Temperature-Sensitive Hydrogels as Carriers for Modulated Delivery of Acetaminophen
Abstract
:1. Introduction
2. Results and Discussion
2.1. Synthesis of p(NIPA/HPMA) Hydrogel
2.2. Differential Scanning Calorimetry
2.3. Swelling Behavior
2.3.1. Temperature Sensitivity Analysis
2.3.2. Analysis of the p(NIPA/HPMA) Hydrogel Swelling Kinetics
2.3.3. The Order of the Swelling Reaction
2.4. Fourier Transform Infrared Spectra
2.4.1. FTIR Spectrum Analysis of Acetaminophen
2.4.2. FTIR Spectrum Analysis of p(NIPA/HPMA) Hydrogel with Loaded Acetaminophen
2.5. Acetaminophen Loading Efficiency into p(NIPA/HPMA) Hydrogels
2.6. Morphology Characterization
2.7. In Vitro Acetaminophen Delivery from p(NIPA/HPMA) Copolymers
3. Conclusions
4. Materials and Methods
4.1. Reagents
4.2. Hydroges Synthesis
4.3. DSC Method
4.4. Swelling Behavior
4.4.1. Temperature Sensitivity
4.4.2. Kinetic Analysis
4.4.3. The Order of the Swelling Reaction
4.5. Acetaminophen Loading into the p(NIPA/HPMA)
4.6. In Vitro Acetaminophen Release Study
4.7. Characterization
4.7.1. FTIR Method
4.7.2. Freeze-Drying of Hydrogels
4.7.3. Scanning Electron Microscopy
4.8. Statistical Analysis
5. Patents
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Poly(N-isopropyl acrylamide-co-2-hydroxypropylmethacrylate) | Melting Transition Temperature, °C | Melting Enthalpy, J∙g−1 | Glass Transition Temperature, Tg, °C | |||
---|---|---|---|---|---|---|
p(NIPA/HPMA) with | Tm1 | Tm2 | ΔHm | Tg1 | Tg2 | Tg3 |
1 mol % of EGDM | 153.90 | 159.07 | 5.99 | 63.41 | 77.53 | 131.76 |
2 mol % of EGDM | 156.49 | 160.73 | 9.85 | 64.79 | 85.17 | 134.16 |
3 mol % of EGDM | 154.16 | 156.98 | 2.79 | 64.23 | 86.47 | - |
p(NIPA/HPMA) * with | Equilibrium Swelling Degree, αe | Diffusion Exponent, n | Kinetic Constant, k × 102, min−1/2 | Linear Correlation Coefficient, R2 | Diffusion Coefficient, D, cm2·min−1 |
---|---|---|---|---|---|
18 °C | |||||
1 mol % of EGDM | 25.960 | 0.822 | 1.998 | 0.981 | 8.998 × 10−6 |
1.5 mol % of EGDM | 14.748 | 0.761 | 1.105 | 0.991 | 2.703 × 10−6 |
2 mol % of EGDM | 10.143 | 0.681 | 0.989 | 0.993 | 0.379 × 10−6 |
3 mol % of EGDM | 6.943 | 0.584 | 0.971 | 0.996 | 0.691 × 10−6 |
38 °C | |||||
1 mol % of EGDM | 6.662 | 0.984 | 3.323 | 0.996 | 0.784 × 10−5 |
1.5 mol % of EGDM | 4.196 | 0.701 | 2.601 | 0.964 | 0.676 × 10−5 |
2 mol % of EGDM | 3.429 | 0.692 | 2.251 | 0.981 | 1.399 × 10−5 |
3 mol % of EGDM | 2.986 | 0.611 | 2.292 | 0.936 | 3.102 × 10−5 |
p(NIPA/HPMA) * with | Equilibrium Swelling Ratio, αe (exp) | Equilibrium Swelling Ratio, αe (I-order) | Rate Constant (I-order), K·103, min−1 | Linear Correlation Coefficient (I-order), R2 | Equilibrium Swelling Ratio, αe (II-order) | Rate Constant (II-order), K·103, min−1 | Linear Correlation Coefficient (II-order), R2 |
---|---|---|---|---|---|---|---|
18 °C | |||||||
1 mol % of EGDM | 25.960 | 27.214 | 2.35 | 0.982 | 26.113 | 26.286 | 0.999 |
1.5 mol % of EGDM | 14.748 | 15.972 | 3.96 | 0.971 | 14.986 | 5.691 | 0.999 |
2 mol % of EGDM | 10.143 | 11.266 | 3.23 | 0.934 | 10.534 | 13.118 | 0.999 |
3 mol % of EGDM | 6.943 | 8.32 | 3.98 | 0.961 | 7.112 | 4.882 | 0.999 |
38 °C | |||||||
1 mol % of EGDM | 6.662 | 8.012 | 9.36 | 0.989 | 6.892 | 6.141 | 0.999 |
1.5 mol % of EGDM | 4.196 | 4.949 | 7.33 | 0.991 | 4.464 | 6.841 | 0.999 |
2 mol % of EGDM | 3.429 | 3.833 | 7.18 | 0.996 | 3.678 | 5.654 | 0.999 |
3 mol % of EGDM | 2.986 | 3.524 | 8.59 | 0.991 | 3.274 | 4.991 | 0.998 |
Wavenumber of Functional Group, cm−1 | Functional Group | Shifts in Relation to the FTIR Spectra, cm−1 | |||
---|---|---|---|---|---|
p(NIPA/HPMA) * | Acetaminophen | p(NIPA/HPMA) with Acetaminophen | p(NIPA/HPMA) | Acetaminophen | |
3438 | 3436 | ν(OH) | −2 | ||
3319 | 3324 | 3326 | ν(NH) | +7 | +2 |
3162 | - | ν(Ar-OH) | - | ||
3035 | - | ν(C-H) Ar | - | ||
2973 | 2929 | 2974 | νas(CH3) | +1 | |
2933 | 2934 | νas(CH2) | +1 | ||
2876 | 2880 | 2877 | νs(CH3) | +1 | −3 |
1728 | 1720 | ν(C=O) ester | −8 | ||
1650 | 1654 | 1656 | ν(C=O) amide I | +6 | +2 |
1610 | 1610 | ν(C=C) Ar | 0 | ||
1544 | 1564 | 1560 | δ(N-H) amide II | +16 | −4 |
1507 | 1507 | ν(C=C) Ar | 0 | ||
1460, 1387 | 1442 | 1453, 1369 | δ(OH) | −7, −9 | +11 |
1367 | 1369 | δ(CH)-isopropyl | +2 | ||
1306 | - | νs(C-N) amide III | |||
1370, 1328 | 1327 | δs(CH3) | −1 | ||
1260 | 1260 | ν(C-O) | |||
1227 | 1243 | ν(NCH) | +16 | ||
1173 | 1172 | 1172 | ν(CN) | −1 | 0 |
1131 | 1131 | νs(C-O) | 0 | ||
837 | 837 | 837 | γ(CH) | 0 | 0 |
808 | 797 | γ(CH) | −11 | ||
674 | 686 | 688 | γ(OH) | +14 | +2 |
p(NIPA/HPMA) * with | Amount of Loaded Acetaminophen, Lg, mg/gxerogel | Acetaminophen Loading Efficiency, ηacetaminophen, % |
---|---|---|
1 mol % of EGDM | 480.34 | 96.06 |
1.5 mol % of EGDM | 460.84 | 92.16 |
2 mol % of EGDM | 467.63 | 93.52 |
3 mol % of EGDM | 480.81 | 96.14 |
Poly(N-isopropyl acrylamide-co-2-hydroxypropylmethacrylate) with | Quantity of Released Acetaminophen, mg/gxerogel% | Diffusion Exponent, n | Kinetic Constant, K, min−1/2 | Linear Correlation Coefficient, R2 | Diffusion Coefficient, D, cm2/min | |
---|---|---|---|---|---|---|
pH 7.40 | ||||||
1 mol % of EGDM | 492.77 | 98.56 | 0.297 | 0.641 | 0.972 | 3.79 × 10−3 |
1.5 mol % of EGDM | 484.11 | 96.82 | 0.325 | 0.694 | 0.997 | 3.74 × 10−3 |
2 mol % of EGDM | 471.59 | 94.32 | 0.297 | 0.756 | 0.972 | 4.48 × 10−3 |
3 mol % of EGDM | 455.58 | 91.12 | 0.375 | 0.639 | 0.944 | 3.21 × 10−3 |
pH 2.2 | ||||||
1 mol % of EGDM | 480.16 | 96.03 | 0.486 | 0.747 | 0.881 | 4.38 × 10−3 |
1.5 mol % of EGDM | 474.78 | 94.96 | 0.541 | 0.737 | 0.846 | 4.26 × 10−3 |
2 mol % of EGDM | 465.66 | 93.12 | 0.533 | 0.722 | 0.961 | 4.10 × 10−3 |
3 mol % of EGDM | 451.43 | 90.32 | 0.662 | 0.666 | 0.961 | 3.48 × 10−3 |
Polymeric Carrier | Experimental Conditions and Released Acetaminophen | Mechanism of Acetaminophen Diffusion | Reference |
---|---|---|---|
Poly(N-isopropyl acrylamide-co-2-hydroxypropylmethacrylate) with ethyleneglycoldimethacrylate | 98.56% at pH = 7.4, and 96.03% at pH = 2.2 during 24 h at 38 °C. | At pH = 7.4—Fickian diffusion. At pH = 2.2—non-Fickian diffusion (gels with 1.5, 2 and 3 mol % of EGDM). | [current study] |
Poly(N-vinylpyrrolidinone-co-acrylic acid) (with 30 wt % AA) and polyethylene glycol 600 dimethacrylate | At pH 2 approx. 24 h pH 6.8 approx. 5 h pH 9 approx. 5 h at 37 °C. | - | [36] |
Sodium alginate and N-isopropyl acrylamide crosslinked with N,N’methylenebisacrylamide | At 37 °C in pH 2.2 for 9 days ~90%. | The first-order kinetic. Non-Fickian (anomalous) diffusion. | [37] |
Poly(acrylamide-co-itaconic acid) crosslinked with N,N-methylenebisacrylamide | At 37 °C during 8 h: at pH = 2.2 ~20–55% pH = 4.5 ~90–99% pH = 6.8 ~90–99%. | Slow drug release under acidic conditions and rapid release at higher pH value. Fickian diffusion. | [38] |
Polyacrylamide with 4-[(4-methacryloyloxy) phenylazo] benzenesulfonic acid and N,N′-hexylenebismethacrylamide | The photoregulated release at 353 nm for 120 min of irradiation, a total of 83.6% was released in aqueous HEPES buffer pH 7.16. | - | [39] |
Poly(2-hydroxyethyl methacrylate-co-N-vinyl-2-pyrrolidone) with N,N’-methylenebisacrylamide | at 37 °C and SGF pH = 1.2, SIF pH = 7.2 ~95% during 240 min (4 h). | The tablet from the polymer NVP3 crumbled within an hour of immersion, resulting in burst release. Non-Fickian (anomalous) diffusion. | [40] |
Hydroxypropyl cellulose with polyacrylamide, 25/75 wt % | In deionized water, pH 7 in phosphate buffer, pH 7.38 at 35 °C, 37 °C, 39 °C, during 6 h. | Drug was crystallized on the gel surface. Fickian diffusion. | [41] |
Polyurethane nanocomposite hydrogels PU/PEG 4000 with 1% of organofillized montmorillonite (Cloisite® 30B) | In water for 24 h at 23 °C and 37 °C. | Easier release from nanocomposites than from a pure hydrogel matrix. Non-Fickian (anomalous) diffusion. | [42] |
Poly(N-isopropylacrylamide-acrylamide) with N,N-methylenbisacrylamide, and N,N,N,N-tetra-methylethylenediamine | pH= 7.4 at 27 °C, 32 °C, 41 °C, 44 °C ± 0.1 °C | The pore mechanism of drug transport. | [43] |
Poly(vinyl alcohol) with nanofibrillated cellulose, (NFC)/PVA, and 2,2,6,6-tetramethylpiperidine-N-oxyl-oxidized nanofibrillated cellulose (TNFC)/PVA without any chemical linkers | At 37 °C and phosphate buffer, 14% from (NFC)/PVA and about 28% from (TNFC)/PVA over 144 h (6 days). | Diffusion-controlled and burst release, with small fractions of relaxation-induced and prolonged-diffusional release. | [44] |
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Ilić-Stojanović, S.; Nikolić, L.; Nikolić, V.; Ristić, I.; Cakić, S.; Petrović, S.D. Temperature-Sensitive Hydrogels as Carriers for Modulated Delivery of Acetaminophen. Gels 2023, 9, 684. https://doi.org/10.3390/gels9090684
Ilić-Stojanović S, Nikolić L, Nikolić V, Ristić I, Cakić S, Petrović SD. Temperature-Sensitive Hydrogels as Carriers for Modulated Delivery of Acetaminophen. Gels. 2023; 9(9):684. https://doi.org/10.3390/gels9090684
Chicago/Turabian StyleIlić-Stojanović, Snežana, Ljubiša Nikolić, Vesna Nikolić, Ivan Ristić, Suzana Cakić, and Slobodan D. Petrović. 2023. "Temperature-Sensitive Hydrogels as Carriers for Modulated Delivery of Acetaminophen" Gels 9, no. 9: 684. https://doi.org/10.3390/gels9090684