Search

An anthocyanin complex (AC), composed of extracts of purple waxy corn and blue butterfly pea petals, and AC niosomes, bilayered vesicles of non-ionic surfactants, were compared in in vitro and clinical studies. Cultured fibroblasts subjected to a scratch wound were monitored for cell viability, cell migration, nuclear morphology and protein expression. Scratched cells showed accelerated wound healing activity, returning to normal 24 h after treatment with AC niosomes (0.002 mg/mL). Western blots and immunocytochemistry indicated upregulation of type I, III and IV collagens, fibronectin and laminins in AC niosome-treated scratched cells. A randomized block placebo-controlled double-blind clinical trial in 60 volunteers (18-60 years old) with oral wounds indicated that AC niosome gel accelerated wound closure, reduced pain due to the oral wounds and improved participants' quality of life more than AC gel, triamcinolone gel and placebo gel. These data are consistent with enhanced delivery of AC to fibroblasts by use of niosomes. AC niosomes activated fibroblasts within wounded regions and accelerated wound healing, indicating that AC niosomes have therapeutic potential., (Copyright © 2021 Elsevier Inc. All rights reserved.)

In this study, the ability of different beta-cyclodextrins to facilitate homogeneous dispersion of triamcinolone acetonide (TA) into chitosan membranes is assessed. Drug loading was assessed through atomic force microscopy (AFM), scanning electron microscopy (MEV-FEG), and X-ray diffraction analyses. Drug interactions with the co-polymer were investigated with Fourier transform infrared spectroscopy, thermal analyses. Swelling assay, and in vitro drug release experiment were used to assess TA release behavior. Undispersed particles of drug were observed to remain in the simple chitosan membranes. Hydroxypropyl-β-cyclodextrin enabled the dispersion of TA into chitosan membranes and subsequent sustained drug release. In addition, the membrane performance as a drug delivery device is improved by adding specified amounts of the co-solvent triethanolamine. The experimental data presented in this study confirm the utility of our novel and alternative approach for obtaining a promising device for slow and controlled release of glucocorticoids, such as triamcinolone acetonide, for topical ulcerations., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Understanding the crosstalk between synoviocytes and macrophages is very important for the development of strategies to regulate inflammatory responses in an inflamed synovium. Simultaneous regulation of the pro- and anti-inflammatory responses of synoviocytes and macrophages (repolarization) is critical for the treatment of arthritis. Thus, the immune regulatory functions of an ideal nanodrug should not only decrease the pro-inflammatory response but also effectively increase the anti-inflammatory response. In this study, crosstalk between synoviocytes and macrophages was found to be significantly involved in the activation and deactivation of inflammatory responses in the synovium. Interestingly, a developed triamcinolone-gold nanoparticle (Triam-AuNP) complex both decreased the pro-inflammatory responses and increased the anti-inflammatory responses of fibroblast-like synoviocytes (FLSs) and macrophages via repolarization of macrophages from the M1 to the M2 phenotype. In contrast, triamcinolone alone only decreased the pro-inflammatory responses of FLSs and macrophages without upregulating their anti-inflammatory responses. In vitro (human), ex vivo (human), and in vivo (mouse) analyses clearly indicated that Triam-AuNPs effectively regulated the expression of both pro- and anti-inflammatory cytokines in FLSs and effectively repolarized activity of macrophages in the inflamed synovium. Furthermore, Triam-AuNPs significantly promoted cartilage regeneration, whereas triamcinolone alone did not induce either FLS anti-inflammatory activity or macrophage repolarization.

Background: Epidural steroid injection (ESI) is a common practice for pain treatment since 1953. In 2014, the FDA issued a warning about ESI. Studies have focused on the effect of the particle size and their ability to generate harmful aggregates. Although steroid aggregates provide longer times for reabsorption, therefore a longer anti-inflammatory effect, they are potentially harmful to the central nervous system via embolic mechanisms.Previous studies have established that steroidal aggregates with asizes over 100 mu m are potentially able to occlude blood vessels. Studies by Tiso et al and Benzon et al addressed the role of steroids on CNS adverse events, with similar outcomes. The main difference was on the role of aggregates with a size over 100 mu m, which Benzon et al. attributed to the ability of certain steroid preparations to rapidly precipitate and form large aggregates., Objectives: Studying the effect of the time elapsed between mixing the steroid preparation and injection on the number and size of aggregates with sizes above 100 mu m., Study Design: Original study in basic science., Setting: Basic scienceMETHODS: Steroids evaluated are commonly used in Spain for ESI: betamethasone, triamcinolone, and dexamethasone. The size and number of the aggregates was determined for undiluted commercial steroid preparations in the usual amount for a single and double dosage used for ESI.Samples were examined with a Leica TCS-SP2 microscope at the first, the fifth and the 30th minute after shaking the preparations. Aggregates observed in the different preparations were manually counted and grouped in the following size range: 0-20, 20-50, 50-100, 100-300, 300-500 and > 500 mu m.Statistical analysis was carried out using the R software. Nonparametric techniques were used in the comparison of aggregate size. Global comparison of the groups using the Kruskal-Wallis test and post-hoc comparisons using the Wilcoxon test, adjusting P-values by the Holm method for multiple comparisonsRESULTS: Aggregates present in triamcinolone and betamethasone samples were statistically larger than in dexamethasone samples. Triamcinolone suspensions produced significantly larger aggregates than betamethasone five minutes after mixing. Triamcinolone preparations produced greater particle aggregates (> 500 mu m), which were not present in dexamethasone and betamethasone preparations., Limitations: Study how the human internal factors like blood elements and spinal fluid could interact with steroids and influence the size of the aggregates formed., Conclusions: This study demonstrates that the size of the particles injected depends on the type of steroid and the time allowed between mixing and injecting. The results demonstrate that waiting longer than 5 minutes between mixing and injecting can predispose the formation of potentially harmful aggregates in triamcinolone and betamethasone samples. The presence of greater particle aggregates (> 500 mu m) may occlude some important vessels and arteries with serious adverse results. Vigorous shaking of the injectable could prevent such events., Key Words: Epidural steroid injection, triamcinolone, betamethasone, dexamethasone, steroid aggregates.

We propose an elastic net made of a biocompatible polymer to wrap silicone implants of various sizes, which also allows for the sustained release of an anti-inflammatory drug, triamcinolone, to prevent fibrosis. For this, we first prepared a strand composed of a mixture of polyurethane and triamcinolone via electrospinning, which was then assembled to prepare the elastic drug-delivery net (DDN). The DDN was prepared to just fit for wrapping the small silicone implant sample herein, but was also able to wrap a sample 7 times as large at 72% strain due to the elastic property of polyurethane. The DDN exhibited sustained drug release for 4 weeks, the profile of which was not very different between the intact and strained DDNs. When implanted in a subcutaneous pocket in living rats, the DDN-wrapped silicone implant samples showed an obvious antifibrotic effect due to the sustained release of triamcinolone. Importantly, this effect was similar for the small and large silicone samples, both wrapped with the same DDN. Therefore, we conclude that this drug-loaded net made of an elastic, biocompatible polymer has high potential for sustained drug delivery around silicone implants manufactured in various sizes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Drug delivery to the posterior eye is limited by epithelial and mucosal barriers limiting the topical administration of drugs leading to invasive modes of repeated long-term painful administration of drugs. Several constructs of liposomes have been prepared to counter this challenge yet are often limited by size and surface charge resulting in poor encapsulation efficiency, low retention time, and poor permeability. In the present study, chitosan coated liposomes (CCL) were prepared to address these challenges. Conventional liposomes encapsulating Triamcinolone Acetonide (TA) were compared with their chitosan coated counterpart for drug loading and release studies. CCL showed a higher encapsulation efficiency (74%), and a highly positive surface charge (+41.1Mv), increased retention time and sustained release. Choroidal neovascularization (CNV) rat models were generated to assess the efficiency of CCLs as nanocarriers in drug delivery. Significant amount of TA was found to be present and retaining in the eye after fifteen days of treatment with CCL, as shown by HPLC analysis. The results showed successful penetration of the construct via corneal mucosal barrier and its accumulation in vitreous body. The analysis shows that this chitosan based liposomal construct can be employed as a potential topical delivery system for treating posterior segment diseases., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Triamcinolone is a long acting corticosteroid used in the treatment of arthritis, eczema, psoriasis and similar conditions which cause inflammation. Triamcinolone has half-life of 88min. Prolonged oral use is associated with gastrointestinal adverse effects as peptic ulcer, abdominal distention and ulcerative esophagitis as described in various patents. Microemulgel offers advantage of better stability, better loading capacity and controlled release especially for drug with short half life., Objective: Objective of the present study was to optimize microemulgel based transdermal delivery of triamcinolone., Method: Saturated solubility of triamcinolone in various oils, surfactants and co-surfactants is estimated. Pseudo-ternary phase diagrams were constructed to determine the region of transparent microemulsion. Microemulsion was evaluated for globule size (FE-SEM, zetasizer), % transmittance, pH, viscosity, conductivity etc. Design of experiment was used to optimize microemulsion based gel. Carbopol 971P and HPMC K100M were used as independent variables. Microemulsion based gel was evaluated for in-vitro as well as ex-vivo parameters., Results: Microemulsion was formulated with oleic acid, lauroglycol FCC and propylene glycol. PDI 0.197 indicated microemulsion is mono-disperse. 32 factorial design gave batch F8 as optimized. Design expert suggested drug release; gel viscosity and bio-adhesive strength were three significant dependant factors affecting the transdermal delivery. F8 showed drug release 92.62.16±1.22% through egg membrane, 95.23±1.44% through goat skin after 8hr and Korsmeyer-Peppas release model was followed., Conclusion: It can be concluded that a stable, effective controlled release transdermal microemulgel was optimised for triamcinolone. This would be a promising tool to deliver triamcinolone with enhanced bioavailability and reduced dosing frequency., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

A second compound is generally associated with oligosaccharides as a strategy to maximize the solubilizing effect for nonpolar compounds. This study elucidated the role and the mechanism whereby liquid compounds interact in these supramolecular aggregates in the solubilization of triamcinolone. Three different oligosaccharides (beta-cyclodextrin, 2-hydroxipropil-beta-cyclodextrin, and randomly methylated beta-cyclodextrin) and two potent co-solvents (triethanolamine and N-methyl pyrrolidone) were carefully evaluated by using three distinct experimental approaches. Incredibly stable complexes were formed with cyclodextrins (CDs). The structure of the complexes was elucidated by magnetic resonance spectra 2D-ROESY. The interactions of the protons of ring "A" of the drug with H(3) and H(5) protons of the CD cavity observed in the binary complexes remained in both ternary complexes. Unlike the observed ternary associations with triethanolamine, N-methyl pyrrolidone competed with the triamcinolone CD cavity and considerably decreased the stability of the complex and the solubility of the drug. The molecular dynamics (MD) and quantum mechanics:molecular mechanics (QM:MM) calculations supported that triethanolamine stabilized the drug-CD interactions for the conformer identified in the 2D-ROESY experiments, improving the quality and uniformity of the formed complex. The role played by the co-solvent in the ternary complexes depends on its specific ability to interact with the CD cavity in the presence of the drug, which can be predicted in theoretical studies to select the best candidate., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Intravitreal sustained delivery of corticosteroids such as dexamethasone is an effective means of treating a number of ocular diseases, including diabetic retinopathy, uveitis, and age-related or diabetic macular edema. There are currently marketed devices for this purpose, yet only one, Ozurdex, is degradable. In vitro release of dexamethasone from the Ozurdex device is limited to approximately 30 days, however. It was the objective of this study to examine the potential for prolonged and sustained release of a corticosteroid in vitro from a degradable polymer prepared from terminally acrylated star co- and ter-prepolymers composed of d,l-lactide, ε-caprolactone, and trimethylene carbonate co-photo-cross-linked with poly(ethylene glycol) diacrylate. Through manipulation of the network polymer glass transition temperature and degradation rate, a sustained release of triamcinolone was achieved, with an estimated release duration greater than twice that of the Ozurdex system. Moreover, a period of nearly constant release was obtained using a network prepared from 5000 Da star-poly(trimethylene carbonate-co-d,l-lactide) triacrylate (3:1 trimethylene carbonate:d,l-lactide) co-cross-linked with 700 Da poly(ethylene glycol diacrylate). These formulations show promise as implantable, intravitreal corticosteroid delivery devices.

A novel triamcinolone loaded polymeric micelle was synthesized based on hyaluronic acid and phospholipid for articular delivery. The newly developed micelle was characterized for physicochemical properties including size, zeta potential, differential scanning calorimetry (DSC) analysis and also morphology by means of transmission electron microscopy. The biocompatibility of micelle was explored by histopathological experiment in rat model. Also biological fate of micelle was investigated in rat by means of real time in vivo imaging system. Triamcinolone loaded micelle was in the size range of 186 nm with negative zeta potential charge. Micelles were spherical in shape with core shell like structure. Triamcinolone was released from micelle during 76 h with almost low burst effect. DSC analysis showed the conversion of crystalline triamcinolone from its crystalline state. Histopathological analysis showed no evidence of tissue damage or phagocytic accumulation in knee joint of rat. The real time in vivo imaging analysis suggested at least three days retention time of micellar system in knee joint post injection., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Pharmaceutical compounding of capsules is still an important corner stone in today's health care. It allows for a more patient specific treatment plan as opposed to the "one size fits all"-approach, used by the pharmaceutical industry when producing fixed dose finished drug products. However, loss of active pharmaceutical ingredient (API) powder during pharmaceutical capsule compounding can lead to under-dosed finished drug products and annul the beneficiary therapeutic effects for the patient. The amount and location of API loss was experimentally determined during capsule compounding of five different preparations: 10 and 20mg hydrocortisone capsules, 4mg triamcinolone capsules and 0.25mg dexamethasone capsules, using a 10% m/m self-made or commercial trituration. The total API amount present in the five capsule preparations varied between 90.8% and 96.6%, demonstrating that for certain preparations, significant API mass loss occurred during the pharmaceutical compounding of capsules. Swabbing results of the different compounding equipment and working areas indicated the mortar surface as the largest API loss location. An agate mortar accounted for the least amount of API loss, whereas an extensively used porcelain mortar accounted for the highest amount of API loss. Optical microscopy and roughness (Ra) determination by profilometry of the different mortar surfaces revealed a significant influence of the mortar surface wear and tear on the observed API loss. This observation can be explained by physical deformation, or scratch formation, of the relatively soft porcelain mortar surface, in which the API particles can become adsorbed. Furthermore, a small effect of the capsulation device material on the API loss was also observed. The presence of a chemical molecule effect on the API loss was demonstrated through data mining using a set of assay results containing 17 different molecules and 1922 assay values. The 17 median assay values were modeled in function of corresponding molecular descriptors, using stepwise multiple linear regression. The obtained MLR model, containing RDF060m, R6e(+) and R3m(+) variables, explained 92.5% of the observed variability between the 17 median assay values., (Copyright © 2014 Elsevier B.V. All rights reserved.)

This study aims at trying to establish a novel method of sterility test for injections based on biothermodynamics, in order to overcome the deficiencies of routine sterility tests such as long detecting cycle, low sensitivity and prone to misjudgments. A biothermodynamics method was adopted to rapidly detect the microorganism contamination of injections by monitoring the heat metabolism during the growth of microbe. The growth rate equal to or greater than zero and the heat power difference of P(i) and P(0) with three folds higher than the noise of baseline were chosen as indexes to study the heat change rule of microbe. In this way, the effectiveness of the new method to detect strains required by conventional sterility test or in injection samples was also investigated. Results showed that the Gram-positive bacteria, Gram-negative bacteria and fungi demanded by sterility testing methodology could be detected by biothermodynamics method within 10 hours, with the sensitivity lower than 100 CFU x mL(-1). Meanwhile, this method was successfully applied to the sterility test of Compound Yinchen injection (FFYC), Shuanghuanglian powder injection (SHL) and Compound Triamcinolone injection (TAND) which were sterilized with different degrees. Therefore, the biothermodynamics method, with advantages of fast detection and high sensitivity, could be a complementary solution for conventional sterility tests.

This article is aimed to discuss the modification of guar gum through microwave irradiation by varying the time of irradiation. The characterization of the modified products was carried out using FTIR spectroscopic analysis. The FT-IR spectrum of the pure guar gum (GG) sample showed a broad peak at 3298 cm(-1) while the modified GG sample displayed a peak at 1541 cm(-1) which was absent in the crude sample. The X-ray diffraction (XRD) analysis confirmed the increase in crystallinity due to grafting of the sample with polyacrylamide (GG-g-PAM). Scanning electron microscope (SEM) images revealed that granular form of guar gum was changed into fibrillar structure after grafting. Thermo-gravimetric analysis of the modified samples was also carried out and discussed. The role of guar gum as a matrix for controlled release of drug triamcinolone was evaluated. The GG-acrylamide grafted samples presented a correlation between drug release and time of microwave exposure. The results revealed that such modified product has potential applications in colonic drug delivery system., (Copyright © 2013 Elsevier B.V. All rights reserved.)

We are proposing folate-decorated polymeric nanoparticles as carriers of poorly soluble drug molecules for intracellular and prolonged delivery to retinal pigment epithelium (RPE) cells. RPE is a monolayer of epithelial cells that forms the outer blood-retinal barrier in the posterior segment of the eye, and is also implicated in the pathology of, such as neovascularization in age-related macular degeneration (AMD). In this study, folate-functionalized poly(ethylene glycol)-b-polycaprolactone (folate-PEG-b-PCL) were synthesized for assembling into nanoparticles of ~130nm. These nanoparticles were internalized into ARPE-19 (human RPE cell line) via receptor-mediated endocytosis, and the cellular uptake was significantly higher than particles without folate modification. Triamcinolone acetonide (TA) was efficiently encapsulated (>97%) into the folate-decorated nanoparticles and was slowly released over a period of 4 weeks at pH 5.5 and 8 weeks at pH 7.4. The enhanced uptake and controlled release resulted in prolonged anti-angiogenic gene expression of RPE cells. In cell culture, the down-regulation of vascular endothelial growth factor (VEGF) and up-regulation of pigment epithelium derived factor (PEDF) lasted for at least 3 weeks. Unlike benzyl alcohol, the surfactant found in commercial formulation, folate-modified nanoparticles were non-toxic. Furthermore, TA became less cytotoxic by being encapsulated in the nanoparticles. Our findings suggest that folate-PEG-PCL nanoparticles are promising drug carriers for RPE targeting., (Copyright © 2013 Elsevier B.V. All rights reserved.)

We report a case of unusually long persistence of triamcinolone crystals after intra-vitreal injection. Crystals were noted on fundus examination predominantly confined to the posterior pole. Optical coherence tomography localized the crystals to the posterior hyaloidal surface. Over 6 years of follow-up the patient has retained good visual acuity and no observable changes in the retina. As the condition clinically resembles both crystalline maculopathy and asteroid hyalosis, we suggest the term 'drug-induced benign crystalline hyaloidopathy'.

Purpose: We sought to better characterize the intravitreal profile of different triamcinolone formulations., Methods: The study was performed in vitro and in vivo. Kenalog-40, Triesence, and Transton were characterized for ocular pharmacokinetics, particle size, crystallinity, and dissolving kinetics in vitreous following an intravitreal injection into 12 rabbit eyes. The relationship of free drug levels in the aqueous and vitreous was investigated through a dual-probe microdialysis and liquid chromatography tandem mass spectrometry., Results: Triesence had the most uniform particle size distribution (mean 11.51 μm) and Kenalog-40 had the largest particle sizes (mean 18.86 μm). Triesence and Kenalog-40 had 100% crystallinity, while Transton had 89% crystallinity. Triesence had a slower dissolution in vitreous than that of Kenalog-40, and Transton had the fastest dissolution, though their solubility was very similar. Following a 1.2 mg intravitreal injection in the rabbit eye, Triesence had a significantly lower ocular free drug level than Kenolog-40 (P = 0.025) and Transton (P = 0.007). Quantitative dual-probe microdialysis revealed that the aqueous free triamcinolone (Kenolog-40) was less than 1% of the vitreous free triamcinolone during the first few hours, and this percentage increased to 26.8% at 2 weeks and was 11.7% at 3 weeks following an intravitreal injection., Conclusions: Triesence demonstrated a significantly slower dissolution profile and lower free drug level in the vitreous than the other preserved triamcinolone, which may translate into a longer therapeutic duration and lower rate of drug-associated complications.

Background: Radiosynovectomy (RSO) is widely used in rheumatoid arthritis (RA). Commercially available radiopharmaceuticals are costly, and therefore new agents may be of interest. Radiocolloids labelled with less costly and more accessible radionuclides are of interest to developing countries. We investigated the efficacy of different formulations in RA., Methods: In a multicentre effort, a cohort of 99 RA patients with knee involvement underwent RSO. Sixty-eight patients were treated with 184 ± 4 MBq Y-90 silicate (Y-90), 15 patients with 53 ± 11 MBq P-32 colloid (P-32), and 16 patients with 451 ± 110 MBq of Re-188 tin colloid (Re-188). Corticosteroid group (CSG) consisting of 46 patients received an intra-articular instillation of 20-40 mg triamcinolone. Pain response was evaluated by a 10-step visual analogue scale (VAS) before, 1 month, 3 months, 6 months and 12 months following the procedure., Results: In the RSO group (n = 99), pain relief by VAS from 6 ± 2 before to 5 ± 3, 4 ± 2, 3 ± 2 and 4 ± 2 at 1, 3, 6, 12 months after RSO was documented (Y-90 group: 6 ± 2 to 3 ± 2; P-32: 5 ± 2 to 3 ± 2, Re-188: 7 ± 2 to 4 ± 2 before vs. 6 months after therapy, respectively). The CSG VAS values were 6 ± 2 before and 5 ± 2, 4 ± 3, 5 ± 2 and 6 ± 2 at 1, 3, 6 and 12 months after corticosteroid instillation, respectively. Pain relief achieved with the three radiocolloid formulations did not differ significantly (P > 0.1). Pain relief at 12 months was more durable in RSO compared to CSG, P < 0.05. At 3 months, pain relief (>2 steps) was reported by 86% of RSO versus 67% of CSG, at 6 months 72 versus 46% and at 12 months 46 versus 21%. Side effects, i.e. swelling or transient pain increase, were recorded in 16% of patients but resolved within 1 month., Conclusion: Therapeutic efficacy of RSO for RA of the knee applying either P-32, Re-188 or Y-90 provides comparable results. Pain relief by RSO is longer lasting as compared to corticosteroid instillation.

Thermal analysis has been widely used for obtaining information about drug-polymer interactions and for pre-formulation studies of pharmaceutical dosage forms. In this work, biodegradable microparticles of poly (d,L-lactide-co-glycolide) (PLGA) containing triamcinolone (TR) in various drug:polymer ratios were produced by spray drying. The main purpose of this study was to study the effect of the spray-drying process not only on the drug-polymer interactions but also on the stability of microparticles using differential scanning calorimetry (DSC), thermogravimetry (TG) and derivative thermogravimetry (DTG), X-ray analysis (XRD), and infrared spectroscopy (IR). The evaluation of drug-polymer interactions and the pre-formulation studies were assessed using the DSC, TG and DTG, and IR. The quantitative analysis of drugs entrapped in PLGA microparticles was performed by the HPLC method. The results showed high levels of drug-loading efficiency for all used drug:polymer ratio, and the polymorph used for preparing the microparticles was the form B. The DSC and TG/DTG profiles for drug-loaded microparticles were very similar to those for the physical mixtures of the components. Therefore, a correlation between drug content and the structural and thermal properties of drug-loaded PLGA microparticles was established. These data indicate that the spray-drying technique does not affect the physico-chemical stability of the microparticle components. These results are in agreement with the IR analysis demonstrating that no significant chemical interaction occurs between TR and PLGA in both physical mixtures and microparticles. The results of the X-ray analysis are in agreement with the thermal analysis data showing that the amorphous form of TR prevails over a small fraction of crystalline phase of the drug also present in the TR-loaded microparticles. From the pre-formulation studies, we have found that the spray-drying methodology is an efficient process for obtaining TR-loaded PLGA microparticles.

The aim of this study is to determine the chemical stability of a suspension of steroid, radiographic contrast material and local anaesthetic. Image-guided steroid injection using a contrast material is widely used for several musculoskeletal conditions. Manufacturers of these agents do not advise mixture in a single syringe, as the chemical stability is unknown. They suggest that, if required, these agents should be injected separately. However, the agents will be mixed together when injected into a contained space within the body. It would seem unethical to continue this in clinical practice until the stability of such a mixture is established. High-performance liquid chromatographic (HPLC) analysis was used to assess the stability of combinations of steroids (triamcinolone and methylprednisolone) and Omnipaque (iohexol). Further analysis was also performed to test the stability of adding local anaesthetics (lidocaine and bupivacaine) to these mixtures. The results demonstrated that all combinations were stable when mixed together. In conclusion, these results support the continued safe use of these products in combination in clinical practice.

Long-term hypokinesia increases sensitivity of the thymus to the hypoplastic effect of glucocorticoid preparation triamcinolone acetonide by potentiating the proapoptotic effect of the glucocorticoid.

The objective of this study was to investigate the mechanism by which hydroxypropyl-beta-cyclodextrin (HPCD) increases transdermal permeation. Hairless mouse skin was pretreated with HPCD solutions for up to 4 h. After removing the HPCD, corticosteroid-containing suspensions were applied and the transdermal flux and skin accumulation of two model drugs were investigated. After pretreatment, changes to the stratum corneum endothermic melting transitions were determined as an indication of HPCD-induced lipid disorganization. Results demonstrated that HPCD pretreatment had no significant effect on the transdermal permeation or skin accumulation of the model corticosteroids. These findings suggest that HPCD functions to enhance the apparent solubility of the drug in the formulation, thus increasing transdermal permeation rather than extracting lipids from the skin.

The glucocorticoide triamcinolone diacetate was investigated for polymorphism. Crystallization experiments in different solvents performed at room-temperature reveal that in most cases solvates has formed (form B) which are isotypic and which crystallize in the orthorhombic space group P2(1)2(1)2(1). In their crystal structure channels are formed in which the solvent molecules are located. In some other solvents the commercial available form A is the thermodynamic most stable form. On heating form A using differential scanning calorimetry (DSC) the compound melts at a peak temperature of 136 degrees C without any further polymorphic transformation. If the solvents are removed at higher temperatures using simultaneous differential thermoanalysis and thermogravimetry coupled to mass spectroscopy (DTA-TG-MS) the remaining residues are amorphous against X-rays because the compound melts directly after desolvation. If the desolvation process is investigated by DSC measurements the same is observed for most solvents but in some cases different peaks for desolvation and melting are observed. In this case a new modification can be isolated after removing the solvent (form C). If the solvent are removed in vacuum or by storage at room-temperature always the commercial available form A is obtained, whereas desolvation experiments at 80 degrees C indicate the formation of a further polymorphic modification (form D).

A new indirect RP-HPLC method was developed for determination of small, ng/ml, concentrations of triamcinolone (TMC) in human plasma, in presence of endogenous corticosteroids: cortisol (hydrocortisone, F), cortisone (E) and their metabolites, after administration of TMC in a free alcohol form. After solid phase extraction (SPE) in cartridges with octadecyl phase, TMC and prednisolone (I.S.) were derivatized by treatment with 9-anthroyl nitrile (9-AN) in a basic mixture, consisting of triethanolamine and quinuclidine, to receive fluorescent esters at 21-hydroxyl group of the steroid chain. Optimal conditions were also established to purify fluorescent TMC and I.S. derivatives before injection into HPLC column. The fluorescent esters were determined using an isocratic RP-HPLC technique in a C18 column. The mobile phase consisted of acetonitrile and 0.3 mM ortho-phoshoric acid. The method was validated before using to pharmacokinetic studies. Calibration curve of TMC was linear in the range of 2.5-100.0 ng/ml. Intra- and inter-day measurement precision and accuracy were equal to or lower than 15%. Percent recovery, and limits of detection (LOD) and quantification (LOQ) of TMC were also determined. The method was applied for in vivo conditions after administration of tablets containing TMC to healthy volunteers. Moreover, the method provided potential to determine TMC and, simultaneously, other glucocorticoids: E, F and their metabolites in one analytical run. Column interactions were observed between endogenous metabolites of E. Usefulness of the elaborated method was confirmed in pharmacokinetic studies following administration of a small (4 mg) dose of TMC to human volunteers. The method can provide an alternative to HPLC coupled with RIA in determination of small quantities of TMC.

A systematic study on the degradation and drug release from L-lactic acid and ricinoleic-acid-based copolyesters is reported. These copolyesters were synthesized by ring opening polymerization (ROP), melt condensation (COND) and transesterification (TRANS) of high molecular weight poly(lactic acid) (PLA) with ricinoleic acid (PLA-RA), and repolymerization by condensation to yield random and block copolymers of weight average molecular weights (Mw) between 3000 and 13,000. All polymers showed an almost zero-order weight loss, with a 20-40% loss after 60 days of incubation. Lactic acid release to the degradation solution is proportional to weight loss of the polymer samples. The main decrease in molecular weight was observed during the first 20 days, followed by a slow degradation phase, which kept the number average molecular weight (Mn) at 4000-2000 for another 40 days. Water-soluble 5FU was released from ricinoleic-acid-based polymers faster than slightly water-soluble triamcinolone. Drug release into phosphate-buffered saline (pH 7.4, 0.1 M) at 37 degrees C from P(LA-RA) 60:40 prepared by condensation of the acids was faster than from pasty P(PLA-RA) 60:40 synthesized by transesterification for both drugs.

A subretinal drug delivery system was developed to overcome the limitations of current treatments for retinal disease. A rod-shaped implant was made by embedding the corticosteroid triamcinolone acetonide within a biodegradable polycaprolactone polymer matrix. The implant was fabricated by homogeneously mixing the polymer and drug in solvent. The mixture was then dried, melted, and extruded, and the prepared solid form was drawn into a filament. The rods were mechanically sectioned to a length of 2 mm with a diameter of up to 320 microm. The rods were successfully implanted into the subretinal space of six rabbits. No complications were observed during the 4-week follow-up period. Initial observations of the implantation and elution characteristics revealed that polycaprolactone is well tolerated by the retinal tissue and that the implant can elute steroid for a period of at least 4 weeks without eliciting inflammatory response or complications. In vitro drug elution rates of different polymer to drug ratios and geometries into a balanced salt solution/bovine serum albumin (1%) solution showed an early rapid-release phase and late first-order phase. Histology and device retrieval after implantation revealed minimal encapsulation and good preservation of cellular morphology during the follow-up period and a more fibrous polymer microstructure of the implant., ((c) 2005 Wiley Periodicals, Inc.)

This study describes the application of a novel, reactive matrix for the mass spectral analysis of steroids by capillary-high performance liquid chromatography (capillary-HPLC) coupled to matrix-assisted laser desorption/ionization (MALDI). The mass spectral analysis of steroids was accomplished after fully automated peak deposition of chromatographic peaks onto MALDI targets. The seven corticosteroids used as test compounds were: triamcinolone, prednisone, cortisone, fludrocortisone, dexamethasone, deoxycorticosterone, and budesonide. They were separated using a PepMap C(18) (3 microm particle size, 100 A pore width) column at five different concentration levels of 25, 15, 7.5, 2.5 and 1 ng/microL, and the peaks were detected at a wavelength of 237 nm. The column effluent was mixed with 2,4-dinitrophenylhydrazine (DNPH) directly following the UV detector. The chromatographic peaks were then deposited onto the MALDI target with a robotic micro-fraction collector triggered by the UV detector signals. A special hydrophobic surface coating allowed the deposition of up to 4 microL (up to 90 % of the chromatographic peak volume) onto one sample spot. The compounds were then identified by MALDI mass spectrometry. Depending on the nature of the analyte, radical cations ([M](+.)) and sodium adduct ions ([M+Na](+)) of the steroids as well as protonated steroid-dinitrophenylhydrazone derivatives ([M(D)+H](+)) were detected in positive ion mode. The detection limits were between 0.5 and 15 ng injected with capillary-HPLC-MALDI-TOF-MS and between 0.3 and 3 ng on target with MALDI-TOF when deposited manually.

The rheological profiles of commercial corticosteroid nasal spray suspensions (Beconase, Nasacort, Flixonase, and Nasonex) were compared using shear and extensional techniques. Thixotropy/shear thinning was investigated (Carri-Med CSL100, concentric cylinder geometry) by (a) the generation of flow curves at low (100 sec-1) and high (1200 sec-1) maximum shear rates and (b) determination of equilibrium shear viscosities at constant shear rates of 10 sec-1, 100 sec-1, or 1200 sec-1. Extensional properties, on which droplet breakup and size depend, were examined using digital camera photography of droplet evolution and the length any trailing filament formed when the suspension was extruded from a 10-ml syringe at 500 microliters/min. All the nasal suspensions were shear thinning and were also thixotropic to varying degrees. The absence of significant thixotropic recovery at short times (5 min) for all the sprays implies that thixotropy is not necessarily the controlling factor for prolonged residence of the spray in the nasal cavity, but rather that it is the high viscosities present in all four sprays, even after structure breakdown. Preliminary extensional flow data identified differences among the four sprays, with extensional filament lengths increasing in the same rank order as the lowest shear rate (10 sec-1) equilibrium viscosities.

In this study, a rapid and accurate particle size determination method using a light-scattering particle size analyzer was developed to measure the particle size and size distribution of a suspension containing three solid components: clotrimazole, triamcinolone, and sarafloxacin, which have different refractive indices. To ensure that data represent the size distribution of the primary particles of the suspension, the optimal sonication prior to and during measurement was determined. It was found that the results obtained using the average relative refractive index (RRI) of the three components agreed with the results obtained using three individual RRIs. In addition, the results from two analysts demonstrated good reproducibility of this method. The size distribution data of the suspension were also compared to those of the bulk drugs. The results showed that the median particle size of this three-component suspension is relatively close to that of clotrimazole, which accounts for 80% of solid particles in the suspension. Furthermore, the results obtained using the light-scattering technique were comparable to those obtained using a polarized light microscope equipped with an image analyzer, indicating acceptable accuracy of this technique.

Glucocorticoid-induced apoptosis in the murine interleukin-2-dependent T-cell line CTLL-2 and in freshly isolated thymocytes was studied. It was demonstrated here that in CTLL-2 cells, dexamethasone (methyl in position 16 alpha) was more efficient in inducing apoptosis than betamethasone (methyl in position 16 beta) or triamcinolone (hydroxyl in position 16). In contrast, no such difference between these three molecules was found in murine thymocytes. In addition, we showed that glucocorticoid-induced apoptosis on the two models was mediated through interaction with the glucocorticoid receptor and did not occur in the presence of inhibitors of transcription, translation or an endonuclease-inhibitor. Furthermore, in CTLL-2 cells, apoptosis took place in the presence of EGTA whereas it was prevented in murine thymocytes, thus indicating that calcium plays a different role in these two models. Finally, higher concentrations of interleukin-2 were needed to protect CTLL-2 cells against dexamethasone-induced apoptosis than that induced by betamethasone or triamcinolone. Thus, structural differences at position 16 of the steroid nucleus correlate with a different apoptosis-inducing activity by glucocorticoids which, however, is only evidenced in the calcium-independent CTLL-2 model.

The commercial anti-inflammatory drug triamcinolone has been shown to rearrange by similar, but distinct pathways when exposed to certain trace metal ions or to dilute aqueous base. In the presence of aqueous base, the 16-hydroxy-20-keto system undergoes reverse aldol cleavage of the 16,17-bond, followed by aldol cyclization linking C-16 to C-20. This base-catalyzed rearrangement gives a 16 beta,17 alpha-dihydroxy product and a corresponding 16 alpha,17 alpha-dihydroxy product in roughly 4 to 1 ratio. Metal-catalyzed rearrangement provides the 16 alpha,17 alpha-dihydroxy product with extremely high stereoselectivity. Mechanistic models are proposed that help explain the ratio of products isolated from each route. The studies presented suggest that similar forms of rearrangement could be of preparative value in syntheses requiring specific stereochemistry of appropriately substituted bicyclic alpha,beta-dihydroxyketones. Under more vigorous conditions of aqueous base treatment these rearrangement products undergo further decomposition with loss of formaldehyde from the hydroxymethyl group, followed by beta-elimination of water. Reaction of the beta-elimination product with formaldehyde results in the formation of a dimeric species linked by a methylene group.

The ability of sodium taurocholate to increase the initial dissolution rate of five steroids was studied in terms of effects on solubility, wetting, and diffusion coefficient. For all compounds, wetting effects predominated over solubilization effects at bile salt concentrations representative of the fasted state. For hydrocortisone, triamcinolone, betamethasone, and dexamethasone, this trend also continued at the higher bile salt concentrations typical of the fed state. Bile salts solubilized these compounds by a factor of two or less, and diffusivity changes were negligible at bile salt concentrations up to 30 mM. For the more lipophilic danazol, the wetting effects were small and of importance only at premicellar levels of bile salt. At higher concentrations, the increase in solubility was the predominant factor. Incorporation into micelles appeared to decrease the diffusivity slightly, but this was important only at bile salts concentrations of 15 mM or higher. In conclusion, it appears that even within a series of structurally related compounds the mechanism by which bile salts mediate increases in dissolution rate can differ considerably.