Добірка наукової літератури з теми "Intra-Articular administration"

Objectives: The aim of our study is to provide a comparison betweenlevobupivacaine and bupivacaine administered intra articulary in the knee joint duringarthroplasty procedures, and compare the postoperative analgesic effects. Method: StudyDesign: Randomized control trial. Period: One year duration from March 2015 to March 2016.Setting: Tertiary care centre in Karachi, Pakistan. The study population consisted of n= 50patients belonging to ASA class II and III, who were scheduled to undergo TKA (total kneearthroplasty). The patient population was divided into two groups, group A consisted of all thepatients who received bupivacaine, and group B consisted of all the patients who receivedlevobupivacaine. All the patients were between the ages of 18 and 70 years, and had normaljoint mobility. After explaining the procedure and taking due informed consent, the patientswere informed about the use of the visual analog scale for pain and the patients controlledepidural anesthesia (PCEA). Readings of echocardiograph, blood pressure and pulse oximetry,sensory and motor characteristics of the established block, side effects, number of bolusesand doses of PCEA, total amount of pain relief medications utilized over the period, VAS scoresand time of mobilization and discharge from the hospital were also noted in a pre-designed.Statistical analysis was done using SPSS version 23. Results: The study population consistedof n= 50 patients. The VAS scores at were found to be lower in the bupivacaine group at 4,8,12and 24 hours and VAS scores at 48 hour were lower in levobupivacaine group having a p valueof less than 0.05, but the VAS scores were similar at the 0,2 and 72 hours in both the groups.The post-operative analgesic requirement was similar for both groups. The sensation of painat the time of post-operative physiotherapy measure with the VAS score, was also similar inthe two groups having a p value of less than 0.05. Similar results were found between the timeof discharge and time of mobility, having a p value of less than 0.05. Conclusion: The use ofmultimodal analgesia with the administration of intra articular local anesthetics combined withPCEA is a very effective method to provide post-operative pain relief in patients undergoing totalknee arthroplasty.

Introduction. Adhesive capsulitis (AC) of the shoulder presents with an insidious onset of pain and progressive limitation of shoulder movement.Objectives. To investigate whether intra-articular hyaluronic acid (HA) administration alone is superior to conventional therapies and whether the addition of intra-articular HA administration to conventional therapies improves clinical outcomes in patients with AC.Methods. The PubMed, EMBASE, CINAHL, and Cochrane Library electronic databases were searched without language restrictions in July 2014 witha prioridefined inclusion and exclusion criteria.Results. Four randomized controlled trials (273 participants, 278 shoulders) were included in this review. Two trials compared intra-articular HA administration with conventional therapies and 2 trials evaluated intra-articular HA administration as an addition to conventional therapies. Pain and shoulder function/disability outcomes in the HA injection group were not superior to those achieved in the conventional therapy groups. No significant differences in pain or shoulder function/disability outcomes were noted between the groups with and without adjunctive HA administration.Conclusions. Intra-articular HA administration alone is not superior to conventional AC treatments, and the addition of intra-articular HA administration to conventional therapies does not provide significant added benefits. HA administration in AC patients who are receiving conventional therapies should be evaluated to avoid unnecessary medical expenditure.

Aims Intra-articular administration of antibiotics during primary total knee arthroplasty (TKA) may represent a safe, cost-effective strategy to reduce the risk of acute periprosthetic joint infection (PJI). Vancomycin with an aminoglycoside provides antimicrobial cover for most organisms isolated from acute PJI after TKA. However, the intra-articular doses required to achieve sustained therapeutic intra-articular levels while remaining below toxic serum levels is unknown. The purpose of this study is to determine the intra-articular and serum levels of vancomycin and tobramycin over the first 24 hours postoperatively after intra-articular administration in primary cementless TKA. Methods A prospective cohort study was performed. Patients were excluded if they had poor renal function, known allergic reaction to vancomycin or tobramycin, received intravenous vancomycin, or were scheduled for same-day discharge. All patients received 600 mg tobramycin and 1 g of vancomycin powder suspended in 25 cc of normal saline and injected into the joint after closure of the arthrotomy. Serum from peripheral venous blood and drain fluid samples were collected at one, four, and 24 hours postoperatively. All concentrations are reported in µg per ml. Results A total of 22 patients were included in final analysis. At one, four, and 24 hours postoperatively, mean (95% confidence interval (CI)) serum concentrations were 2.4 (0.7 to 4.1), 5.0 (3.1 to 6.9), and 4.8 (2.8 to 6.9) for vancomycin and 4.9 (3.4 to 6.3), 7.0 (5.8 to 8.2), and 1.3 (0.8 to 1.8) for tobramycin; intra-articular concentrations were 1,900.6 (1,492.5 to 2,308.8), 717.9 (485.5 to 950.3), and 162.2 (20.5 to 304.0) for vancomycin and 2,105.3 (1,389.9 to 2,820.6), 403.2 (266.6 to 539.7), and 98.8 (0 to 206.5) for tobramycin. Conclusion Intra-articular administration of 1 g of vancomycin and 600 mg of tobramycin as a solution after closure of the arthrotomy in primary cementless TKA achieves therapeutic intra-articular concentrations over the first 24 hours postoperatively and does not reach sustained toxic levels in peripheral blood. Cite this article: Bone Joint J 2021;103-B(11):1702–1708.

Introduction and aim. Osteoarthritis (OA) is generally a progressive disease that affects synovial joints, resulting in abnormalities to articular cartilage subchondral bone, synovium, and adjacent soft tissues. The purpose of this work was to investigate the specific activity of chondroitin sulfate (CS) in intra-articular and intramuscular administration to laboratory rabbits in experimental OA. Material and methods. OA was induced in rabbits by a single injection of mono-iodoacetate in knee joint. CS was administered intra-articularly and intramuscularly. The analysis of biochemical markers and macroscopic assessment of rabbit knee joints was performed. Results. Intramuscular and intra-articular injection of CS reduces the intensity of the degenerative-dystrophic process due to the impact on inflammatory and the activation of anabolic mechanisms. Intra-articular administration of CS leads to a greater increase in the level of factors of bone and cartilage formation and a greater decrease in the levels of factors of the acute phase of inflammation and factors that destroy the cartilage matrix. Conclusion. Intramuscular administration of CS revealed a lower intensity of destructive changes in the cartilaginous surface of the knee joint, and intramuscular – the absence of cartilage destruction and defects of the cartilaginous surface, which indicates the peculiarity of the topical effect of the CS.

Four adult, client owned dogs with diagnosed bilateral elbow dysplasia undergoing elbow arthroscopy for removal of fragmented medial coronoid process were identified via a retrospective database search, who also received intra-articular administration of pentosan polysulfate sodium (PPS) (Cartrophen Vet, Biopharm Australia Pty Ltd., Bondi Junction, New South Wales). Dogs had postoperative administration of 5 ml PPS injected into each elbow joint following elbow arthroscopy. Within 1-3 hours of administration, each dog experienced hemorrhage from arthroscopy incisions that was determined to be independent of surgical trauma given lack of hemorrhage intraoperatively. Pressure bandages were placed, and the hemorrhage and elevated coagulation parameters resolved 12-18 hours following intra-articular injection. No further intervention was required, and the dogs were discharged 20-26 hours postoperatively. The purpose of this case series is to describe 4 dogs who experienced transient and focal hemorrhage following off-label intra-articular administration of pentosan polysulfate sodium (PPS). While this case series is limited due to small number of cases, results following bilateral, intra-articular injection of PPS support a transient systemic coagulopathy. Though this report represents administration of PSS via a route and at doses beyond that recommended on the label, results suggest that administration of PSS in the manner described in this report should be avoided.

Objective: To compare the blood loss between intra-articular and intra-venous administration of tranexamic acid (TXA) in patients undergoing primary total knee arthroplasty. Design of study: It was a randomized controlled trial. Study duration and settings: This study was carried out at the Orthopedic Departments of Combined Military Hospital Lahore and Rawalpindi from Jan 2016 to March 2018. Methodology: Patients of both the genders were involved this study who had age in the rage of 40–80 years undergoing primary unilateral total knee arthroplasty for degenerative conditions like osteoarthritis and rheumatoid arthritis. These patients were randomly divided into two treatment groups. Patients in IA group received intra-articular tranexamic acid while those in IV group received intravenous tranexamic acid. From all the patients, a written signed consent was taken. Findings: Females were predominant with male-to-female ratio of 1:3.7. The mean age of the patients was 67.3 ± 8.2 years while the mean BMI was 30.9 ± 2.9 Kg/m2. Majority (n = 191, 95.5%) of the patients had osteoarthritis while remaining 9 (4.5%) patients had rheumatoid arthritis. There was no statistically significant difference between intra-articular and intra-venous administration of tranexamic acid in terms of mean post-operative hemoglobin (9.93 ± 1.14 vs. 9.87 ± 1.26 g/dL; p-value = 0.724), mean post-operative hematocrit (34.8 ± 1.66 vs. 34.73 ± 1.27%; p-value = 0.594), and mean fall in hemoglobin (2.27 ± 0.34 vs. 2.25 ± 0.30 g/dL; p-value = 0.587) and hematocrit (2.34 ± 0.94 vs. 2.46 ± 0.28%; p-value = 0.216). Conclusion: Intra-articular administration of tranexamic acid was found to be as effective and safe as intra-venous administration in reducing blood loss in primary total knee arthroplasty. Due to convenience, the use of intra-articular administration of tranexamic acid after primary TKA may be considered in future practice.

La rapamycine est un inhibiteur de mTOR actuellement utilisé comme immunosuppresseur, notamment dans le domaine des greffes. Elle inhibe la voie de signalisation mTOR entrainant la restauration de l'autophagie, processus déficient lors de la physiopathologie de l'arthrose, rendant son utilisation intéressante dans le traitement des arthropathies dégénératives. La rapamycine est cependant responsable d'effets indésirables médicamenteux systémiques notables. Pour réduire ce risque, son injection locale, au sein de l'articulation, est une alternative avantageuse. Néanmoins, cette voie d'administration a des inconvénients : le contact direct du tissu articulaire à des concentrations importantes de principe actif, sa clairance à partir de la cavité articulaire, et la difficulté d'administrer un tel composé hydrophobe. De fait, le développement de nanoparticules est une alternative séduisante pour améliorer son utilisation par voie intra-articulaire. Dans ces travaux, nous avons évalué la cytotoxicité de la rapamycine sur les cellules de l'articulation, à savoir les chondrocytes et les synoviocytes à différentes concentrations et différents temps. Nous avons observé une cytotoxicité dose-dépendante, et une sensibilité plus importante des synoviocytes par rapport aux chondrocytes. La cytotoxicité sur des cellules souches mésenchymateuses osseuses, qui sont utilisées en ingénierie articulaire, a également montré une toxicité dose-dépendante. La rapamycine à 10 µM, décrite comme retardant les lésions cartilagineuses dans l'arthrose expérimentale, n'induit pas de toxicité et permet de réduire l'effet catabolique de la MMP13 induite par l'IL-1ß sur les chondrocytes et les synoviocytes. Dans cette étude, des nanoparticules de PLGA ont été développées pour libérer de façon prolongée la rapamycine après une administration intra-articulaire à cette concentration. Elles n'ont pas été responsables de cytotoxicité sur les chondrocytes, les synoviocytes. Enfin, nous avons constaté in vivo que l'administration de 50 µL de rapamycine à 10 µM sous forme de nanoparticules par voie intra-articulaire chez le rat augmentait sa demi-vie et son temps de rétention moyen dans l'articulation comparativement à une administration locale de la forme libre, tout en diminuant sa diffusion systémique
Rapamycin is an mTOR inhibitor currently used as an immunosuppressant, particularly in the field of transplantation. It inhibits the mTOR signaling pathway leading to the restoration of autophagy, a process that is deficient in the pathophysiology of osteoarthritis, making its use interesting in the treatment of degenerative arthropathies. However, rapamycin is responsible for significant systemic adverse drug reactions. To reduce this risk, its local injection, within the joint, is an advantageous alternative. Nevertheless, this route of administration has disadvantages: direct contact of the joint tissue with high concentrations of active drug, its clearance from the joint cavity, and the difficulty of administering such a hydrophobic compound. Therefore, the development of nanoparticles is an attractive alternative to improve its use by intra-articular application. In this work, we evaluated the cytotoxicity of rapamycin on joint cells, namely chondrocytes and synoviocytes at different concentrations and different times. We observed a dose-dependent cytotoxicity, and a higher sensitivity of synoviocytes compared to chondrocytes. Cytotoxicity on bone mesenchymal stem cells, which are used in cartilage engineering, also showed dose-dependent toxicity. Rapamycin at 10 µM, described as delaying cartilage damage in experimental osteoarthritis, does not induce toxicity and reduces the catabolic effect of IL-1ß-induced MMP13 on chondrocytes and synoviocytes. In this study, PLGA nanoparticles were developed to release rapamycin in a sustained manner after intra-articular administration at this concentration. Free and rapamycin-loaded nanoparticles were not responsible for cytotoxicity on chondrocytes, synoviocytes. Finally, we found in vivo that administration of 50 µL of 10 µM rapamycin-loaded nanoparticle intra-articularly in rats increased its half-life and mean retention time in the joint, compared to local administration of the free form, while decreasing its systemic diffusion

L’arthrose et l’arthrite rhumatoïde sont deux pathologies articulaires caractérisées par la dégradation du cartilage articulaire, subséquente à la production de divers médiateurs inflammatoires. Le traitement de ces pathologies se limite généralement à soulager le patient des épisodes douloureux et inflammatoires et à améliorer sa qualité de vie. Dans le cas de l’arthrose, peu de traitements permettent d’enrayer significativement l’évolution de la dégradation du cartilage et donc de la maladie. Par contre, l’arthrite rhumatoïde peut être efficacement ralentie grâce à l’administration de certaines molécules. Néanmoins, ces traitements n’ont généralement montré qu’une efficacité à court-terme, requérant une administration fréquente. L’objectif de ce travail repose donc sur l’élaboration de nouvelles options thérapeutiques permettant de réduire la fréquence d’administration ainsi que les effets indésirables des traitements actuels. La délivrance de molécules en intra-articulaire associée à une libération prolongée offre l’avantage d’exposer les sites directement impliqués dans l’évolution de la maladie à une ou plusieurs molécules efficaces contre l’inflammation et la douleur, et aidant à la régénération du cartilage, durant plusieurs semaines, voire des mois.

Des microparticules de PLGA chargées en clonidine ou en bétaméthasone ont donc été optimisées afin d’obtenir des efficacités d’encapsulation appréciables (clonidine HCl :EE ≈ 20% ;dipropionate de bétaméthasone :EE ≈ 70%), une taille adaptée à l’administration intra-articulaire (12 – 38 µm) et une libération de la molécule s’échelonnant sur 5 à 8 semaines. La libération prolongée de la clonidine implique des mécanismes de diffusion de la molécule ainsi que de dégradation/érosion du polymère. Au vu de l’absence de réaction inflammatoire, les microparticules développées sont correctement tolérées par les chondrocytes, synoviocytes, PBMC et neutrophiles, principales cellules impliquées dans les mécanismes inflammatoires de l’arthrose et de l’arthrite rhumatoïde. L’évaluation de l’efficacité anti-inflammatoire des microparticules vides et chargées en clonidine ou en bétaméthasone via l’étude de l’expression et de la sécrétion de différents médiateurs de l’inflammation a permis d’aboutir à plusieurs conclusions :(i) les microparticules vides sont associées à un effet anti-inflammatoire, (ii) les microparticules chargées en clonidine n’ont pas montré d’activité anti-inflammatoire propre pouvant être attribuée à la clonidine, et (iii) les microparticules de bétaméthasone ont confirmé l’effet anti-inflammatoire de la bétaméthasone. Enfin, l’étude de la toxicité des principes actifs et microparticules vides ou chargées a montré une toxicité significative de la clonidine sur les synoviocytes. Néanmoins, l’encapsulation des principes actifs dans les microparticules de PLGA a permis d’éliminer cette toxicité, protégeant donc efficacement les cellules articulaires.

Les microparticules développées permettent alors d’envisager l’encapsulation d’autres molécules anti-inflammatoires ou une combinaison de molécules ayant des effets complémentaires (anti-inflammatoire et antidouleur). L’utilisation de la clonidine dans ces indications devra être réévaluée en étudiant de façon approfondie son efficacité dans la douleur. / Both osteoarthritis and rheumatoid arthritis are articular diseases characterized by the degeneration of the joint cartilage, resulting from the production of various inflammatory mediators. The current treatment of these diseases is restricted to alleviate the painful and inflammatory episodes of the patients and to improve its quality of life. In osteoarthritic patients, few treatments allow to significantly stop the evolution of the degradation of the cartilage and, consequently, the disease. In rheumatoid arthritis, the evolution can be slowed down following the administration of some drugs. Nevertheless, these treatments are often associated to a short-term efficacy. The objective of this work is to develop new therapeutic options that allow to reduce the frequency of administration and the side effects of the current treatments. The intraarticular delivery combined to controlled-release presents the advantage to expose the sites directly involved in the evolution of the disease to one or more molecules effective to relieve the pain, inflammation and to help the regeneration of the cartilage.

Clonidine or betamethasone-loaded PLGA microparticles were optimized to reach suitable encapsulation efficiencies (clonidine HCl: EE ≈ 20%; betamethasone dipropionate: EE ≈ 70%), an appropriate size for an intraarticular delivery (12 – 38 µm) and a controlled-release of the molecule over 5 to 8 weeks. The release of clonidine implies mechanisms of diffusion and degradation/erosion of the polymer. Given the absence of an inflammatory reaction, the developed microparticles were properly tolerated by the chondrocytes, synoviocytes, PMBC and neutrophils, which are the main cells involved in the inflammatory reaction of osteoarthritis and rheumatoid arthritis. The assessment of the anti-inflammatory efficacy of the drug-free and drug-loaded microparticles through the evaluation of the expression and the secretion of various inflammatory mediators allowed to draw several conclusions: (i) drug-free microparticles were associated to an anti-inflammatory effect, (ii) clonidine-loaded microparticles did not show any anti-inflammatory activity that could be attributed to clonidine, and (iii) betamethasone- loaded microparticles confirmed the anti-inflammatory effect of betamethasone. Finally, the evaluation of the toxicity of the drugs and microparticles showed a significant toxicity of clonidine against synoviocytes. Nevertheless, the encapsulation of the drugs in PLGA microparticles induced the suppression of this toxicity, protecting in this way the articular cells.

Entrapping other anti-inflammatory molecules or a combination of molecules with complementary effects (anti-inflammatory and anti-nociceptive drugs) in the PLGA microparticles developed has to be considered. Moreover, the use of clonidine in these indications has to be reassessed by a thorough study of its anti-nociceptive potential.

Doctorat en Sciences biomédicales et pharmaceutiques
info:eu-repo/semantics/nonPublished

Future changes in the incidence and prevalence of OA are difficult to predict. As incidence and prevalence rise with increasing age, extending life expectancy will result in greater numbers with OA. Actually, usual therapeutic approaches are really restricted because of important side effects with long-term use. Therefore, there is a need to develop improved formulations which are well tolerated, biocompatible and biodegradable. Ideally, these new treatments should be able to deliver locally sufficient amount of anti-inflammatory or analgesic drugs into the site of arthritic inflammation while stabilizing or better restoring the mechanical integrity of the joint. In this way, the objective of this project is to develop slow-release gels that are sterile, injectable, characterized by viscoelastic properties and capable to sustain the in situ release of both hydrophilic and lipophilic drugs. The intraarticular delivery combined to sustained-release property should be interesting to reduce the number of injection required while prolonging the local drug activity over weeks. For that purpose, glycerol monooleate (GMO), also called “monolein” was selected for its capacity to form highly viscous crystalline phase structures upon contact with an aqueous fluid (e.g. synovial fluid).

In the first step of this work, it was decided to develop and characterize hydro-lipidic gels based on the use of monolein and hyaluronic acid in order to provide in vitro sustained release of hydrophilic drugs such as clonidine and lipophilic drugs such as betamethasone. Initially, a compatibility study was performed on the main ingredients selected in order to check that there were not physico-chemical incompatibilities, which could be deleterious regarding to their stability in formulation. Then, the development of hydro-lipidic gels was initiated by considering on the first hand the solubility of each ingredient and on the other hand the syringeability, the rheological properties and the in vitro dissolution profiles obtained for the developed formulations. The objective of this preformulation program was to identify potential candidates that presented suitable syringeability while being able to sustain the release of drugs over weeks and being characterized by interesting viscoelastic properties for the long-term management of osteoarthritis. Moreover, several methods of quantification and characterization were developed in order to allow the physico-chemical properties (rheology, syringeability, water uptake, stability and dissolution profiles) of the developed formulations to be studied.

Results of the compatibility study showed that the concomitant use of monolein, hyaluronic acid and clonidine/betamethasone is not contraindicated. Next, the preformulation program allowed many injectable drug delivery systems to be prepared. However, the carrier that best meets our needs was composed of 10,0 % (wt/wt) absolute ethanol ;15,0 % propylene glycol (wt/wt) ;15,0 % (wt/wt) water ;55,0 % (wt/wt) de monolein ;5,0 % (wt/wt) purified soybean oil ;0,03 % (wt/wt) α-tocophérol and 7,5 mg/g sodium hyaluronate (1.9 MDa). This carrier assured suitable syringeability and rheological properties. Indeed, it presented marked pseudoplastic flow behavior that allowed relatively fast injection through a narrow needle, followed by an increase in viscosity upon contact with aqueous fluids to obtain an in vitro sustained release of hydrophilic and lipophilic drugs over a few weeks. As a consequence, it was assumed that this carrier should be able to jellify in situ upon contact with physiological fluid such as synovial fluid. Then, according to EMA recommendations, a fast and easy manufacturing process that could be applied in a cleanroom at industrial scale was validated in our Laboratory. Finally, according to these promising results obtained in vitro, a stability study was performed on the carrier alone and containing clonidine or betamethasone according to ICH recommendations described for products intended for storage in a refrigerator. In that purpose, several parameters such as the quantification of drugs, the pH, the molecular weight of hyaluronic acid, the dissolution profiles of drugs and the rheological properties of the formulations were recorded depending on time and conditions of storage. This stability study showed clearly the importance to adjust the pH value of the formulation. Indeed, it was demonstrated that a pH value of 6.5, adjusted with diluted NaOH, allowed the stability of the formulation to be significantly improved. During this first step of this project, our Laboratory initiated two new collaborations. On the first hand, collaboration with the Laboratory of Professor Siepmann (University of Lille 2 – Faculty of Pharmacy) was started for their expertise on mathematical modeling. On the other hand, collaboration with the Laboratory of Professor Jerôme (ULg – Faculty of sciences) was started for their expertise on macromolecular chemistry and more particularly on rheological properties.

In the second step of this work, it was decided to evaluate in vitro the safety and the efficiency of the developed carrier and formulations containing clonidine or betamethasone. In this way, it was suggested to test selected drugs and potential candidates formulations on equine polymorphonuclear leukocytes (PMN) by measuring the production of reactive oxygen species (ROS) by PMNs stimulated or not with phorbol 12-myristate 13-acetate (PMA). For that purpose, our Laboratory initiated a new collaboration with the Laboratory of Professor Serteyn (ULg – Faculty of veterinary) for their expertise on equine PMNs and quantification of (ROS) produced in particular in inflammatory diseases.

This in vitro study has shown that no pro-inflammatory effect appeared by incubating carrier with unstimulated PMNs in comparison with the control assay. However, the production of ROS was quickly and considerably decreased when stimulated cells were placed in contact with carrier regardless on the incorporation of clonidine or betamethasone. This observation demonstrated that developed carrier provided a strong antioxidant effect, certainly by trapping the ROS produced. These results were very promising because that antioxidant effect of carrier could inhibit oxidative damages and might consequently potentiate the prevention of inflammatory conditions. Concerning the clonidine and betamethasone, only the last one provided significant inhibition of the ROS activity.

Finally, by considering the very promising results obtained with the in vitro study on PMNs, an in vivo study on rabbits, which seemed to be the most appropriate small animal model for this kind of intraarticular formulations, was performed to evaluate the toxicity and the efficiency of the developed carrier and formulation containing betamethasone. Therefore, our Laboratory started collaboration with the unit of research in osteo-articular pathologies (UROC) of Pr. Henrotin (ULg) for their expertise in animal models, in particular rabbits with osteoarticular pathologies such as osteoarthritis. For this purpose, this in vivo study was outsourced by TNO (Delft, Holland) and was designed as follow: (i) 0.9 % saline buffered (n=8); (ii) carrier (n=8); (iii) formulation containing betamethasone (n=8); (iv) Durolane® (n=8) a marketed product of HA. Surprisingly, it seemed that the control group (saline buffered) presented macroscopical and histological scores that were globally low according to literature. As a consequence, it was difficult to conclude about the efficiency of the developed treatments by considering only this pilot study. However, it is important to note that it seemed that the expected viscoelastic protection of the carrier to prevent the degradation of articular cartilage was not optimal regardless on the incorporation of betamethasone. Nevertheless, the histological analyses of synovial membranes from each treated groups demonstrated that there was no pro-inflammatory reaction. This meant that all formulations tested were well tolerated despite of the apparition of lumps (in 37.5 % of treated rabbits) that are probably due to both the high volume injected (900 µL) and an excessive and unexpected in situ water uptake of developed formulations based on GMO. However, this lack of rejection of the developed carrier could be very important since it allowed new perspectives to be considered. For example, other articular disorders could be targeted by incorporating drugs, for which in situ sustained release or mechanical protection could be beneficial.

Our laboratory is member of a collaborative project "JOINT-AIC" from BioWin and is supported by a grant from the Walloon Region. The development of analytical methods, the evaluation of physico-chemical properties and finally the preparation of sterile batches of formulations based on GMO intended for in vitro and in vivo studies were performed in the Laboratory of Galenic and Biopharmacy of the Faculty of Pharmacy of ULB./L’arthrose est une pathologie dont la prévalence et le coût ne font qu’augmenter dans notre société vieillissante. Les moyens thérapeutiques actuels étant fort limités suite à de sérieux effets secondaires à long terme, il existe réellement un besoin médical important de développer de nouveaux traitements locaux qui soient bien tolérés, biocompatibles et biodégradables. Idéalement, ceux-ci devraient être actifs au niveau du processus inflammatoire ou de la douleur tout en étant capable de stabiliser, voire de restaurer, l’intégrité mécanique de l’articulation.

Dans cette optique, l’objectif de ce projet a été de développer des systèmes hydrolipidiques stériles, injectables et viscoélastiques qui soient capables de prolonger in situ la libération de principes actifs hydrophiles et lipophiles. Cette caractéristique devait permettre de réduire le nombre d’injections nécessaires dans le cadre du traitement symptomatique de l’arthrose et de maintenir l’effet des composés sur un minimum de quatre à six semaines. Cette étude entre dans le cadre du projet JOINT-AIC entièrement financé par le programme BioWin de la Région Wallonne. Le développement, la validation des méthodes analytiques, l’évaluation des propriétés physico-chimiques ainsi que la préparation stérile des lots de formulation destinés aux tests in vitro et in vivo ont été réalisés au sein du Laboratoire de Galénique et Biopharmacie de la Faculté de Pharmacie de l’ULB.

Au cours de ce projet, il a donc fallu dans un premier temps développer et caractériser des formulations hydrolipidiques à base de monoléine et d’acide hyaluronique permettant une libération in vitro prolongée de principes actifs tels que la clonidine (hydrophile) et le dipropionate de bétaméthasone (lipophile). Une étude de compatibilité a ainsi été préalablement réalisée afin de s’assurer qu’aucun des constituants principaux de la formulation ne présentaient d’incompatibilité physico-chimique qui pourrait être délétère vis-à-vis de leur stabilité en formulation. Ensuite, le développement de préparations hydro-lipidiques a été initié en tenant compte, d’une part de la solubilité des différents composants et, d’autre part de l’injectabilité, des propriétés rhéologiques et des profils de libération de la clonidine obtenus à partir des gels développés. Cette étude visait à obtenir une composition de référence qui soit à la fois injectable et capable de libérer un principe actif hydrophile sur plusieurs jours, voire plusieurs semaines, tout en possédant des propriétés rhéologiques intéressantes dans le cadre d’une viscosupplémentation articulaire. Enfin, un protocole de fabrication en milieu aseptique a été développé et plusieurs méthodes pour étudier les propriétés physico-chimiques des gels développés telles que la rhéologie, l’injectabilité, l’indice de gonflement, la stabilité et les profils de libérations ont été mises en place.

Les résultats ont montré qu’aucune incompatibilité ne semblait exister entre les trois composés majeurs de notre préparation, la monoléine, l’acide hyaluronique et la clonidine. Le développement des formulations nous a ensuite permis d’obtenir de nouveaux systèmes hydrolipidiques stériles et injectables à délivrance prolongée. Le véhicule qui remplissait au mieux nos objectifs était composé de 10,0% (m/m) d’éthanol ;de 15,0% de propylène glycol (m/m) ;de 15,0% (m/m) d’eau ;de 55,0% (m/m) de monoléine ;5,0% (m/m) d’huile de soja purifiée ;0,03% (m/m) d’α-tocophérol, de 7,5 mg/g d’HA et son pH était ajusté à 6,5 avec du NaOH 1N. Ce véhicule a montré un intérêt réel dans le cadre du développement de préparations biodégradables et biocompatibles pour le traitement de pathologies articulaires.En effet, cette composition présentait un écoulement de type pseudoplastique et des propriétés rhéologiques qui lui procuraient une bonne injectabilité. De plus, cette formulation a démontré in vitro une excellente capacité à gélifier au contact de fluides aqueux et à ralentir efficacement sur plusieurs semaines la libération des différents principes actifs incorporés (clonidine et dipropionate de bétaméthasone). Nous pouvions, dès lors, envisager que celle-ci serait capable de gélifier in situ au contact d’un fluide physiologique tel que le liquide synovial. Ensuite, suivant les recommandations de l’EMA, nous avons décidé d’utiliser l’association d’une filtration stérilisante et d’une préparation en milieu aseptique pour obtenir des formulations qui répondaient aux exigences en matière de préparation parentérale. C’est ainsi qu’un protocole de fabrication stérile de nos gels a été développé par nos soins en vue d’une éventuelle mise à l’échelle industrielle. Enfin, une étude de stabilité sur une année, suivant les normes ICH décrites pour des formulations destinées à être conservées au frigo, a été réalisée sur différents véhicules développés et contenant soit la clonidine, soit le dipropionate de bétaméthasone. Dans cette optique, plusieurs paramètres, tels que le dosage en principe actif, l’évolution du pH et du poids moléculaire de HA, le profil de libération ainsi que la rhéologie des formulations ont été évalués au cours du temps aux différentes conditions de conservation testées. Cette étude a permis de démontrer toute l’importance d’ajuster le pH de la préparation pour prévenir l’hydrolyse de l’HA, et cela indépendamment de l’incorporation de principe actif. Ainsi, il a pu être montré que l’ajustement du pH du véhicule à 6,5 à partir de NaOH dilué permettait d’améliorer considérablement la stabilité de la formulation puisqu’aucune modification significative de ses différents paramètres physico-chimiques et teneurs n’a été observée après un an de conservation à 5 et à 25 °C (60% HR) mais également après six mois à 30 °C (65% HR). Au cours de cette première partie, deux collaborations ont été initiées, l’une avec le Laboratoire du Prof. Siepmann de l’Université de Lille 2 et l’autre avec le Prof. Jerôme de l’Université de Liège. Avec l’aide du Prof. Siepmann, il a été possible de mettre au point un modèle mathématique pour caractériser les profils de libération des principes actifs à partir des différents véhicules développés. Le Prof. Jerôme a, quant à elle, mis à notre disposition un rhéomètre qui a permis d’approfondir nos connaissances sur les propriétés rhéologiques et viscoélastiques des formulations.

Ensuite, la seconde partie de notre travail a consisté à évaluer la tolérance, ainsi que l’efficacité des principes actifs sélectionnés et des formulations développées, à travers un modèle in vitro de cellules de l’inflammation (neutrophiles équins). Cette étude avait pour objectif d’évaluer deux aspects importants de la formulation :d’une part vérifier l’absence de réaction pro-inflammatoire qui pourrait être in vivo destructrice vis-à-vis du véhicule ainsi que des tissus environnants, et d’autre part vérifier l’effet anti-inflammatoire propre à la clonidine et au dipropionate de bétaméthasone seuls et en formulation. Cette étude a été réalisée avec la collaboration du Laboratoire du Prof. Serteyn de l’Université de Liège.Cette étude in vitro a démontré que les cellules restaient viables au moins pendant quatre heures lorsqu’elles étaient exposées à la matrice épurée de ses solvants. Ensuite, de manière surprenante, il a même pu être démontré que le véhicule permettait à la fois de prévenir et de réduire significativement la production des espèces réactives de l’oxygène (ROS) par les neutrophiles équins lorsque ceux-ci étaient stimulés au phorbol 12-myristate 13-acetate (PMA). Cette propriété peut être d’un grand intérêt dans le cadre de la prise en charge de l’arthrose car cette activité antioxydante pourrait permettre d’inhiber les dommages oxydatifs générés par les ROS et ainsi prévenir les dommages liés au développement du processus inflammatoire et qui peut, à long terme, s’avérer délétère pour les tissus environnants tels que le cartilage. Cette propriété du véhicule semble trouver son origine dans la monoléine qui, de par sa composition en alpha-tocophérol (200 ppm), présente également une activité antioxydante vis-à-vis des ROS. Toutefois, une action synergique liée à l’HA, à l’huile de soja ou à l’alpha-tocophérol incorporés aux formulations, n’est pas à exclure. Enfin, parmi les deux principes actifs sélectionnés, seul le dipropionate de bétaméthasone a montré une inhibition significative de la production des ROS.

Enfin, en tenant compte des résultats obtenus sur cellules, une étude in vivo pilote a été réalisée sur base d’un modèle de lapins. Cette étude visait à vérifier la tolérance ainsi que l’efficacité en prophylaxie de l’arthrose du véhicule développé ainsi que de la formulation contenant le dipropionate de bétaméthasone. Dans ce but, quatre groupes d’animaux (n=8) ont été constitués pour chacun des traitements testés :(i) groupe témoin :0,9 % tampon salin pH 7,4 ;(ii) véhicule à base de GMO développé; (iii) véhicule contenant du dipropionate de bétaméthasone ;(iv) groupe référence :Durolane®. Cette étude a été réalisée avec l’aide du Laboratoire du Prof. Henrotin de l’Université de Liège. L’hébergement des animaux ainsi que les actes chirurgicaux ont, quant à eux, été sous-traités par TNO (Delft, Pays-Bas).

De manière étonnante, il s’est avéré que le groupe contrôle présentait des scores macroscopique et histologique globalement peu élevés par rapport à ce qui est rapporté dans la littérature. Compte tenu de cette observation, il est difficile de se prononcer, sur base uniquement de cette étude, sur l’efficacité des différents traitements testés. Toutefois, il faut reconnaître que l’effet protecteur attendu pour le véhicule vis-à-vis de la dégradation du cartilage ne semble pas optimal et cela indépendamment de l’incorporation de dipropionate de bétaméthasone. Par ailleurs, l’étude des membranes synoviales a permis de démontrer qu’il n’y avait aucune différence significative en termes d’inflammation et de structure entre le groupe contrôle et les différents groupes traités. Ce qui signifie qu’aucun rejet n’a été observé vis-à-vis des formulations et que celles-ci ont, par conséquent, été bien tolérées malgré la formation de masses liées probablement au volume important injecté (900 µL) et au gonflement in situ du produit chez 37,5 % des lapins. Cette observation est importante puisqu’elle permet d’envisager de nouvelles perspectives telles que l’incorporation d’autres principes actifs pouvant éventuellement viser d’autres pathologies articulaires et pour lesquels une libération prolongée ou une protection mécanique du principe actif in situ serait bénéfique.

Doctorat en Sciences biomédicales et pharmaceutiques
info:eu-repo/semantics/nonPublished

Intra-articular injection therapy is widely used in the management of osteoarthritis (OA). It has advantages over oral therapy in that it can provide targeted therapy to individual joint sites and at higher dose than could be achieved through oral administration and with fewer adverse effects. Intra-articular steroid therapy, the most widely used intra-articular therapy, is safe and effective in the short term particularly at the knee; though more studies are needed to better characterize the longer-term benefit. The role of intra-articular hyaluronic acid in clinical management of OA is less clear though it may have a role in selected patients in whom other therapies are contraindicated. Currently there are no factors which have been identified as being predictors of response to therapy with intra-articular therapy. Many other intra-articular agents have been used in the management of OA, however, because of the limited evidence base relating to efficacy and safety they cannot currently be recommended for use in routine clinical practice.

This chapter provides an important overview of drug therapies that are administered by intra-articular, subcutaneous, or intravenous injection. Key factors including choice of steroids for injection, preparing the patient, and equipment required are discussed. For the nurse supporting the administration of intra-articular injections, care of the patient is discussed, together with guidance for more advanced nurses who may be trained to administer intra-articular injections. Management of specimens obtained during aspiration together with patient preparation and post-injection advice are outlined. An overview for all nurses responsible for administering intravenous or subcutaneous injections as well as those who need to educate and prepare patients to self-administer drug therapies is given. This chapter focuses on drug therapies used within the field including biological therapies, methylprednisolone, iloprost used for pulmonary hypertension, and treatments used to manage osteoporosis. Checklists, practical considerations, and nursing care (pre and post administration) are given. Finally, resources including key references, information for patients, and further reading are provided for each of the intravenous and subcutaneous therapies outlined.