Development of an Intranasal In Situ System for Ribavirin Delivery: In Vitro and In Vivo Evaluation
Abstract
:1. Introduction
1.1. Specifics of Intranasal Administration
1.2. Selection of an Optimal Gelation Stimulus
2. Materials and Methods
2.1. Equipment
2.2. Excipients and Chemicals
2.3. Design of Experiment
2.4. Methods
2.4.1. In Vitro Studies
Determination of In Situ Gelation Ability
pH Measurement
Viscosity Measurement
Gelation Temperature
Gelation pH
Determination of the Completeness of Retention on the Mucosal Surface In Vitro
Spray Torch Measurement
2.4.2. In Vivo “Animal” Studies
Animals
Sample Collection
Pharmacokinetic Study
Statistical Analysis
3. Results
3.1. Preparation of Stimulus-Sensitive Compositions
3.2. In Vitro Studies Results
3.2.1. Gelation Ability of Placebo Compositions
3.2.2. pH of Placebo Compositions
3.2.3. Plastic Viscosity of Placebo Compositions
3.2.4. Gelation Temperature
3.2.5. Completeness of Retention of Placebo Formulations
3.2.6. Spray Torch of Placebo Formulations
3.2.7. Results of In Vitro Studies after API Addition
3.3. In Vivo “Animal” Studies Results
3.3.1. Analytical Study of Brain, Olfactory Bulb, and Blood Plasma Samples
3.3.2. Pharmacokinetic Study of Brain
3.3.3. Pharmacokinetic Study of Olfactory Bulb
3.3.4. Pharmacokinetic Study of Blood Plasma
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Appendix A
Appendix A.1. Reagents
Appendix A.2. Method
Analyte | Retention Time (min) | Precursor (m/z) | Product (m/z) | Fragmentor (V) | CE (V) |
---|---|---|---|---|---|
Ribavirin | 1.57 | 245 | 113 | 80 | 7 |
13C5-Ribavirin | 1.57 | 250 | 113 | 80 | 7 |
Uridine | 2.01 | 245 | 113 | 60 | 5 |
Cytidine | 2.33 | 244 | 112 | 60 | 5 |
Appendix A.3. Selectivity
Appendix A.4. Linearity
Analyte | Linear Range (ng/mL) | Slope Mean ± SD | Intercept Mean ± SD | R Mean ± SD |
---|---|---|---|---|
Blood plasma | ||||
Ribavirin | 1–1000 | 1.214 ± 0.017 | 0.065 ± 0.021 | 0.9991 ± 0.0002 |
Brain | ||||
Ribavirin | 1–1000 | 1.085 ± 0.045 | 0.047 ± 0.013 | 0.9989 ± 0.0005 |
Olfactory bulb | ||||
1–1000 | 1.101 ± 0.014 | 0.074 ± 0.005 | 0.9998 ± 0.0003 |
Appendix A.5. Lowest Limit of Quantification
Appendix A.6. Accuracy and Precision
Analyte | Spiked Concentration (ng/mL) | Calculated Concentration (ng/mL) | RSD (%) | Accuracy, % |
---|---|---|---|---|
Ribavirin | 3 | 3.17 ± 0.34 | 10.7 | 105.7 |
300 | 310.1 ± 9.4 | 3.0 | 103.4 | |
750 | 765 ± 38 | 4.9 | 102.0 |
Analyte | Spiked Concentration (ng/mL) | Calculated Concentration (ng/mL) | RSD (%) | Accuracy, % |
---|---|---|---|---|
Ribavirin | 3 | 3.05 ± 0.14 | 4.6 | 101.7 |
300 | 316.6 ± 7.2 | 2.3 | 105.5 | |
750 | 785 ± 21 | 2.7 | 104.7 |
Analyte | Spiked Concentration (ng/mL) | Calculated Concentration (ng/mL) | RSD (%) | Accuracy, % |
---|---|---|---|---|
Ribavirin | 3 | 3.21 ± 0.42 | 13.1 | 107.0 |
300 | 284.1 ± 22.5 | 7.91 | 94.7 | |
750 | 675 ± 54 | 8.0 | 90.0 |
Analyte | Spiked Concentration (ng/mL) | Calculated Concentration (ng/mL) | RSD (%) | Accuracy, % |
---|---|---|---|---|
Ribavirin | 3 | 3.18 ± 0.11 | 3.5 | 106.0 |
300 | 297.3 ± 13.5 | 4.5 | 99.1 | |
750 | 691 ± 47 | 6.8 | 108.9 |
Analyte | Spiked Concentration (ng/mL) | Calculated Concentration (ng/mL) | RSD (%) | Accuracy, % |
---|---|---|---|---|
Ribavirin | 3 | 3.01 ± 0.14 | 4.71 | 100.3 |
300 | 307.2 ± 11.6 | 3.86 | 102.4 | |
750 | 849 ± 17 | 2.0 | 113.2 |
Analyte | Spiked Concentration (ng/mL) | Calculated Concentration (ng/mL) | RSD (%) | Accuracy, % |
---|---|---|---|---|
Ribavirin | 3 | 3.00 ± 0.12 | 1.05 | 100.1 |
300 | 304.6 ± 9.6 | 3.2 | 101.5 | |
750 | 817 ± 26 | 3.1 | 108.9 |
Appendix A.7. Recovery and Matrix Effect
Appendix A.8. Stability
Name | Sample | Concentration Level | Accuracy, % | Precision, %RSD |
---|---|---|---|---|
Short-term stability in working solutions (RT, 6 h) | LQC | 95.1 ± 1.4 | 4.8 | |
HQC | 94.8 ± 1.3 | 9.2 | ||
Short-term stability in biological samples (RT, 6 h) | Plasma | LQC | 87.4 ± 4.5 | 3.5 |
HQC | 101.9 ± 1.9 | 4.8 | ||
Brain | LQC | 98.4 ± 5.4 | 9.4 | |
HQC | 102.4 ± 8.8 | 12.3 | ||
Olfactory bulb | LQC | 104.7 ± 0.8 | 11.8 | |
HQC | 100.9 ± 1.7 | 10.9 | ||
Autosampler stability in biological samples (+10 °C, 24 h) | Plasma | LQC | 104.8 ± 5.5 | 8.4 |
HQC | 104.2 ± 6.4 | 5.6 | ||
Brain | LQC | 100.1 ± 1.1 | 4.0 | |
HQC | 97.8 ± 0.4 | 1.2 | ||
Olfactory bulb | LQC | 97.5 ± 4.8 | 5.9 | |
HQC | 99.4 ± 6.5 | 4.9 | ||
Post-preparative stability in biological samples (+4 °C, 24 h) | Plasma | LQC | 95.4 ± 3.2 | 7.8 |
HQC | 89.5 ± 3.7 | 6.1 | ||
Brain | LQC | 99.8 ± 2.4 | 10.2 | |
HQC | 100.8 ± 1.9 | 6.5 | ||
Olfactory bulb | LQC | 97.7 ± 4.1 | 1.5 | |
HQC | 97.5 ± 0.8 | 11.9 | ||
Freeze–thaw stability in biological samples | Plasma | LQC | 94.8 ± 2.4 | 12.8 |
HQC | 88.7 ± 1.8 | 13.6 | ||
Brain | LQC | 110.1 ± 6.4 | 1.0 | |
HQC | 97.6 ± 4.7 | 0.6 | ||
Olfactory bulb | LQC | 99.4 ± 6.4 | 5.9 | |
HQC | 101.4 ± 1.1 | 4.8 | ||
Long-term stability in biological samples (−20 °C, 22 days) | Plasma | LQC | 100.8 ± 9.4 | 1.5 |
HQC | 87.5 ± 0.4 | 0.5 | ||
Brain | LQC | 96.8 ± 1.3 | 5.8 | |
HQC | 96.4 ± 5.4 | 4.9 | ||
Olfactory bulb | LQC | 95.7 ± 8.1 | 1.9 | |
HQC | 93.4 ± 0.9 | 2.5 |
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Factor | Target | Justification |
---|---|---|
Route of administration | Intranasal | Directed delivery to the brain |
Site of effect | Brain | Transport of AFI by cranial nerves (olfactory and trigeminal) to the brain |
API administration | 100 mg/mL | Test concentration with antitumor effect |
pH | 5.5–7.5 | Optimal range for comfortable administration |
Viscosity before gelation | Below 100 mPa·s | Phase transition is due to the selected nebulization system—NEST Pre-filled Disposable Intranasal Atomization Device (China) |
Gelation stimulus | Temperature, ions (Na+, K+, Ca2+) | Gel formation conditions correspond to the physiologic parameters of the nasal cavity |
Phase transition temperature | Below 32 °C | Nasal cavity temperature (applicable for thrmoreversible systems) |
Spray torch | 6–9 cm | Targeting the olfactory bulb |
Retention on nasal cavity model | >80% | Similar retention percentage to highly adhesive compositions |
CQA | CMA | CPP |
---|---|---|
Gelation stimulus | Smart-polymer concentration | Stirring time |
Solution viscosity | Additional ingredient | Dispergating speed |
Spray torch | Concentration of additional ingredient | Dispergating time |
pH | Type of solvent | Manufacturing temperature |
Retention on nasal cavity model | Concentration of API |
Animals | Groups | Number of Animals | Drug/Dose/Administration Volume | Manipulations |
---|---|---|---|---|
Rats, intranasal administration | 0 min | 3 | In situ gel with ribavirin, 10 mg per kg, 15 µL in each nostril per 300 g (rat weight) | Vital manipulations—intranasal injection, blood sampling. After euthanasia—collection of brain and olfactory bulbs with further homogenization and analytical study. |
15 min | 3 | |||
30 min | 3 | |||
1 h | 3 | |||
2 h | 3 | |||
5 h | 3 | |||
8 h | 3 | |||
12 h | 3 | |||
24 h | 3 | |||
Control group | ||||
Rats, intranasal administration | 0 min | 3 | Ribavirin water solution, 10 mg per kg, 15 µL in each nostril per 300 g (rat weight) | Vital manipulations—intranasal injection, blood sampling. After euthanasia—collection of brain and olfactory bulbs with further homogenization and analytical study. |
15 min | 3 | |||
30 min | 3 | |||
1 h | 3 | |||
2 h | 3 | |||
5 h | 3 | |||
8 h | 3 | |||
12 h | 3 | |||
24 h | 3 |
Time, min | “A” Phase Amount, % | “B” Phase Amount, % |
---|---|---|
0 | 100 | 0 |
1.5 | 100 | 0 |
2.0 | 10 | 90 |
6.0 | 10 | 90 |
6.10 | 100 | 0 |
8.0 | 100 | 0 |
Parameter | Value |
---|---|
Ionization type | Electrospraying with heated atomizing gas stream |
Gas Temp | 300 °C |
Gas Flow | 11 L/min |
Nebulizer | 35 psi |
SheathGasHeater | 300 °C |
SheathGasFlow | 11 L/min |
Capillary Voltage | 2.5 kV |
Mode of Analysis | MRM, positive ion |
№ | P407 | P188 | P124 | GG | Ch | PBS | XG | GuG | PVA | HPMC | Pec | Carb | PEG 1500 |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
1 | 16 | 3 | - | - | - | - | - | - | - | - | - | - | - |
2 | 16 | 2 | - | - | - | - | - | - | - | - | - | - | - |
3 | 18 | 3 | - | - | - | - | - | - | - | - | - | - | - |
4 | 18 | 2 | - | - | - | - | - | - | - | - | - | - | - |
5 | 16 | - | 2 | - | - | - | - | - | - | - | - | - | - |
6 | 16 | - | 1 | - | - | - | - | - | - | - | - | - | - |
7 | 18 | - | 2 | - | - | - | - | - | - | - | - | - | - |
8 | 18 | - | 1 | - | - | - | - | - | - | - | - | - | - |
9 | 16 | - | - | - | - | - | - | - | - | - | - | - | 1 |
10 | 16 | - | - | - | - | - | - | - | - | - | - | - | 0.5 |
11 | 18 | - | - | - | - | - | - | - | - | - | - | - | 1 |
12 | 18 | - | - | - | - | - | - | - | - | - | - | - | 0.5 |
13 | 16 | - | - | - | 2 | - | - | - | - | - | - | - | - |
14 | 16 | - | - | - | 1 | - | - | - | - | - | - | - | - |
15 | 18 | - | - | - | 2 | - | - | - | - | - | - | - | - |
16 | 18 | - | - | - | 1 | - | - | - | - | - | - | - | - |
17 | 16 | - | - | - | - | - | - | - | - | - | - | - | - |
18 | 18 | - | - | - | - | - | - | - | - | - | - | - | - |
19 | 16 | - | - | 0.25 | - | - | - | - | - | - | - | - | - |
20 | 16 | - | - | 0.5 | - | - | - | - | - | - | - | - | - |
21 | 18 | - | - | 0.25 | - | - | - | - | - | - | - | - | - |
22 | 18 | - | - | 0.5 | - | - | - | - | - | - | - | - | - |
23 | - | - | - | 0.25 | - | - | - | - | - | - | - | - | - |
24 | - | - | - | 0.5 | - | - | - | - | - | - | - | - | - |
25 | - | - | - | 0.25 | - | 10 | - | - | - | - | - | - | - |
26 | - | - | - | 0.25 | - | 15 | - | - | - | - | - | - | - |
27 | - | - | - | 0.5 | - | 10 | - | - | - | - | - | - | - |
28 | - | - | - | 0.5 | - | 15 | - | - | - | - | - | - | - |
29 | - | - | 2 | 0.25 | - | - | - | - | - | - | - | - | - |
30 | - | - | 1 | 0.25 | - | - | - | - | - | - | - | - | - |
31 | - | - | 2 | 0.5 | - | - | - | - | - | - | - | - | - |
32 | - | - | 1 | 0.5 | - | - | - | - | - | - | - | - | - |
33 | - | - | - | 0.25 | - | - | 0.25 | - | - | - | - | - | - |
34 | - | - | - | 0.25 | - | - | 0.5 | - | - | - | - | - | - |
35 | - | - | - | 0.5 | - | - | 0.25 | - | - | - | - | - | - |
36 | - | - | - | 0.5 | - | - | 0.5 | - | - | - | - | - | - |
37 | - | - | - | 0.25 | - | - | - | 0.25 | - | - | - | - | - |
38 | - | - | - | 0.25 | - | - | - | 0.5 | - | - | - | - | - |
39 | - | - | - | 0.5 | - | - | - | 0.25 | - | - | - | - | - |
40 | - | - | - | 0.5 | - | - | - | 0.5 | - | - | - | - | - |
41 | - | - | - | 0.25 | - | - | - | - | 0.25 | - | - | - | - |
42 | - | - | - | 0.25 | - | - | - | - | 0.5 | - | - | - | - |
43 | - | - | - | 0.5 | - | - | - | - | 0.25 | - | - | - | - |
44 | - | - | - | 0.5 | - | - | - | - | 0.5 | - | - | - | - |
45 | - | - | - | 0.25 | - | - | - | - | - | 0.1 | - | - | - |
46 | - | - | - | 0.25 | - | - | - | - | - | 0.2 | - | - | - |
47 | - | - | - | 0.5 | - | - | - | - | - | 0.1 | - | - | - |
48 | - | - | - | 0.5 | - | - | - | - | - | 0.2 | - | - | - |
49 | - | - | - | 0.25 | - | - | - | - | - | - | - | 0.1 | - |
50 | - | - | - | 0.25 | - | - | - | - | - | - | - | 0.2 | - |
51 | - | - | - | 0.5 | - | - | - | - | - | - | - | 0.1 | - |
52 | - | - | - | 0.5 | - | - | - | - | - | - | - | 0.2 | - |
53 | - | - | - | - | - | - | 0.25 | - | - | - | - | - | - |
54 | - | - | - | - | - | - | 0.5 | - | - | - | - | - | - |
55 | - | - | - | 0.25 | - | - | - | - | - | - | 0.1 | - | - |
56 | - | - | - | 0.25 | - | - | - | - | - | - | 0.2 | - | - |
57 | - | - | - | 0.5 | - | - | - | - | - | - | 0.1 | - | - |
58 | - | - | - | 0.5 | - | - | - | - | - | - | 0.2 | - | - |
59 | - | - | - | - | - | - | - | - | - | - | 0.25 | - | - |
60 | - | - | - | - | - | - | - | - | - | - | 0.5 | - | - |
№ | Gelation 1 | № | Gelation 1 | № | Gelation 1 | № | Gelation 1 |
---|---|---|---|---|---|---|---|
1 | +++ | 17 | +++ | 33 | + | 49 | ++ |
2 | +++ | 18 | +++ | 34 | ++ | 50 | ++ |
3 | +++ | 19 | +++ | 35 | ++ | 51 | +++ |
4 | +++ | 20 | +++ | 36 | ++ | 52 | +++ |
5 | +++ | 21 | +++ | 37 | - | 53 | - |
6 | +++ | 22 | +++ | 38 | + | 54 | - |
7 | +++ | 23 | ++ | 39 | + | 55 | - |
8 | +++ | 24 | +++ | 40 | - | 56 | + |
9 | +++ | 25 | ++ | 41 | + | 57 | - |
10 | +++ | 26 | ++ | 42 | + | 58 | + |
11 | +++ | 27 | +++ | 43 | ++ | 59 | - |
12 | +++ | 28 | +++ | 44 | ++ | 60 | + |
13 | +++ | 29 | ++ | 45 | ++ | ||
14 | +++ | 30 | ++ | 46 | ++ | ||
15 | +++ | 31 | +++ | 47 | +++ | ||
16 | +++ | 32 | +++ | 48 | +++ |
№ | pH Value | № | pH Value | № | pH Value | № | pH Value |
---|---|---|---|---|---|---|---|
1 | 6.32 | 17 | 7.52 | 33 | 7.21 | 49 | 4.32 |
2 | 6.71 | 18 | 8.04 | 34 | 7.11 | 50 | 4.21 |
3 | 6.34 | 19 | 7.92 | 35 | 7.3 | 51 | 4.15 |
4 | 6.51 | 20 | 8.1 | 36 | 6.99 | 52 | 4.25 |
5 | 6.96 | 21 | 7.89 | 37 | 6.76 | 55 | 6.75 |
6 | 6.84 | 22 | 7.3 | 38 | 6.6 | 56 | 6.88 |
7 | 6.89 | 23 | 6.93 | 39 | 6.89 | 57 | 6.92 |
8 | 7 | 24 | 6.9 | 40 | 6.91 | 58 | 7.07 |
9 | 6.7 | 25 | 6.95 | 41 | 6.54 | 59 | 7.04 |
10 | 6.44 | 26 | 7.02 | 42 | 6.77 | 60 | 6.89 |
11 | 6.58 | 27 | 7.14 | 43 | 6.72 | ||
12 | 6.7 | 28 | 7.21 | 44 | 6.81 | ||
13 | 6.51 | 29 | 7.04 | 45 | 7.49 | ||
14 | 6.1 | 30 | 6.98 | 46 | 7.62 | ||
15 | 6.12 | 31 | 6.82 | 47 | 6.44 | ||
16 | 6.3 | 32 | 6.91 | 48 | 6.58 |
№ | Viscosity, mPa·s | № | Viscosity, mPa·s | № | Viscosity, mPa·s | № | Viscosity, mPa·s |
---|---|---|---|---|---|---|---|
1 | 45.6 | 17 | 21.2 | 33 | 40.1 | 49 | 27.4 |
2 | 41.3 | 18 | 29.2 | 34 | 32.2 | 50 | 27.5 |
3 | 69.1 | 19 | 59.9 | 35 | 40.1 | 51 | 28.7 |
4 | 62.4 | 20 | 59.1 | 36 | 75.3 | 52 | 29.9 |
5 | 45.7 | 21 | 53.3 | 37 | 138.9 | 55 | 22.2 |
6 | 42 | 22 | 84.5 | 38 | 134.2 | 56 | 29.7 |
7 | 82.6 | 23 | 40.5 | 39 | 129.9 | 57 | 69.7 |
8 | 32.8 | 24 | 61.1 | 40 | 131.2 | 58 | 94.6 |
9 | 28.2 | 25 | 56.8 | 41 | 59.8 | 59 | 115.1 |
10 | 24.3 | 26 | 54.8 | 42 | 59.7 | 60 | 106.9 |
11 | 29.3 | 27 | 30.1 | 43 | 54.1 | ||
12 | 27.2 | 28 | 33.3 | 44 | 58.2 | ||
13 | 41 | 29 | 27.1 | 45 | 39.8 | ||
14 | 39.8 | 30 | 28 | 46 | 42.2 | ||
15 | 42.3 | 31 | 27.8 | 47 | 39.7 | ||
16 | 40.9 | 32 | 59.8 | 48 | 45.6 |
№ | Gelation t, °C | № | Gelation t, °C |
---|---|---|---|
1 | 31.2 | 12 | 36.6 |
2 | 30.9 | 13 | 36 |
3 | 39.9 | 14 | 31.1 |
4 | 33.1 | 15 | 28.1 |
5 | 32.3 | 16 | 29.2 |
6 | 34.7 | 17 | 27.6 |
7 | 35.3 | 18 | 28.5 |
8 | 31.2 | 19 | 36.4 |
9 | 31.4 | 20 | 32.1 |
10 | 35 | 21 | 27.4 |
11 | 34.6 | 22 | 28.3 |
№ | Gelation t, °C 1 | № | Gelation t, °C 1 | № | Gelation t, °C 1 | № | Gelation t, °C 1 |
---|---|---|---|---|---|---|---|
1 | + | 17 | + | 33 | - | 49 | - |
2 | + | 18 | + | 34 | - | 50 | - |
3 | - | 19 | - | 35 | - | 51 | - |
4 | - | 20 | - | 36 | - | 52 | - |
5 | - | 21 | + | 37 | - | 53 | - |
6 | - | 22 | + | 38 | - | 54 | - |
7 | - | 23 | - | 39 | - | 55 | - |
8 | + | 24 | - | 40 | - | 56 | - |
9 | + | 25 | - | 41 | - | 57 | - |
10 | - | 26 | - | 42 | - | 58 | - |
11 | - | 27 | - | 43 | - | 59 | - |
12 | - | 28 | - | 44 | - | 60 | - |
13 | - | 29 | - | 45 | - | ||
14 | + | 30 | - | 46 | - | ||
15 | + | 31 | - | 47 | - | ||
16 | + | 32 | - | 48 | - |
№ | Retention, % | № | Retention, % | № | Retention, % | № | Retention, % |
---|---|---|---|---|---|---|---|
1 | 33 | 17 | 35 | 33 | 15 | 49 | 10 |
2 | 30 | 18 | 39 | 34 | 25 | 50 | 15 |
3 | 10 | 19 | 70 | 35 | 20 | 51 | 15 |
4 | 18 | 20 | 72 | 36 | 23 | 52 | 17 |
5 | 64 | 21 | 65 | 37 | 29 | 53 | 5 |
6 | 68 | 22 | 60 | 38 | 35 | 54 | 10 |
7 | 70 | 23 | 67 | 39 | 35 | 55 | 15 |
8 | 70 | 24 | 70 | 40 | 40 | 56 | 18 |
9 | 39 | 25 | 70 | 41 | 55 | 57 | 20 |
10 | 31 | 26 | 77 | 42 | 49 | 58 | 18 |
11 | 37 | 27 | 85 | 43 | 65 | 59 | 18 |
12 | 35 | 28 | 90 | 44 | 63 | 60 | 20 |
13 | 72 | 29 | 80 | 45 | 53 | 61 | 8 |
14 | 76 | 30 | 75 | 46 | 87 | 62 | 6 |
15 | 85 | 31 | 95 | 47 | 87 | 63 | 20 |
16 | 80 | 32 | 90 | 48 | 90 | 64 | 15 |
№ | Spray Torch, cm | № | Spray Torch, cm | № | Spray Torch, cm | № | Spray Torch, cm |
---|---|---|---|---|---|---|---|
1 | 11 | 17 | 8 | 33 | 9 | 49 | 5 |
2 | 9 | 18 | 9 | 34 | 11 | 50 | 6 |
3 | 8 | 19 | 5.5 | 35 | 6 | 51 | 5.5 |
4 | 10 | 20 | 6 | 36 | 8 | 52 | 4.5 |
5 | 9.5 | 21 | 4 | 37 | 2.5 | 53 | 6 |
6 | 8.5 | 22 | 3.5 | 38 | 3 | 54 | 8 |
7 | 10 | 23 | 12 | 39 | 3 | 55 | 8.5 |
8 | 11 | 24 | 13.5 | 40 | 6.5 | 56 | 5 |
9 | 11 | 25 | 9 | 41 | 7.5 | 57 | 8 |
10 | 10.5 | 26 | 8.5 | 42 | 8.5 | 58 | 3 |
11 | 9.5 | 27 | 10 | 43 | 8 | 59 | 3.5 |
12 | 13 | 28 | 10.5 | 44 | 9 | 60 | 6 |
13 | 11 | 29 | 12 | 45 | 8.5 | ||
14 | 9.5 | 30 | 11 | 46 | 7 | ||
15 | 8.5 | 31 | 8 | 47 | 8 | ||
16 | 9 | 32 | 7.5 | 48 | 9.5 |
With Ribavirin | ||||||
---|---|---|---|---|---|---|
№ | Gelation | Gelation t, °C | pH Value | Retention, % | Viscosity, mPa·s | Spray Torch |
15 | +++ | 25 | 6.12 | 45 | 27.1 | 12 |
16 | +++ | 24.6 | 6.3 | 60 | 39.9 | 9 |
27 | +++ | - | 7.14 | 80 | 37.8 | 9.5 |
28 | +++ | - | 7.21 | 85 | 30.2 | 10 |
31 | +++ | - | 6.82 | 98 | 28.1 | 8.5 |
32 | +++ | - | 6.91 | 90 | 24.1 | 9 |
46 | ++ | - | 7.62 | 85 | 29.4 | 10.5 |
47 | +++ | - | 6.44 | 83 | 35.1 | 7.5 |
48 | +++ | - | 6.58 | 85 | 29.9 | 8 |
Without ribavirin | ||||||
15 | +++ | 28.1 | 6.12 | 85 | 42.3 | 8.5 |
16 | +++ | 29.2 | 6.3 | 80 | 40.9 | 9 |
27 | +++ | - | 7.14 | 85 | 30.1 | 10 |
28 | +++ | - | 7.21 | 90 | 33.3 | 10.5 |
31 | +++ | - | 6.82 | 95 | 27.8 | 8 |
32 | +++ | - | 6.91 | 90 | 59.8 | 7.5 |
46 | ++ | - | 7.62 | 87 | 42.2 | 7 |
47 | +++ | - | 6.44 | 87 | 39.7 | 8 |
48 | +++ | - | 6.58 | 90 | 45.6 | 9.5 |
Parameter * | Unit | Plasma Value | Brain Value | Olfactory Bulbs Value |
---|---|---|---|---|
Experimental group | ||||
Λ_z | 1/h | 0.1289 | 0.0335 | 0.0378 |
t1/2 | h | 5.3791 | 20.6782 | 18.3222 |
Tmax | h | 0.5 | 5 | 5 |
Cmax | ng/ml | 152.6586 | 931.1437 | 2542.7953 |
Tlag | h | 0 | 0 | 0 |
Clast_obs/Cmax | - | 0.0228 | 0.5890 | 0.4073 |
AUC 0-t | ng/mL*h | 629.5281 | 17,535.4248 | 38,105.3782 |
AUC 0-inf_obs | ng/mL*h | 656.5046 | 33,897.8019 | 65,483.2040 |
AUC 0-t/0-inf_obs | - | 0.9589 | 0.5173 | 0.5819 |
AUMC 0-inf_obs | ng/mL*h2 | 4569.5688 | 1,085,744.771 | 1,796,570.896 |
MRT 0-inf_obs | h | 6.9605 | 32.0299 | 27.4356 |
Vz/F_obs | (μg/kg)/(ng/mL) | 0.1182 | 0.0088 | 0.0040 |
Cl/F_obs | (μg/kg)/(ng/mL)/h | 0.0152 | 0.0003 | 0.0002 |
Control group | ||||
Λ_z | 1/h | 0.0960 | 0.0837 | 0.1549 |
t1/2 | h | 7.2175 | 8.2803 | 4.4754 |
Tmax | h | 0.25 | 1 | 0.5 |
Cmax | ng/ml | 154.3622 | 924.4831 | 2062.3333 |
Tlag | h | 0 | 0 | 0 |
Clast_obs/Cmax | - | 0.0220 | 0.0857 | 0.0232 |
AUC 0-t | ng/mL*h | 421.3711 | 7412.3988 | 11,029.7240 |
AUC 0-inf_obs | ng/mL*h | 456.7740 | 8359.1850 | 11,338.1257 |
AUC 0-t/0-inf_obs | - | 0.9225 | 0.8867 | 0.9728 |
AUMC 0-inf_obs | ng/mL*h2 | 3885.3060 | 85,566.0065 | 68,537.7786 |
MRT 0-inf_obs | h | 8.5060 | 10.2361 | 6.0449 |
Vz/F_obs | (μg/kg)/(ng/mL) | 0.2280 | 0.0143 | 0.0057 |
Cl/F_obs | (μg/kg)/(ng/mL)/h | 0.0219 | 0.0012 | 0.0009 |
CQA/CPP | Stirring Time | Dispergating Speed | Dispergating Time | Manufacturing Temperature | Cross-Linking Time |
---|---|---|---|---|---|
Gelation stimulus | Low | Low | Low | High | Low |
Solution viscosity | Medium | Low | Low | Low | Low |
Spray torch | Low | Low | Low | Low | Low |
pH | Low | Low | Low | Low | Low |
Retention on nasal cavity model | Low | Low | Low | Low | Low |
CQA/CMA | Smart-Polymer Concentration | Additional Ingredient | Concentration of Additional Ingredient | Type of Solvent | Concentration of API |
---|---|---|---|---|---|
Gelation stimulus | High | High | High | High | Low |
Solution viscosity | High | High | High | High | Medium |
Spray torch | High | High | High | High | Medium |
pH | Medium | Medium | Medium | High | Medium |
Retention on nasal cavity model | High | High | High | High | Medium |
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Mikhel, I.B.; Bakhrushina, E.O.; Petrusevich, D.A.; Nedorubov, A.A.; Appolonova, S.A.; Moskaleva, N.E.; Demina, N.B.; Kosenkova, S.I.; Parshenkov, M.A.; Krasnyuk, I.I., Jr.; et al. Development of an Intranasal In Situ System for Ribavirin Delivery: In Vitro and In Vivo Evaluation. Pharmaceutics 2024, 16, 1125. https://doi.org/10.3390/pharmaceutics16091125
Mikhel IB, Bakhrushina EO, Petrusevich DA, Nedorubov AA, Appolonova SA, Moskaleva NE, Demina NB, Kosenkova SI, Parshenkov MA, Krasnyuk II Jr., et al. Development of an Intranasal In Situ System for Ribavirin Delivery: In Vitro and In Vivo Evaluation. Pharmaceutics. 2024; 16(9):1125. https://doi.org/10.3390/pharmaceutics16091125
Chicago/Turabian StyleMikhel, Iosif B., Elena O. Bakhrushina, Danila A. Petrusevich, Andrey A. Nedorubov, Svetlana A. Appolonova, Natalia E. Moskaleva, Natalia B. Demina, Svetlana I. Kosenkova, Mikhail A. Parshenkov, Ivan I. Krasnyuk, Jr., and et al. 2024. "Development of an Intranasal In Situ System for Ribavirin Delivery: In Vitro and In Vivo Evaluation" Pharmaceutics 16, no. 9: 1125. https://doi.org/10.3390/pharmaceutics16091125