Reduced Frequency Of Administration Research Articles

Innovative Nanotechnology in Drug Delivery Systems for Advanced Treatment of Posterior Segment Ocular Diseases.

Funduscopic diseases, including diabetic retinopathy (DR) and age-related macular degeneration (AMD), significantly impact global visual health, leading to impaired vision and irreversible blindness. Delivering drugs to the posterior segment of the eye remains a challenge due to the presence of multiple physiological and anatomical barriers. Conventional drug delivery methods often prove ineffective and may cause side effects. Nanomaterials, characterized by their small size, large surface area, tunable properties, and biocompatibility, enhance the permeability, stability, and targeting of drugs. Ocular nanomaterials encompass a wide range, including lipid nanomaterials, polymer nanomaterials, metal nanomaterials, carbon nanomaterials, quantum dot nanomaterials, and so on. These innovative materials, often combined with hydrogels and exosomes, are engineered to address multiple mechanisms, including macrophage polarization, reactive oxygen species (ROS) scavenging, and anti-vascular endothelial growth factor (VEGF). Compared to conventional modalities, nanomedicines achieve regulated and sustained delivery, reduced administration frequency, prolonged drug action, and minimized side effects. This study delves into the obstacles encountered in drug delivery to the posterior segment and highlights the progress facilitated by nanomedicine. Prospectively, these findings pave the way for next-generation ocular drug delivery systems and deeper clinical research, aiming to refine treatments, alleviate the burden on patients, and ultimately improve visual health globally.

Enhancing the hypotensive effect of latanoprost by combining synthetic phosphatidylcholine liposomes with hyaluronic acid and osmoprotective agents

The first line of glaucoma treatment focuses on reducing intraocular pressure (IOP) through the prescription of topical prostaglandin analogues, such as latanoprost (LAT). Topical ophthalmic medicines have low bioavailability due to their rapid elimination from the ocular surface. Nanotechnology offers innovative ways of enhancing the ocular bioavailability of antiglaucoma agents while reducing administration frequency. This study aims to combine LAT-loaded synthetic phosphatidylcholine liposomes with hyaluronic acid (0.2% w/v) and the osmoprotectants betaine (0.40% w/v) and leucine (0.90% w/v) (LAT-HA-LIP) to extend the hypotensive effect of LAT while protecting the ocular surface. LAT-HA-LIP was prepared as a mixture of 1,2-dioleoyl-sn-glycero-3-phosphocholine and 1,2-dimyristoyl-sn-glycero-3-phosphocholine, cholesterol and α-tocopherol acetate. LAT-HA-LIP exhibited high drug-loading capacity (104.52 ± 4.10%), unimodal vesicle sizes (195.14 ± 14.34 nm) and a zeta potential of -13.96 ± 0.78 mV. LAT-HA-LIP was isotonic (284.00 ± 1.41 mOsm L−1), had neutral pH (7.63 ± 0.01) and had suitable surface tension (44.07 ± 2.70 mN m−1) and viscosity (2.69 ± 0.15 mPa s−1) for topical ophthalmic administration. LAT-HA-LIP exhibited optimal in vitro tolerance in human corneal and conjunctival epithelial cells. No signs of ocular alteration or discomfort were observed when LAT-HA-LIP was instilled in albino male New Zealand rabbits. Hypotensive studies revealed that, after a single eye drop, the effect of LAT-HA-LIP lasted 24 h longer than that of a marketed formulation and that relative ocular bioavailability was almost three times higher (p < 0.001). These findings indicate the potential ocular protection and hypotensive effect LAT-HA-LIP offers in glaucoma treatment.Graphical abstract

Evaluation of drug release, mucoadhesive and viscoelastic performances of Netildex gel versus an antibiotic‐steroid combination system

Purpose: The poor bioavailability and therapeutic response exhibited by conventional antibiotic‐steroid ophthalmic solutions due to rapid precorneal elimination of the drug may be overcome using a gel systems. Netildex gel is a preservative‐free product based on netilmicin and dexamethasone indicated for the treatment of inflammatory ocular conditions of the anterior segment and ocular adnexa including post‐cataract surgery. The current investigation evaluated the in vitro drug release, viscosity and mucoadhesion profile of Netildex gel in comparison to a gel matrix with regard to steroid and antibiotic delivery.Methods: In vitro drug release was assessed using Franz‐type diffusion cells, under sink condition, exploiting a simulated tear solution (STS) as dissolution medium and a regenerated cellulose membrane. Evaluation of mucoadhesive and viscoelastic properties were performed by texture analyzer TA‐XT2 and rheometer.Results: The dexamethasone and netilmicin release curves in Netildex gel exhibited a better sustained and controlled pattern over an extended time period (48 h) with respect to another gel system containing anti‐inflammatory and antibiotic drugs. The results were expressed as cumulative percentage of drug release and the antibiotics‐release kinetics from the polymeric matrix, evaluated by different mathematical models. The determination of detachment force demonstrated a significant mucoadhesive strength of Netildex gel compared to mucin. Moreover, rheological analysis of Netildex gel highlighted a strong pseudo‐plastic behaviour under shear strain due to its formulation features.Conclusions: Overall, Netildex gel exhibits a sustained and controlled drug release of both dexamethasone and netilmicin from polymeric matrix thanks to its viscoelastic and mucoadhesive properties allowing to prolong drug residence time on the ocular surface. These data support the reduced administration frequency while maintaining the same efficacy and simultaneously favouring patients' compliance [1].Reference1. Mencucci R. et al. Adv Ther (2022) 39: 5474–5486.

Moxifloxacin loaded microspheres-composed gel for controlled release and enhanced penetration in ocular tissues: In vitro, ex vivo and in vivo proof of concept

Microspheres-enriched ocular gels are proposed in this work for the loading of a model quinolone antibiotic of broad-spectrum - moxifloxacin hydrochloride (MXF) - as an approach to achieve a controlled release profile and enhance drug's bioavailability in ocular milieu. MXF is a synthetic fluoroquinolone antibacterial agent used for treatment of ocular diseases caused by strains of aerobic gram positive and gram-negative bacteria, besides others. MXF-loaded Eudragit RS microspheres were prepared by emulsion solvent evaporation method, as previously described by us. Optimized microspheres were characterized and then formulated in an ocular gel. Hydrophilic polymeric base HPMC K100 was used as gelling agent. Ocular gel enriched with microspheres was evaluated for its physicochemical parameters, in vitro drug release, ex vivo corneal and scleral permeation and bioadhesion, in vivo primary eye irritation and in vivo efficacy study. The developed MXF microspheres dispersed in an ocular gel showed an in vitro drug release over a period 12 h, improved corneal and scleral penetration and increased therapeutic efficacy with a reduced administration frequency which may contribute to increase patient's compliance to ocular treatment.

Nanomaterial-Based Drug Delivery Systems for Pain Treatment and Relief: From the Delivery of a Single Drug to Co-Delivery of Multiple Therapeutics.

The use of nanomaterials in drug delivery systems for pain treatment is becoming increasingly common. This review aims to summarize how nanomaterial-based drug delivery systems can be used to effectively treat and relieve pain, whether via the delivery of a single drug or a combination of multiple therapeutics. By utilizing nanoformulations, the solubility of analgesics can be increased. Meanwhile, controlled drug release and targeted delivery can be realized. These not only improve the pharmacokinetics and biodistribution of analgesics but also lead to improved pain relief effects with fewer side effects. Additionally, combination therapy is frequently applied to anesthesia and analgesia. The co-encapsulation of multiple therapeutics into a single nanoformulation for drug co-delivery has garnered significant interest. Numerous approaches using nanoformulation-based combination therapy have been developed and evaluated for pain management. These methods offer prolonged analgesic effects and reduced administration frequency by harnessing the synergy and co-action of multiple targets. However, it is important to note that these nanomaterial-based pain treatment methods are still in the exploratory stage and require further research to be effectively translated into clinical practice.

Dissolving Microneedle Patch Integrated with Microspheres for Long-Acting Hair Regrowth Therapy

Androgenetic alopecia (AGA) is the most common type of progressive hair loss in both men and women that severely reduces life quality and affects patients' self-esteem. Due to the shortcomings of traditional therapeutic formulations (e.g., topical minoxidil and oral finasteride), such as low bioavailability, frequent dosing, and significant side effects, there is an urgent need to develop a safe and effective strategy for AGA treatment. Here, we report a water-soluble microneedle (MN) patch integrated with biodegradable minoxidil (MXD)-loaded microspheres for long-acting AGA treatment with reduced administration frequency and improved patient compliance. When the patch pierces the skin, the MNs rapidly dissolve and deliver MXD-encapsulated polylactic-co-glycolic acid (PLGA) microspheres into the skin, which, subsequently act as drug reservoirs for the sustained release of the therapeutics for over 2 weeks. Additionally, the application of the MN patch provided a mechanical stimulation on mouse skin, which was also helpful for hair regrowth. Compared with the topical MXD solutions that have been commercialized on the market and require daily application, the long-acting MN patch contains a much lower drug amount and shows a similar or superior hair regeneration effect in AGA mice while only requiring monthly or weekly administration. These encouraging results suggest a simple, safe, and effective strategy for long-acting hair regeneration in clinics.

Saudi Consensus Recommendations on the Management of Multiple Sclerosis: Family Planning within the Management of MS

This review article addresses the complex issues faced by individuals with Multiple Sclerosis (MS) who are planning a family, becoming pregnant, or wishing to breastfeed their baby. Recommendations and guidelines were discussed and agreed upon by neurologists, neuroradiologists, nurses, and pharmacists involved in the management of MS in the Kingdom of Saudi Arabia (KSA). MS itself does not harm a pregnancy, and people with MS of childbearing age can be encouraged to enjoy family life. Family planning should be a part of the initial conversation with a newly diagnosed patient of childbearing age. Interferons and glatiramer acetate can be continued throughout pregnancy and can be administered during breastfeeding if the benefits outweigh the risks. These DMTs may be considered for a woman with well-controlled MS who is planning a pregnancy or otherwise not using contraception, according to an individualized risk-benefit analysis. The use of contraception should be maintained during the administration of other disease-modifying therapies (DMTs). Natalizumab can be administered at a reduced administration frequency to women with high MS disease activity up to 30 weeks gestation (this agent may induce hematological abnormalities in the fetus). Other DMTs should be withdrawn for variable periods before contraception is stopped and immediately after the discovery of a pregnancy (beware of rebound disease activity after withdrawing natalizumab or fingolimod). Resumption of treatment should not be delayed in women at risk of relapse during the postpartum period and especially in those who do not wish to breastfeed.

Cost-effectiveness of ravulizumab compared with eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria in the Netherlands.

The aim of this study was to evaluate the cost-effectiveness of ravulizumab compared with eculizumab for the treatment of adult patients with paroxysmal nocturnal hemoglobinuria (PNH) in the Netherlands. A cost-effectiveness analysis was conducted based on a Markov cohort model simulating the course of patients with PNH with clinical symptom(s) indicative of high disease activity, or who are clinically stable after having been treated with eculizumab for at least the past sixmonths. Costs, quality of life, and the incremental cost-effectiveness ratio (ICER) were estimated over a lifetime horizon from a Dutch societal perspective. Several additional analyses were performed, including a one-way sensitivity analysis, a probabilistic sensitivity analysis, and scenario analysis. When compared with eculizumab, ravulizumab saves €266,833 and 1.57 quality adjusted life years (QALYs) are gained, resulting in a dominant ICER. Drug costs account for the majority of the total costs in both intervention groups. Cost savings were driven by the difference in total treatment costs of ravulizumab compared with eculizumab caused by the reduced administration frequency, accounting for 98% of the total cost savings. The QALY gain with ravulizumab is largely attributable to the improved quality of life associated with less frequent infusions and BTH events. At a willingness-to-pay threshold of €20,000/QALY, there is a 76.6% probability that ravulizumab would be cost-effective. The cost reduction and QALY gain associated with the lower rates of BTH and less frequent administration make ravulizumab a cost-saving and clinically beneficial substitute for eculizumab for adults with PNH in the Netherlands.

Development of multifunctional drug delivery system via hot-melt extrusion paired with fused deposition modeling 3D printing techniques

The model of core–shell structured tablets is gaining increased interest due to its advantages in controlled-release and combinational drug delivery. Through the encapsulation of the drug by the outer shell, this model exhibits huge potential for reduced administration frequency, improved taste-masking, and personalized medication strategy. Although different types of core–shell tablets have been recently developed, most of them focused on the embedding of the solid tablets. Therefore there is still a need to investigate an optimized model in which multiple dosage forms can be loaded. This work uses hot-melt extrusion and fused deposition modeling 3D printing (FDM 3DP) techniques to develop a multifunctional core–shell model for controlled drug delivery. Acetaminophen (APAP) was used as the model drug. Hydroxypropyl cellulose (HPC) and hydroxypropyl methylcellulose (HPMC) was used as the matrix materials. Polyethylene oxide (PEO) and Eudragit RS PO (E RSPO) were used to adjust the printability while the E RSPO was expected to act as an extended-release agent due to its hydrophobicity. Liquid, semi-solid and solid dosage forms could be successfully loaded into the produced shells. The formulations were characterized by scanning electron microscopy, three point-bend tests, differential scanning calorimetry, and dissolution studies. The dissolution results suggested the modified-release character of the designed model. Overall, the designed core–shell model could be successfully produced via hot-melt extrusion paired with FDM 3DP techniques and could be utilized for the delivery of distinct dosage forms which improve the on-demand formulation development for patient-centered medication.

Injectable leonurine nanocrystal-loaded microspheres for long-term hyperlipidemia management.

Hyperlipidemia is a lipid metabolism disorder that requires long-term and daily medication. Leonurine (Leo), an active alkaloid derived from Herba leonuri, can effectively ameliorate lipid profiles in mammals and serve as a candidate antihyperlipidemic agent for clinical applications. In this paper, poly(lactic-co-glycolic acid) (PLGA) microsphere (MP)-based drug delivery platforms were for the first time employed for hyperlipidemia management by encapsulating leonurine nanocrystals (Leo-nano) by a modified solid-in-oil-in-water (S/O/W) double emulsion-solvent emulsion technique. The optimal formulation (Leo-nano@MP) was characterized by a high drug loading and encapsulation efficiency of 19.90 ± 0.82% and 79.62 ± 3.57%, respectively, which followed first-order drug release kinetics over 20 days in vitro. Interestingly, Leo-nano@MP exhibited a unique morphology with a condensed surface yet a porous internal structure, which potentially contributed to the enhanced drug loading and release properties. Furthermore, subcutaneous injection of Leo-nano@MP every two weeks significantly ameliorated the lipid profiles and alleviated liver and kidney injury in HFD-fed rats in comparison with daily administration of free Leo. Besides, no abnormalities in the heart, lung, spleen, and skin tissues at injection sites were observed. In summary, Leo-nano@MP with enhanced therapeutic efficacy, reduced administration frequency, and good biosafety constitutes a promising sustained-release platform for hyperlipidemia management.

Phenylboronic acid modified hydrogel materials and their potential for use in contact lens based drug delivery

The use of hydrogel-based contact lens materials holds promise for ophthalmic drug delivery by increasing drug residence time, improving drug bioavailability, reducing administration frequency, and enhancing special site targeting. Issues such as ease of manufacturing, lens comfort and appropriate release kinetics must be considered. Furthermore, the high water content of hydrogel materials can result in rapid and poorly controlled release kinetics. Herein, we modified common hydrogels used in contact lens manufacturing with phenylboronic acid (PBA). PBA addresses these material design issues since boronate esters are easily formed when boron acid and diols interact, opening up a pathway for simple modification of the model lens materials with saccharide based wetting agents. The wetting agents have the potential to improve lens comfort. Furthermore, the hydrophobicity of PBA and the presence of diols can be useful to help control drug release kinetics. In this work, polymerizable 3-(acrylamido)phenylboronic acid (APBA) was synthesized and incorporated into various hydrogels used in contact lens applications, including poly(2-hydroxyethylmethacrylate) (PHEMA), polyvinylpyrrolidone (PVP) and poly(N,N-dimethyl acrylamide) (PDMA) using UV induced free radical polymerization. The APBA structure and its incorporation into the hydrogel materials were confirmed by NMR and FTIR. The materials were shown to interact with and bind wetting agents such as hyaluronan (HA) and hydroxypropyl guar (HPG) by simple soaking in an aqueous solution. The equilibrium water content of the modified materials was characterized, demonstrating that most materials are still in the appropriate range after the introduction of the hydrophobic PBA. The release of three model ophthalmic drugs with varying hydrophilicity, atropine, atropine sulfate and dexamethasone, was examined. The presence of PBA in the materials was found to promote sustained drug release due to its hydrophobic nature. The results suggest that the modification of the materials with PBA was able to not only provide a mucoadhesive property that enhanced wetting agent interactions with the materials, but had the potential to alter drug release. Thus, the modification of contact lens materials with mucoadhesive functionality may be useful in the design of hydrogel contact lenses for ophthalmic drug release and wetting agent binding.

γ-Cyclodextrin-based polypseudorotaxane hydrogels for ophthalmic delivery of flurbiprofen to treat anterior uveitis

Anterior uveitis is a sight-threatening inflammation inside the eyes. Conventional eye drops for anti-inflammatory therapy need to be administered frequently owing to the rapid elimination and corneal barrier. To address these issues, polypseudorotaxane hydrogels were developed by mixing Soluplus micelles (99.4 nm) and cyclodextrins solution. The optimized hydrogels exhibited shear-thinning and sustained release properties. The hydrogels exhibited higher transcorneal permeability coefficient (Papp, 1.84 folds) than that of drug solutions. Moreover, animal study indicated that the hydrogels significantly increased the precorneal retention (AUC, 21.2 folds) and intraocular bioavailability of flurbiprofen (AUCAqueous humor, 17.8 folds) in comparison with drug solutions. Importantly, the hydrogels obviously boosted anti-inflammatory efficacy in rabbit model of endotoxin-induced uveitis at a reduced administration frequency. Additionally, the safety of hydrogels was confirmed by cytotoxicity and ocular irritation studies. In all, the present study demonstrates a friendly non-invasive strategy based on γ-CD-based polypseudorotaxane hydrogels for ocular drug delivery.

Effect of dose rate and timing of administration of pegbovigrastim on white blood cell responses in grazing dairy cows

Transition dairy cows experience a decline in immune function that increases the risk of peripartum disease. One strategy to improve peripartum immune function involves the use of a commercially available cytokine: bovine granulocyte-colony stimulating factor, with the addition of polyethylene glycol to increase duration of effectiveness. Treatment with Imrestor (15 mg pegbovigrastim; Elanco) one week before expected calving date (d -7) and again on the day of calving (d 0) was previously reported to increase the neutrophil number and improve neutrophil function; as a result, the incidence of clinical mastitis was reduced. We conducted 2 experiments over consecutive years to investigate the effect of a lower dose rate (half or quarter dose rate) of Imrestor in grazing dairy cattle and reduced administration frequency: one dose instead of the recommended 2. White blood cell counts were measured to determine changes in relative cell populations in response to treatment. Neutrophil function was assessed by measuring myeloperoxidase activity. Imrestor treatment increased the numbers of neutrophils, band cells, lymphocytes, and monocytes until 14 d postcalving in a dose-dependent manner; it also increased neutrophil myeloperoxidase activity. One dose of Imrestor increased white blood cell counts and myeloperoxidase activity, but the timing, degree, and duration of the response were different relative to the recommended 2 doses and were also dependent upon when Imrestor treatment was given. One dose at d -7 relative to expected calving date did not have a lasting effect postcalving, whereas one dose only on d 0 caused a delayed effect relative to cows that received 2 doses. There was no effect of Imrestor on milk yield or on blood indicators of transition cow health. A lower dose rate of Imrestor or a single dose of Imrestor on the day of calving may be sufficient to improve neutrophil function during the early postpartum in grazing dairy cows. Large-scale field studies are required to determine whether the smaller response from lower dose rates or the timing of the immunological response to drug delivery affect animal health in early lactation.

Ketorolac Tromethamine for Sustained Ocular Delivery; Novel In-Situ Gels Development and Evaluation

Objective: Ophthalmic ketorolac is used to treat itchy eyes caused by allergies. It also is used to treat swelling and redness (inflammation) that can occur after cataract surgery. Ketorolac is in a class of medications called nonsteroidal anti-inflammatory drugs (NSAIDs).&#x0D; Methods: Ocular bioavailability is always poor from conventional ophthalmic drops due to spillage and nasolachrymal drainage. Ocular in situ gels can increase the drug residence time thus increasing bioavailability. Polyacrylic acid (Carbopol 934) was used as the gelling agent in combination with hydroxypropylmethylcellulose (Methocel K4M) which acted as a viscosity enhancing agent. Compatibility studies of the drug excipients were carried out using differential scanning calorimetry. The prepared formulations were characterized for clarity, pH, drug content, sol-to-gel transition by scanning electron microscopy, in-vitro and in-vivo drug release, ocular irritation and stability.&#x0D; Results: FTIR spectras revealed that, there was no interaction between LEV and excipients. The formulated gels were transparent, uniform in consistency and had spreadability with a pH range of 7.1 to 7.4. Rheological studies revealed that the formulations were psuedoplastic in nature, drug content of sterile in situ gels was found to be 92-98%.Release kinetic study showed that the formulation followed first order diffusion controlled and the optimized formulations was having good antibacterial efficacy.&#x0D; Conclusion: The said promising formulation (F4) would be able to offer benefits such as increase residence time, prolonged drug release, reduction in frequency of administration and thereby definitely prove to improve the patient compliance.&#x0D;

Improved efficacy and safety of low doses of benznidazole-loaded multiparticulate delivery systems in experimental Chagas disease therapy

Benznidazole (BZ) is a first-line drug for the treatment of Chagas disease; however, it presents several disadvantages that could hamper its therapeutic success. Multiparticulate drug delivery systems (MDDS) are promising carriers to improve the performance of drugs. We developed BZ-loaded MDDS intended for improving Chagas disease therapy. To assess their efficacy and safety, Trypanosoma (T) cruzi infected BALB/c mice were orally treated with free BZ or BZ-MDDS at different regimens (doses of 50 and 100 mg/kg/day, administered daily or at 2- or 5-days intervals) and compared with infected non-treated (INT) mice. At 100 mg/kg/day, independent of the administration regimen, both treatments were able to override the parasitemia, and at 50 mg/kg/day significantly reduced it compared to INT mice. BZ-MDDS at a dose of 100 mg/kg/day administered every 5 days (BZ-MDDS 100–13d) induced the lowest cardiac parasite load, indicating an improved efficacy with lower total dose of BZ when loaded to the MDDS. Reactive oxygen species produced by leukocytes were higher in INT and mice treated with BZ at 50 mg/kg/day compared to 100 mg/kg/day, likely because of persistent infection. BZ-MDDS treatments markedly reduced heart and liver injury markers compared to INT mice and those receiving the standard treatment. Therefore, BZ-MDDS exhibited enhanced activity against T. cruzi infection even at lower doses and reduced administration frequency compared to free BZ while increasing the treatment safety. They likely avoid undesired side effects of BZ by keeping a sustained concentration, avoiding plasmatic drug peaks. BZ-MDDS evidenced significant improvements in experimental Chagas disease treatment and can be considered as a potential improved therapeutic alternative against this illness.

Morphological characterization of optimized risperidone-loaded in-situ gel forming implants with pharmacokinetic and behavioral assessments in rats

The present study aims to emphasize the enhanced efficacy of long acting in-situ gel forming implants (ISGFI) based on poly (lactic-co-glycolic acid) (PLGA) matrix to deliver anti-psychotic risperidone over extended time periods with reduced administration frequency. Schizophrenic patients show considerable difficulties in adherence and compliance to oral medications associated with negative outcomes including symptoms exacerbation and psychotic relapse. The studied optimized ISGFI formulation, comprised of 2.85:1 ratio of DMSO solvent:PLGA (type 75:25), was subjected to various characterization studies including morphological real-time changes, scanning electron microscopy and in-vitro drug release study. Pharmacokinetics and behavioral evaluations of anti-psychotic action of ISGFI systems were pursued on healthy and schizophrenia-induced rats respectively then compared to results of marketed microspheres. Morphological observations showed the immediate formation of whitish smooth ISGFI system owing to the rapid PLGA solidification after rapid DMSO dissipation into the external medium. Scanning electron microscopy confirmed the slow gradual biodegradation of the formed ISGFI. The optimized formulation assured its effectiveness to produce satisfactory initial burst and cumulative risperidone release and obviate costs of additional tablets needed during the commercial product use. Pharmacokinetic study manifested the effective performance of ISGFI to extend risperidone release for longer period (72 days) in comparison to the marketed formulations (48 days). Besides, optimized ISGFI were more effective in improving ketamine-induced schizophrenia-like symptoms in experimental rats, particularly in the first week of study period. Meanwhile, in-vitro, pharmacokinetic and pharmacodynamic evaluations had advocated the potential advantages of ISGFI systems for treating schizophrenia with improved adherence and compliance of patients.

Drug-Integrating Amphiphilic Nanomaterial Assemblies: 1. Spatiotemporal control of cyclosporine delivery and activity using nanomicelles and nanofibrils

Immunomodulatory therapies are limited by unavoidable side effects as well as poor solubility, stability, and pharmacokinetic properties. Nanomaterial-based drug delivery may overcome these limitations by increasing drug solubility, site-targeting, and duration of action. Here, we prepared innovative drug-integrating amphiphilic nanomaterial assemblies (DIANA) with tunable hydrophobicity, size, and morphology, and we evaluated their ability to deliver cyclosporine A (CsA) for immunomodulatory applications. We synthesized amphiphilic block copolymers made of poly(ethylene glycol)-poly(propylene sulfide) (PEG-PPS) and poly(ethylene glycol)-oligo(ethylene sulfide) (PEG-OES) that can self-assemble into solid core nanomicelles (nMIC, with ≈20 nm diameter) and nanofibrils (nFIB, with ≈5 nm diameter and > 500 nm length), respectively. nMIC and nFIB displayed good CsA encapsulation efficiency (up to 4.5 and 2 mg/mL, respectively in aqueous solution), superior to many other solubilization methods, and provided sustained release (>14 and > 7 days for the nMIC and nFIB) without compromising CsA's pharmacological activity. Treatment of insulin-secreting cells with unloaded DIANAs did not impair cell viability and functionality. Both CsA-loaded DIANAs inhibited the proliferation and activation of insulin-reactive cytotoxic T cells in vitro. Subcutaneous injections of CsA-loaded DIANAs in mice provided CsA sustained release, decreasing alloantigen-induced immune responses in the draining lymph node at lower doses and reduced administration frequency than unformulated CsA. While nMIC solubilized higher amounts and provided more sustained release of CsA in vitro, nFIB enhanced cellular uptake and promoted local retention due to slower trafficking in vivo. DIANAs provide a versatile platform for a local immune suppression regimen that can be applied to allogeneic cell transplantation.

Formulation and optimization of captopril-loaded microspheres based compressed tablets: in vitro evaluation

The core objective of this work was to formulate compressed tablets containing captopril-loaded microspheres for controlled delivery. Captopril is rapidly absorbed orally and has a bioavailability of ∼75%. The duration of action after a single oral dose is 6–8 h. Due to its relatively short half-life, a controlled released captopril formulation would bring benefits to patients, including reduction in frequency of administration, increased patient compliance and effectiveness of treatment, reduction in plasma concentration fluctuations, as well as a reduction in side effects. Double emulsification technique accompanied by solvent evaporation was employed for manufacturing captopril-loaded microspheres. Developed polymeric carriers were characterized for particle size analysis, entrapment efficiency, DSC, TGA, XRD, EDS, SEM, swelling index, and release studies. Microspheres have displayed spherical geometry and a size within micrometric range. They have shown high encapsulation efficiency (95%) at polymer to drug ratio (1:5:5). All the ingredients were compatible with each other. Optimized formulation ST1 has depicted zero-order drug release.

Extended Half-life rFVIII for the Treatment of Hemophilia A: Drugs Consumption and Patients’ Perspective

Prophylaxis is recognized as the most effective treatment regimen for patients with severe hemophilia A. Prophylaxis with standard half-life (SHL) FVIII products requires frequent intravenous administrations, at least two-three times per week. Frequency of injections is reported as one of the major obstacles to adherence to treatment and caused impairment in quality of life (QoL) and possible clinical implications. The extended half-life (EHL) rFVIII products recently reimbursed by Italian National Health Service (NHS), give the possibility of prophylactic dosage regimens characterized by reduced administration frequency with the potential to increase adherence to therapy and to improve QoL and clinical outcomes. Based on the approved dosing regimens the minimum and maximum number of administrations per year and the annual consumption for the marketed EHL rFVIII products were estimated. Compared to Adynovi® and Elocta®, Jivi® is the drug associated with the lowest number of administrations per year while versus Esperoct® is associated to a slightly higher maximum number of administrations per year. Furthermore, Jivi® has an annual mean consumption per kg lower than Adynovi®, Elocta® and Esperoct® (-24%, -27% and -22%, respectively). The contemporary reduction of number of injections per year and the lower annual mean consumption (IU) represent important benefits for the patient. From the economic point of view, at the prices published in Italian Official Journal, Jivi® weighted average annual expenditure per patient is 26% lower than Adynovi® and 29% lower than Elocta® and a saving is possible even considering a 10% increase in Jivi®’s price per IU versus comparators. Among the EHL rFVIII concentrates Jivi® appears to be more suitable to cover patients’ needs due to the possibility to adopt different dosage regimens (up to every 7 days) and is associated with the lowest average annual consumption per patient allowing a more predictable budget forecast and overall reducing the NHS expenditure.

Reduced administration frequency for the treatment of fungal keratitis: a sustained natamycin release from a micellar solution

ABSTRACT Background Natamycin is the only topical ophthalmic antifungal drug approved by the Food and Drug Administration (FDA) of the United States, but has unsatisfactory factors such as high dosing frequency. Methods We report the synthesis and preparation of self-assembled poly(ethylene glycol)-block-poly(glycidyl methacrylate) (PEG-b-PGMA) micelles. These nanoparticles exhibit sustained delivery of a hydrophobic natamycin by topical administration on eye due to the hydrolysable properties of PGMA segments of micelle. Hydrolysis of glycidyl groups within a physiologically relevant environment provides an additional driving force for drug release by generation of hydrophilic hydroxyl groups to ‘push’ the encapsulated hydrophobic drug away from the resultant hydrophilic domains and into surrounding environment. Results In vitro and in vivo results revealed that the self-assembled micelles and the encapsulated natamycin were not cytotoxic and the released drug have strong antifungal ability to Candida albicans. Importantly, sustained natamycin release from micelles leads to the reduced administration frequency of natamycin from 8 times per day to 3 times per day in rabbits suffering from fungal keratitis (FK). Conclusion This study demonstrates a facile method that can greatly reduce dosing frequency of natamycin administration and thus improve long-term patient compliance.