Versatile Nasal Application of Cyclodextrins: Excipients and/or Actives?
Abstract
:1. Introduction
2. Cyclodextrin as Excipient in Nasal Formulations
2.1. Nasal Formulations and the Role of CDs as Modulators of the Drug Absorption
2.2. Nasal Formulations with CDs for the Local Therapeutic Effect
2.3. Toxicity Studies of CDs
2.4. CDs and Modulation of Drug Permeation across Lipophilic Membranes
2.5. CDs and Modulation of Systemic Absorption of Nasally Administered Drugs
2.6. Nasal Formulations and the Modulation of Central Drug Absorption by CDs
2.7. Nasal Formulations and CDs Modulation of Systemic and Central Absorption of Neuroactive Agents
2.8. CDs as Carriers of Nasal Vaccines
3. Cyclodextrins as Actives
CDs for the Control of Viral Infections
4. Experimental Models for Studying Nasal Drug Delivery
4.1. Cell Lines as In Vitro Models to Investigate Drug Permeation across the Nasal Mucosa
4.2. Combining Intranasal Administration with Plasma and Cerebrospinal Fluid Sample Collections: Useful Strategies to Evaluate Nose-to-Brain Drug Delivery in Preclinical Studies
5. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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CD Type | Drug | Formulation Type | Other Excipients | Experimental Procedures | Aim | Ref. |
---|---|---|---|---|---|---|
β-CD, HP-β-CD, SBE-β-CD | Thalidomide (anti-epistaxis therapy) | Nasal powder | Lecithin | Permeation across ex vivo rabbit nasal mucosa | Local action | [47] |
HP-β-CD; RM-β-CD, β-CD | -- | Sodium phosphate solutions of CDs | -- | In vivo administration to rats and histological analysis of nasal mucosa | Integrity analysis of mucosa | [48] |
α-CD, β-CD | -- | Solutions in Eagle’s minimal essential medium | β-D-mannitol, sodium hyaluronate, polyvinyl alcohol, methyl-cellulose (as an alternative to CDs) | Toxicity analysis on RPMI 2650 human nasal septum tumor epithelial cells | Toxicity analysis of several excipients | [49] |
Positively charged β-CDs and their polymers | -- | Hank’s salt solutions | -- | Toxicity and internalization analysis on PC12 and Caco-2 cells | Model of nasal absorption | [50] |
DM-β-CD | Disoxaril (WIN 51711) (Antiviral) | Inclusion complexes in PBS | HPMC | Permeation across ex vivo bovine nasal mucosa | In vitro and in vivo studies on the nasal mucosa | [51] |
HP-β-CD; RM-β-CD | Melatonin (MT) (sleep disorders) | Gel formulations with CDs and micronized MT | HPMC | Permeation on EpiAirway™-100 cells | Model of nasal absorption | [52] |
SBE-β-CD; HP-β-CD | Tacrine (Alzheimer’s disease) | Albumin NP with CDs | Albumin | Permeation across ex vivo sheep nasal mucosa | Model of nasal absorption | [53] |
β-CD | Loratidine (antihistaminic) | Mucoadhesive nasal gel | Poloxamer 407, carbopol 934P | Permeation across ex vivo sheep nasal mucosa | Model of nasal absorption | [54] |
HP-β-CD | Buspirone hydrochloride (BH) (anxiolytic) | Microemulsion | Chitosan aspartate | Permeation across ex vivo sheep nasal mucosa; in vivo BH administration to rats and quantification in plasma and brain | Study of CD effect on BH brain uptake following nasal administration | [55] |
RM-β-CD | Deferoxamine (DF) (neuroprotective) | Spray-dried microparticles | Chitosan chloride (as an alternative) | Permeation studies across PC 12 and Caco-2 cells; in vivo DF administration to rats and quantification in plasma and CSF | Study of CD effect on DF brain uptake following nasal administration | [34] |
HP-β-CD | Paliperidone (PLPD) (treatment of schizophrenia) | Nasal in situ gel | Carbopol 934, HPMC | Permeation across ex vivo sheep nasal mucosa; mucoadhesive studies | Model of nasal absorption | [56] |
α-CD | Ribavirin (RBV) (antiviral) | Micronized RBV and microspheres | Lecithin and mannitol, chitosan | Permeation across ex vivo rabbit nasal mucosa; in vivo RBV administration to rats and quantification in plasma and brain | Study of formulative effects on RBV brain uptake following nasal administration | [57] |
HP-β-CD | Idebenone (IDE) (antioxidant) | IDE/HP-β-CD inclusion complex | -- | IDE protection studies in human glioblastoma astrocytoma (U373) cells; permeation across ex vivo bovine nasal mucosa | Model of nasal absorption and drug protection in glioblastoma | [58] |
HP-β-CD | Curcumin (CUR) (Alzheimer’s disease) | CUR/HP-β-CD inclusion complexes | PLGA nanoparticles chitosan-coated (as an alternative) | Uptake studies on SH-SY5Y cells; in vivo CUR nasal administration to mice and quantification in plasma and brain | In vitro and in vivo comparison between inclusion complexes and nanoparticles | [59] |
RM−β-CD | Quercetin (Que) (Alzheimer’s disease) | Que/RM-β-CD inclusion complex | -- | Permeation across ex vivo rabbit nasal mucosa | Model of nasal absorption | [60] |
RM-β-CD | Clonazepam (CLZ) (antiseizure) | CLZ/RM-β-CD inclusion complex in thermosensitive, in-situ gel | Poloxamer 407, sodium hyaluronate and chitosan glutamate | Cytotoxicity and transport studies on Caco-2 cells | Study of formulative effects on CLZ systemic delivery | [61] |
SBE-β-CD | Midazolam (sedative) | Aqueous nasal spray | HPMC | In vivo pharmacokinetic studies on human volunteers | Study of systemic absorption from nasal way | [62] |
DM-β-CD | Salmon Calcitonin (hypercalcemia) | Solutions | Chitosan (as an alternative) | In vivo bioavailability studies on rats | Study of systemic absorption from nasal way | [63] |
RM-β-CD | Midazolam (sedative) | Aqueous solutions | Chitosan | In vivo bioavailability studies on human volunteers | Study of systemic absorption from nasal way | [64] |
β-CD, α-CD, HP-β-CD | PACAP 1 (neurotrophic and neuroprotectant) | Ringer’s solution with BSA | BSA | In vivo uptake studies in brain regions after nasal administration to mice | To study the influence of CDs on PACAP uptake in different brain regions | [65] |
β-CD, HP-β-CD, RM-β-CD, γ-CD | 17β-estradiol (E2) (spatial learning and memory) | Saline | NaCl 0.9% | In vivo uptake studies in brain regions after nasal administration to rats | To study the influence of CDs on PACAP uptake in different brain regions | [66] |
HP-β-CD | Carnosic acid (neuroprotective) | Aqueous solutions | Chitosan | In vivo studies of brain neurotrophin production after nasal administration to rats | To study the influence of CD on brain uptake of carnosic acid | [67] |
β-CD | Glucagon-like peptide2 (GLP-2) (antidepressant) | Phosphate buffer solution | Polyoxyethylene; lauryl ether | In vivo uptake studies in brain regions after nasal administration to rats | To study the influence of CD on GLP-2 uptake in different brain regions | [68] |
SBE-β-CD | Dopamine (Parkinson’s disease) | NPs of chitosan crosslinked by SBE-β-CD | Chitosan | In vivo uptake studies in brain regions after nasal administration to rats | Uptake studies in different brain regions of NPs | [69] |
SBE-β-CD | Allopregnanolone (antiseizure) | Saline | NaCl 0.9% | In vivo uptake studies in brain regions after nasal administration to mice | Allopregnanolone uptake studies in different brain regions | [71] |
HP-β-CD | Berberine (antidepressant) | Thermoresponsive hydrogel | Poloxamers P407 and P188, benzalkonium chloride | In vivo bioavailability studies of berberine in rat hippocampus after oral and nasal administration | To study the influence of nasal formulation on berberine brain uptake | [72] |
HP-β-CD | Timosaponin BII (Alzheimer’s disease) | Temperature/ion-sensitive in situ hydrogel | Deacetylated gellan gum; poloxamer | Nasal administration to mice for 38 days; analysis of spatial memory and spontaneous behavior; in vivo fluorescence imaging | Formulation study for local prevention of Alzheimer’s disease | [73] |
HP-β-CD | Disulfiram (DSF) (anti-cancer) | DSF/HP-β-CD inclusion complex | -- | Nasal administration with Cu; fluorescence and glioma inhibition studies | Evaluation of the distribution and therapeutic effects of the inclusion complex | [74] |
RM-β-CD | Estradiol (ES) (menopausal symptoms) | ES/RM-β-CD inclusion complex in saline | NaCl 0.9% | ES pharmacokinetic studies after intravenous or intranasal nasal administration to rats | Comparison of ES distribution between plasma and CSF | [75] |
HP-β-CD | L-dopa (Parkinson’s disease) | L-dopa/HP-β-CD inclusion complex in maleic acid aqueous solution | Carbidopa | Pharmacokinetic studies after oral or nasal administration to rats | Comparison of L-dopa distribution between bloodstream and brain | [76] |
HP-β-CD | HP-β-CD (neuroprotective) | Spray-dried microparticles | Chitosan, alginate | Neuroprotection studies against amyloid plaques after nasal administration to rats | Neuroprotective studies on brain synaptosomes | [77] |
HP-β-CD | Scutellarin (SC) (antiischemic) | HP-β-CD –chitosan nanoparticles | Chitosan, sodium tripolyphosphate | Pharmacokinetic studies on plasma and brain after oral and intranasal administration to mice | Comparison of SC distribution after oral or intranasal administrations | [78] |
RM−β-CD | N6-cyclopentyl-adenosine (CPA) (antiischemic) | Spray-dried microparticles | Chitosan | Pharmacokinetic studies on bloodstream and CSF after nasal administration to rats | Comparison of CPA distribution in dependence on Me−β-CD and chitosan in MPs | [37] |
HP-β-CD | Butylidenephthalide (BP) (anti-cancer) | BP/HP-β-CD inclusion complex encapsulated in liposomes | 1,2-dimyristoyl-sn-glycero-3-phospho-choline; cholesterol | BP quantification in the brain of mice after oral and nasal administration | Comparison of antitumor effects between oral and nasal administrations | [79] |
HP-β-CD | Donepezil hydrochloride (Alzheimer’s disease) | Thermosensitive in situ gel | Poloxamers 407 and 188, ethylparaben | Pharmacokinetic studies on plasma and brain after intra-gastric and nasal administrations to rats | Comparison of donepezil distribution after intra-gastric and nasal administrations | [80] |
β-CD, HP-β-CD | Geraniol (GER) (Parkinson’s disease) | Inclusion GER/β-CD and GER/HP-β-CD complexes in ultrapure water | -- | Pharmacokinetic studies on bloodstream and CSF after nasal administration to rats | Comparison of GER distribution after nasal administration of inclusion complexes | [41] |
β-CD | mRNA vaccine | Nanoparticles | Polyethyleneimine (PEI600 or PEI2k) | In vivo studies to evaluate the efficacy as an intranasal mRNA vaccine | Evaluation of local and systemic immune responses | [81,82] |
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Rassu, G.; Sorrenti, M.; Catenacci, L.; Pavan, B.; Ferraro, L.; Gavini, E.; Bonferoni, M.C.; Giunchedi, P.; Dalpiaz, A. Versatile Nasal Application of Cyclodextrins: Excipients and/or Actives? Pharmaceutics 2021, 13, 1180. https://doi.org/10.3390/pharmaceutics13081180
Rassu G, Sorrenti M, Catenacci L, Pavan B, Ferraro L, Gavini E, Bonferoni MC, Giunchedi P, Dalpiaz A. Versatile Nasal Application of Cyclodextrins: Excipients and/or Actives? Pharmaceutics. 2021; 13(8):1180. https://doi.org/10.3390/pharmaceutics13081180
Chicago/Turabian StyleRassu, Giovanna, Milena Sorrenti, Laura Catenacci, Barbara Pavan, Luca Ferraro, Elisabetta Gavini, Maria Cristina Bonferoni, Paolo Giunchedi, and Alessandro Dalpiaz. 2021. "Versatile Nasal Application of Cyclodextrins: Excipients and/or Actives?" Pharmaceutics 13, no. 8: 1180. https://doi.org/10.3390/pharmaceutics13081180
APA StyleRassu, G., Sorrenti, M., Catenacci, L., Pavan, B., Ferraro, L., Gavini, E., Bonferoni, M. C., Giunchedi, P., & Dalpiaz, A. (2021). Versatile Nasal Application of Cyclodextrins: Excipients and/or Actives? Pharmaceutics, 13(8), 1180. https://doi.org/10.3390/pharmaceutics13081180