Nanomedicine for Drug Delivery throughout the Alimentary Canal.

The field of nanomedicine continues to grow with new technologies and formulations in development for several disease states. Much research focuses on the use of injectable nanomedicines for treatment of neoplasms; however, there are several formulations in development that use nanotechnology that can be administered enterally for noncancer indications. These nanomedicine treatments have been developed for systemic drug delivery or local drug delivery along the gastrointestinal tract. This Review gives a brief overview of the alimentary canal and highlights new research in nanomedicine in noncancer disease states delivered via enteral routes of administration. Relevant recent research is summarized on the basis of the targeted site of action or absorption, including the buccal, sublingual, stomach, small intestine, and large intestine areas of the alimentary canal. The benefits of nanodrug delivery are discussed as well as barriers and challenges for future development in the field.

Exploring Different Strategies for Efficient Delivery of Colorectal Cancer Therapy.

Colorectal cancer (CRC) is the third most common cancer and the fourth leading cause of cancer death in the world. Currently available chemotherapy of CRC usually delivers the drug to both normal as well as cancerous tissues, thus leading to numerous undesirable effects. Much emphasis is being laid on the development of effective drug delivery systems for achieving selective delivery of the active moiety at the anticipated site of action with minimized unwanted side effects. Researchers have employed various techniques (dependent on pH, time, pressure and/or bacteria) for targeting drugs directly to the colonic region. On the other hand, systemic drug delivery strategies to specific molecular targets (such as FGFR, EGFR, CD44, EpCAM, CA IX, PPARγ and COX-2) overexpressed by cancerous cells have also been shown to be effective. This review aims to put forth an overview of drug delivery technologies that have been, and may be developed, for the treatment of CRC.

Formulation and investigation of differently charged ß-cyclodextrin-based meloxicam potassium containing nasal powders.

Nasal systemic drug delivery may provide an easy way to substitute parenteral or oral dosing, however, the excipients have an important role in nasal formulations to increase the permeability of the mucosa and prolong the residence time of the drug. In this work, we aimed to produce meloxicam potassium monohydrate (MXP) containing nasal powders by a nano spray drier with the use of a neutral, an anionic and a cationic ß-cyclodextrin as permeation enhancers, and (polyvinyl)alcohol (PVA) as a water soluble polymer. The following examinations were performed in order to study the effect of the applied excipients on the nasal applicability of the formulations: laser scattering, scanning electron microscope measurement, XRPD, DSC and FTIR measurements, adhesivity, in vitro drug release and permeability tests through an artificial membrane and RPMI 2650 cells. Based on our results, spherical particles were prepared with a size of 1.89-2.21 µm in which MXP was present in an amorphous state. Secondary interactions were formed between the excipients and the drug. The charged cyclodextrin-based formulations showed significantly higher adhesive force values regardless of the presence of PVA. The drug release was fast and complete. The passive diffusion of MXP was influenced not only by the charge of the cyclodextrin, but the presence of PVA, too. The permeation of the drug was enhanced in the presence of the anionic cyclodextrin testing it on RPMI 2650 cell model.

Advances and future perspectives of intranasal drug delivery: A scientometric review.

Intranasal drug delivery is as a noninvasive and efficient approach extensively utilized for treating the local, central nervous system, and systemic diseases. Despite numerous reviews delving into the application of intranasal drug delivery across biomedical fields, a comprehensive analysis of advancements and future perspectives remains elusive. This review elucidates the research progress of intranasal drug delivery through a scientometric analysis. It scrutinizes several challenges to bolster research in this domain, encompassing a thorough exploration of entry and elimination mechanisms specific to intranasal delivery, the identification of drugs compatible with the nasal cavity, the selection of dosage forms to surmount limited drug-loading capacity and poor solubility, and the identification of diseases amenable to the intranasal delivery strategy. Overall, this review furnishes a perspective aimed at galvanizing future research and development concerning intranasal drug delivery.

A comparison between the effect of systemic and coated drug delivery in osteoporotic bone after dental implantation.

The increased life expectancy has boomed the demand of dental implants in the elderly. As a consequence, considering the effect of poorer bone quality, due to aging or associated diseases such as osteoporosis, on the success of dental restoration is becoming increasingly important. Bisphosphonates are one of the most used drugs to overcome the effect of osteoporosis as they increase bone density. Bisphosphonates modify the physiological bone remodeling process by adhering to the bone surface, reducing the activity of osteoclasts. This study aims at comparing the effect on bone remodeling of two drug delivery methods of Bisphosphonates: local delivery by coating the implant surface and systemic delivery. A chemo-mechano-biological bone remodeling model validated in a previous paper was used here. The two drug delivery schemes were modeled by means of a finite element approach. In the systemic drug delivery case, the amount of drug that reaches the bone compartment was calculated using a pharmacokinetic model while in the local drug delivery system, the dose was calculated using Fickean diffusion. In particular, the effect of Zoledronate is studied here. The two drug delivery approaches are compared between them and with a control case with no drug. The results show that the use of Bisphosphonates increases the mechanical strength of bone, thus improving the implant fixation along time. Systemic drug delivery affects the entire skeleton, while local drug delivery only affects the area around the dental implant, which reduces the side effects of Bisphosphonates, such as increasing the mineral content, which may promote bone brittleness and microdamage far from the implant. These results support the conclusion that dental implants coated with Bisphosphonates can be a good solution for osteoporotic or low bone density patients without the long-term side effects of systemic drug delivery.

The design of multi-responsive nanohydrogel networks of chitosan for controlled drug delivery.

High swelling hydrogel networks (HSHNs) are materials with the ability to high swelling and outstanding candidates for sustained drug delivery systems (DDSs). The present paper demonstrates three different chitosan nanohydrogel networks (CNHN I-III) prepared through covalent and non-covalent interactions. These hydrogels have a high swelling ratio (up to 38-fold their dry weight) in various conditions. Two types of these hydrogels (CNHN I and II), swelled rapidly in an acidic environment, were able to successfully load an extraordinary amount (up to 95 %) of a model drug doxorubicin hydrochloride (DOX.HCl) at a 1:1 ratio (wt./wt.). The CNHN III had substantial swelling in pH 7.4, with a loading capacity of 92 % 5-fluorouracil (5-FU) at a 1:1 ratio (wt./wt.). The CNHN I and II have been considered for systemic drug delivery, while the CNHN III is one of the best candidates for oral drug delivery.

Targeting gliomas with STAT3-silencing nanoparticles.

Glioblastoma is an aggressive brain tumor with poor prognosis. The brain is protected by the blood-brain barrier, which precludes transport of chemotherapeutics. We developed nanoparticles that achieve delivery of small-interfering RNA against Stat3 after systemic administration. Nanoparticles combined with radiation inhibited tumor progression and elicited anti-glioblastoma immunity in mice.

Versatile Nasal Application of Cyclodextrins: Excipients and/or Actives?

Cyclodextrins (CDs) are oligosaccharides widely used in the pharmaceutical field. In this review, a detailed examination of the literature of the last two decades has been made to understand the role of CDs in nasal drug delivery systems. In nasal formulations, CDs are used as pharmaceutical excipients, as solubilizers and absorption promoters, and as active ingredients due to their several biological activities (antiviral, antiparasitic, anti-atherosclerotic, and neuroprotective). The use of CDs in nasal formulations allowed obtaining versatile drug delivery systems intended for local and systemic effects, as well as for nose-to-brain transport of drugs. In vitro and in vivo models currently employed are suitable to analyze the effects of CDs in nasal formulations. Therefore, CDs are versatile pharmaceutical materials, and due to the continual synthesis of new CDs derivatives, the research on the new nasal applications is an interesting field evolving in the coming years, to which Italian research will still contribute.

Systemic and Local Silk-Based Drug Delivery Systems for Cancer Therapy.

For years, surgery, radiotherapy, and chemotherapy have been the gold standards to treat cancer, although continuing research has sought a more effective approach. While advances can be seen in the development of anticancer drugs, the tools that can improve their delivery remain a challenge. As anticancer drugs can affect the entire body, the control of their distribution is desirable to prevent systemic toxicity. The application of a suitable drug delivery platform may resolve this problem. Among other materials, silks offer many advantageous properties, including biodegradability, biocompatibility, and the possibility of obtaining a variety of morphological structures. These characteristics allow the exploration of silk for biomedical applications and as a platform for drug delivery. We have reviewed silk structures that can be used for local and systemic drug delivery for use in cancer therapy. After a short description of the most studied silks, we discuss the advantages of using silk for drug delivery. The tables summarize the descriptions of silk structures for the local and systemic transport of anticancer drugs. The most popular techniques for silk particle preparation are presented. Further prospects for using silk as a drug carrier are considered. The application of various silk biomaterials can improve cancer treatment by the controllable delivery of chemotherapeutics, immunotherapeutics, photosensitizers, hormones, nucleotherapeutics, targeted therapeutics (e.g., kinase inhibitors), and inorganic nanoparticles, among others.

Enhanced pulmonary systemic delivery of protein drugs via zwitterionic polymer conjugation.

Pulmonary delivery of protein drugs into the systemic circulation is highly desirable as the lung provides a large absorption surface area and a more favorable environment for biologics compared to other delivery routes. However, pulmonary systemic delivery of proteins presents several challenges such as poor protein stability and limited bioavailability, especially for large proteins (molecular weight > 50 kDa), which exhibit an average bioavailability of 1% to 5% when delivered via the pulmonary route. Here, we demonstrated that with the conjugation of zwitterionic poly(carboxybetaine) (pCB) polymer, the bioavailability of organophosphate hydrolase (OPH) was significantly increased from 5% to 53%. OPH conjugated with pCB delivered through intubation-assisted intratracheal instillation (IAIS) into the lung exhibited improved pharmacokinetic properties and prophylactic efficacy against organophosphate poisoning, showing its application potential. Zwitterionic polymer conjugation provides the possibility for a favorable, non-invasive delivery of biological therapeutics into the systemic circulation.

Advances in drug delivery technology for the treatment of glioblastoma multiforme.

Glioblastoma multiforme (GBM) is a particularly aggressive and malignant type of brain tumor, notorious for its high recurrence rate and low survival rate. The treatment of GBM is challenging mainly because several issues associated with the GBM microenvironment have not yet been resolved. These obstacles originate from a variety of factors such as genetics, anatomy, and cytology, all of which collectively hinder the treatment of GBM. Recent advances in materials and device engineering have presented new perspectives with regard to unconventional drug administration methods for GBM treatment. Such novel drug delivery approaches, based on the clear understanding of the intrinsic properties of GBM, have shown promise in overcoming some of the obstacles. In this review, we first recapitulate the first-line therapy and clinical challenges in the current treatment of GBM. Afterwards, we introduce the latest technological advances in drug delivery strategies to improve the efficiency for GBM treatment, mainly focusing on materials and devices. We describe such efforts by classifying them into two categories, systemic and local drug delivery. Finally, we discuss unmet challenges and prospects for the clinical translation of these drug delivery technologies.

Oromucosal films: from patient centricity to production by printing techniques.

Introduction: Oromucosal films, comprising mucoadhesive buccal films (MBFs) and orodispersible films (ODFs), are considered patient-centric dosage forms. Target groups are patients with special needs. Various active pharmaceutical ingredients have been shown to be suitable for oromucosal film production. A shift is seen in the production techniques, from conventional solvent casting to printing techniques. Areas covered: In this review, the patient acceptability of oromucosal films is discussed. An overview is given of the small molecule drugs, biopharmaceuticals and herbal extracts that have been incorporated so far. Finally, the current state of 2D and 3D printing techniques for production purposes is discussed. Expert opinion: The patient-centric features are important for the further development and acceptance of this oral solid dosage form. Oromucosal films perfectly fit in the current attention for personalized medicine. Both MBFs and ODFs are intended for either a local or a systemic effect. For buccal absorption, sufficient mucoadhesion is one of the most important criteria an oromucosal film must comply with. For the preparation, the solvent casting technique is still predominately used. Some limitations of this production method can be tackled by printing techniques. However, these novel techniques introduce new requirements, yet to be set, for oromucosal film preparation.

Comparative impact of systemic delivery of atorvastatin, simvastatin, and lovastatin on bone mineral density of the ovariectomized rats.

PURPOSE: In addition to lipid-lowering properties, statins have been suggested to affect bone turnover by increasing the osteoblastic bone formation and blocking the osteoclastogenesis. However, there are many controversial reports regarding the beneficial effect of statins on osteoporosis. In this study, we investigated the therapeutic effects of the most important lipophilic statins administered orally for 60 days to the ovariectomized (OVX) female Sprague-Dawley rats and compared the effects on different harvested trabecular and compact bones. METHODS: Thirty female rats were divided into five equal groups including the normal rats, untreated OVX rats (negative control), and the OVX rats treated with atorvastatin (20 mg/kg/day), simvastatin (25 mg/kg/day), and lovastatin (20 mg/kg/day). The osteoporotic animals were treated daily for 60 days and euthanized at the end of experiments. The effectiveness of these treatments was evaluated by biomechanical testing, histopathologic, histomorphometric, micro-CT scan, real-time PCR, and serum biochemical analysis. Moreover, the hepatotoxicity and rhabdomyolysis related with these treatments were assessed by biochemistry analysis and histopathological evaluation. RESULTS: The results and statistical analysis showed that systemic delivery of simvastatin and lovastatin significantly increased serum calcium level, expression of osteogenic genes, bone mineral density (BMD), and biomechanical properties in comparison to the untreated OVX rats, especially in trabecular bones (P < 0.05). The results of different analysis also indicated that there was no statistical difference between the atorvastatin-treated animals and the negative control. Among all treatments, only atorvastatin showed an evident hepatotoxicity and myopathy. CONCLUSIONS: It was concluded that the lovastatin and simvastatin efficiently ameliorated the OVX-induced osteoporosis. Moreover, the simvastatin-treated animals showed more resemblance to the normal group in terms of BMD, expression of osteogenic genes, serum biochemical parameters, histomorphometric findings, and biomechanical performance with no significant side-effects.

Surfactant-free solubilization and systemic delivery of anti-cancer drug using low molecular weight methylcellulose.

Docetaxel, an advanced taxoid, has been widely used as an anti-mitotic agent, but further augmentation of its properties is still required, including improvement in low aqueous solubility. Herein, we report the development of bio-eliminable low molecular weight methylcellulose-based surfactant-free injectable formulation for the delivery of docetaxel. Crude methylcellulose, a hydrophobically modified cellulose derivative, was hydrolyzed by an enzymatic degradation method to obtain low molecular weight methylcellulose (LMwMC). Docetaxel was successfully loaded in micelles with small particle sizes high drug loading and sustained release profile. The in vivo anti-cancer effects of intravenously injected nanoparticle systems in B16F10 melanoma xenograft mice were evaluated and demonstrated a significantly enhanced therapeutic effect with the docetaxel-LMwMC micellar aggregates compared to a commercially available docetaxel, Taxotere®. Surfactant-free solubilization of docetaxel could be a promising delivery method for effective insoluble drug delivery for anti-tumor efficacy.

The expanding role of aerosols in systemic drug delivery, gene therapy and vaccination: an update.

Until the late 1990s, aerosol therapy consisted of beta2-adrenergic agonists, anti-cholinergics, steroidal and non-steroidal agents, mucolytics and antibiotics that were used to treat patients with asthma, COPD and cystic fibrosis. Since then, inhalation therapy has matured to include drugs that: (1) are designed to treat diseases outside the lung and whose target is the systemic circulation (systemic drug delivery); (2) deliver nucleic acids that lead to permanent expression of a gene construct, or protein coding sequence, in a population of cells (gene therapy); and (3) provide needle-free immunization against disease (aerosolized vaccination). During the evolution of these advanced applications, it was also necessary to develop new devices that provided increased dosing efficiency and less loss during delivery. This review will present an update on the success of each of these new applications and their devices. The early promise of aerosolized systemic drug delivery and its outlook for future success will be highlighted. In addition, the challenges to aerosolized gene therapy and the need for appropriate gene vectors will be discussed. Finally, progress in the development of aerosolized vaccination will be presented. The continued expansion of the role of aerosol therapy in the future will depend on: (1) improving the bioavailability of systemically delivered drugs; (2) developing gene therapy vectors that can efficiently penetrate the mucus barrier and cell membrane, navigate the cell cytoplasm and efficiently transfer DNA material to the cell nucleus; (3) improving delivery of gene vectors and vaccines to infants; and (4) developing formulations that are safe for acute and chronic administrations.