| Poly(ortho ester) (POE) semi solid (54) | N/A | Semi-solid for drug delivery | 20-40 kGy at −78 °C using dry ice | 1H NMR, 13C NMR, IR, GPC, viscosity | •Structural change observed on the IR spectra •Polymer used was affected by gamma irradiation at 20–40 kGy to a varying amount •Doses between 15 and 20 kGy limited the amount of degradation
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| Caprolactone and ethylene oxide tri-block copolymer (CL6E90CL6) (55) | N/A | Implantable drug delivery system | Solid and aqueous; up to 72 kGy in the presence of oxygen | 1H NMR, 13C NMR, GPC, DSC | •Crystallinity did not change with gamma irradiation as shown in the DSC •Solid—in the presence of oxygen no changes in molar mass, melting point, or relaxation spectra •Aqueous—the presence of oxygen resulted in reduction of Mn due to chain scission
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| Poly(lactic-co-glycolic acid) (PLGA) (RG 503 and RG503H) (56) | N/A | Microspheres for drug delivery | 5, 15, 25 kGy at dose rates 0.64 kGy/h | Microsphere morphology, GPC, DSC, EPR, | •Both raw polymers (P) and microspheres (Ms) showed a trend of decreasing their molecular weight (MW) as a function of irradiation dose •The decay in MW of RG 503 polymer was negligible for doses below 15 kGy, while it was about 10% for 25 kGy •Concentration of radiation-induced free radicals was higher in RG 503H (both P and Ms) and they were more stable than the free radical species observed in the case of RG 503
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| PLGA | Tetracycline-HCl (57) | Antibiotic | −80 °C using dry ice; 26.8 kGy and 54.9 kGy | EPR, GPC, GC-MS, DSC, HPLC, SEM | |
| PLGA | 17β-Estradiol (58) | Hypoestrogenism | Irradiation on dry ice −78.5 °C; 5.1 to 26.6 kGy | RP HPLC, drug release, GPC, DSC, SEM, particle size, bioburden | |
| Poly(glycolide-lactide), poly (lactide-caprolactone | Cladribine (59) | Anti-cancer | Solid samples purged with N2 in vials under vacuum. Irradiation at −80 °C using dry ice; 10–25 kGy | TLC, HPLC, UV, IR, DSC, rentgenography and electron microscopy | |
| PLGA | Indomethacin (60) | NSAID | 25 kGy with and without dry ice | Morphological, size distribution, encapsulation efficiency X-ray diffraction, DSC, GPC, in vitro release study | •Microsphere properties were minimally affected by sterilization •Particle size distribution of the product and x-ray diffraction of the drug were preserved •Low temperature (dry ice) controlled the drug elution profile
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| PLGA | Ovalbumin OVA (61) | Vaccine | No humidity, under reduced pressure, dry nitrogen, dry ice at −80 °C; 12.5 kGy and 25 kGy | ELISA, particle size | |
| PLGA | Glial cell line-derived neurotrophic factor (GDNF) alone or with vitamin E (62) | Protein | 25 kGy at room temperature and −78 °C | GPC, protein integrity (SDS-PAGE), in vitro bioassays | |
| Chitosan | Diclofenac (63) | Non-steroidal anti-inflammatory (NSAID) | Ambient temperature, 3.62 kGy/h; 5, 15, and 25 kGy. | Size, drug content, swelling, surface morphology, drug release behavior, UV, FT-IR, electron paramagnetic resonance (EPR), X-diffraction, DSC | •No drug degradation was observed by UV spectroscopy under all irradiation conditions •No polymer cross-linking was observed by FT-IR analysis •EPR demonstrated one kind of free radical being formed by gamma irradiation •Drug release behavior, swelling, and surface morphology were affected by sterilization •Gamma irradiation could be used to positively influence these product quality attributes and improve pharmacokinetic behavior
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| Hydrogel sponges of hydroxyethyl methacrylate (64) | N/A | Drug delivery | 25 kGy [compared to EtO/heat sterilization (121 °C for 30 min)] | Morphological imaging, thermal analysis, mechanical testing, gel absorption capacity, swelling profile, drug loading and release profile | •Shape and dimensions of hydrogel sponges did not change after gamma irradiation •Pore size and shape were maintained following irradiation; depending on the selling matrix employed there was effect on the swelling time profiles •Mechanically, the irradiated sponge was slightly stiffer than non-irradiated samples with a small decrease in water absorbance •Gamma irradiation was the most suitable sterilization method for dried hydrogels
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| Glutaraldehyde | Levonorgestrel (65) | Contraception | 25 kGy | Microparticles size, agitation, drug encapsulation efficiency, IR, DSC, moisture content, X-ray, sterility | •Gamma irradiation did not affect the flow of the product and showed no tendency of clumping and aggregation •Color did not change after gamma irradiation •Microparticle size change was not significant
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| PLGA | Levonorgestrel (66) | Contraception | Dry ice; Irradiation in the presence of air and at room temperature; 25 kGy | Sphericity of the microspheres, moisture content, HPTLC, HPLC, IR, DSC, residual solvent contents, X-ray, sterility, radioimmunoassay | •Color of the product did not change after irradiation •Microsphere system was free-flowing with no clumping or aggregation behavior •Particle size of the product was not affected
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| Poly(α-hydroxy acids) | Cisplatin (67) | Chemotherapy | 28.4 and 37.7 kGy; vials sealed under dry atmosphere; irradiation temperature not controlled | SEM, in vitro study, GPC | •Initial microsphere morphology maintained after irradiations for 6 weeks •After 8 weeks, microspheres became fragile and ruptured, but their spherical shape and smooth surface remained the same •After 12 weeks, the microspheres became misshapen and lost their surface regularity, becoming completely alveolar in structure •Gamma affected the MW of various polymers regardless of the amount of glycolic units in the lactic chains •Room temperature storage—degradation of PLA37.5 GA25 was still observed after 9 months •Gamma irradiation reduced the period of controlled release of cisplatin-loaded microspheres prepared with PLA37.5 GA25 •For drugs with poly (a-hydroxy acids) attention must be paid to the effect of gamma irradiation on drug release
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| Hydroxypropylmethylcellulose (HPMC) (Metolose 60 SH 50, Pharmacoat 605, and Pharmacoat 615) (68) | NA | Excipient | 1, 5, 15, and 25 kGy | Coloration, UV, IR and calorimetry, rhelogical behavior | •Gradual discoloration with dose on Pharmacoat 605 and Metolose 60 SH 50 •Pharmacoat 605 and 615—progressive attenuation of the 257 nm peak at 15 kGy •Metolose 60 SH 50 not significantly different when dose rate were increased •Tg and energy related to the endothermic peak were similar •Non-irradiated samples showed greater extent of pseudo-plastic behavior, whereas irradiated samples resulted in an average mass change with increasing dose but hardness and friability were unchanged
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| PLGA | Captopril (69) | ACE inhibitor | Vials sealed under vacuum and irradiated at −78.5, 6.9, 15, 27.7, and 34.8 °C | HPLC, DSC, SEM, particle size (laser diffractometry), GPC | •Captopril did not decompose by gamma radiation using doses up to 34.8 kGy •When encapsulated with PLG, the solid solution was sensitized to gamma radiation, thus yielding more disulfide and other byproducts
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| Poly(bis-1,3,carboxy-phenoxypropane-sebacic acid P(CPP-SA), Poly(fumaric-sebacic acid (PFA-SA), Polylactic acid (PLA), Polysebacic acid (PSA) | Gentamycin sulfate (70) | Antibiotic | 25 kGy at 25 °C and dry ice temperature | EPR, NMR | •Polymer composition and the incorporation of drugs influence radicals that were formed by ionizing radiation •Irradiation temperature had a minor effect on the radical yield and the shape of the EPR spectra •Polymers irradiated at room temperature with high melting point and crystallinity gave the highest yields of observable radicals
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| PLGA | Dexamethasone and Bovine serum albumin (BSA) (71) | Anti-inflammatory (model protein) | 25 kGy | HPLC, drug loading, in vitro drug release and particle size | •The BSA release increased with the decrease in polymer MW •Faster BSA release in smaller MW polymers •Drug loading in nanoparticles ranges from 10% to 30% •Gamma irridation had no adverse effect on particle size, drug release behavior, or ex vivo arterial uptake of the nanoparticles
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| Polypropylene | Phosphate antioxidants (72) | Antioxidant | 25, 50, 100 and 150 kGy at room temperature and presence of air | Reversed-phase HPLC, IR, and DSC | |
| PLGA | 5-Iodo-2′-deoxyuridine (IdUrd) (73) | Antiviral | 26.7 kGy | Microsphere size distribution, crystal size distribution, spectrophotometry, FT Raman spectrometry | •No evidence for drug–polymer interactions in microspheres was found •For the microspheres with IdUrd varying from 2% to 27% of the total weight, the methodology used provided good reproducibility and precision (1%) •Samples exposed to sterilization doses of 27 kGy did not exhibit marked changes in the drug structure
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| Phospholipids – Distearoylphosphatidyl-choline, Distearoylphosphatidyl-glycerol (74) | N/A | N/A | 25 kGy solid and lyophilized phospholipids | 31P NMR, FTIR, TGA, size/diffusion constant, turbidity, viscosity, zeta-potential, DSC, X-ray diffraction | •31P NMR revealed minor chemical degradation by lower dynamic viscosity and pseudoplasticity, lower turbidity, higher diffusion constant, smaller size, more negative zeta potential, and changes in the phase transition behavior of the liposomes
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| PLGA | Clonazepam (75) | Anxiolytic, anticonvulsant | Either under vacuum or in air at a dose of 25 kGy | SEM, EPR, Karl Fischer volumetric titration, DSC, HPLC, in vitro release test | •Microspheres irradiated under vacuum were stable over the 6 month period •After irradiation, the drug release increased by ∼10% and did not change further over in the following period of storage •EPR showed radicals arising from both the polymeric matrix and the active ingredient
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| PLGA | Diclofenac sodium or Naproxen sodium (76) | NSAIDs | Microspheres in vials sealed under vacuum, room temperature; 25 kGy | Particle size, drug solubility, internal morphology, solvent type, temperature, polymer composition, viscosity and drug loading, DSC | •Slow increase in Tg with higher irradiation dose •Surface morphology of Naproxen sodium (NS)- and Diclofenac sodium (DS)-loaded PLGA microspheres were affected by gamma irradiation •Increase in particle size after irradiation •Irradiation may cause deleterious changes in the mean of diameters of the microspheres, MW, and morphology of the polymer
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| PLGA | 5-Fluorouracil (77) | Anti-cancer | 0 to 33 kGy | Size exclusion chromatography, DSC, SEM, particle size analysis, drug loading, in vitro drug release | •Both models (Fick's second and Higuchi-like pseudo-steady state) were used to predict the drug release kinetics as a function of the irradiation dose •Exponential relationships between gamma irradiation dose and the initial drug diffusivity with the microparticles were established
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| PLGA | Insulin-like growth factor-I (IGF-I) (78) | Hormone | 25 kGy at a 3.33 kGy/h | SEM,UV spectrophotometer, DSC, SDS-PAGE, in vitro release studies (circular dichroism) | •No difference was noticed in microsphere size and morphology before and after irradiation •Drug loading remains essentially the same after the sterilization •Protein aggregation was detected in addition to subtle changes in the DSC pattern from the irradiated microspheres •In vitro drug release from irradiated microspheres resulted in an increased burst effect
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| Hydroxypropylmethyl-cellulose matrices | Diltiazem hydrochloride (79) | Calcium channel blocker | 7.5-50 kGy under air at room temperature at a dose rate of 1.1 kGy/h | EPR, HPLC, viscosity, dilution tests, morphology | •Gamma irradiation induced chemical modifications in the structure of the active agent and also the hydrophilic polymer •Major radical products from the HPMC polymer radiolysis have been attributed to chain scission events •Chemical modifications may be responsible for the alteration of the drug release mechanism and the reduced polymer efficacy in controlling drug release
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| Poly(lactic-co-glycolic acid) (PLGA), Hydroxyethylcellulose (HEC), poly vinyl alcohol (PVA), poloxamer and carbomers nanoparticles | Ciprofloxacin HCl (80) | Antibiotic | Dose – 25 kGy; Drug is freeze dried before sterilization | Physicochemical properties (particle size, zeta potential, and drug efficiency), viscosity | •After freeze-drying and gamma sterilization, PVA, HEC, CP 974, CP 980 or CP 1342 caused similar and comparable drug release profiles from the nanoparticles
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| Poly(lactic-co-glycolic acid) (PLGA) | Acyclovir and gelatin additive (81) | Infections | 25 kGy in aluminum sealed vials surrounded with dry ice to maintain low temperature | Loading efficiency, IR, particle size, DSC, SEM, GPC, X-ray diffraction | •No surface changes after irradiation on SEM •Microparticles' mean diameter and acyclovir loading efficiency were not affected by gamma irradiation •IR, DSC, and x-ray diffraction showed no modification on the bulk properties •Controlled release profile was not altered for 73 days after gamma irradiation •GPC showed a decrease in MW •Gamma sterilization is suitable for acyclovir-loaded microspheres
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| Poly(lactic-co-glycolic acid) (PLGA) (82) | N/A | Microspheres for drug delivery | Vacuum (10−4 Torr & 30 °C) 26.6 kGy | EPR, water content, MW, Tg | •No considerable change in water content or Tg but slight decrease in molecular weight •Radical formation was identified but was not dependent on irradiation type (related to polymer compositions) •The overall relative concentration of the radicals was higher with gamma-irradiated PLGA microspheres compared to β-irradiation
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| PLGA | Ovalbumin and excipients polyethylene glycol (PEG) and sodium chloride (83) | Vaccine | 25 kGy at room temperature | SEM, particle size distribution, OVA and PEG content, in vitro OVA release, EPR, NMR | •Irradiations led to microsphere aggregation and caused the highly porous system to rupture •Gamma caused particle size to increase •Release rate was induced by gamma radiation
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| PLGA | Ciprofloxacin HCl (84) | Antibiotic | Freeze dried samples; 25 kGy | Particle size, zeta potential analysis, aggregation, viscosity | |
| Poly(lactic-co-glycolic acid) (PLGA)-Collagen microparticles | Gentamicin (85) | Antibiotic | 28.9 kGy | Visual inspection (microscopy), atomic force microscopy, release testing, molecular weight determination, DSC, ESR, NMR, microbiological assay | •Slight decrease in polymer molecular weight •Slight decrease in the glass transition temperature •No chemical change in the polymer and gentamicin was observed by NMR •EPR changes were observed, indicating presence of free radicals; however, given the NMR data, stability of the product was not a concern •Drug release profile was slightly altered after gamma irradiation
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| Cyclodextrin nanoparticle (86) | N/A | Nanoparticles for drug delivery | 25 kGy at 1.88 kGy/h | Particle size, yield, zeta potential, drug encapsulation and release | •Gamma irradiation had no negative influence on nanoparticle yield, mean diameter, or polydispersity index •Slight changes in zeta potential
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| PLGA | SPf66 malaria antigen (87) | Vaccine | Glass vials sealed with aluminum, vials covered with dry ice; 25 kGy | Particle size, DSC, peptide integrity, ELISA | •No difference in the loading properties of irradiated and non-irradiated microspheres •Small reduction of Tg is caused by the irradiation •In-vitro release rate is slightly faster in the irradiated samples compared to the non-irradiated samples •In-vivo immunogenicity results suggest that the antigen remain immunogenic after gamma irradiation
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| PLGA | Granisetron HCl (88) | Antiemetic | 25 kGy | Drug release | |
| Poly(ε-caprolactone) and poly(D,L-lactic acid) (PLA) | Ciprofloxacin, Dexamethasone Indomethacin Simvastatin (89) | Antibiotic, Anti-inflammatory, NSAID, Hypolipidemic | Below 42 °C, > 25 kGy | Stents were leached in NaPBS, 37 °C pH 7.4 ± 0.02 mL, UV, SEM | •Controlling the temperature of irradiation helped with polymers that were heat-sensitive •Drug elution profile was dependent on the drug •Irradiated stents resulted in a second “burst” in the elution profile after 60 days
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| Polyanhydride or poly(methylvinylether-co-maleic anhydride) | Brucella ovis (90) | Vaccine | Sealed glass vials, room temperature, for quantification of HS samples freeze dried then irradiated; 10 kGy and 25 kGy | SDS-PAGE, release study by agitation, stability my measuring turbidity | •Gamma irradiation negatively influenced the hot saline (HS) antigenic extract release from the carriers but had the same release pattern •Physiochemical properties of the nanoparticles as well as the integrity and antigenicity were not affected with gamma sterilization
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| Gelatin LNG | Levonorgestrel (91) | Contraception | Vials containing 5 mL toluene; 25 kGy | Particle size, HPTLC, drug encapsulation efficiency, sphericity, moisture content, HPLC, SEM, IR, DSC, x-ray, sterility, radioimmunoassay | •Physical characteristics of the microparticles were not altered after gamma radiation •The color of the product did not change after long exposure •Drug content before and after the irradiation process was compared, and no decrease was reported •Insignificant particle size change after irradiation
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| Poly(oxoethylene)-poly (oxypropylene) | Ciprofloxacin (92) | Antibiotic | Aqueous, drug stability and release profiles; 0, 15, 25, 50, 75, and 100 kGy | HPLC, sterility, drug release | •25% w/v of pluronic concentration resulted in low radiation doses (15 and 20 kGy), not harming the drug •Release study showed a significant decrease in drug release after 180 min
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| Monoglycerides (93) | Macromolecular drugs (proteins, peptides, siRNA/oligonucleotides) | Drug delivery | 10, 15, 20, and 25 kGy | Viscosity, in vitro drug and solvent release, bioburden determination, sterility test | •Different drugs were be used for the release •Sterility was achieved at 15 kGy and above •No changes were observed by visual inspection using polarized light microscopy after irradiation
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| PLGA | Paclitaxel (94) | Brain glioma | Sealed vial (argon atmosphere), 25 kGy under dry ice (−78.5 °C) | Encapsulation efficiency | |
| PLGA | Granisetron HCl (95) | Antiemetic | Liquid samples in glass and aluminum sealed vial; 25 kGy | SEM, in vitro drug release | •The drug release increased after gamma irradiation •Low-MW drugs with high water solubility caused an initial burst followed by an acceptable in vitro drug release from phase-sensitive injectable in situ implants systems •The implants were sensitive to gamma irradiation with regard to drug release; thus, an investigation should be performed in advance
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| PLGA | N. Meningitidis strains (96) | Vaccine | Vials purged with nitrogen; 15 kGy and 30 kGy | Protein loading on microparticle (SDS page), RP HPLC, SBA assay, gas chromatography | |
| Poly(lactic-co-glycolic acid) (PLGA) with ferulic acid (PLGA-g-FA) and pyrogallic acid (PLGA-g-PA) (97) | N/A | Microspheres for drug delivery | 25 kGy in the presence of air at 25 °C | ATR-FTIR, DSC, GPC, in vitro degradation | •PLGA-g-PA—increase of polymer resistance upon irradiation •Slight decrease in MW observed •Higher stability compared to non-irradiated PLGA •PLGA-g-PA was promising in the development of biodegradable drug delivery systems
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| Mucic acid acylated with lauroyl chloride (encapsulating hydrophobic molecules) (98) | NA | LDL uptake inhibitor | Solid; 25 and 50 kGy | 1H NMR, GPC, DLS, PBMC | •Amphiphilic macromolecule composition, molecular weight, micelle behavior, and biological activity were not substantially affected by radiation
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| PLGA | Vancomycin (99) | Antibiotic | Microparticles in solution; 25 kGy | DSC, SEM, bioactivity (antibiotic disk diffusion) | •Decrease of the crystallinity of the polymeric material •At 30 kGy and higher, the drug release period dropped to 22 days •Less than 25kGy—biodegradable composites can release high concentration of vanomycin •Glass transition temperature decreased with increasing the irradiation dose
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