Translational Considerations in the Development of Intranasal Treatments for Epilepsy
Abstract
:1. Introduction
2. Relationships between the Nose and Epilepsy
2.1. Historical and Epidemiological
2.2. Neurological
2.2.1. The Olfactory System
2.2.2. Epilepsy and the Olfactory System
2.2.3. Clinical and Social
3. The Anatomy and Physiology of Intranasal Administration to the Brain
3.1. The Nasal Passage and Epithelia
3.2. Respiratory Epithelium
3.3. Olfactory Epithelium
4. Nasal Routes of Absorption for Therapeutics
4.1. Systemic Transport
4.2. Intracellular Transport
4.3. Extracellular Transport
5. Animal Models for Intranasal Delivery
6. Animals as Seizure and Epilepsy Models for the Evaluation of Anti-Seizure Therapeutics
6.1. Overview of Key Models
6.1.1. Maximal Electroshock Seizure Test
6.1.2. Maximal Electroshock Seizure Threshold Test
6.1.3. Pentylenetetrazole Test
6.1.4. 6-Hz “Psychomotor” Seizure Test
6.1.5. Kindling
6.2. Relevance to the Evaluation of Intranasal Delivery Pathways
7. Pharmaceutical Formulation of Anti-Seizure Therapeutics
7.1. Role of Pharmaceutical Formulation
7.2. Studies of Pharmaceutical Formulation for Anti-Seizure Therapeutic Delivery
7.2.1. Administration Technique
ASD | Delivery System | Materials | Tox. | PK | Efficacy | Ref. |
---|---|---|---|---|---|---|
CBZ | Gel | Carbopol 974P (mucoadhesive polymer, hypromellose, pH 7.4 | X | ✓ | X | [124] |
Thermo-reversible gel | Carbopol 974P (mucoadhesive polymer), Pluronic F127 | X | ✓ | X | [125] | |
Mucoadhesive o/w nanoemulgel | Oleic acid, Labrasol, xanthan gum (anionic mucoadhesive polymer) | X | X | ✓ | [125] | |
Microemulsion | Oleic acid, Tween 80, Propylene glycol | ✓ | X | ✓ | [113] | |
Oleoyl polyoylglycerides, Polyoxyl 40 hydrogenated castor oil, Diethylene glycol monoethyl ether, Polycarbopil (mucoadhesive) | ✓ | ✓ | X | [126] | ||
Polymeric nanoparticles | Carboxymethyl chitosan | X | ✓ | X | [127] | |
LMT | Thermo-reversible gel | Carbopol 974P (mucoadhesive polymer), Pluronic F127 | X | ✓ | X | [128] |
Microemulsion | Glyceryl monostearate, Oleic acid, Tween 80, Pluronic P188 | X | ✓ | ✓ | [111] | |
Microspheres (as suspension) | Chitosan, glutaraldehyde | ✓ | X | ✓ | [129] | |
Nanoliposomes | Phospholipon 90G, cholesterol | ✓ (in vitro) | X | X | [130] | |
Polymeric nanoparticles | PLGA and Poloxamer 407 | ✓ | ✓ | ✓ | [131] | |
PHT | Microemulsion | Capmul MCM (glyceryl monocaprylate), Labrasol, PEG-8 caprylic/capric glycerides and Transcutol (diethylene glycol monoethyl ether) | ✓ | ✓ | ✓ | [112] |
Nanoparticles | Lecithin-chitosan | X | ✓ | ✓ | [132] | |
PBT | Gel | Carbopol 974P (mucoadhesive polymer, hypromellose, pH 9.5 | X | ✓ | ✓ | [123] |
LZM | Lipid nanoparticles in a gel | Glycerol monostearate, oleic acid and Tween 80, chitosan, Pluronic F127, β-glycerol phosphate disodium salt pentahydrate | X | ✓ | X | [133] |
DZP | Polymeric nanoparticles | PLGA (Poly(D,L-lactide-co-glycolide), Pluronic F127 | X | ✓ | X | [134] |
TRH | Polymeric nanoparticles | PLA (Polylactide) | X | X | ✓ | [17,18] |
VA | Lipid nanoparticles | Cetyl palmitate, soy lecithin, octyldodecanol | X | ✓ | ✓ | [135] |
LVT | Thermo-reversible gel | Pluronic F127; Carbopol 974P and Noveon® Polycarbophil. | ✓ | ✓ | X | [136] |
ZNA | Thermo-reversible gel | Pluronic F127; Carbopol 974P and Noveon® Polycarbophil | X | ✓ | X | [137] |
Drug | Animal Model | Dose (µg) | Volume | Anaesthesia | Method | Ref. |
---|---|---|---|---|---|---|
CBZ | Mouse | 12 to 16 | 12 to 16 µL in one nostril | Ketamine and xylazine (i.p.) | Tubing | [128] |
625 | 100 µL in one nostril | Diethyl ether | Cannula strengthened by jacketed non-protruding needle | [125] | ||
40 to 60 | 25 µL in each nostril | Not reported | Tubing | [127] | ||
Rat | 35 to 40 | 10 µL in each nostril | Ketamine (i.m.) | Tubing | [126] | |
50 (administered) 40 (accepted) | 50 mg gel into one nostril. Estimated that 80% was accepted | None | Tubing | [124] | ||
1600 to 2000 | 55 µL in each nostril | Not reported | Tubing | [113] | ||
LMT | Mouse | 110 to 125 | Not reported Both nostrils. | Ketamine and xylazine (route not stated) | Tubing | [129] |
120 to 160 | 12 to 16 µL in one nostril | Ketamine and xylazine (i.p.) | Tubing | [138] | ||
Rat | 720 to 970 | 100 µL in each nostril | Ketamine (i.m.) | Not reported | [111] | |
166 to 291 | Not reported | Not reported | Not reported | [131] | ||
PHT | Rat | 3520 | 88 µL in each nostril | Not reported | Tubing | [112] |
Mouse | 280 to 420 | 60 µL (number of nostrils not reported) | None | Dropper | [132] | |
PBT | Rat | 1100 to 1200 2000 to 2200 6000 to 6600 | 7 to 40 µL in each nostril | Propofol (i.v.) | Deposited at opening of nares or using tubing | [123] |
LZM | Rat | 200 | 50 µL in each nostril | Not reported | Tubing | [133] |
VA | Rat | 720 to 840 | 100 µL in each nostril over a few minutes | Light ether | Tubing | [135] |
DZP | Rat | 40 to 50 | 10 µL each nostril | Ketamine (i.p.) | Tubing | [134] |
TRH | Rat | 20 | 25 µL in each nostril (chronic administration) | Isoflurane | Surgically inserted cannulae | [17,18] |
LVT | Mouse | 625 | 25 µL (left nostril only) | Ketamine and xylazine (i.p.) | MicroSprayer® Aerosolizer coupled to a high-pressure syringe | [136] |
ZNA | Mouse | 418 to 501 | 50 µL (left nostril only) | Ketamine and xylazine (i.p.) | MicroSprayer® Aerosolizer coupled to a high-pressure syringe | [137] |
7.2.2. Adverse Effects and Toxicity
7.2.3. Quantification of Drug in Tissues
7.2.4. Qualitative Distribution in Tissue
7.2.5. Efficacy
7.2.6. In the Pipeline
8. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Parameter | Human | Rat |
---|---|---|
Nasal cavity volume | 25 cm3 | 0.26 to 0.4 cm3 |
Nasal cavity surface area | 150 to160 cm2 | 13.4 to 14 cm2 |
Surface area per unit volume | 6.4 | 51.5 |
Olfactory epithelium area (area, %) | 12.5 cm2, 8% | 6.75 cm2, 50% |
CSF volume | 160 mL | 150 µL |
CSF volume replacement frequency | 5 h | Hourly |
Shape of upper airways | L-shaped | Linear |
Type of breathing at rest | Oronasal | Obligate nose |
Connection between nasal cavity and oral cavity | No (incisive canal is not patent) | Yes (nasopalatine canal is patent) |
Vascular swell bodies in septum | No | Yes |
Turbinates (number and shape) | 3; comma shaped | 3; t-shaped with elaborate scrolls |
Presence of ethmoid sinuses (air cells) and spheroid sinuses | Yes | No |
Maxillary sinuses | Large; open | Small; closed |
Nasal secretion movement | Mostly posteriorly (to nasopharynx) | Mostly anteriorly (towards nostril) |
Inspiratory airflow route | Close to floor of nasal passage | Upward and laterally |
ASD | Tissues Analysed | PK Parameters Reported | Time Points after Administration | Routes/Formulations Compared | Test | Endpoint | Time of Test | Anaesthesia | Ref. |
---|---|---|---|---|---|---|---|---|---|
CBZ | Brain—olfactory bulbs, frontal cortex, remainder; plasma; liver | DTE; brain, plasma and liver concentration; B:P; Tmax; Cmax; AUC; kel; t1/2, MRT; F | 5, 10, 15, 30, 60 min | i.n. (form.); i.v. (form.) | - | - | - | Ketamine and xylazine (i.p.) | [128] |
Brain; plasma | Brain and plasma concentration; AUC; Tmax; Cmax; kel; t1/2; %DTE; %DTP | 30, 60, 120, 240, 480 min | i.n. (form. x 2); i.n. (sol.); i.v. (form.) | - | - | Ketamine (i.m.) | [126] | ||
Brain; plasma | Brain and plasma concentration; B:P ratio; AUC; Cmax; Tmax; MRT, AUC (B:P) | 5, 10, 15, 20, 30, 45, 60, 90, 120 min | No treatment; i.n. (sol.); i.n. (form.); p.o. (sol.) | - | - | - | None | [124] | |
- | - | - | i.n. (sol.); i.n. (form.); p.o. (form.); i.n. (sol.); No treatment | MES (auricular) | Duration of HLE | 60 min | None reported | [113] | |
- | - | - | i.n. (form.); i.n. (sol.); No treatment | MES variant (auricular) PTZ (i.p.) | MES variant: number of trials until death PTZ: onset to convulsion, time until death | 5 min (MES variant) 15 min (PTZ) | Diethyl ether | [125] | |
Brain; plasma | Brain and plasma concentration; AUC; Tmax; Cmax; MRT | 0.25, 0.5, 1, 2, 3, 4 h | i.n. (form); i.n. (sol.) | - | - | - | None | [127] | |
DZP | Brain, plasma | %DTE; brain and plasma concentration; Cmax; Tmax; AUC | 30, 60, 120, 240, 480 min | i.n. (sol.); i.n. (form.); i.v. (sol.) | - | - | - | Ketamine (i.p.) | [134] |
VA | Brain; plasma | Brain and plasma concentration; B:P | 60 min | i.n. (form. no drug); i.n. (form.); i.n. (sol.); i.p. (form. no drug); i.p. (form.); i.p. (sol.) | MES variation (auricular) | E:F ratio of hindlimbs | 15, 30, 60, 90, 120 min | Light ether | [135] |
PHT | Brain | Brain concentration | 15 and 30 min | No treatment; i.n. (form.); p.o. (form.); i.p. (sol.) | MES (auricular) | Duration of HLE | 60 min | None reported | [112] |
Brain, serum, liver, spleen and kidneys | DTE% and DTP%; Brain, plasma and liver concentration; Cmax; Tmax; AUCbrain/AUCplasma ratio; t1/2 | 5, 15, 60, 240, 1440, 2880, 4320, 5760, 7200 min | i.n. (form); i.p. (sol) | PTZ (s.c.) | Duration; frequency; total number of EEG signal | 1, 4, 48 h | Ketamine and xylazine (i.p.) | [132] | |
PBT | Whole brain. OB, frontal cortex, piriform cortex, amygdala, hippocampus, parahippocampal cortex, caudal cortex, cerebellum, pons. Frontal cortex dialysate; plasma. | D:P; (microdialysis in frontal cortex); brain and plasma concentration (homogenate); B:P (homogenate) | 10 min (microdissected regions) 2, 5, 10, 20, 30, 60, 200, 240 min (whole brain and plasma) 15, 30, 60, 90, 120, 180, 240 min (dialysate) | i.n. (form. no drug); i.n. (form.); i.v. (form. no drug); i.v. (form.) | Amygdala kindling | ADT; seizure severity and duration; ADD; GST | 60 min | Propofol (i.v.) | [123] |
LMT | - | - | - | Saline (route not reported); i.n. (form.); i.p. (form.) | PTZ (s.c.) | Onset to clonic convulsion Protection against mortality | 30 min | Ketamine and xylazine (route not reported) | [129] |
Brain—olfactory bulbs, frontal cortex, remainder; plasma; liver | DTE; Brain, plasma and liver concentration; B:P; Cmax; Tmax; AUC; kel; k; t1/2; MRT; Absolute i.n. F; AUC ratio (L:P) | 5, 10, 15, 30, 60, 120, 240 min | i.n. (form.); i.v. (form.) | - | - | - | Ketamine and xylazine (i.p.) | [138] | |
Brain; plasma | Brain and plasma concentration | 24 h | i.n. (sol.); i.n. (form.); p.o. | MES (auricular) | HLE incidence; Latency to HLE; Duration of HLE | 60 min 24 h | Ketamine (i.m.) | [111] | |
Brain; plasma | Brain, plasma concentration; B:P; Tmax; Cmax; AUC; i.n. F; t1/2, MRT; F | 15, 30, 60, 120, 240, 480 min | i.n. (form.); i.n. (sol.); i.v. (sol) | PTZ (route of administration not reported) | Onset to seizure | 15, 30 and 60 min | Not reported | [131] | |
THR | - | - | - | i.n. (form.); i.n. (form. no drug) | Amygdala kindling | ADD Number of seizures until first Stage 5; Number of seizures until fully kindled | Daily stimulations until fully kindled; Doses administered at both 60 and 30 min before stimulation | Isoflurane | [17,18] |
LZM | - | - | - | i.n. (form.); i.n. (form. no drug); i.p. (sol.) | PTZ (s.c.) | Lag time of incidence; severity of symptoms in trunk (0–3); severity of symptoms in hands and feet (0–3); duration of symptoms | - | Not reported | [13] |
LVT | Brain, plasm, lung and kidney | tmax; Cmax; AUCt; AUCinf; AUCextrap; kel; t1/2el; MRT; F; AUCt; AUCbrain/AUCplasma; AUClung/AUCplasma; AUCkidney/AUCplasma | 5, 15, 30, 60, 90, 120 and 240 min | i.n. (form.); i.v. (sol) | Ketamine and xylazine (i.p.) | [136] | |||
ZNA | Brain, plasm, lung and kidney | tmax; Cmax; AUCt; AUCinf; AUCextrap; kel; t1/2el; MRT; F; AUCt; AUCbrain/AUCplasma; AUClung/AUCplasma; AUCkidney/AUCplasma | 5, 15, 30, 60, 90, 120, 240, 360, 480 and 720 min | i.n. (form.); i.n. (form. no drug); i.v. (sol); p.o. (sol.) | - | - | Ketamine and xylazine (i.p.) | [137] |
ASM | Plasma Half-Life (h) [138,143,144,145] | Time (min) to Peak Effect after Single Parenteral Dose [92,146] | |||
---|---|---|---|---|---|
Rats | Mice | Human | Rats | Mice | |
Carbamazepine | 1.2–3.5 | 30–60 | 25–50 | 30 | 15 |
Phenobarbital | 9–20 | 7.5 | 70–100 | 60 | 30 |
Lamotrigine | 12–30 | 8 * | 21–50 | 60 | 120 |
Phenytoin | 1–8 | 16 | 15–20 | 30 | 120 |
Valproic acid | 1–5 | 0.8 | 8–15 | 15 | 5 |
Diazepam | 1.4 | 7.7 | 24–72 | 15 | 15 |
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Prentice, R.N.; Rizwan, S.B. Translational Considerations in the Development of Intranasal Treatments for Epilepsy. Pharmaceutics 2023, 15, 233. https://doi.org/10.3390/pharmaceutics15010233
Prentice RN, Rizwan SB. Translational Considerations in the Development of Intranasal Treatments for Epilepsy. Pharmaceutics. 2023; 15(1):233. https://doi.org/10.3390/pharmaceutics15010233
Chicago/Turabian StylePrentice, Richard N., and Shakila B. Rizwan. 2023. "Translational Considerations in the Development of Intranasal Treatments for Epilepsy" Pharmaceutics 15, no. 1: 233. https://doi.org/10.3390/pharmaceutics15010233
APA StylePrentice, R. N., & Rizwan, S. B. (2023). Translational Considerations in the Development of Intranasal Treatments for Epilepsy. Pharmaceutics, 15(1), 233. https://doi.org/10.3390/pharmaceutics15010233