Transcutaneous Delivery of Dexamethasone Sodium Phosphate Via Microneedle-Assisted Iontophoretic Enhancement - A Potential Therapeutic Option for Inflammatory Disorders.

AIM: This study aimed to fabricate dexamethasone sodium phosphate loaded microneedle arrays (MNA) and investigate their efficiency in combination with iontophoresis for the treatment of hind paw oedema in rats. METHODS: Drug loaded polyvinyl alcohol, polyvinyl pyrrolidone and D-sorbitol-based MNA11 were fabricated by vacuum micromolding. Physicochemical, morphological, thermal, in-silico, in-vitro insertion ability (on parafilm) and drug release studies were performed. Ex-vivo permeation, in-vivo insertion and anti-inflammatory studies were performed in combination with iontophoresis. RESULTS: MNA11 displayed sharp-tipped projections and acceptable physicochemical features. Differential scanning calorimetry results indicated that drug loaded MNA11 were amorphous solids. Drug interacted with PVP and PVA predominately via hydrogen bonding. Parafilm displayed conspicuously engraved complementary structure of MNA11. Within 60 min, 91.50 ± 3.1% drug released from MNA11. A significantly higher i.e., 95.06 ± 2.5% permeation of drug was observed rapidly (within 60 min) from MNA11-iontophoresis combination than MNA11 i.e., 84.07 ± 3.5% within 240 min. Rat skin treated using MNA11 and MNA11-iontophoresis showed disruptions / microchannels in the epidermis without any damage to underlying anatomical structures. MNA11-iontophoresis combination led to significant reduction (83.02 ± 3.9%) in paw oedema as compared to MNA11 alone (72.55 ± 4.1%). CONCLUSION: MNA11-iontophoresis combination can act as a promising candidate to deliver drugs transcutaneously for treating inflammatory diseases.

Simultaneous Determination of Moxifloxacin Hydrochloride and Dexamethasone Sodium Phosphate in Rabbit Ocular Tissues and Plasma by LC-MS/MS: Application for Pharmacokinetics Studies.

Treatment of ocular infection involves pharmacotherapy with steroids and antibiotic drops, such as moxifloxacin hydrochloride (MFH) and dexamethasone sodium phosphate (DSP). To characterize the pharmacokinetics of these two compounds, we performed and validated a liquid chromatography-mass spectrometry (LC-MS/MS) method to quantify them in rabbit ocular tissues and plasma. We used protein precipitation to extract the compounds. The analyte and internal standard (IS) were separated using a Shim-pack Scepter C18 column. The mobile phase was composed of 0.1% formic acid water (A) and methanol (B). MFH and DSP were detected using positive ion electrostatic ionization (ESI) in multiple reaction monitoring mode (MRM). The calibration curves for both compounds showed good linearity over concentrations ranging from 0.5 to 200 ng/mL in rabbit ocular tissues and plasma. The lower limit of quantification for both MFH and DSP was 0.5 ng/mL. We validated this method for selectivity, linearity (r2 > 0.99), precision, accuracy, matrix effects, and stability. Thus, we used this method to assess the pharmacokinetic (PK) characteristics of MFH and DSP in rabbit ocular tissues and plasma after single doses. Our results indicate that this method can be used for the simultaneous analysis of moxifloxacin hydrochloride and dexamethasone sodium phosphate in clinical samples.

The preparation of dexamethasone sodium phosphate multivesicular liposomes thermosensative hydrogel and its impact on noise-induced hearing loss in the Guinea pigs.

OBJECTIVE: The aim of this study is to establish the dexamethasone sodium phosphate multivesicular liposomes thermosensative hydrogel (DEX-MVLs-Gel) drug delivery system and to analyze the pharmacodynamics, pharmacokinetics and safety of DEX-MVLs-Gel as well as to explore whether the prepared DEX-MVLs-Gel can protect the hearing in the guinea pigs following noise exposure. METHODS: DEX-MVLs formulations were constructed by double emulsion method, and the DEX-MVLs-Gel was prepared after adding P407 and P188 into the DEX-MVLs. A total of 20 adult albino guinea pigs were chosen to establish the animal models with noise-induced hearing loss. After animals were treated with DEX-MVLs-Gel at concentrations of 20, 6 and 2 mg/mL, and 5 mg/mL Dexamethasone Sodium Phosphate (DEX-P) solution, respectively, the hearing function, drug concentration in the peripheral lymph fluid, and hair cell morphology were assessed. RESULTS: The ABR threshold of the 20 mg/mL DEX-MVLs-Gel treated group at the frequencies of 4, 8, 16 and 24 kHz were measured as 47.5 ± 5.2, 48.3 ± 4.1, 55.8 ± 3.8 and 57.5 5 ± 5.2 dB SPL, respectively. Statistical significances were noted between the 20 mg/mL DEX-MVLs-Gel treated group and control group at each frequency (all P < 0.05), between the 2 mg/mL and 6 mg/mL DEX-MVLs-Gel treated groups at the frequencies of 4 and 8 kHz (both P < 0.05). High Performance Liquid Chromatography (HPLC) demonstrated that the drug concentrations in the peripheral lymph in all groups were gradually decreased on the 1st, 3rd and 7th d after intratympanic injection. Scattered hair cell loss could be observed mainly in the basal and middle turn in the saline administrated group and the 20 mg/mL DEX-MVLs-Gel administration group, and the hair cell loss was not identified in the apical turn. CONCLUSIONS: A high concentration (20 mg/mL) of DEX-MVLs-Gel exerts significant protective effects upon the guinea pigs with noise-induced hearing loss. The prepared DEX-MVLs-Gel can be effectively maintained in the peripheral lymph fluid of guinea pigs for 3-7 d and MVLs-Gel causes no obvious ototoxicity.

Exosome-based biomimetic nanoparticles targeted to inflamed joints for enhanced treatment of rheumatoid arthritis.

BACKGROUND: Glucocorticoids (GCs) show powerful treatment effect on rheumatoid arthritis (RA). However, the clinical application is limited by their nonspecific distribution after systemic administration, serious adverse reactions during long-term administration. To achieve better treatment, reduce side effect, we here established a biomimetic exosome (Exo) encapsulating dexamethasone sodium phosphate (Dex) nanoparticle (Exo/Dex), whose surface was modified with folic acid (FA)-polyethylene glycol (PEG)-cholesterol (Chol) compound to attain FPC-Exo/Dex active targeting drug delivery system. RESULTS: The size of FPC-Exo/Dex was 128.43 ± 16.27 nm, with a polydispersity index (PDI) of 0.36 ± 0.05, and the Zeta potential was - 22.73 ± 0.91 mV. The encapsulation efficiency (EE) of the preparation was 10.26 ± 0.73%, with drug loading efficiency (DLE) of 18.81 ± 2.05%. In vitro study showed this system displayed enhanced endocytosis and excellent anti-inflammation effect against RAW264.7 cells by suppressing pro-inflammatory cytokines and increasing anti-inflammatory cytokine. Further biodistribution study showed the fluorescence intensity of FPC-Exo/Dex was stronger than other Dex formulations in joints, suggesting its enhanced accumulation to inflammation sites. In vivo biodistribution experiment displayed FPC-Exo/Dex could preserve the bone and cartilage of CIA mice better and significantly reduce inflamed joints. Next in vivo safety evaluation demonstrated this biomimetic drug delivery system had no obvious hepatotoxicity and exhibited desirable biocompatibility. CONCLUSION: The present study provides a promising strategy for using exosome as nanocarrier to enhance the therapeutic effect of GCs against RA.

Mucoadhesive buccal film containing ornidazole and dexamethasone for oral ulcers: in vitro and in vivo studies.

A bilayered mucoadhesive buccal film containing a combination of ornidazole (OD) and dexamethasone sodium phosphate (DEX) was prepared using solvent casting to treat oral ulcers. Films were systematically evaluated in vitro to obtain the optimum formulation. The therapeutic effects of these films were investigated in the rabbit oral ulcer model and the in vivo release of OD and DEX in the human oral cavity was also evaluated. The backing layer contained ethyl cellulose and an optimal mucoadhesive layer containing both OD and DEX was produced. Films from the optimum formulation were 0.427 ± 0.015 mm thick, weighed 55.89 ± 0.79 mg, and had a surface pH of 6.34 ± 0.01. The drug content of the optimum formulation approximated the theoretical value with good uniformity (2.959 ± 0.106 mg/cm2 for OD and 0.877 ± 0.031 mg/cm2 for DEX). The formulation showed favorable swelling characteristics and both drugs were released at >95% after 4 h. Moreover, the compound film had a statistically significant effect on mucosal repair and reduced ulcer inflammation without stimulating the human oral mucosa. Cmax of OD in saliva was 37.04 µg/ml and that of DEX was 9.737 µg/ml. Given promising therapeutic effects, the compound film developed here could become a local drug delivery device for treating oral ulcers.

Synthesis and Characterization of Poly(2-hydroxyethylmethacrylate) Contact Lenses Containing Chitosan Nanoparticles as an Ocular Delivery System for Dexamethasone Sodium Phosphate.

PURPOSE: Dexamethasone sodium phosphate (DXP) is an anti-inflammatory drug commonly used to treat acute and chronic ocular diseases. It is routinely delivered using eye-drops, where typically only 5% of the drug penetrates the corneal epithelium. The bioavailability of such ophthalmic drugs can be enhanced significantly using contact lenses incorporating drug-loaded nanoparticles (NPs). METHODS: The mechanism of release from chitosan NPs (CS-NPs), synthesized by ionic gelation, was studied in vitro. The DXP loaded CS-NPs were subsequently entrapped in contact lenses and the optical and drug-release properties were assessed. RESULTS: DXP release from CS-NPs followed diffusion and swelling controlled mechanisms, with an additional proposed impact from the electrostatic interaction between the drug and the CS-NPs. The release rate was found to increase with an increase in drug loading from 20 to 50 wt%. However, an inverse effect was observed when initial loading increased to 100 wt%. NP-laden lenses were optically clear (95-98% transmittance relative to the neat contact lens) and demonstrated sustained DXP release, with approximately 55.73% released in 22 days. CONCLUSIONS: The release profile indicated that drug levels were within the therapeutic requirement for anti-inflammatory use. These results suggest that these materials might be a promising candidate for the delivery of DXP and other important ophthalmic therapeutics.

Formulation and development of ophthalmic in situ gel for the treatment ocular inflammation and infection using application of quality by design concept.

CONTEXT: The conventional liquid ophthalmic delivery systems exhibit short pre-corneal residence time and the relative impermeability to the cornea which leads to poor ocular bioavailability. OBJECTIVE: The aim of this study was to apply quality by design (QbD) for development of dexamethasone sodium phosphate (DSP) and tobramycin sulfate (TS)-loaded thermoresponsive ophthalmic in situ gel containing Poloxamer 407 and hydroxyl propyl methyl cellulose (HPMC) K4M for prolonging the pre-corneal residence time, ocular bioavability and decreases the frequency of administration of dosage form. The material attributes and the critical quality attributes (CQA) of the in situ gel were identified. Central composite design (CCD) was adopted to optimize the formulation. MATERIALS AND METHODS: The ophthalmic in situ forming gels were prepared by cold method. Materials attributes were the amount of Poloxamer 407 and HPMC and CQA identified were Gel strength, mucoadhesive index, gelation temperature and % of drug release of both drug. RESULTS AND DISCUSSION: Optimized batch (F*) containing 16.75% poloxamer 407 and 0.54% HPMC K4M were exhibited all results in acceptable limits. Compared with the marketed formulation, optimized in situ gel showed delayed Tmax, improved Cmax and AUC in rabbit aqueous humor, suggesting the sustained drug release and better corneal penetration and absorption. CONCLUSION: According to the study, it could be concluded that DSP and TS would be successfully formulated as in situ gelling mucoadhesive system for the treatment of steroid responsive eye infections with the properties of sustained drug release, prolonged ocular retention and improved corneal penetration.

Isolation and identification of dexamethasone sodium phosphate degrading Pseudomonas alcaligenes.

Glucocorticosteroids such as dexamethasone have polluted hospital wastewater, urban sewage, and river water in varying degrees. However, dexamethasone degradation by bioremediation technology is less understood. This study aims to isolate bacteria that could degrade dexamethasone and to identify their degradation characteristics. Hospital wastewater contaminated by dexamethasone was collected. After culturing in inorganic salt medium and in carbon deficient medium containing dexamethasone sodium phosphate, a bacterial strain with dexamethasone sodium phosphate as the sole carbon and energy source was enriched and isolated from the contaminated wastewater. The strain was identified as Pseudomonas alcaligenes by morphology, Gram staining, biochemical test, and 16S rDNA sequencing. Isolated bacteria were domesticated. Then its degradation characteristic was determined by high-performance liquid chromatography method. The degradation rate of P. alcaligenes on dexamethasone sodium phosphate was 50.86%. Of the degraded dexamethasone sodium phosphate, 75.23% of dexamethasone sodium phosphate was degraded to dexamethasone and 23.63% was degraded to other metabolites. In conclusion, the isolated P. alcaligenes in this study would provide experimental evidence for further research on the bioremediation technology to treat dexamethasone sodium phosphate and dexamethasone polluted water and further for the elimination of side effects of dexamethasone.

Engineering a novel water-in-oil biocompatible microemulsion system for the ocular delivery of dexamethasone sodium phosphate in the treatment of acute uveitis.

Due to their unique characteristics, microemulsions (ME) represent one of the most promising delivery systems which can conquer poor ocular drug bioavailability providing long residence time. Development of a ME system, relying on the use of a safe and non-irritant surfactant combination derived from sustainable resources and which can consolidate the small ME droplets, is the goal of this work. Herein, we report the design and characterization of a novel biocompatible, eco-friendly ME system loaded with the hydrophilic dexamethasone sodium phosphate (DEXP) using a novel surfactant mixture composed of D-α-tocopherol polyethylene glycol succinate (TPGS) and Plantacare® (coco-Glycosides). Capryol™ PGMC and double-distilled water were used as the respective oil and aqueous phases and the MEs were prepared by the water titration method, suitable for scaling up. Optimization of ME formulae was conducted by varying Plantacare® grades, TPGS to Plantacare® mass ratios and drug loading. The formulae were characterized in terms of physical appearance, droplet size (PS), size distribution (PDI), zeta potential (ZP), and stability. The optimized DEXP-loaded ME formula attained acceptable PS, PDI, and ZP values of 43 ± 5 nm, 0.35 ± 0.07, -12 ± 4 mV, respectively. TEM images confirmed a small PS ≤ 100 nm. The in vivo safety of ME was proved by the Draize test. The ME formula prompted excellent mucoadhesion and transcorneal permeation. The confocal studies showed deep penetration into the rabbits' corneas. In vivo studies using endotoxin-induced uveitis showed high ocular efficacy and a significant reduction in inflammatory cells, including interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). The obtained results elect the novel engineered ME system as a promising tool for the ocular delivery of hydrophilic moieties in the management of various ophthalmic diseases.

Development of chitosan/sodium carboxymethyl cellulose-based polyelectrolyte complex of dexamethasone for treatment of anterior uveitis.

Anterior uveitis is one of the most prevalent forms of ocular inflammation caused by infections, trauma, and other idiopathic conditions if not treated properly, it can cause complete blindness. Therefore, this study aimed to formulate and evaluate dexamethasone sodium phosphate (DSP) loaded polyelectrolyte complex (PEC) nanoparticles (NPs) for the treatment of anterior uveitis. DSP-loaded PEC-NPs were formed through complex coacervation by mixing low molecular weight chitosan and the anionic polymer carboxy methyl cellulose (CMC). The formulations were optimized using Box-Behnken design and evaluated the effect of independent variables: Chitosan concentration, CMC concentration, and pH of chitosan solution on the dependent variables: particle size (PS), Polydispersity Index (PDI), pH of the formulation, and % entrapment efficacy (%EE). The PS, PDI, zeta potential, and pH of the optimized formulation were found 451 ± 82.0995 nm, 0.3807 ± 0.1862, +20.33 ± 1.04 mV and 6.8367 ± 0.0737 respectively. The %EE and drug loading of formulation were 61.66 ± 4.2914% and 21.442 ± 1.814% respectively.In vitrodrug release studies of optimized formulation showed the prolonged release up to 12 h whereas, the marketed formulation showed the burst release 85.625 ± 4.3062% in 1 h and 98.1462 ± 3.0921% at 6 h, respectively. Fourier transform infrared studies suggested the effective incorporation of the drug into the PEC-NPs formulation whereas differential scanning calorimetry and x-ray diffraction studies showed the amorphized nature of the drug in the formulation. Transmission electron microscopy study showed self-assembled, nearly spherical, core-shell nanostructures. The corneal permeation study showed higher permeation of the drug from PEC-NPs compared to the marketed formulation. Hen's Eggs test-Chorioallantoic Membrane test of the optimized formulation revealed non-irritant and safe for ocular administration. Therefore, DSP-loaded PEC-NPs are an effective substitute for conventional eye drops due to their ability to increase bioavailability through longer precorneal retention duration and sustained drug release.

Improving corneal permeability of dexamethasone using penetration enhancing agents: First step towards achieving topical drug delivery to the retina.

With an ever-increasing burden of vision loss caused by diseases of the posterior ocular segment, there is an unmet clinical need for non-invasive treatment strategies. Topical drug application using eye drops suffers from low to negligible bioavailability to the posterior segment as a result of static and dynamic defensive ocular barriers to penetration, while invasive delivery systems are expensive to administer and suffer potentially severe complications. As the cornea is the main anatomical barrier to uptake of topically applied drugs from the ocular surface, we present an approach to increase corneal permeability of a corticosteroid, dexamethasone sodium-phosphate (DSP), using a novel penetration enhancing agent (PEA). We synthesised a novel polyacetylene (pAc) polymer and compared its activity to two previously described cell penetrating peptide (CPP) based PEAs, TAT and penetratin, with respect to increasing transcorneal permeability of DSP in a rapid ex-vivo porcine corneal assay over 60 min. The transcorneal apparent permeability coefficients (Papp) for diffusion of pAc, and fluorescein isothiocyanate (FITC) conjugated TAT and penetratin were up to 5 times higher (p < 0.001), when compared to controls. When pAc was used in formulation with DSP, an almost 5-fold significant increase was observed in Papp of DSP across the cornea (p = 0.0130), a significant 6-fold increase with TAT (p = 0.0377), and almost 7-fold mean increase with penetratin (p = 0.9540). Furthermore, we investigated whether the PEAs caused any irreversible damage to the barrier integrity of the corneal epithelium by measuring transepithelial electrical resistance (TEER) and immunostaining of tight junction proteins using zonula occludens-1 (ZO-1) and occludin antibodies. There was no damage or structural toxicity, and the barrier integrity was preserved after PEA application. Finally, an in-vitro cytotoxicity assessment of all PEAs in human retinal pigment epithelium cells (ARPE-19) demonstrated that all PEAs were very well-tolerated, with IC50 values of 64.79 mM for pAc and 1335.45 µM and 87.26 µM for TAT and penetratin, respectively. Our results suggest that this drug delivery technology could potentially be used to achieve a significantly higher intraocular therapeutic bioavailability after topical eye drop administration, than currently afforded.

A Stereolithography-Based Modified Spin-Casting Method for Faster Laboratory-Scale Production of Dexamethasone-Containing Dissolving Microneedle Arrays.

Microneedle arrays (MNAs) consist of a few dozens of submillimeter needles, which tend to penetrate through the stratum corneum layer of the skin and deliver hardly penetrating drugs to the systemic circulation. The application of this smart dosage form shows several advantages, such as simple use and negligible pain caused by needle punctures compared to conventional subcutaneous injections. Dissolving MNAs (DMNAs) represent a promising form of cutaneous drug delivery due to their high drug content, biocompatibility, and ease of use. Although different technologies are suitable to produce microneedle arrays (e.g., micromilling, chemical etching, laser ablation etc.), many of these are expensive or hardly accessible. Following the exponential growth of the 3D-printing industry in the last decade, high-resolution desktop printers became accessible for researchers to easily and cost-effectively design and produce microstructures, including MNAs. In this work, a low force stereolithography (LFS) 3D-printer was used to develop the dimensionally correct MNA masters for the spin-casting method. The present study aimed to develop and characterize drug-loaded DMNAs using a two-level, full factorial design for three factors focusing on the optimization of DMNA production and adequate drug content. For the preparation of DMNAs, carboxymethylcellulose and trehalose were used in certain amounts as matrices for dexamethasone sodium phosphate (DEX). Investigation of the produced DexDMNAs included mechanical analysis via texture analyzer and optical microscopy, determination of drug content and distribution with HPLC and Raman microscopy, dissolution studies via HPLC, and ex vivo qualitative permeation studies by Raman mapping. It can be concluded that a DEX-containing, mechanically stable, biodegradable DexDMNA system was successfully developed in two dosage strengths, of which both efficiently delivered the drug to the lower layers (dermis) of human skin. Moreover, the ex vivo skin penetration results support that the application of DMNAs for cutaneous drug delivery can be more effective than that of a conventional dermal gel.

Interpenetrating Polymer Networks of Poly(2-hydroxyethyl methacrylate) and Poly(N, N-dimethylacrylamide) as Potential Systems for Dermal Delivery of Dexamethasone Phosphate.

In this study, a series of novel poly(2-hydroxyethyl methacrylate) (PHEMA)/poly(N,N'-dimethylacrylamide) (PDMAM) interpenetrating polymer networks (IPNs) were synthesized and studied as potential drug delivery systems of dexamethasone sodium phosphate (DXP) for dermal application. The IPN composition allows for control over its swelling ability as the incorporation of the highly hydrophilic PDMAM increases more than twice the IPN swelling ratio as compared to the PHEMA single networks, namely from ~0.5 to ~1.1. The increased swelling ratio of the IPNs results in an increased entrapment efficiency up to ~30% as well as an increased drug loading capacity of DXP up to 4.5%. X-ray diffraction (XRD) and differential scanning calorimetry (DSC) show the formation of a solid dispersion between the drug DXP and the polymer (IPNs) matrix. Energy-dispersive X-ray (EDX) spectroscopy shows an even distribution of DXP within the IPN structure. The DXP release follows Fickian diffusion with ~70% of DXP released in 24 h. This study demonstrates the potential of the newly developed IPNs for the dermal delivery of DXP.

Efficacy of Dexamethasone Diluted Saline Irrigant on Postoperative Sequelae in Patients Undergoing Lower Third Molar Surgery: A Prospective Clinical Study.

Background Third molar impaction surgery is one of the most common yet challenging procedures done as a part of minor oral surgery. Years of research and improvisation of techniques have been done, yet there are still a lot of postoperative sequelae after surgical removal of the impacted tooth. In our study, we have compared the efficacy of dexamethasone diluted saline solution over plain saline solution used as an irrigant in the reduction of postoperative sequelae for lower third molar surgery. Aim The aim of the study was to evaluate the efficacy of dexamethasone diluted saline solution over plain saline solution in the reduction of postoperative sequelae for lower third molar surgery. Materials and methods The research was conducted at Saveetha Dental College and Hospital in the Department of Oral and Maxillofacial Surgery. The study consisted of 48 individuals, 24 of whom had dexamethasone saline as an irrigant (8 mg of dexamethasone was diluted in 100 ml of plain saline) (Group 1), and 24 in whom plain saline was used as an irrigant (Group 2) in the lower third molar surgery. Patients were evaluated postoperatively for pain and swelling. The postoperative swelling was measured on postoperative day two and day seven. Postoperative pain was measured on day two, day four, and day seven after surgery using a visual analog scale. Data were analyzed using SPSS (IBM Corp., Armonk, NY) with P-values less than 0.05 considered statistically significant. The statistical test used to compare the outcomes between the two groups was the independent samples t-test. Results It was found that study participants in the dexamethasone saline irrigation group reported statistically significantly lesser pain than participants receiving plain saline irrigation on day two (P = 0.001), day four (P = 0.001), and day seven (P = 0.001), respectively. Also, there was a reduction in swelling among participants in the dexamethasone saline irrigation group when compared to the normal saline irrigation group, which was statistically significant (P = 0.001) on day two, while the postoperative swelling was not statistically significant on day seven (P = 0.08) between the two study groups. Conclusion Based on the results obtained, it can be concluded that dexamethasone saline solution (8 mg/100 mL) was more effective as an irrigant in reducing the postoperative sequelae than regular saline solution in the lower third molar surgery.

Conceptualization and Investigation of Multicomponent Polymer Networks as Prospective Corticosteroid Carriers.

Dexamethasone (DXM) is a highly potent and long-acting synthetic glucocorticoid with anti-inflammatory, anti-allergic, and immunosuppressive effects. However, the systemic application of DXM can cause undesirable side effects: sleep disorders, nervousness, heart rhythm disorders, heart attack, and others. In the present study, multicomponent polymer networks were developed as potential new platforms for the dermal application of dexamethasone sodium phosphate (DSP). First, a copolymer network (CPN) comprising hydrophilic segments of different chemical structures was synthesized by applying redox polymerization of dimethyl acrylamide onto poly(ethylene glycol) in the presence of poly(ethylene glycol) diacrylate (PEGDA) as a crosslinker. On this basis, an interpenetrating polymer network structure (IPN) was obtained by introducing a second network of PEGDA-crosslinked poly(N-isopropylacrylamide). Multicomponent networks obtained were characterized by FTIR, TGA, and swelling kinetics in different solvents. Both CPN and IPN showed a high swelling degree in aqueous media (up to 1800 and 1200%, respectively), reaching the equilibrium swelling within 24 h. Additionally, IPN showed temperature-responsive swelling in an aqueous solution as the equilibrium swelling degree decreased considerably with an increase in the temperature. In order to evaluate the networks' potential as drug carriers, swelling in DSP aqueous solutions of varied concentration was investigated. It was established that the amount of encapsulated DSP could be easily controlled by the concentration of drug aqueous solution. In vitro DSP release was studied in buffer solution (BS) with pH 7.4 at 37 °C. The results obtained during DSP loading and release experiments proved the feasibility of the developed multicomponent hydrophilic polymer networks as effective platforms for potential dermal application.

Trilayer microneedle array assisted transdermal and intradermal delivery of dexamethasone.

Dexamethasone is a synthesised glucocorticoid that is widely used in the treatment of various inflammatory skin conditions. Novel trilayer dissolving microneedle arrays were manufactured to assist dexamethasone delivery via the skin. Both transdermal delivery and intradermal delivery of dexamethasone can be achieved this way. Additionally, we proposed a novel strategy of co-formulating dexamethasone and its pro-drug dexamethasone sodium phosphate into the same dissolving microneedle array, with a view to achieving a fast onset of action and also sustained treatment. Here, a 3D-printing technique was employed, for the first time, to fabricate a baseplate for these microneedle arrays. The 3D-printed baseplates provided strong support to aid the insertion of the drug-encapsulated tips. A simple and rapid HPLC method was developed, and validated, to separate and quantify dexamethasone and dexamethasone sodium phosphate in the same sample. Ex-vivo studies found that these trilayer dissolving microneedle arrays could achieve a delivery efficiency of over 40% in intradermal delivery and over 50% in transdermal delivery. Trilayer microneedle-assisted delivery of this glucocorticoid provided a promising alternative to oral and parenteral routes of dexamethasone administration.

ZIF-8 nanoparticles coated with macrophage-derived microvesicles for sustained, targeted delivery of dexamethasone to arthritic joints.

Dexamethasone sodium phosphate (Dex) is widely used in the clinic for the treatment of rheumatoid arthritis. However, it circulates in the blood for a short time and it is linked to a high risk of severe side effects caused by repeated dosing. Here, we encapsulated Dex onto zeolitic imidazolate framework-8 (ZIF-8) to prepare metal-organic framework nanoparticles with high drug loading efficiency. To prevent clearance by the mononuclear phagocyte system and extend time in circulation, the nanoparticles were also camouflaged with macrophage-derived microvesicles (MV) to obtain the biomimetic drug delivery system MV/Dex/ZIF-8. In vitro and in vivo experiments showed that the nanosystem had high drug loading and encapsulation efficiency, high stability, and long circulation time, and it permitted sustained drug release longer in inflamed joint tissues. Our study provides new insights into designing camouflaged drug carriers to prevent their phagocytosis and prolong their time in circulation.

Advanced application of stimuli-responsive drug delivery system for inflammatory arthritis treatment.

Inflammatory arthritis is a major cause of disability in the elderly. This condition causes joint pain, loss of function, and deterioration of quality of life, mainly due to osteoarthritis (OA) and rheumatoid arthritis (RA). Currently, available treatment options for inflammatory arthritis include anti-inflammatory medications administered via oral, topical, or intra-articular routes, surgery, and physical rehabilitation. Novel alternative approaches to managing inflammatory arthritis, so far, remain the grand challenge owing to catastrophic financial burden and insignificant therapeutic benefit. In the view of non-targeted systemic cytotoxicity and limited bioavailability of drug therapies, a major concern is to establish stimuli-responsive drug delivery systems using nanomaterials with on-off switching potential for biomedical applications. This review summarizes the advanced applications of triggerable nanomaterials dependent on various internal stimuli (including reduction-oxidation (redox), pH, and enzymes) and external stimuli (including temperature, ultrasound (US), magnetic, photo, voltage, and mechanical friction). The review also explores the progress and challenges with the use of stimuli-responsive nanomaterials to manage inflammatory arthritis based on pathological changes, including cartilage degeneration, synovitis, and subchondral bone destruction. Exposure to appropriate stimuli induced by such histopathological alterations can trigger the release of therapeutic medications, imperative in the joint-targeted treatment of inflammatory arthritis.

Quantitative determination of dexamethasone sodium phosphate in bulk and pharmaceuticals at suitable pH values using the spectrophotometric method.

Dexamethasone sodium phosphate (DSP) is an ester of dexamethasone with anti-inflammatory action. This study provides new insights to develop a simple, precise, and accurate spectrophotometric method for the quantitative determination of DSP in bulk and pharmaceuticals. The method was validated before being applied to determine the DSP in six pharmaceutical injection forms from different companies. DSP is soluble in phosphate buffer, so it was used as a solvent, and a pH of 6 was found to be suitable for determination purposes. The DSP solution was scanned in the ultraviolet range (200-400 nm) using a double-beam spectrophotometer with a 1-cm quartz cell. The wavelength (λ max) of DSP was set at 242.5 nm, following the Beer-Lambert law for concentrations from 2 to 50 µg/ml. Dexa AIWA (Germany) showed the best results, being very close to the bulk value with no significant variation. Similarly, Dexamed (Cyprus) and HEMAZON (Syria) showed no significant differences from the bulk; however, the three remaining injections, DEXAKAL (India), DEXABRU (India), and DEXARON (China), showed significant variations from the bulk. Estimated limit of detection and limit of quantitation values for DSP were 0.83 and 2.5 µg/ml, respectively, with a regression coefficient of 0.999. Recovery studies were then used to determine the accuracy of the suggested method. The percentage of recovery was found to be 98.58%-102.52%. All results are suggesting a pivotal method for the routine analysis of DSP both in pure form and the commercially pharmaceutical forms.

Rapid and simultaneous determination of dexamethasone and dexamethasone sodium phosphate using HPLC-UV: Application in microneedle-assisted skin permeation and deposition studies.

Dexamethasone is a fluorinated derivative of the natural glucocorticoid, cortisone, with a very high systemic anti-inflammatory effect. In this study, a simple and rapid high performance liquid chromatography (HPLC) method was developed and validated to quantify dexamethasone and its prodrug dexamethasone sodium phosphate in skin permeation studies. The separation of both the compounds was achieved on a Vydac Denali C18 column(250 × 4.6 mm, 5 µm) with a mobile phase composed of 5 mM ammonium acetate buffer-acetonitrile-methanol (43:32:25, v/v) at a flow rate of 0.9 mL/min and UV detection at 240 nm. The standard curves were found to be linear in the range from 0.5 to 100 µg/mL for both the drugs and the method could successfully separate the drug peaks from interfering peaks of endogenous skin constituents. Accuracy values of both the drugs were within 98.60 to 108.60% (intra-day) and 98.70 to 107.20% (inter-day) and precision values were within 2% at the studied concentrations. The developed method was used to investigate the effect of microneedles on transdermal delivery of dexamethasone sodium phosphate. The hydrolysis of dexamethasone sodium phosphate to dexamethasone in the presence of rat skin homogenate and rat plasma was also evaluated to confirm the conversion that occurs during skin permeation and in the blood circulation. The skin permeation and deposition characteristics of microneedle-assisted diffusion were compared to those achieved by passive diffusion. The observed data demonstrated that transdermal permeation of dexamethasone is significantly enhanced with microneedle pretreatment of rat skin, showing a marked increase in flux and permeability coefficient, compared to passive diffusion. This simple isocratic HPLC method can, be effectively applied for the evaluation of skin permeation of topical/transdermal dexamethasone formulations.