Formulation and optimization of a single-layer coat for targeting budesonide pellets to the descending Colon.

The current budesonide formulations are inadequate for addressing left-sided colitis, and patients might hesitate to use an enema for a prolonged time. This study focuses on developing a single-layer coating for budesonide pellets targeting the descending colon. Pellets containing budesonide (1.5%w/w), PVP K30 (5%w/w), lactose monohydrate (25%w/w) and Avicel pH 102 (68.5%w/w) were prepared using extrusion spheronization technique. Coating formulations were designed using response surface methodology with pH and time-dependent Eudragits. Dissolution tests were conducted at different pH levels (1.2, 6.5, 6.8, and 7.2). Optimal coating formulation, considering coating level and the Eudragit (S + L) ratio to the total coating weight, was determined. Budesonide pellets were coated with the optimized composition and subjected to continuous dissolution testing simulating the gastrointestinal tract. The coating, with 48% S, 12% L, and 40% RS at a 10% coating level, demonstrated superior budesonide delivery to the descending colon. Coated pellets had a spherical shape with a uniform 30 µm thickness coating, exhibiting pH and time-dependent release. Notably, zero-order release kinetics was observed for the last 9 h in colonic conditions. The study suggests that an optimized single-layer coating, incorporating pH and time-dependent polymers, holds promise for consistently delivering budesonide to the descending colon.

One-Minute Preparation of Iron Foam-Drug Implant for Ultralow-Power Magnetic Hyperthermia-Based Combination Therapy of Tumors in Vivo.

The magnetic hyperthermia-based combination therapy (MHCT) is a powerful tumor treatment approach due to its unlimited tissue penetration depth and synergistic therapeutic effect. However, strong magnetic hyperthermia and facile drug loading are incompatible with current MHCT platforms. Herein, an iron foam (IF)-drug implant is established in an ultra-facile and universal way for ultralow-power MHCT of tumors in vivo for the first time. The IF-drug implant is fabricated by simply immersing IF in a drug solution at an adjustable concentration for 1 min. Continuous metal structure of IF enables ultra-high efficient magnetic hyperthermia based on eddy current thermal effect, and its porous feature provides great space for loading various hydrophilic and hydrophobic drugs via "capillary action". In addition, the IF has the merits of low cost, customizable size and shape, and good biocompatibility and biodegradability, benefiting reproducible and large-scale preparation of IF-drug implants for biological application. As a proof of concept, IF-doxorubicin (IF-DOX) is used for combined tumor treatment in vivo and achieves excellent therapeutic efficacy at a magnetic field intensity an order of magnitude lower than the threshold for biosafety application. The proposed IF-drug implant provides a handy and universal method for the fabrication of MHCT platforms for ultralow-power combination therapy.

Influence of talc and hydrogenated castor oil on the dissolution behavior of metformin-loaded pellets with acrylic-based sustained release coating.

Multi-unit pellet system (MUPS) is of great interest as it is amenable to customization. MUPS comprises multi-particulates, usually as pellets or spheroids, which can be coated with diffusion barrier coatings. One commonly used diffusion barrier coating is the methacrylic acid copolymer, which can be used as a taste masking, enteric or sustained release polymer. While the versatility of methacrylic acid copolymers makes them pliable for pellet coating, there are impediments associated with their use. Additives commonly required with this polymer, including plasticizer and anti-adherent, have been shown to weaken the film strength. The objective of this study was to investigate the impact of osmotic pressure within the core on the sustained release coat integrity and functionality. Hydrogenated castor oil (HCO) was chosen as the additive to be studied. Metformin-loaded pellets, prepared via extrusion-spheronization, were coated with ethyl acrylate and methyl methacrylate copolymer (Eudragit RS 30 D) containing talc, talc-HCO, or HCO to different coat thicknesses. Drug release was investigated using the USP dissolution apparatus 2 and an ultraviolet imager. The swelling of the pellets when wetted was monitored by video imaging through a microscope. When coated to 7.5 % coat weight gain, coats with HCO slowed down drug release more than the other pellets. The pellets also swelled the most, which suggests that they were more resistant to the osmotic pressure exerted by metformin. For drugs which exert high osmotic pressure, HCO can serve as an efficient alternative to talc in the preparation of methacrylic acid copolymer coatings.

Tailoring therapeutic effect for chronotherapy of variant angina based on pharmacodynamic/deconvolution integrated model method.

The onset of variant angina (VA) shows circadian rhythmicity that its attacks occur most often from midnight to early morning. Thus, chronotherapeutic treatments should be tailored accordingly to its occurrence frequency. Tanshinol (TS), the bioactive component of Salvia miltiorrhiza was used as the model drug. The pharmacokinetics, pharmacodynamics and PK-PD relationship of TS was investigated in angina model rabbits. The therapeutic effect of TS was evaluated from different aspects including cardiac injury, oxidative stress and vascular endothelium by measuring the serum levels of cTn-I, CK-MB, SOD and NO. In addition, the change of cTn-I levels from baseline as the pharmacodynamic endpoint was used for establishing the pharmacodynamic model. To synchronize the therapeutic effect profile of TS to the occurrence frequency of VA, ideal time courses of therapeutic effect, plasma concentration and drug release were simulated and calculated based on pharmacodynamic/deconvolution integrated model method. Then, sustained release pellets of TS (TS-SRPs) were developed according to the above calculated results and evaluated in vitro-in vivo. The established pharmacodynamic model of TS could precisely quantify the relationship between its effect and concentration. Then, ideal time courses of therapeutic effect, plasma concentration and release of TS were simulated and calculated successfully. After formulation optimization, the prepared TS-SRPs exhibited similar in vitro and in vivo behaviors to the corresponding ideal ones. Meanwhile, the effect curves of TS were synchronous with the occurrence frequency of VA, implying that appropriate therapeutic effect could be provided according to the needs of patients. In conclusion, the tailor of therapeutic effect based on integrated model method is efficient, feasible and reliable.

The Gliopeptide ODN, a Ligand for the Benzodiazepine Site of GABAA Receptors, Boosts Functional Recovery after Stroke.

Following stroke, the survival of neurons and their ability to reestablish connections is critical to functional recovery. This is strongly influenced by the balance between neuronal excitation and inhibition. In the acute phase of experimental stroke, lethal hyperexcitability can be attenuated by positive allosteric modulation of GABAA receptors (GABAARs). Conversely, in the late phase, negative allosteric modulation of GABAAR can correct the suboptimal excitability and improves both sensory and motor recovery. Here, we hypothesized that octadecaneuropeptide (ODN), an endogenous allosteric modulator of the GABAAR synthesized by astrocytes, influences the outcome of ischemic brain tissue and subsequent functional recovery. We show that ODN boosts the excitability of cortical neurons, which makes it deleterious in the acute phase of stroke. However, if delivered after day 3, ODN is safe and improves motor recovery over the following month in two different paradigms of experimental stroke in mice. Furthermore, we bring evidence that, during the subacute period after stroke, the repairing cortex can be treated with ODN by means of a single hydrogel deposit into the stroke cavity.SIGNIFICANCE STATEMENT Stroke remains a devastating clinical challenge because there is no efficient therapy to either minimize neuronal death with neuroprotective drugs or to enhance spontaneous recovery with neurorepair drugs. Around the brain damage, the peri-infarct cortex can be viewed as a reservoir of plasticity. However, the potential of wiring new circuits in these areas is restrained by a chronic excess of GABAergic inhibition. Here we show that an astrocyte-derived peptide, can be used as a delayed treatment, to safely correct cortical excitability and facilitate sensorimotor recovery after stroke.

Unanticipated Consequences of Switching to Sugammadex: Anesthesia Provider Survey on the Hormone Contraceptive Drug Interaction.

BACKGROUND: Sugammadex binds progesterone with high affinity and may interfere with hormonal contraceptive effectiveness. The clinical, economical, and ethical implications of unintended pregnancy should prompt anesthesiologists to actively consider and manage this pharmacologic interaction. We surveyed anesthesiology providers at our institution about knowledge of this potential adverse drug interaction, how they manage it clinically, and the extent to which they involve patients in shared decision-making regarding choice of neuromuscular blocker antagonist. METHODS: A survey instrument was distributed to anesthesiology providers at a large, tertiary-care medical center. The survey explored prior experience using neostigmine and sugammadex, knowledge about potential sugammadex interference with hormonal contraception, pre-/postoperative counseling practices, clinical management, and shared decision-making regarding potential use of neostigmine in lieu of sugammadex to avoid this drug-drug interaction. RESULTS: Of 259 surveys distributed, 155 were fully completed, and 10 were partially completed. Overall response rate was 60% (residents 85%, student nurse anesthetists 53%, certified registered nurse anesthetists 58%, attendings 48%). All but 1 respondent recognized the potential for sugammadex interference with oral hormonal contraception. Far fewer accurately identified potential interference with hormonal intrauterine devices (44%) and hormonal contraceptive implants (55%). The manufacturer's recommended 7-day duration of alternative contraception was correctly identified by 72% of respondents; others (22%) reported longer durations (range 10-30 days). Most (78% overall) agreed/strongly agreed that potential interference with contraceptive effectiveness should be discussed with patients preoperatively. Despite the majority (86% overall) that endorsed shared decision-making and inviting patient input regarding choice between sugammadex and neostigmine, many respondents reported "rarely/never" having discussed this drug interaction with patients in actual clinical practice, either preoperatively (67%) or postoperatively (80%). Furthermore, most respondents (79%) reported "rarely/never" administering neostigmine to intentionally avoid this drug interaction. CONCLUSIONS: Two years after designating sugammadex as antagonist of choice, physician and nurse anesthesia providers reported seldom inquiring about contraceptive use among women of childbearing potential and rarely discussing potential risk of contraceptive failure from sugammadex exposure. Most lack accurate knowledge of sugammadex interference with hormonal intrauterine and subcutaneous contraceptive devices. Although most endorse preoperative counseling and support patient autonomy or shared decision-making regarding choice of reversal agent, the same respondents report rarely, if ever, actualizing these positions in clinical practice. These conflicting findings highlight the need for education regarding residual neuromuscular block versus adverse drug interactions, collaboration among providers involved in patient counseling, and intentional mindfulness of reproductive justice when caring for women of childbearing potential.

Modelling of combination therapy using implantable anticancer drug delivery with thermal ablation in solid tumor.

Local implantable drug delivery system (IDDS) can be used as an effective adjunctive therapy for solid tumor following thermal ablation for destroying the residual cancer cells and preventing the tumor recurrence. In this paper, we develop comprehensive mathematical pharmacokinetic/pharmacodynamic (PK/PD) models for combination therapy using implantable drug delivery system following thermal ablation inside solid tumors with the help of molecular communication paradigm. In this model, doxorubicin (DOX)-loaded implant (act as a transmitter) is assumed to be inserted inside solid tumor (acts as a channel) after thermal ablation. Using this model, we can predict the extracellular and intracellular concentration of both free and bound drugs. Also, Impact of the anticancer drug on both cancer and normal cells is evaluated using a pharmacodynamic (PD) model that depends on both the spatiotemporal intracellular concentration as well as characteristics of anticancer drug and cells. Accuracy and validity of the proposed drug transport model is verified with published experimental data in the literature. The results show that this combination therapy results in high therapeutic efficacy with negligible toxicity effect on the normal tissue. The proposed model can help in optimize development of this combination treatment for solid tumors, particularly, the design parameters of the implant.

Achieving delayed release of freeze-dried probiotic strains by extrusion, spheronization and fluid bed coating - evaluated using a three-step in vitro model.

Intake of probiotics is associated with many health benefits, which has generated an interest in formulating viable probiotic supplements. The present study had two aims. The first aim was to achieve gastrointestinal protection and delayed release of viable probiotics by pelletizing and coating freeze-dried probiotic strains, using riboflavin as a marker for release. The second aim was to set up a dynamic three-step in vitro model simulating the conditions in the human gastric, duodenum/jejunum and ileum compartments using physiologically relevant media to evaluate delayed release of the formulations. To simulate lowered bile acid concentrations in the ileum area of the gastrointestinal tract, a novel method using the bile acid sequestrant cholestyramine to lower bile acid concentrations in the small intestinal medium to physiologically relevant levels was attempted. Granulation, extrusion and spheronization was used to develop pellets containing viable probiotics using freeze-dried Lactobacullus reuteri as a model strain. Fluid bed coating the pellets with the pH-sensitive polymers Eudragit S100 or Eudragit FS30D resulted in targeted release in the ileum step of the three-step in vitro model based on release of the marker riboflavin.

Interventional pain management in patients with cancer-related pain.

Invasive interventional procedures for managing pain in cancer patients are often underutilized following the popularization of the WHO analgesic ladder. The procedures that were successfully used until then were relegated away from mainstream palliative care practice, with the advent of newer opioids and adjuvants. Even though nerve blocks, intrathecal pumps and spinal cord stimulation were reintroduced as the fourth step of the WHO ladder, often referrals for these procedures are too late to produce a meaningful effect on quality of life. At this point most patients have advanced disease and are requiring end of life care. Additionally, it is becoming evident that at least 10% of patients do not achieve good quality analgesia with oral opioids and are often troubled by unacceptable side effects. There is an increasing public awareness of the problems with long-term opioid therapy and some of these patients would certainly benefit from invasive procedures to alleviate their pain and improve their quality of life. Improving life quality and expectancy with better treatment options and increasing number of cancer survivors should be heralding a change and hence neurolytic procedures are to be used only in patients with limited life expectancy. ITDDs, neuromodulation and ever-increasing use of procedures routinely used in treating chronic nonmalignant pain would be the mainstay of interventional management until AI and nanotechnology would open doors for novel treatment options. Interventions should not be used as a last resort after multiple failed attempts at opioid therapy, but as an integral part of a management strategy including medical management, psychological and emotional welfare, and supportive care of the patient in a holistic manner. The curriculum of specialists should include appropriate training to safely perform and produce better quality evidence to validate the efficacy and safety of these challenging procedures.

Single-stage treatment of chronic localized tibial osteomyelitis with local debridement and antibiotic-loaded calcium sulfate implantation: a retrospective study of 42 patients.

BACKGROUND: Although various methods have been introduced, the management of chronic tibial osteomyelitis remains a challenge. This study aims to assess a combined treatment method, local debridement combined with antibiotic-loaded calcium sulfate implantation, for the management of the local (Cierny-Mader type III) tibial osteomyelitis. METHODS: Forty-two patients (43 limbs) with type III tibial osteomyelitis, from January 2012 to December 2018, who received the treatment method mentioned above were included in the study. The infection remission rate, recurrence rate, complications rate, and bone healing rate were respectively analyzed. RESULTS: With a mean follow-up of 42.8 months, 38 limbs (37 patients) (88.4%, 38/43) achieved infection remission without recurrence. Among those patients pain, limitation of movement, sinus tracts, topical redness, and swelling were generally eliminated. Only 4 patients felt slight pain after a long-distance walk, while another 6 patients showed minor but acceptable discomfort in affected limbs. Five patients (11.6%) suffered from osteomyelitis recurrence that required secondary surgical and medical treatment, but no amputation was necessary to eliminate the infection. Prolonged aseptic drainage was the most frequent complication that was observed in 13 patients (30.0%). They were successfully managed by appropriate wound caring in 10 patients and by surgical intervention, months later, in 3 patients. According to the final X-ray examination, bone losses caused by local debridement were generally repaired, though the shape of the tibia was not well-restored to its initial form in 17 limbs. No fracture was recorded during follow-up. CONCLUSION: Local debridement combined with antibiotic-loaded calcium sulfate implantation is effective and safe in a single-stage treatment of chronic Cierny-Mader III tibial osteomyelitis.

Multiple drug delivery from the drug-implants-laden silicone contact lens: Addressing the issue of burst drug release.

A fixed combination of bimatoprost/timolol eye drop solution is used to manage the elevated intra-ocular pressure in glaucoma patients, including individuals whose condition is poorly controlled by monotherapy. Eye drop solutions are generally given in high dose, due to poor ocular bioavailability. The high ocular dose of bimatoprost and timolol lead to hyperaemia and systemic cardiac side effects respectively. Here, we introduce multiple implant-laden contact lenses (IM) to passively deliver timolol, bimatoprost and hyaluronic acid at therapeutically relevant doses without high burst release. The drug-loaded implants were individually implanted in the outer periphery of the silicone contact lenses. Atomic force microscopy showed the smooth surface of the implant contact lens, as the implants were inside the contact lens matrix. The implant lens (IM) showed major loss of drugs [timolol = 60.60%, bimatoprost = 61.75% and HA = 46.03%] during the monomer extraction and wet sterilization, while the option of dry radiation sterilization (IM-R lens) and hydration for 24 h prior to use showed relatively lower loss of drugs [timolol = 16.87%, bimatoprost = 47.95% and HA = 24.41%]. The in-vitro drugs release data of IM-R lens, showed sustained release for 72 h, with low burst release in comparison to the soaked (SM) and direct drug-laden contact lenses (DL). The in vivo drug release data in the rabbit tear fluid showed sustained release using IM-R lens in comparison to the SM lens and eye drop therapy. The burst release with the IM-R lens was many folds reduced, which could bypass the side effects associated with multiple eye drop therapy. The in vivo pharmacodynamic study in the rabbit model showed peak and valley profile with multiple eye drop therapy, while IM-R lens showed prolong reduction in intra ocular pressure (IOP) for 120 h. The study demonstrates the application of implantation technology to deliver multiple drug through contact lenses to treat glaucoma.

Exogenous melatonin and male foetuses improve the quality of sheep colostrum.

Colostrum is the first product secreted by the mammary gland to transfer immunity to the newborn, especially through immunoglobulins (Ig) G. Melatonin is an immunomodulatory factor and there is evidence that it has a direct effect on IgG production. To evaluate the effects of melatonin treatment during pregnancy, litter size and offspring sex on colostrum quality, sixty pregnant Rasa Aragonesa ewes were divided into three groups: one group received a melatonin implant at the third month of pregnancy (3M, n = 13), another group at the fourth month (4M, n = 18) and the remaining ewes were not implanted (Control, C, n = 29). Immediately after lambing, a sample of colostrum was collected and IgG, crude protein and fat content analysed. Timing of melatonin implantation (p < .001), and offspring sex (p < .01) had a significant effect on IgG concentration. Colostrum of treated ewes had a higher mean (±SEM) IgG concentration than that of the control ewes (55.54 ± 3.09 and 49.50 ± 4.36 mg/ml, respectively; p < .05), mainly because the concentration in the 4M group was significantly (p < .001) higher than it was in the other groups. The relationship between lamb sex and IgG (p < .01) and %CP (p < .05) was evident in singletons (ewes with a male lamb: 54.57 ± 5.37 mg IgG/ml, 15.42 ± 0.82%CP; ewes with a female lamb: 34.66 ± 4.30 mg/ml, 13.18 ± 0.73%CP). The presence of a female in the litter was associated with significantly (p < .01) lower colostrum IgG levels (litters with at least one female: 49.33 ± 3.42 mg/ml; litters with no females: 58.24 ± 4.00 mg/ml). Among 4M ewes, female foetuses had significantly (p < .01) lower IgG levels whether they carried singletons or multiple lambs. In conclusion, treatment with melatonin implants at the fourth month of pregnancy resulted in a higher colostrum quality based on IgG concentration.

In-situ forming chitosan implant-loaded with raloxifene hydrochloride and bioactive glass nanoparticles for treatment of bone injuries: Formulation and biological evaluation in animal model.

In-situ forming implants receive great attention for repairing serious bone injuries. The aim of the present study was to prepare novel chitosan in-situ forming implants (CIFI) loaded with bioactive glass nanoparticles and/or raloxifene hydrochloride (RLX). Incorporating raloxifene hydrochloride (RLX) as a selective estrogen receptor modulator was essential to make use of its anti-resorptive properties. The prepared formulae were tested for their in-vitro gelation time, drug release, injectability, rheological properties, erosion rate and morphological properties. Results revealed that the formulation composed of 1% (w/v) chitosan with 2% (w/v) NaHCO3 and 1% (w/v) bioactive glass nanoparticles (CIFI-BG) possessed the most sustained drug release profile which extended over four months with low burst release effect compared to the same formulation lacking bioactive glass nanoparticles (CIFI). Selected formulations were tested for their ability to enhance bone regeneration in induced puncture in rate tibia. Results declared that these formulations were able to enhance bone regeneration after 12 weeks in comparison to the untreated tibial punctures and that containing bioactive glass could be considered as novel approach for treatment of serious bone injuries which require long term treatment and internal mechanical bone support during healing.

Efficacy of Antibiotic-Loaded Hydroxyapatite/Collagen Composites Is Dependent on Adsorbability for Treating Staphylococcus aureus Osteomyelitis in Rats.

Osteomyelitis remains one of the most challenging disorders for orthopedic doctors despite the advancement of therapeutic techniques. The purpose of this study was to investigate the feasibility of local antibiotic administration using hydroxyapatite/collagen (HAp/Col) as a drug delivery system. We hypothesized that higher adsorbability of antibiotics onto HAp/Col will result in more efficacious activity and therefore, treatment of osteomyelitis. Eight antibiotics were examined in this study: amikacin, cefazolin, cefotiam, daptomycin, minocycline, piperacillin, teicoplanin, and vancomycin. Aligning with their adsorbability onto HAp/Col, minocycline, teicoplanin, and vancomycin showed antibacterial effects up to 14 days after subcutaneous implantation in Wistar rats; while antibiotics with reduced adsorbability (cefazolin, cefotiam, piperacillin) had diminished antibacterial effects. Furthermore, when implanted into a rat femur, vancomycin levels from the Hap/Col were detected in the medullary space above the minimum inhibitory concentration for Staphylococcus aureus for 7 days, while cefazolin levels were undetectable. Aligning with these results, implantation of Hap/Col impregnated with vancomycin to the femur in an acute osteomyelitis rat model had a greater therapeutic effect than cefazolin, as measured by the number of bacteria, the extent of bone destruction, and bone regeneration. These results indicated that the adsorbability of antibiotics onto their carrier is important when locally administered and that HAp/Col scaffolds might be a useful antibiotic delivery system for osteomyelitis. © 2019 The Authors. Journal of Orthopaedic Research® published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society J Orthop Res 38:843-851, 2020.

Fluocinolone Acetonide Intravitreal Implant for Treating Recurrent Non-infectious Uveitis: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

The National Institute for Health and Care Excellence (NICE) invited Alimera Sciences, the company manufacturing fluocinolone acetonide intravitreal implant (FAc) 0.19 mg (tradename ILUVIEN®), to submit evidence on the clinical and cost-effectiveness of FAc for treating recurrent non-infectious uveitis. Kleijnen Systematic Reviews Ltd, in collaboration with Maastricht University Medical Centre + , was commissioned to act as the independent Evidence Review Group (ERG). This paper contains a summary of the clinical and cost-effectiveness evidence submitted by the company, the ERG's critique on the submitted evidence, and the guidance issued by the NICE Appraisal Committee (AC). The company submission (CS) was mainly informed by the PSV-FAI-001 trial in which FAc was compared with (limited) current practice [(L)CP], which was not considered to be representative of UK clinical practice by the ERG. There was no comparison of FAc to any treatment listed in the final scope, and especially to the dexamethasone intravitreal implant (dexamethasone), which was considered to be a relevant comparator by the AC. The primary outcome of the PSV-FAI-001 was recurrence of uveitis in the treated eye. Most of the events for the primary outcome were imputed during the PSV-FAI-001 trial, which probably led to an overestimation of the number of recurrences of disease, and a biased estimate of the relative effectiveness of FAc versus (L)CP. Finally, the place of FAc in the treatment pathway was not clearly defined by the company. Substantial uncertainty surrounded the cost-effectiveness results due to the shortcomings of the clinical evidence. Additionally, the quality of life of patients was not measured during the PSV-FAI-001 trial and long-term effectiveness data of FAc were lacking. The ERG adjusted several issues identified in the CS and added dexamethasone as a comparator in the decision analytic model. The ERG presented multiple analyses as base-cases because several elements of the assessment remained uncertain. The fully incremental ERG results ranged from dexamethasone (extendedly) dominating FAc (when assuming a hazard ratio of 1 or 0.7 for dexamethasone versus FAc) to an incremental cost-effectiveness ratio (ICER) of £30,153 per quality-adjusted life-year (QALY) gained for FAc versus (L)CP [when assuming a hazard ratio of 0.456 for dexamethasone versus (L)CP]. The ICER of FAc versus (L)CP ranged from £12,325 to £30,153 per QALY gained. After a second AC meeting where alternative company scenarios comparing FAc with dexamethasone were considered by the AC, the AC concluded that "the results of the company's analyses ranged from the fluocinolone acetonide implant being dominant (that is, it was more effective and costs less), to an ICER of £29,461 per QALY gained, and most of the ICERs were below £20,000 per QALY gained". Therefore, the AC recommended FAc as a cost-effective use of National Health Service (NHS) resources for treating recurrent non-infectious uveitis affecting the posterior segment of the eye in the final TA590 guidance (published July 2019).

A preformulation strategy for the selection of controlled-release components to simulate a subcutaneous implant / Una estrategia de preformulación para la selección de componentes de liberación controlada para simular un implante subcutáneo

Many chronic diseases require repetitive injections as maintenance treatment. It is therefore important to investigate a possible alternative. A simulated subcutaneous implant prototype was fabricated as a polymer matrix covered by cylinder-shape tubing having a porous membrane. Sucrose, bovine serum albumin, and gelatin were selected as matrix excipients. Eight APIs with different physiochemical properties were used to investigate the releasing mechanism. Drug release was tested through an in vitrodissolution apparatus. Drug release of eight APIs followed zero-order kinetics with a minimum 12-hour duration. Release rates also showed linear correlations with the APIs' solubilities under physiological pH. For releasing mechanism studies, different combinations of matrix and membrane were investigated in detail. A 144-hour continuous zero-order release of caffeine was achieved as the best controlled simulated prototype. The results showed that drug release of our simulated prototype was primarily achieved by drug diffusion rather than dissolution.

Muchas enfermedades crónicas requieren inyecciones repetitivas como tratamiento de mantenimiento. Por lo tanto, es importante investigar una posible alternativa. Se fabricó un prototipo de implante subcutáneo simulado a partir de una matriz de polímero cubierta por un tubo en forma de cilindro que tiene una membrana porosa. La sacarosa, la albúmina de suero bovino y la gelatina se seleccionaron como excipientes matriciales. Se utilizaron ocho APIs con diferentes propiedades fisicoquímicas para investigar el mecanismo de liberación. La liberación del fármaco se probó a través de un aparato de disolución in vitro. La liberación del fármaco de las ocho APIs siguió una cinética de orden cero con una duración mínima de 12 horas. Las tasas de liberación también mostraron correlaciones lineales con las solubilidades de las APIs a pH fisiológico. Para los estudios de mecanismos de liberación, se investigaron en detalle diferentes combinaciones de matriz y membrana. El prototipo simulado con mejor control logró una liberación continua de cafeína de orden cero durante 144 horas. Los resultados mostraron que la liberación del fármaco del prototipo simulado ocurrió principalmente mediante la difusión del fármaco en lugar de la disolución.

Long lasting in-situ forming implant loaded with raloxifene HCl: An injectable delivery system for treatment of bone injuries.

Bone injury is very serious in elder people or osteoporotic patients. In-situ forming implants (IFI) for bone rebuilding are usually poly-lactic-co-glycolic acid (PLGA)-based, which have a burst release effect. This study aimed to prepare novel liquid lipid-based PLGA-IFI loaded with raloxifene hydrochloride for prolonged non-surgical treatment of bone injuries by applying solvent-induced phase inversion technique. Labrasol® and Maisine® were added to the selected IFI forming long lasting lipid-based IFI (LLL-IFI). The formulations were characterized by analysing their in-vitro drug release, solidification time, injectability, rheological properties, and DSC in addition to their morphological properties. Results revealed that the LLL-IFI composed of 10%w/v PLGA with a lactide to glycolide ratio of 75:25 with ester terminal and 10% Maisine® possessed the most sustained drug release and lowest burst effect, as well as delayed pore formation compared to its counterpart lacking Maisine®. The selected LLL-IFI and PLGA-IFI formulations were tested for their capability to enhance bone regeneration in bone injuries induced in rats. Both formulations succeeded in healing the bones completely with the superiority of LLL-IFI in the formation of well-organized bone structures lacking fibrous tissues. The results suggest that LLL-IFI and PLGA-IFI are innovative approaches for treating critical and non-critical sized bone injuries.

Long-term biochemical outcomes using cesium-131 in prostate brachytherapy.

PURPOSE: Long-term outcomes reveal equivalent biochemical outcomes with low-dose-rate (LDR) brachytherapy (BT) compared with radical prostatectomy and external-beam radiotherapy for the management of prostate cancer. Iodine-125, the most commonly used isotope, may be associated with long-term urinary consequences. Cesium-131 (131Cs) has a higher dose rate and shorter dose delivery time, predicting a shorter duration of urinary morbidity. We report our institution's high-volume experience and the most mature data to date on outcomes with 131Cs prostate BT. METHODS AND MATERIALS: 571 men (median age: 65.38 years) with low (55%)-, intermediate (36%)-, and high-risk disease (9%) received monobrachytherapy, dual-modality, or trimodality using 131Cs at a single institution. Risk groups were defined according to the National Comprehensive Cancer Network definition. Median prescription dose for definitive LDR-BT and LDR-BT boost was 115 Gy and 70 Gy, respectively. Median initial PSA was 6.1 ng/mL (IQR: 4.6-8.7). RESULTS: Median followup time was 5 years. 5/7-year overall survival for low-, intermediate-, and high-risk patients was 96.9%/96/9%, 92.8%/89.7%, and 95.8%/87.1%, respectively (p = 0.02). 5/7-year freedom from biochemical failure for low-, intermediate-, and high-risk patients was 98.5%/96.3%, 94.1%/86.4%, and 93.2%/74.5%, respectively (p < 0.01). 5/7-year prostate cancer -specific survival was 100%/100%, 99.3%/99.3%, and 98.0%/98.0% for low-, intermediate-, and high-risk patients, respectively (p < 0.01). CONCLUSIONS: 131Cs is a viable alternative isotope for prostate brachytherapy for organ-confined disease. Long-term biochemical control and survival outcomes are excellent and on par with those attained with the use of 125I or 103Pd. This report therefore supports the continued use of 131Cs as an effective and comparable alternative isotope.

In-situ forming implants loaded with chlorhexidine and ibuprofen for periodontal treatment: Proof of concept study in vivo.

Control of infection and inflammation is crucial for the success of periodontal treatment. In this study, in-situ forming implants (ISFI) loaded with chlorhexidine dihydrochloride (CHX) and ibuprofen (IBU) were developed and tested to optimize periodontal treatment outcomes. Release profiles were promising. Exposure to 1.5% and 5.3% CHX-IBU loaded ISFI's release media decreased significantly the P. gingivalis growth up to 20-fold and 35-fold, respectively, after 48 h (p < 0.05). The metabolic activity assay of gingival epithelial cells (EC) demonstrated 1.5% CHX-IBU-loaded ISFI to be non-toxic, therefore, it was selected for further experimentation. Furthermore, significant down-regulation of TNF-α release (34% at 6 h and 43% at 24 h, p < 0.05) in P. gingivalis lipopolysaccharide (Pg-LPS) stimulated EC exposed to 1.5% CHX-IBU ISFI release medium was demonstrated by ELISA. In vivo, 1.5% CHX-IBU ISFI was injected into the periodontal pocket in an experimental periodontitis mouse model and the reduction in inflammation and improvement in periodontal wound healing was evaluated through inflammatory cell scoring and histomorphometry at 7- and 15-days post-treatment. The results indicate that CHX-IBU loaded ISFI could be efficient as adjuvant to periodontal therapy for the control of infection and inflammation. Moreover, other (e.g., pro-regenerative) drugs could be incorporated into ISFI to further improve periodontal treatment outcomes.