Special Issue "Depot Delivery Systems: Recent Advances on Materials, Technologies, and Beyond"

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Drug Delivery and Controlled Release".

Deadline for manuscript submissions: closed (31 July 2020).

Special Issue Editor

Prof. Dr. Paola Luciani
Website SciProfiles
Guest Editor
Department of Chemistry and Biochemistry, University of Bern, Bern, Switzerland
Interests: liposomes and lipid-based nanocarriers; depot injectables; targeted delivery; contrast agents for fluorescence functional imaging; cell-derived therapeutics and diagnostics
Special Issues and Collections in MDPI journals

Special Issue Information

Dear Colleagues,

By direct deposition of the drug at the site of action, depot delivery systems enable to limit the immediate exposure of the active principle at a systemic level and to reduce the frequency of administration. A reliable, steady, and prolonged drug release achieved with a non-invasive biocompatible system that can be conveniently produced and administered is an appealing solution to address various unmet clinical needs.

A large range of therapeutics, from small molecular drugs to larger biomacromolecules, can be loaded in in situ forming implants, microspheres, and injectable depots, to name a few, enabling to control the release from weeks till months. Despite the commercial success of a number of formulations, critical aspects such as the lack of correlation of in vitro with in vivo release profiles deriving from the inherent complexity of the physiological milieu, drug stability in the chosen matrix, burst release, low tolerability or foreign body reactions upon administration may affect dramatically product performance, jeopardizing a possible clinical success.

This Special Issue has the aim of highlighting current progress in the development of depot delivery systems with a particular attention to new technologies and new materials. Investigations on local tissue response to injections as well as studies on prototypes presenting a strong clinical potential will be also warmly welcomed.

Contributions could be submitted in the form of original research papers and review articles.

Prof. Dr. Paola Luciani
Guest Editor

Manuscript Submission Information

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Keywords

  • depot
  • sustained release
  • long acting injectables
  • in situ forming implants
  • controlled release injectables

Published Papers (10 papers)

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Research

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Open AccessArticle
Therapeutic Efficacy of Curcumin Enhanced by Microscale Discoidal Polymeric Particles in a Murine Asthma Model
Pharmaceutics 2020, 12(8), 739; https://doi.org/10.3390/pharmaceutics12080739 - 06 Aug 2020
Abstract
Curcumin is considered a potential anti-asthmatic agent owing to its anti-inflammatory properties. The objective of the present study was to prepare curcumin-containing poly(lactic-co-glycolic acid)-based microscale discoidal polymeric particles (Cur-PLGA-DPPs) and evaluate their anti-asthmatic properties using a murine asthma model. Cur-PLGA-DPPs were [...] Read more.
Curcumin is considered a potential anti-asthmatic agent owing to its anti-inflammatory properties. The objective of the present study was to prepare curcumin-containing poly(lactic-co-glycolic acid)-based microscale discoidal polymeric particles (Cur-PLGA-DPPs) and evaluate their anti-asthmatic properties using a murine asthma model. Cur-PLGA-DPPs were prepared using a top-down fabrication method. The prepared Cur-PLGA-DPPs had a mean particle size of 2.5 ± 0.4 μm and a zeta potential value of −34.6 ± 4.8 mV. Ex vivo biodistribution results showed that the Cur-PLGA-DPPs mainly accumulated in the lungs and liver after intravenous injection. Treatment with Cur-PLGA-DPPs effectively suppressed the infiltration of inflammatory cells in bronchoalveolar lavage fluid, and reduced bronchial wall thickening and goblet-cell hyperplasia compared to those in the phosphate-buffered-saline-treated control group. No significant changes in hematology and blood biochemistry parameters were observed after treatment with Cur-PLGA-DPPs. At equal curcumin concentrations, treatment with Cur-PLGA-DPPs exhibited better therapeutic efficacy than treatment with free curcumin. Our results suggest that the microscale Cur-PLGA-DPPs can be potentially used as a lung-targeted asthma therapy. Full article
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Open AccessArticle
Preparation and Evaluation of Intraperitoneal Long-Acting Oxaliplatin-Loaded Multi-Vesicular Liposomal Depot for Colorectal Cancer Treatment
Pharmaceutics 2020, 12(8), 736; https://doi.org/10.3390/pharmaceutics12080736 - 05 Aug 2020
Abstract
Colorectal cancer with peritoneal metastasis has a poor prognosis because of inadequate responses to systemic chemotherapy. Cytoreductive surgery followed by intraperitoneal (IP) chemotherapy using oxaliplatin has attracted attention; however, the short half-life of oxaliplatin and its rapid clearance from the peritoneal cavity limit [...] Read more.
Colorectal cancer with peritoneal metastasis has a poor prognosis because of inadequate responses to systemic chemotherapy. Cytoreductive surgery followed by intraperitoneal (IP) chemotherapy using oxaliplatin has attracted attention; however, the short half-life of oxaliplatin and its rapid clearance from the peritoneal cavity limit its clinical application. Here, a multivesicular liposomal (MVL) depot of oxaliplatin was prepared for IP administration, with an expected prolonged effect. After optimization, a combination of phospholipids, cholesterol, and triolein was used based on its ability to produce MVL depots of monomodal size distribution (1–20 µm; span 1.99) with high entrapment efficiency (EE) (92.16% ± 2.17%). An initial burst release followed by a long lag phase of drug release was observed for the MVL depots system in vitro. An in vivo pharmacokinetic study mimicking the early postoperative IP chemotherapy regimen in rats showed significantly improved bioavailability, and the mean residence time of oxaliplatin after IP administration revealed that slow and continuous erosion of the MVL particles yielded a sustained drug release. Thus, oxaliplatin-loaded MVL depots presented in this study have potential for use in the treatment of colorectal cancer. Full article
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Open AccessArticle
PLGA Microspheres of hGH of Preserved Native State Prepared Using a Self-Regulated Process
Pharmaceutics 2020, 12(7), 683; https://doi.org/10.3390/pharmaceutics12070683 - 20 Jul 2020
Abstract
The challenges of formulating recombinant human growth hormone (rhGH) into sustained-release polymeric microspheres include two mutual causal factors, protein denaturing by the formulation process and severe initial burst release related with relative high dose. The stabilizers to protect the proteins must not evoke [...] Read more.
The challenges of formulating recombinant human growth hormone (rhGH) into sustained-release polymeric microspheres include two mutual causal factors, protein denaturing by the formulation process and severe initial burst release related with relative high dose. The stabilizers to protect the proteins must not evoke osmotic pressure inside the microspheres, and the contact of the protein with the interface between water and organic solution of the polymer must be minimized. To meet these criteria, rhGH was pre-formulated into polysaccharide particles via an aqueous–aqueous emulsion in the present study, followed by encapsulating the particles into microspheres through a self-regulated process to minimize the contact of the protein with the water–oil interface. Polysaccharides as the protein stabilizer did not evoke osmotic pressure as small sugar stabilizers, the cause of severe initial burst release. Reduced initial burst enabled reduced protein loading to 9% (from 22% of the once commercialized Nutropin depot), which in turn reduced the dosage form index from 80 to 8.7 and eased the initial burst. A series of physical chemical characterizations as well as biologic and pharmacokinetic assays confirmed that the present method is practically feasible for preparing microspheres of proteins. Full article
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Open AccessArticle
In Vitro Bioeffects of Polyelectrolyte Multilayer Microcapsules Post-Loaded with Water-Soluble Cationic Photosensitizer
Pharmaceutics 2020, 12(7), 610; https://doi.org/10.3390/pharmaceutics12070610 - 30 Jun 2020
Cited by 1
Abstract
Microencapsulation and targeted delivery of cytotoxic and antibacterial agents of photodynamic therapy (PDT) improve the treatment outcomes for infectious diseases and cancer. In many cases, the loss of activity, poor encapsulation efficiency, and inadequate drug dosing hamper the success of this strategy. Therefore, [...] Read more.
Microencapsulation and targeted delivery of cytotoxic and antibacterial agents of photodynamic therapy (PDT) improve the treatment outcomes for infectious diseases and cancer. In many cases, the loss of activity, poor encapsulation efficiency, and inadequate drug dosing hamper the success of this strategy. Therefore, the development of novel and reliable microencapsulated drug formulations granting high efficacy is of paramount importance. Here we report the in vitro delivery of a water-soluble cationic PDT drug, zinc phthalocyanine choline derivative (Cholosens), by biodegradable microcapsules assembled from dextran sulfate (DS) and poly-l-arginine (PArg). A photosensitizer was loaded in pre-formed [DS/PArg]4 hollow microcapsules with or without exposure to heat. Loading efficacy and drug release were quantitatively studied depending on the capsule concentration to emphasize the interactions between the DS/PArg multilayer network and Cholosens. The loading data were used to determine the dosage for heated and intact capsules to measure their PDT activity in vitro. The capsules were tested using human cervical adenocarcinoma (HeLa) and normal human dermal fibroblast (NHDF) cell lines, and two bacterial strains, Gram-positive Staphylococcus aureus and Gram-negative Escherichia coli. Our results provide compelling evidence that encapsulated forms of Cholosens are efficient as PDT drugs for both eukaryotic cells and bacteria at specified capsule-to-cell ratios. Full article
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Open AccessArticle
PLGA Microspheres with Alginate-Coated Large Pores for the Formulation of an Injectable Depot of Donepezil Hydrochloride
Pharmaceutics 2020, 12(4), 311; https://doi.org/10.3390/pharmaceutics12040311 - 01 Apr 2020
Abstract
As the main symptom of Alzheimer’s disease-related dementia is memory loss, patient compliance for donepezil hydrochloride (donepezil), administered as once-daily oral formulations, is poor. Thus, we aimed to design poly(lactic-co-glycolic acid) (PLGA) microspheres (MS) with alginate-coated large pores as an injectable [...] Read more.
As the main symptom of Alzheimer’s disease-related dementia is memory loss, patient compliance for donepezil hydrochloride (donepezil), administered as once-daily oral formulations, is poor. Thus, we aimed to design poly(lactic-co-glycolic acid) (PLGA) microspheres (MS) with alginate-coated large pores as an injectable depot of donepezil exhibiting sustained release over 2–3 weeks. The PLGA MS with large pores could provide large space for loading drugs with high loading capacity, and thereby sufficient amounts of drugs were considered to be delivered with minimal use of PLGA MS being injected. However, initial burst release of donepezil from the porous PLGA MS was observed. To reduce this initial burst release, the surface pores were closed with calcium alginate coating using a spray-ionotropic gelation method. The final pore-closed PLGA MS showed in vitro sustained release for approximately 3 weeks, and the initial burst release was remarkably decreased by the calcium alginate coating. In the prediction of plasma drug concentration profiles using convolution method, the mean residence time of the pore-closed PLGA MS was 2.7-fold longer than that of the porous PLGA MS. Therefore, our results reveal that our pore-closed PLGA MS formulation is a promising candidate for the treatment of dementia with high patient compliance. Full article
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Open AccessArticle
An Injectable Click-Crosslinked Hydrogel that Prolongs Dexamethasone Release from Dexamethasone-Loaded Microspheres
Pharmaceutics 2019, 11(9), 438; https://doi.org/10.3390/pharmaceutics11090438 - 01 Sep 2019
Cited by 2
Abstract
Our purpose was to test whether a preparation of injectable formulations of dexamethasone (Dex)-loaded microspheres (Dex-Ms) mixed with click-crosslinked hyaluronic acid (Cx-HA) (or Pluronic (PH) for comparison) prolongs therapeutic levels of released Dex. Dex-Ms were prepared using a monoaxial-nozzle ultrasonic atomizer with an [...] Read more.
Our purpose was to test whether a preparation of injectable formulations of dexamethasone (Dex)-loaded microspheres (Dex-Ms) mixed with click-crosslinked hyaluronic acid (Cx-HA) (or Pluronic (PH) for comparison) prolongs therapeutic levels of released Dex. Dex-Ms were prepared using a monoaxial-nozzle ultrasonic atomizer with an 85% yield of the Dex-Ms preparation, encapsulation efficiency of 80%, and average particle size of 57 μm. Cx-HA was prepared via a click reaction between transcyclooctene (TCO)-modified HA (TCO-HA) and tetrazine (TET)-modified HA (TET-HA). The injectable formulations (Dex-Ms/PH and Dex-Ms/Cx-HA) were fabricated as suspensions and became a Dex-Ms-loaded hydrogel drug depot after injection into the subcutaneous tissue of Sprague Dawley rats. Dex-Ms alone also formed a drug depot after injection. The Cx-HA hydrogel persisted in vivo for 28 days, but the PH hydrogel disappeared within six days, as evidenced by in vivo near-infrared fluorescence imaging. The in vitro and in vivo cumulative release of Dex by Dex-Ms/Cx-HA was much slower in the early days, followed by sustained release for 28 days, compared with Dex-Ms alone and Dex-Ms/PH. The reason was that the Cx-HA hydrogel acted as an external gel matrix for Dex-Ms, resulting in the retarded release of Dex from Dex-Ms. Therefore, we achieved significantly extended duration of a Dex release from an in vivo Dex-Ms-loaded hydrogel drug depot formed by Dex-Ms wrapped in an injectable click-crosslinked HA hydrogel in a minimally invasive manner. In conclusion, the Dex-Ms/Cx-HA drug depot described in this work showed excellent performance on extended in vivo delivery of Dex. Full article
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Review

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Open AccessReview
Injectables and Depots to Prolong Drug Action of Proteins and Peptides
Pharmaceutics 2020, 12(10), 999; https://doi.org/10.3390/pharmaceutics12100999 - 21 Oct 2020
Abstract
Proteins and peptides have emerged in recent years to treat a wide range of multifaceted diseases such as cancer, diabetes and inflammation. The emergence of polypeptides has yielded advancements in the fields of biopharmaceutical production and formulation. Polypeptides often display poor pharmacokinetics, limited [...] Read more.
Proteins and peptides have emerged in recent years to treat a wide range of multifaceted diseases such as cancer, diabetes and inflammation. The emergence of polypeptides has yielded advancements in the fields of biopharmaceutical production and formulation. Polypeptides often display poor pharmacokinetics, limited permeability across biological barriers, suboptimal biodistribution, and some proclivity for immunogenicity. Frequent administration of polypeptides is generally required to maintain adequate therapeutic levels, which can limit efficacy and compliance while increasing adverse reactions. Many strategies to increase the duration of action of therapeutic polypeptides have been described with many clinical products having been developed. This review describes approaches to optimise polypeptide delivery organised by the commonly used routes of administration. Future innovations in formulation may hold the key to the continued successful development of proteins and peptides with optimal clinical properties. Full article
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Open AccessReview
Engineering Smart Targeting Nanovesicles and Their Combination with Hydrogels for Controlled Drug Delivery
Pharmaceutics 2020, 12(9), 849; https://doi.org/10.3390/pharmaceutics12090849 - 07 Sep 2020
Cited by 1
Abstract
Smart engineered and naturally derived nanovesicles, capable of targeting specific tissues and cells and delivering bioactive molecules and drugs into them, are becoming important drug delivery systems. Liposomes stand out among different types of self-assembled nanovesicles, because of their amphiphilicity and non-toxic nature. [...] Read more.
Smart engineered and naturally derived nanovesicles, capable of targeting specific tissues and cells and delivering bioactive molecules and drugs into them, are becoming important drug delivery systems. Liposomes stand out among different types of self-assembled nanovesicles, because of their amphiphilicity and non-toxic nature. By modifying their surfaces, liposomes can become stimulus-responsive, releasing their cargo on demand. Recently, the recognized role of exosomes in cell-cell communication and their ability to diffuse through tissues to find target cells have led to an increase in their usage as smart delivery systems. Moreover, engineering “smarter” delivery systems can be done by creating hybrid exosome-liposome nanocarriers via membrane fusion. These systems can be loaded in naturally derived hydrogels to achieve sustained and controlled drug delivery. Here, the focus is on evaluating the smart behavior of liposomes and exosomes, the fabrication of hybrid exosome-liposome nanovesicles, and the controlled delivery and routes of administration of a hydrogel matrix for drug delivery systems. Full article
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Open AccessReview
Injectable Lipid-Based Depot Formulations: Where Do We Stand?
Pharmaceutics 2020, 12(6), 567; https://doi.org/10.3390/pharmaceutics12060567 - 19 Jun 2020
Cited by 1
Abstract
The remarkable number of new molecular entities approved per year as parenteral drugs, such as biologics and complex active pharmaceutical ingredients, calls for innovative and tunable drug delivery systems. Besides making these classes of drugs available in the body, injectable depot formulations offer [...] Read more.
The remarkable number of new molecular entities approved per year as parenteral drugs, such as biologics and complex active pharmaceutical ingredients, calls for innovative and tunable drug delivery systems. Besides making these classes of drugs available in the body, injectable depot formulations offer the unique advantage in the parenteral world of reducing the number of required injections, thus increasing effectiveness as well as patient compliance. To date, a plethora of excipients has been proposed to formulate depot systems, and among those, lipids stand out due to their unique biocompatibility properties and safety profile. Looking at the several long-acting drug delivery systems based on lipids designed so far, a legitimate question may arise: How far away are we from an ideal depot formulation? Here, we review sustained release lipid-based platforms developed in the last 5 years, namely oil-based solutions, liposomal systems, in situ forming systems, solid particles, and implants, and we critically discuss the requirements for an ideal depot formulation with respect to the used excipients, biocompatibility, and the challenges presented by the manufacturing process. Finally, we delve into lights and shadows originating from the current setups of in vitro release assays developed with the aim of assessing the translational potential of depot injectables. Full article
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Open AccessReview
Adjuvant Drug-Assisted Bone Healing: Advances and Challenges in Drug Delivery Approaches
Pharmaceutics 2020, 12(5), 428; https://doi.org/10.3390/pharmaceutics12050428 - 06 May 2020
Abstract
Bone defects of critical size after compound fractures, infections, or tumor resections are a challenge in treatment. Particularly, this applies to bone defects in patients with impaired bone healing due to frequently occurring metabolic diseases (above all diabetes mellitus and osteoporosis), chronic inflammation, [...] Read more.
Bone defects of critical size after compound fractures, infections, or tumor resections are a challenge in treatment. Particularly, this applies to bone defects in patients with impaired bone healing due to frequently occurring metabolic diseases (above all diabetes mellitus and osteoporosis), chronic inflammation, and cancer. Adjuvant therapeutic agents such as recombinant growth factors, lipid mediators, antibiotics, antiphlogistics, and proangiogenics as well as other promising anti-resorptive and anabolic molecules contribute to improving bone healing in these disorders, especially when they are released in a targeted and controlled manner during crucial bone healing phases. In this regard, the development of smart biocompatible and biostable polymers such as implant coatings, scaffolds, or particle-based materials for drug release is crucial. Innovative chemical, physico- and biochemical approaches for controlled tailor-made degradation or the stimulus-responsive release of substances from these materials, and more, are advantageous. In this review, we discuss current developments, progress, but also pitfalls and setbacks of such approaches in supporting or controlling bone healing. The focus is on the critical evaluation of recent preclinical studies investigating different carrier systems, dual- or co-delivery systems as well as triggered- or targeted delivery systems for release of a panoply of drugs. Full article
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