Table 2.
Summarized data.
| № | System; Method; Size Obtained |
Cell Line/In Vitro/In Vivo Models; Dose | Diflunisal Release, Biodistribution | Refs. |
|---|---|---|---|---|
| 1 | Poly(propylene sulfide; oil-in-water emulsion method; 65.4 ± 0.4 nm |
10 μg/mL, parenterally; -murine preosteoblast MC3T3-E1 subclone 4 cell line; -colony of S. aureus from a tryptic soy agar; -inhibits the cytotoxicity of S. aureus supernatants; -decreases S. aureus-induced cortical bone loss during osteomyelitis (on Day 14); -had no effect on bacterial burdens. |
-maximum release is reached at 33% of H2O2 at 24 h; -biodistribution (FVB/NJ mice with osteomyelitis of livers, kidneys, and spleens) up to 24 h post injection. |
[23] |
| 2 | Carbopol 934, Glyceryl dibehenate (Compritol® ATO 888); microemulsification method; 124.0 ± 2.07 nm |
-mice air pouch model; -in vivo pharmacodynamic studies; -better percentage suppression of oedema in mice ear oedema model (xylene induced) and rat hind paw oedema (carrageenan induced); -mean leukocyte count was reduced to 4500 ± 436 cells/mm3 in SLN gel from 173 800 ± 1950 cells/mm3 in positive control; -gastrointestinal and hepatic side effects were avoided; -anti-inflammatory efficacy of DIF SLN gel as compared with conventional cream; -did not cause any type of histopathology. |
-permeation flux was maximum for solid lipid nanoparticles dispersion; -skin retention was maximum for solid lipid nanoparticles gel; -high-efficacy therapeutic effects were observed at a much less reduced dose as compared with conventional oral dose. |
[25] |
| 3 | k-Carrageenan and chitosan; layer-by-layer assembly technique; 300 nm |
-nanocarriers with three and four coatings demonstrated Case II diflunisal transport mechanism and zero-order type of kinetics; | -the release profile is directly dependent on the number of layers; -maximum of cumulative release was reached at 100 min for all compositions with maximum as 95% for nanoemulsion and minimum as 45% for four (NE(k-CAR/CS)2) polyelectrolyte layers. |
[26] |
| 4 | Chitosan–poly(vinyl alcohol) hydrogels without crosslinking agents; the freeze–thawing method |
-swelled 10-fold their initial weight, and after 20 h, hydrogel samples swelled up to 15-fold; -encapsulation efficiency was equal to 70% in all cases. |
-the release of diflunisal from the hydrogels was for 30 h; -higher release profile is for sample CP4-80; -burst effect was not detected for any type of the hydrogels. |
[35] |
| 5 | 70% soya bean lecithin, 30% butyl lactate and 23% water; Lipoid S75 and Phospholipoin 85 G; lipogel form and hydrogel microemulsion; |
-skin penetration; -gel has better spreadability and demonstrates a 5.07-fold increase in the transdermal flux as it was compared to Carbomer® 934 gel; -lipogel LO1 demonstrated the ultimate permeability level (210.8 µg cm−2 h−1) and advanced percentage diflunisal permeated; -the in vivo antihyperalgesia assay showed significant reduction of the licking time in the treated group compared to the control group. |
− | [36,37] |
| 6 | pH-Sensitive hydrogels based on bovine serum albumin hydrophilic microspheres | − | -release profile depends on diflunisal–polymer matrix interacting and diffusional restriction related to degree of crosslinking in the microparticles; -at pH 6.8, the diflunisal released amount increased (w/w > 75% after 24 h). |
[38] |
| 7 | β-Cyclodextrin (βCD), γ-cyclodextrin (γCD), and hydroxypropyl-β-cyclodextrin (HPβCD) | -hydrophilic polymers (carboxymethyl cellulose sodium, polyvinyl alcohol, and poloxamer-188 (PXM188)) were used, the effect of the polymer addition on the solubility and dissolution has been studied. -better solubility was for βCD and HPβCD inclusion complexes. -maximum of diflunisal solubility (1259.5 ± 0.5 µg/mL) was detected for the complex with hydroxypropyl β-cyclodextrin and Poloxamer-188. |
-the diflunisal release from β-cyclodextrin and hydroxypropyl β-cyclodextrin complexes was higher than of pure diflunisal in 11–21 times; -hydrophilic polymers allow increasing the release rate of diflunisal in 15–28 times. |
[45,46] |
| 8 | Cobalt(III)–polypyridyl complexes | -kill the cancer stem cells and the majority of bulk cancer cells even at low concentrations; -killing mechanism of cancer cells by composition number 5 includes the DNA damage and inhibition of COX-2; -against breast cancer cells HMLER and breast cancer stem cells-enriched HMLER-shEcad; -did not possess any toxicity toward normal skin fibroblast cells (line GM07575). |
-differentially release the drug under acidic conditions; -complexes selectively release diflunisal/1,10-phenanthroline-bearing complex 5 displays selective potency toward hard-to-kill cancer stem cells (CSCs) (IC50 = 2.1 ± 0.1 μM) over bulk cancer (IC50 = 3.9 ± 0.2 μM) and normal cells (IC50 = 21.2 ± 1.3 μM). This complex induces CSC apoptosis by DNA damage and cyclooxygenase-2 inhibition. |
[51] |
| 9 | Copper (II) complexes with O-donor ligand N,N-dimethylformamide or N-donor heterocyclic ligands (2,2′-bipyridine, 2,2′-bipyridylamine, 1,10-phenanthroline and pyridine) | -good binding ability to bovine and human serum as well as to calf–thymus DNA. | − | [52] |
| 10 | Poly(ethylene glycol) (PEG) | − | The better release was for the drug–polymer ratio of 1:7. | [64] |
| 11 | Eudragit RS100 and RL100 | − | Changes in the release profile, leading to slow and prolonged kinetic profile. | [66] |
| 12 | Eudragit RS100, S100, L100, and ethyl cellulose; pH-dependent, time dependent, and combined pH and time-dependent systems. |
-the ratio 2:3:1 Eudragit S100/Eudragit RS100/diflunisal is the most successful; -colon-specific delivery for the treatment of a variety of diseases, such as nonspecific ulcerative colitis, cirrhosis disease, intestinal amoebiasis, colon tumor. |
The release was 0.22 ± 0.03% of the drug included in it in the stomach pH and 26.29 ± 0.91% of the drug in the intestine pH and 77.59 ± 1.79% of the drug in the colon pH. | [67] |
| 13 | Ethylenediamine (EDA) core polyamidoamine (PAMAM) dendrimers | -improve transdermal delivery of diflunisal and its pharmacokinetic and pharmacodynamics profiles; - enhance transdermal delivery of diflunisal; -diflunisal–PAMAM complexes lead to 2.48-fold increase in drug level. |
− | [72] |
Abbreviated terms: COX-2—cyclooxygenase-2; CS—chitosan; CSC—cancer stem cells; DIF—diflunisal; DNA—deoxyribonucleic acid; EDA—ethylenediamine; FVB/NJ—multipurpose inbred mice strain; GM07575—normal skin fibroblast cells; HMLER—bulk breast cancer cells; HMLER-shEcad—breast cancer stem cells-enriched; HPβCD—hydroxypropyl-β-cyclodextrin; k-CAR—k-carrageenan; Lipogel LO1—organogel based on Lipoid S75; MC3T3-E1—osteoblast precursor cell line derived from musculus (mouse) calvaria; NE—nanoemulsion; PAMAM—polyamidoamine; PEG—poly(ethylene glycol; PXM188—poloxamer-188; SLN gel—solid lipid nanoparticles gel; βCD—β-cyclodextrin; γCD—γ-cyclodextrin.