 mT), ensuring precise and reproducible drug delivery (9.9 ± 0.17 μg per actuation, maximum actuation number: 180) and excellent anti-magnetic capability (critical trigger field intensity: ∼90 mT). IMAC as a tetherless robot can navigate to and anchor at the lesion sites driven by a gradient magnetic field (∇ Bg = 3 T/m, |Bg| < 60 mT), and on-demand release drug actuated by a uniform magnetic field (|Ba| = ∼100 mT) within the gastrointestinal tract. During a 15-day insulin administration in vivo, the diabetic rats treated with IMAC exhibited highly similar pharmacokinetic and pharmacodynamic profiles to those administrated via subcutaneous injection, demonstrating its robust and on-demand drug release performance. Moreover, IMAC is biocompatible, batter-free, refillable, miniature (only Φ 6.3 × 12.3 mm3), and lightweight (just 0.8 g), making it an ideal alternative for precise implantable drug delivery and friendly patient-centered drug administration.

Biocompatible antibiotic-loaded mesoporous silica/bioglass/collagen-based scaffolds as bone drug delivery systems

Local delivery of antibiotics has gained increasing interest in the treatment of osteomyelitis due to its effectiveness and safety. Since the regeneration of bone tissue at the site of infection is as important as bacterial eradication, implantable drug delivery systems should not only release the drugs in a proper manner but also exert the osseointegration capability. Herein, we present an implantable drug delivery system in a scaffold form with a unique set of features for local treatment of osteomyelitis. For the first time, collagen type I, ciprofloxacin-loaded mesoporous silica, and bioglass were combined to obtain scaffolds using the molding method. Drug-loaded mesoporous silica was blended with polydimethylsiloxane to prolong the drug release, whereas bioglass served as a remineralization agent. Collagen-silica scaffolds were evaluated in terms of physicochemical properties, drug release rate, mineralization potential, osteoblast response in vitro, antimicrobial activity, and biological properties using an in vivo preclinical model – chick embryo chorioallantoic membrane (CAM). The desirable multifunctionality of the proposed collagen-silica scaffolds was confirmed. They released the ciprofloxacin for 80 days, prevented biofilm development, and induced hydroxyapatite formation. Moreover, the resulting macroporous structure of the scaffolds promoted osteoblast attachment, infiltration, and proliferation. Collagen-silica scaffolds were also biocompatible and effectively integrated with CAM.

Development and characterization of AgHNTs@SPU film loaded with letrozole as drug delivery system and its anticancer activity

Polyurethane is an excellent implant biomaterial due to its elasticity, flexibility, resistance to abrasions and chemicals, and highly hydrophobic nature. The risk of hydrophobic nature is a significant drawback for an ideal drug delivery system. To enhance the hydrophilicity and compatibility of polyurethane via surface modification, such as (1) Introducing salicylic acid into the polymer backbone can create voids for the release of drugs from the matrix. (2) Doping silver onto HNTs by a simple one-pot precipitation method can enable silver to rupture the nucleus of cancer cells and induce ROS formation. The polyurethane and its mixed matrix were cast into the film to improve the initial effect of the drug, duration, and dosing than other conventional methods. The benefits of surface modification and thin film technology resulted in degradability, cytocompatibility, and excellent anticancer activity. The in vitro release studies depict that the letrozole-loaded film has a sustained release effect for a longer period based on the swelling ratio. The MTT assay showed that the [email protected] film could cause THP-1 cell death due to silver, polyols of PU, and HNTs. Salicylic acid played a vital role in increasing the antibacterial activity of the film. Furthermore, the increased oxidative stress was seen in [email protected]/Let film due to the biomaterial's active presence. Thus, [email protected]/Let a film is a potential approach for producing an implantable anticancer drug delivery system for the future with higher tumor cell death and prolonged drug release.