Delivery Of Non-steroidal Anti-inflammatory Drugs Research Articles

Mechanistic insight into heat enhanced permeation of diclofenac and piroxicam in combination with chemical penetration enhancers across skin

The topical application of heat offers considerable potential for enhancing the delivery of non-steroidal anti-inflammatory drugs across the skin barrier. A better understanding of the mechanisms underpinning the improved skin permeation and how heat can be best used to work with complementary enhancement strategies would help to realise this potential. In this study the effect of heat on the permeation of diclofenac and piroxicam across different membranes, including human skin was investigated along with use of complementary enhancement strategies including selection of formulation pH, drug salt form and inclusion of chemical penetration enhancers. Heat alone improved drug delivery across human skin for both drugs, with larger increases for piroxicam. This increase was produced by improvements in drug release, molecular diffusivity and partitioning into the stratum corneum. In combination with chemical penetration enhancers, heat synergistically increased the skin permeation of diclofenac and piroxicam up to 13 and 40-fold respectively, with the increase in permeation being ascribed primarily to improvements in drug and enhancer partitioning into the stratum corneum. An Arrhenius plot of diclofenac permeation across skin was linear indicating that the orthorhombic to hexagonal stratum corneum lipid packing transition did not have a significant effect on skin permeation in response to heat.

Strategies to Improve the Transdermal Delivery of Poorly Water-Soluble Non-Steroidal Anti-Inflammatory Drugs.

The transdermal delivery of non-steroidal anti-inflammatory drugs (NSAIDs) has the potential to overcome some of the major disadvantages relating to oral NSAID usage, such as gastrointestinal adverse events and compliance. However, the poor solubility of many of the newer NSAIDs creates challenges in incorporating the drugs into formulations suitable for application to skin and may limit transdermal permeation, particularly if the goal is therapeutic systemic drug concentrations. This review is an overview of the various strategies used to increase the solubility of poorly soluble NSAIDs and enhance their permeation through skin, such as the modification of the vehicle, the modification of or bypassing the barrier function of the skin, and using advanced nano-sized formulations. Furthermore, the simple yet highly versatile microemulsion system has been found to be a cost-effective and highly successful technology to deliver poorly water-soluble NSAIDs.

Carboxymethylcellulose/layered double hydroxide dispersions for topical ocular delivery of non-steroidal anti-inflammatory drugs

Drug delivery to ocular tissues is hindered by anatomical and physiological barriers that diminish their bioavailability. LDH/CMC dispersions are promising due to their sustained drug release and mucoadhesive ability.

A photocrosslinkable and anti-inflammatory hydrogel of loxoprofen-conjugated chitosan methacrylate.

Polymer-drug conjugates are widely used for drug delivery. Herein, we report an injectable hydrogel for local delivery of nonsteroidal anti-inflammatory drugs (NSAIDs) using chitosan (CS) as a carrier polymer. Loxoprofen (LOX) was conjugated to the backbone of CS via carbodiimide chemistry to obtain the LOX-CS conjugate. This conjugation transformed the water-insoluble unmodified CS into the water-soluble LOX-CS conjugate. In particular, the LOX-CS conjugate did not precipitate at pH 7, allowing smooth subsequent chemical modification with methacrylic anhydride (MA) to synthesize LOX-CS methacrylate (LOX-CS-MA) with significantly higher methacrylation substitution. The LOX-CS-MA was capable of in situ gel formation under visible light irradiation in the presence of a benzoin-2,4,6-trimethylbenzoylphosphinate lithium (LAP) photoinitiator. Our results show that the LOX-CS-MA hydrogel exhibited good cytocompatibility and blood compatibility. It promoted M2 polarization, inhibited pro-inflammatory gene expression, and upregulated anti-inflammatory gene expression of macrophages. Furthermore, the LOX-CS-MA hydrogel significantly reduced reactive oxygen species (ROS) and nitric oxide (NO) produced by lipopolysaccharide (LPS)-stimulated macrophages. A subcutaneous implanted LOX-CS-MA hydrogel in a rat model revealed significantly reduced inflammatory cell density, decreased cell infiltration, and a much thinner fibrous capsule compared to the CS methacrylate (CS-MA) hydrogel, thus markedly alleviating the inflammatory response. This study highlights the feasibility of CS-drug conjugates in preparing CS-based methacrylate hydrogels for sustained drug release.

Electrospun Nanofiber-Based Drug Carrier to Manage Inflammation.

Significance: Nonsteroidal anti-inflammatory drugs (NSAIDs) are one of the most widely prescribed drugs to treat inflammation and related ailments. In recent years, loading these drugs onto nanodevices like nanoparticles, nanofibers, etc. as a drug delivery system has gained momentum due to its desirable properties and advantages. The purpose of this review is to examine the existing research on the potential and novel use of nanofiber-assisted delivery of NSAIDs. Recent Advances: Electrospun nanofibers have recently garnered considerable attention from researchers in a variety of sectors. They have proved to be promising vehicles for drug delivery systems because of their exceptional and favorable features like prolonged drug release, controllable porosity, and high surface area. In this article, various polymers and even combinations of polymers loaded with single or multiple drugs were analyzed to achieve the desired drug release rates (burst, sustained, and biphasic) from the electrospun nanofibers. Critical Issues: The administration of these medications can induce major adverse effects, causing patients discomfort. Thus, encapsulating these drugs within electrospun nanofibers helps to reduce the severity of side effects while also providing additional benefits such as targeted and controlled drug release, reduced toxicity, and long-lasting effects of the drug with lower amounts of administration. Future Directions: This review covers previous research on the delivery of NSAIDs using electrospun nanofibers as the matrix. Also, this study intends to aid in the development of enhanced drug delivery systems for the treatment of inflammation and related issues.

Development of Topical Nanogel as a Promising Delivery of NSAID’s Tenoxicam using Natural Permeation Enhancer Essential Oil (Euckolyptus)

Tenoxicam (TNX) is an effective non-steroidal anti-inflammatory drug (NSAIDs) used to treat rheumatoid arthritis. Like other NSAIDs, tenoxicam has the disadvantage of being linked to gastrointestinal side effects. Furthermore, this drug is having weak transdermal penetration, preventing transdermal administration. The goal of this study was to develop a TNX nanogel with a smaller particle size to improve the anti-inflammatory drug's bioavailability and assess its potential in rheumatoid arthritis. The modified emulsification-diffusion method is used to develop nanosized dispersion of TNX using noveon polycarbophil AA-1 as a gelling agent. Moreover, essential oils increase skin penetration by interacting with the stratum corneum (SC). They were found to be successful in increasing skin penetration of both lipophilic and hydrophilic drugs. The rheology, particle size, drug content, % drug release, and in-vitro diffusion study of prepared TNX nanogel were performed. Based on the rheological features of the formulations it was found to be substantial, with the particle size of 125.05nm and zeta potential -8.47mV, drug content of 97.05%, % drug release 97.40% drug diffusion of 97.42%, and pH of 6.2. Tenoxicam nanogel was prepared by using noveon polycarbophil AA-1 and eucalyptus oil as a permeation enhancer was proven to be suitable as a typical topical gel formulation for the treatment of edema and rheumatoid arthritis.

Fabrication of swellable PEGylated hydrogel by free radical polymerization for controlled delivery of non-steroidal anti-inflammatory drug; characterization and statistical analysis

The main objective of the current research work was to fabricate polyethylene glycol-based hydrogels for the controlled delivery of Ketorolac. Polyethylene glycol was chemically cross-linked with acrylic acid using 2-hydroxyethyl methacrylate as a cross-linker with ammonium persulfate and sodium metabisulphite as initiators. To determine the efficiency of the synthesized system, it was subjected to various structural characterization, such as Fourier transform infrared spectroscopy, Differential scanning calorimetry, Thermogravimetric analysis, and Scanning electron microscopy. All the results obtained from structural characterizations confirmed a well-cross-linked, thermally stable, and a porous system. Swelling and in-vitro release studies performed in pH 1.2 and 7.4 showed pH responsiveness as more swelling and drug release were observed in pH 7.4 as compared to pH 1.2. The drug release was considered as non-Fickian transport from kinetic modeling and partially controlled by the viscoelastic relaxation of hydrogel. Sol-gel fraction depicted that gel content was increased as the concentrations of the polymer, monomer, and cross linker were increased. Similarly, the results obtained from stability studies confirmed a stable synthesized system. Moreover, statistical analysis was also employed for a better comparison of the swelling and in-vitro results.

Synthesis of calcium carbonate-quince bio-composite for programmed and on-demand drug release of paracetamol at target site: a green chemistry approach.

In this study, an inorganic–organic composite system was developed through biomineralization of calcium carbonate in the quince-seed mucilage-based hydrogel. Drug-polymer interactions were studied by FTIR, DSC, XRD and SEM analysis. The water absorption capacity was calculated by swelling index. Drug release was determined at various pH. Several in vitro kinetic models were applied to observe drug release behaviour. Studies of drug-polymer interactions and particle flow characteristics of the developed composite material have shown that there is good compatibility between drug and the excipients. The XRD and SEM results confirmed calcite polymorphs in the developed composite material. Thermograms showed that the developed composite material was heat stable. A restricted drug release was observed in an acidic medium (pH 1.2). A controlled drug release was depicted from the developed system at pH 6.8. The drug release mechanism of Super Case II was suggested. The developed system was considered to be an effective drug carrier for colon targeted oral delivery of non-steroidal anti-inflammatory drugs (NSAIDs) to avoid gastric irritation and risk of ulceration. Graphical abstractAn illustration of extraction of quince hydrogel and development of calcium carbonate-quince (CaCO3-Q) composite system; QSM = Quince seed mucilage Supplementary InformationThe online version contains supplementary material available at 10.1007/s00289-022-04400-1.

Enhancement of the Transdermal Delivery of Nonsteroidal Anti-inflammatory Drugs Using Liposomes Containing Cationic Surfactants

New hybrid liposomes based on cationic amphiphiles with different structures of the head group (cetyltrimethylammonium bromide (CTAB), 3-hexadecyl-1-hydroxyethylimidazolium bromide (IA-16(OH)), 1-(butylcarbamoyl)oxyethyl-3-hexadecylimidazolium bromide (IAC 16(Bu)), and hexadecylmethylpyrrolidinium bromide (PR-16)) were developed for transdermal administration of nonsteroidal anti-inflammatory drugs. The different surfactant/lipid compositions were studied to obtain stable liposomes with high functionality. The hydrodynamic diameter of cationic liposomes was ∼110 nm. An admixture of cationic surfactants and PC liposomes improves the physicochemical properties of vesicles and transdermal diffusion rate and prolongs the release of drugs. Liposomal diclofenac sodium (DS) and ketoprofen (KP) were tested (using Franz cells) for transdermal penetration. Drug diffusion monitoring for 48 h demonstrated that the maximum DS and KP penetration through the synthetic membranes (Strat-M) is characterized by values of 255 ± 2 and 186 ± 3 μg/cm2, respectively. The influence of the surfactant head group on the properties (stability, release profile, permeability) of cationic liposomes was shown for the first time. While the drug specificity is evident for the rate of release, the permeability increases as follows: conventional liposomes < CTAB/PC < PR-16/PC < IAC-16(Bu)/PC < IA-16(OH)/PC for both medicines. The rat paw edema model was used to assess the anti-inflammatory effect of the IA-16(OH)/PC leader formulation in vivo. It was found that liposomal DS and KP are effective for relieving rat paw edema. It should be noted that DS-loaded hybrid liposomes demonstrated the highest therapeutic efficacy compared to conventional vesicles.

Long-term anti-inflammatory effects of injectable celecoxib nanoparticle hydrogels for Achilles tendon regeneration

The treatment of chronic Achilles tendonitis (AT) often requires prolonged therapy and invasive therapeutic methods such as surgery or therapeutic endoscopy. To prevent the progression of chronic AT, excessive inflammation must be alleviated at an early stage. Corticosteroids or nonsteroidal anti-inflammatory drugs are generally prescribed to control inflammation; however, the high doses and long therapeutic periods required may lead to serious side effects. Herein, a local injectable poly(organophosphazene) (PPZ) – celecoxib (CXB) nanoparticle (PCNP) hydrogel system with long-term anti-inflammatory effects was developed for the treatment of tendonitis. The amphiphilic structure and thermosensitive mechanical properties of PPZ means that the hydrophobic CXB can be easily incorporated into the hydrophobic core to form PCNP at 4 °C. Following the injection of PCNP into the AT, PCNP hydrogel formed at body temperature and induced long-term local anti-inflammatory effects via sustained release of the PCNP. The therapeutic effects of the injectable PCNP system can alleviate excessive inflammation during the early stages of tissue damage and boost tissue regeneration. This study suggests that PCNP has significant potential as a long-term anti-inflammatory agent through sustained nonsteroidal anti-inflammatory drugs (NSAIDs) delivery and tissue regeneration boosting. Statement of significanceIn the treatment of Achilles tendinitis, a long-term anti-inflammatory effect is needed to alleviate excessive inflammation and induce regeneration of the damaged Achilles tendon. Injectable poly(organophosphazene)(PPZ)-celecoxib(CXB) nanoparticles (PCNP) generated a long-term, localized-anti-inflammatory effect in the injected region, which successfully induced the expression of anti-inflammatory cytokines and suppressed pro-inflammatory cytokines, while the PCNPs degraded completely. Accordingly, regeneration of the damaged Achilles tendon was achieved through the long-term anti-inflammatory effect induced by a single PCNP injection. The PCNP system therefore has great potential in long-term NSAIDs delivery for various tissue engineering applications.

Isobolographic analysis of antinociceptive effect of ketorolac, indomethacin, and paracetamol after simultaneous peripheral local and systemic administration.

This study was designed to characterize the type of interaction (subadditive, additive, or synergistic) after simultaneous administration by two different routes (intraperitoneal plus peripheral local) of the same nonsteroidal anti-inflammatory drugs (NSAID) ketorolac and indomethacin or paracetamol. The antinociceptive effects of locally or intraperitoneally delivery of NSAIDs or paracetamol, and the simultaneous administration by the two routes at fixed-dose ratio combination were evaluated using the formalin test. Pain-related behavior was quantified as the number of flinches of the injected paw. Isobolographic analysis was used to characterize the interaction between the two routes. ED30 values were estimated for individual drugs, and isobolograms were constructed. Ketorolac, indomethacin, or paracetamol and fixed-dose ratio combinations produced a dose-dependent antinociceptive effect in the second but not in the first phase of the formalin test. The analysis of interaction type after simultaneous administration by the two routes the same NSAID or paracetamol (on basis of their ED30), revealed that the simultaneous administration of ketorolac or paracetamol was additive and for indomethacin was synergistic. Since the mechanisms underlying the additive effect of ketorolac or paracetamol and the synergistic effect of indomethacin were not explored; it is possible that the peripheral and central mechanism is occurring at several anatomical sites. The significance of these findings for theory and pain pharmacotherapy practice indicates that the combination of one analgesic drug given simultaneously by two different administration routes could be an additive or it could lead to a synergistic interaction.

Relevance of non-steroidal anti-inflammatory drugs in periodontology

Relevance. Non-steroidal anti-inflammatory drugs (NSAIDs) are frequently prescribed in dental practice to relieve pain and swelling. This study reviews information on NSAIDs, with a particular focus on those aspects that are relevant to the practice of dentistry.Materials and methods. A systematic literature search was conducted, which included studies dating from 1970 to June 2021. The search in the electronic databases e-LIBRARY.ru, Embase, Pubmed and Medline identified the studies. Articles were reviewed by meeting the inclusion and non-inclusion criteria.Results. Initially, the electronic search identified 589 studies. After reviewing the titles and abstracts, 69 potentially relevant studies were subject to full-text evaluation. Of these, 34 studies were excluded based on study design, research question, or lack of numerical data on all variables to be assessed in this study, so 35 studies with a detailed list of such data could be included in the quantitative comparison.Conclusion. The use of non-steroidal anti-inflammatory drugs may alter the inflammatory response in the treatment of oral diseases. The conducted studies have brought up questions about the effectiveness and alternative ways of NSAID delivery in dentistry, namely, dispersible formulation.

Cationic liposomes mediated transdermal delivery of meloxicam and ketoprofen: Optimization of the composition, in vitro and in vivo assessment of efficiency

New liposomes modified with pyrrolidinium surfactants containing a hydroxyethyl fragment (CnPB, n = 12, 14, 16) were prepared for transdermal delivery of non-steroidal anti-inflammatory drugs. In order to obtain the optimal composition, the surfactant/lipid molar ratio (0.02/1; 0.029/1; 0.04/1) and the amphiphile hydrocarbon tail length were varied. Rhodamine B was loaded in all formulations, while meloxicam and ketoprofen in selected ones. For liposomes studied the hydrodynamic diameter was in the range of 80–130 nm, the zeta potential ranged from +35 to +50 mV, EE was 75–99%. Liposome modification leads to a prolonged release of the rhodamine B (up to 10–12 h) and faster release of non-steroidal drugs (up to 7–8 h) in vitro. The ability to cross the skin barrier using Franz cells was investigated for liposomal meloxicam and ketoprofen. The total amount of meloxicam and ketoprofen passed through the Strat-M® membranes during 51 h was 51–114 μg/cm2 and 87–105 μg/cm2 respectively. The evaluation of transdermal diffusion ex vivo showed that total amount of liposomal ketoprofen passed through the skin during 51 h was 140–162 μg/cm2. Liposomes modified with C16PB were found as the most effective inflammation reducing formulation in the carrageenan edema model of rat paw.

Dissociation of the DCF-Hb complex in presence of cationic micelles: A spectroscopic and computational approach

Diclofenac sodium (DCF) is a derivative of phenyl acetic acid and a model representative of the family of non-steroidal anti-inflammatory drugs (NSAIDs). It is extensively consumed for treating inflammation and degenerative disorders like rheumatoid arthritis. The micelles or aggregates of surfactants have ability to solubilize poorly soluble drugs thereby increasing bioavailability of the drugs. Thus, in the current study we have shown a systematic approach for the association of diclofenac with haemoglobin and deintercalation of DCF from hemoglobin (Hb) by hexadecyltrimethylammonium bromide (CTAB) micelles by using various spectroscopic techniques. The fluorescence and UV–visible spectral results revealed that DCF interacts with CTAB micelles and resides in its hydrophobic core. Thus, steady fluorescence and UV–visible measurements provides a strong sign for the relocation of DCF molecules from the hemoglobin interior to the micellar interface of CTAB above cmc. The CD results hinted that CTAB micelles do not disturb the structure of hemoglobin, which further supported that CTAB micelles can be applied as a reliable delivery vehicle for DCF. The present study may be significant for the discovery of improved micelle-based vehicles to the delivery of non-steroidal anti-inflammatory drugs in their targeted site.

Topical NSAIDs for acute local pain relief: in vitro characterization of drug delivery profiles into and through human skin

Objective The efficacy of topical nonsteroidal anti-inflammatory drugs (NSAIDs) relates not only to the individual NSAID used but also to differences in formulation design. The aim of this study was to investigate the fundamental differences in ibuprofen and diclofenac drug delivery vehicles, specifically gels and plasters, compared to a recently launched 200 mg ibuprofen medicated plaster and characterize the resulting dermatologic–pharmacokinetic profiles into and through ex vivo human skin layers. Methods In vitro skin permeation testing over 24 h and sacrificial timepoint penetration experiments (at 1, 4, 8, 12, and 24 h) were conducted using an automated flow-through diffusion cell system. The amount of drug delivered to the epidermis, dermis, and receptor solution (representing deeper tissue) was determined by liquid chromatography-tandem mass spectrometry. Skin protein binding of ibuprofen and diclofenac was investigated by spiking skin homogenate with increasing concentrations of each drug and determining the fraction unbound. Results Differences were observed in the amount of drug recovered at sacrificial timepoints and rate at which drug was delivered to the target site between plaster and gel formulations of ibuprofen and diclofenac and between plaster formulations of the same drug (ibuprofen). While the amount of drug quantified at sacrificial timepoints did not necessarily determine in vivo flux rates, differences in drug distribution within the skin layers indicated where drug reservoirs were formed. Conclusions These findings highlight the importance of intelligent formulation design in determining NSAID delivery through skin layers. Further work is required to quantify drug delivery into deeper tissues and the resultant local anti-inflammatory effects.

Lidocaine as eutectic forming drug for enhanced transdermal delivery of nonsteroidal anti-inflammatory drugs

Co-application of local anesthetics as lidocaine and nonsteroidal anti-inflammatory drugs (NSAIDs) can enhance local analgesia. Co-formulation of lidocaine with NSAIDs can modulate physicochemical properties like melting point which can affect transdermal delivery. The purpose was to probe lidocaine as eutectic forming drug for enhanced transdermal delivery of a series of NSAIDs with increasing melting points. NSAIDs included ketoprofen, flurbiprofen, aceclofenac, tenoxicam and meloxicam. Each drug was co-ground with lidocaine at increasing molar ratios. The products were characterized by thermal analysis and Fourier-transform infrared (FTIR). Saturated aqueous solutions containing excess of optimum NSAID/lidocaine were evaluated for transdermal delivery with reference to the corresponding saturated aqueous solution of each drug. Thermal analysis and FTIR suggested eutectic system formation. Drugs with lower melting points formed eutectic with smaller proportion of lidocaine. Ketoprofen, flurbiprofen and aceclofenac separated as oily liquid from the saturated aqueous solution of their mixtures with lidocaine. Eutectic mixtures of lidocaine with tenoxicam and meloxicam melted above 50 °C and separated from saturated aqueous solution as solid system. Eutexia increased the transdermal flux of NSAIDs. The extent of increase depended on the melting point of the developed system. The study introduced lidocaine as eutectic co-former for enhanced skin delivery of NSAIDs.

Naproxen/Layered Double Hydroxide Composites for Tissue-Engineering Applications: Physicochemical Characterization and Biological Evaluation

AbstractInjured bone tissues can be healed with bone grafts, but this procedure may cause intense pain to the patient. A slow and localized delivery of nonsteroidal anti-inflammatory drugs (NSAIDs) could help to reduce the pain without affecting bone regeneration. The objective of the present study was to use [Mg-Al]-layered double hydroxide (LDH) as a matrix for controlled release of sodium naproxen (NAP). This system could be applied in biomaterial formulations (such as bone grafts) to achieve a local delivery of naproxen. [Mg-Al]-LDH successfully incorporated up to 80% (w/w) of naproxen by the structural reconstruction route, with the [Mg-Al]-LDH interlayer space increasing by 0.55 nm, corresponding to the drug molecule size. The evaluation of the naproxen release kinetics showed that 40% of the drug was delivered over 48 h in aqueous medium (pH 7.4 ± 0.1), indicating the potential of [Mg-Al]-LDH/NAP for local release of naproxen at adequate concentrations. Kinetic modeling showed that the naproxen release process was closely related to the Higuchi model, which considers the drug release as a diffusional process based on Fick’s law. The chemical stability of NAP after the release tests was verified by 1H NMR. The [Mg-Al]-LDH/NAP also exhibited low cytotoxicity toward fibroblast cells (L929 cell line), without modifications in their morphology and adhesion capacity. These results describe a suitable approach for preparing efficient systems for local delivery of nonsteroidal anti-inflammatory drugs for biomedical applications.

Montmorillonite-Enveloped Zeolitic Imidazolate Framework as a Nourishing Oral Nano-Platform for Gastrointestinal Drug Delivery.

Oral administration of medicine faces physiological constraints imposed by the gastrointestinal tract (GIT) and simultaneously causes irritation to GI mucosa, which motivates us to pursue the innovation of a GI drug delivery system. Inspired by the mucosa-nutrient functions of Zinc element and smectite clay, a montmorillonite (MMT)-enveloped zeolitic imidazolate framework (M-ZIF-8) is developed in a successive one-pot fabrication of ZIF-8 encapsulated medicine, and followed MMT coating to yield a core-shell nanoplatform for GI drug delivery. ZIF-8 encapsulated medicines can maintain their intrinsic structure, and MMT layer potentiates mucous-adhesion and optimizes medicine release. Validated in gastritis and colitis models, M-ZIF-8 not only achieves efficient GI delivery of nonsteroidal anti-inflammatory drugs (NSAIDs) for inflammation inhibition, but also reduces the NSAIDs-induced GI irritation, promoting mucosal healing in GIT. Coupled with the facile construction and biocompatibility, M-ZIF-8 shows a significant advancement in GI drug delivery.

Impact of terminating reimbursement of symptomatic slow-acting drugs in osteoarthritis in France on volume and cost of drug deliveries, assessed with administrative databases

With osteoarthritis (OA)As one of the leading causes of disability in adults worldwide, its toll on patients and its economic burden for payers are substantial. The issue of change in OA management with the evolution of reimbursement schemes needs to be addressed. ObjectiveTo assess the impact of terminating the reimbursement of symptomatic slow-acting drugs in OA (SYSADOAs) in France in terms of volume and cost, from a healthcare payer perspective. Principal resultsWe obtained costs and volumes from French public national databases. We considered three exposure periods around cutoff dates according to decisions of decreased then terminated SYSADOA reimbursement. The periods included 19 345 (control), 20 066 (secondary), and 16 200 (primary) patients, respectively. Mean ages were 66.2 (±11.8), 65.3 (±11.6) and 64.6 (±11.5) years and about 70% were women. The volume of nonsteroidal anti-inflammatory drug (NSAID) deliveries estimated by defined daily doses (DDDs) decreased during the periods from 40.5 (±76.3) DDDs per patient in 2008 to 29.6 (±66.4) in 2015. The volume of analgesic deliveries increased slowly over the three periods, from 70.2 (±108.9) DDDs in 2008 to 76.9 (±123.1) in 2015 for all patients. Major conclusionsOur results did not show a measurable impact of terminating SYSADOA reimbursement on the delivery of NSAIDs and analgesics or on hospitalizations. However, neither do they allow for concluding that terminating SYSADOA reimbursement did not generate an increase in deliveries of non-reimbursed drugs, with their associated potential risks for public health.

Flavosomes, novel deformable liposomes for the co-delivery of anti-inflammatory compounds to skin.

Flavosomes, novel deformable liposomes for the topical delivery of anti-inflammatory compounds have been developed and characterized in this study. The carriers were prepared by incorporating flavonoids, specifically quercetin and dihydroquercetin, into transfersome and evaluated as a potential topical delivery system for meloxicam (MX), a potent hydrophobic NSAID (non-steroidal anti-inflammatory drug). Characterization of the flavosomes was conducted in terms of their vesicle size, zeta potential, entrapment efficiency and deformability index. Ex vivo skin permeation and confocal laser scanning microscopy studies demonstrated that the flavosome formulations improved the skin permeation of meloxicam compared to that for transfersomes. The dermal and transdermal delivery of meloxicam using these formulations has the potential of being a promising alternative to conventional oral delivery of non-steroidal anti-inflammatory drugs (NSAIDs) with enhanced local and systemic onset of action and reduced gastrointestinal side effects.