Excipients Used for Modified Nasal Drug Delivery

Excipients Used for Modified Nasal Drug Delivery: History

Please note this is an old version of this entry, which may differ significantly from the current revision.

Contributor:

Panagoula Pavlou

Intranasal absorption is a favored route because it avoids the gastrointestinal and hepatic metabolism, leading to an increase in drug bioavailability, and a reduction in the side effects and the required dose administered. The ongoing challenging task in the field of nasal drug delivery is the maintenance of an efficient concentration of the active substance in the target area for an adequate period of time.

nasal drug delivery
poloxamer
chitosan
gellan gum
vaccines
excipients
nanoparticles

1. Introduction

Oral administration of medicines is the most convenient method of drug dispensing with the highest compliance rates, as patients can self-administer their medications in a noninvasive and painless manner, providing a variable and customizable dosing schedule at home ^[1]. On the other hand, the harsh chemical environment in the stomach and intestines, the first-pass effect, and the barrier of the gastrointestinal tract pose major difficulties for the efficacy of drugs ^[2]^[3]. Thus, alternative routes of administration have been developed to circumvent those hurdles and achieve the requisite results (Figure 1). The major alternative routes are pulmonary, transdermal, buccal, nasal, and parenteral ^[2], and each of these has its own advantages and disadvantages, as shown in Table 1.

Figure 1. Different routes of drug administration.

Table 1. Advantages and disadvantages of each route of administration.

Route (Absorption Site)	Advantages	Disadvantages	Barrier Properties and Delivery Challenges
Intravenous	100% bioavailability Reproducibility	Painful injection Requires medical personnel	None
Subcutaneous	Self-administered Avoids first-pass metabolism	Painful injection	Extracellular Matrix Limited space for injectable volumes
Inhalation (lungs)	Large surface area of absorption Rapid absorption Non-invasive Avoids first-pass metabolism	Variability in dosing can depend on inhaler technique, requiring patient training	Airways transport Surfactant Mucus Epithelial cells Macrophages
Oral (intestines)	Non-invasive Self-administered	Harsh chemical environment Degraded by first-pass metabolism	Epithelial cells Mucus Bacteria Gastrointestinal transit time Acid, enzymes, and proteases
Transdermal (skin)	Non-invasive Self-administered Avoids first-pass metabolism	Major transport barriers Slow absorption	Stratum corneum Constant cell shedding Lipid bilayers that surround corneocytes
Nasal (nasal mucosa surface)	Non-invasive Self-administered Rapid absorption Avoids first-pass metabolism	Low surface area for absorption, which limits total dose Prone to cause irritation	Mucus Epithelial cells
Buccal (oral mucosal surface)	Non-invasive Self-administered Rapid absorption Avoids first-pass metabolism	Low surface area for absorption, which limits total dose Prone to cause irritation	Mucus Epithelial cells

Intranasal absorption is a favored route because it avoids the gastrointestinal and hepatic metabolism, leading to an increase in drug bioavailability, and a reduction in the side effects and the required dose administered ^[4]. Furthermore, the intranasal route also has several practical advantages for both the patient and the pharmaceutical industry. The former can benefit from the non-invasive, highly tolerable, easy to administer, and pain-free drug delivery systems, and pharma avoids the need to sterilize the nasal products ^[5]. Moreover, acid-sensitive drugs, such as biologics (peptides, hormones, etc.), which are prone to degradation in the gastrointestinal tract, and drugs that cannot be absorbed orally, may be administered nasally. The inclusion of enhancers, mainly excipients, can increase the nasal absorption of such drugs ^[6]. Recently, many pharmaceutical companies have become involved in the commercialization of absorption promoters and absorption modulators for nasal drug delivery ^[7].

Even though the nasal epithelium acts as a tight barrier, the intercellular junctional complex of the nasal mucosa is not impervious, due to the leaky epithelial tissue ^[8]^[9]. Thus, in combination with the high vascularization of the nasal surface, a favorable profile for therapeutic purposes, more than just the topical nasal drug delivery is achieved ^[10]^[11].

2. Anatomy and Physiology of the Nose

The primary roles of the nasal cavity are olfaction and breathing ^[12]. Nonetheless, the breathing air is filtered, humidified, and headed by the nasal cavity before reaching the lungs, whilst the inhaled particles and pathogens are trapped from the hair and the mucus layer present in the nasal cavity. Other functions of the nasal structure are the metabolism of endogenous substances and the immunological activities ^[13]^[14].

The nasal cavity is located between the roof of the mouth and the base of the skull supported from above by the ethmoid bones and from the side by the ethmoid, maxillary, and inferior conchae bones. The entire surface area is almost 150 cm² and has a total volume of 15–20 mL ^[11]^[15]. The nasal cavity consist of three definite parts: the vestibule, the respiratory, and the olfactory regions (Figure 2) ^[16]. The anterior part of the nasal cavity is the nasal vestibule, which is part of the nostrils, covering an area of about 0.6 cm², and includes the nasal hairs (vibrissae) ^[17]. Histologically this part is covered by a keratinized and stratified squamous epithelium with sebaceous glands ^[10]. These nasal regions prevent the insertion of toxic materials, but at the same time, drug absorption is also limited ^[18]. The respiratory region represents the largest part of the nasal cavity. It is split into three turbinates—the superior, middle, and inferior—which are responsible for the humidification and temperature adjustment of the inhaled air ^[19].

Figure 2. Schematic representation of the nasal cavity.

The most important area for systemic drug delivery is the nasal respiratory mucosa, which consists of the epithelium, the basement membrane, and the lamina propria. The epithelium contains the pseudostratified columnar epithelial cells, goblet cells, basal cells, and mucous and serous gland cells. Many of the epithelial cells are coated by microvilli, which enhance the respiratory surface area, and the cilia, which are fine projections essential for mucus transport towards the nasopharynx ^[20]. The secretory glands and the goblet cells produce mucus through granules filled with mucin, a glycoprotein that define the mucus viscosity. The mucus is deposited as a thin layer (about 5 μm) in the epithelium, composed of water (95%), 2.5–3% of mucin, and 2% of other substances, such as electrolytes, proteins, enzymes, lipids, antibodies, sloughed epithelial cells, and bacterial products ^[21]. It is responsible for the humidification and warming of the inhaled air, it has a pH between 5–6.5, and it provides protection to the nasal epithelium against foreign particles and drugs ^[22]^[23].

The olfactory region is located on the top of the nasal cavity and continues down the septum and the lateral wall. The olfactory epithelium is pseudostratified and consists of specialized olfactory receptor cells essential for smell recognition ^[24].

3. Nasal Drug Delivery

The nasal route of administration is used for treating local inflammation, allergic and common rhinitis, and nasal congestion. The active compounds that are commonly used against these diseases are antihistamines, glucocorticoids, or decongestants in the form of nasal spray, drops, solutions, gels, or powders and other types of formulations, including emulsions, suspensions, and microparticles ^[6]^[25]. The nasal route is used for either local or systemic action. The drug is administered locally for rapid alleviation of the symptoms of the disease, reducing the administered dose, as the drug is placed directly in the affected area, thus avoiding the systemic metabolism. On the other hand, the nasal administration of pharmacologically active substances for systemic action is used in the case of drugs with poor intestinal absorption and limited stability in the gastrointestinal fluids, with extensive hepatic first-pass metabolism, such as biologics and polar drugs ^[10]^[11]. The administration of the drug through the nasal passages can also bypass the blood–brain barrier (BBB), so it can be used for central nervous system (CNS) action. This route has been further studied for administrating vaccines ^[11]^[26].

The drug absorption through the nose is based on the physicochemical properties of the administered drug. The drug cannot penetrate the mucosa and manifest its action if it has a large size (greater than 1 kDa), a high degree of ionization, or is too lipophilic. Another factor that can affect absorption is the drug’s pH, which may affect the stability and the ionization of the drug, as well as cause nasal irritation. Formulations that have high viscosity can more easily enter the nasal mucosa, but simultaneous, they may be less absorbed. When the hyper- or hypotonicity is very high, the ciliary movement can be altered, resulting in lower absorption ^[6]. Finally, the drug’s concentration and quantity, the position of the head during administration, the nasal surface, and the physical condition of the dosage form all play a vital role in the absorption of the drug ^[27].

4. Factors That Affect the Nasal Drug Absorption

Drug delivery through the nasal route of administration has some limitations, which are crucial because they influence drug concentration and bioavailability and therefore, the absorption and the pharmacological effect of the administered drug. The first main barrier is the range of pathological and physiological conditions linked to the nasal mucosa, which can affect the absorption and efficacy of the drug ^[28]. For example, a physiological change in nasal mucosa based on illness and allergy (irritation and the inflammation of the nasal cavity, which is intensified by itching and sneezing) may influence drug absorption ^[6].

In addition, there is a restriction regarding the absorption of the poorly water-soluble drugs due to the low volume of the nasal cavity, which reduces the administered amount to 100–150 μL ^[28]. The permeability also decreases for the polar and large molecules and for peptides and proteins ^[25]. However, by using the correct excipients, including bioadhesive polymers, enhancers, and enzymatic inhibitors, the drug permeability and residency in the nasal cavity can be improved ^[29].

Another crucial barrier is the mucociliary clearance (MCC) of the mucosa, which by replacing the mucus layer every ~15 min with 5–6 mm/min, the transmucosal absorption is decreased. The mucus can also decrease the drug absorption by binding the drug to mucin, which is the primary protein of the mucus. While the small moieties can pass through easily, the charged or larger units can be caught in the mucus gel ^[25]. Mucus also contains different enzymes which can influence the stability of protein- and peptide-based drugs; proteases degrade peptides and proteins by attacking them. These xenobiotic enzymes [e.g., P450 monooxygenase, Phase I enzymes (flavin monooxygenases, aldehyde dehydrogenases, epoxide hydrolases, carboxylesterases, etc.) and Phase II enzymes (glucuronyl and sulphate transferases, glutathione transferase) can also metabolize intranasally administered small-molecule drugs, such as opioids, histamines, corticosteroids, etc. ^[30].

Last but not least, there will always be concerns about the safety of nasal medicines, even though recent breakthroughs in both in vitro and in vivo models are a major benefit in speeding up clinical development and eventually, the time-to-market of new treatments ^[31].

5. Excipients Used in Modified Drug Release Semi-Solid Pharmaceutical Dosage Forms for Nasal Administration

To improve nose-to-brain drug transfer and to extend drug residence time in the nasal cavity, several approaches could be employed, such as the use of semi-solid dosage forms, permeation enhancers, mucoadhesive and temperature responsive gels, or nano-sized drug carriers (Figure 3). In this section, the excipients and methods used in the recent achievements (2017–2022) in the modified release semi-solid formulations for nasal administration are reviewed and summarized, as shown in Table 2.

Figure 3. Different semi-solid formulations for nasal administration.

Table 2. Semi-solid formulations for modified release nasal drug delivery.

Nasal Dosage Form	Drug Release Rate *	API	Excipients	Refs.
in situ gel	biphasic	huperzine A	poloxamers (407, 188), CS, castor oil, polyoxyl 40 hydrogenated castor oil, 1,2- propanediol, Ringer’s solution	^[32]
in situ gel	biphasic	almotriptan	poloxamer (407, 188), Na-CMC, glyceryl behenate glyceryl palmitostearate, glyceryl monostearate, precirol	^[33]
in situ gel	biphasic	sumatriptan	poloxamers (407, 188), carrageenan, soybean phospholipids, cholesterol, tween 80, sodium caprate, sodium cholate, clostridium perfringens enterotoxin, sodium caprate	^[34]
in situ gel	controlled	ziprasidone	poloxamers (407, 188) β-cyclodextrin, HPMC E5, PEG 6000, PEG 4000, polyethylene, HPMCK4M	^[35]
in situ gel	controlled	geniposide	poloxamers (407, 188), HPMC, borneol, benzalkonium chloride, NaCl	^[36]
in situ gel	sustained	rivastigmine hydrogen tartrate	poloxamer 407, poly (lactic-co-glycolic acid), polymeric NPs	^[37]
in situ gel	sustained	mometasone furoate	poloxamer 407, Carbopol^® 974P NF, PEG 400, NaCl, benzalkonium chloride, dexpanthenol, triethanolamine	^[38]
in situ gel	controlled	montelukast sodium	poloxamer 407, HPMC K4M, PEG 400, methyl paraben	^[39]
in situ gel	controlled	hydrocortisone	poloxamer 188, Carbopol 934, PG, benzalkonium chloride, triethanolamine, isopropyl alcohol	^[40]
NP	biphasic	pramipexole dihydrochloride	CS, sodium tripolyphosphate	^[41]
NP	biphasic	efavirenz	CS chloral hydrate, glucosamine chloral hydrate, N-acetylglucosamine, HP-β-CD, Tween 80	^[42]
NP	controlled	sitagliptin	CS, glacial acetic acid, tripolyphosphate	^[43]
NP	delayed	human serum albumin	CS low molecular weight, acetic acid, mucin, sialic acid	^[44]
in situ misemgel	controlled	raloxifene hydrochloride	peppermint oil, n-propanolol, n-butanol, Tween^® 80, PEG 200, PG, GG, TPGS, linoleic acid, Kolliphor^®, RH 40	^[45]
in situ gel loaded NPs	biphasic	voriconazole	GG, clove oil, nanotransferosomes, Tween 80, lecithin	^[46]
nanoemulsion	biphasic	quetiapine	Capmul MCM, Emalex LWIS 10, PEG 400, Transcutol P, Tween 80, water, Labrafil M 1944 CC, isopropyl myristate, sesame oil, Lauroglycol 90, miglyol 840	^[47]
NPs	sustained	dolutegravir sodium	HP-β-CD, DPC, Tween 80, DMSO	^[48]
NPs	slow	acetylcholinesterase reactivator	L-α-phosphatidylcholine, 75% soybean phosphatidylcholine, dihexadecylmethylhydroxyethylammonium bromide, Tween 80, Phospholipon 80, Lipoid S75, 1-(o-tolylazo)-2-naphthol, pyrene, pyridine-2-aldoxime methochloride (Pralidoxime)	^[49]

* Drug release rate as stated by the author(s); CS: chitosan, DPC: diphenyl carbonate, GG: gellan gum, HPMC: hydroxypropylmethylcellulose, HP-β-CD: hydroxypropyl-β-cyclodextrin, Na-CMC: sodium carboxymethylcellulose, NPs: nanoparticles, PEG: polyethylene glycol, PG: propylene glycol, TPGS: d-α-tocopheryl polyethylene glycol 1000 succinate.

6. Excipients Used in Modified Drug Release Vaccines for Nasal Administration

The majority of current vaccinations are designed to be administered systemically by intravenous, intramuscular, subcutaneous, or intradermal routes. Parenterally given intranasal vaccination formulations increase cellular and humoral protection against infections. Because the mucosal and systemic immune systems work differently, the parenteral vaccine cannot make contact with a mucosal barrier to induce mucosal immunity. Vaccine delivery through the nasal route, on the other hand, induces systemic immunity, as well as a powerful mucosal immune response. As a result, nasal administration can be used to deliver proteins, and peptides, as well as medicines. Various carriers of different systems for nasal vaccine delivery include powders, gels, and solutions ^[50]. The excipients and methods used in the recent developments (2017–2022) in the modified release intranasal vaccines are reviewed and summarized, as shown in Table 3.

Table 3. Vaccines for modified release intranasal immunization.

Vaccine	Release Rate *	API	Excipients	Refs.
NPs	extended	Encephalitis-chimeric virus	trimethyl CS, glycol CS, 6-maleimidohexanoic acid, 1-ethyl-3-(3-dimethylamino propyl)carbodiimide, N-hydroxysuccinimide, sodium tripolyphosphate, phenylmethylsulphonyl fluoride, fluorescein isothiocyanate-conjugated bovine serum albumin, bovine serum albumin, polystyrene microplates, IFN-γ, IL-4 cytokine	^[51]
NPs	slow	plasmid DNA encoding 5p36/LACK leishmanial antigen	CS microparticles, glyceraldehyde	^[52]
NPs	controlled	bovine serum albumin	aminated CS, aminated and thiolated CS, CS, N-(2-hydroxyethyl) ethylenediamine, N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride, thioglycolic acid, (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide), trypsin-EDTA	^[53]
hydrogel	prolonged	antigen that generates nasal tissue resident memory CD8+ T cells	CS, poloxamers (188 and 407), ovalbumin protein, lipopolysaccharide	^[54]
NPs	biphasic	r4M2e.HSP70c antigen	N,N,N-trimethyl CS, trimethyl CS, glycerin	^[55]
NPs	biphasic	tetanus toxoid	CS, NPs, paraffin oil, nanospheres	^[56]
NPs	biphasic	tetanus toxoid	N-trimethyl CS, CS, dextran microspheres, tripolyphosphate, lactose, Span 80, Tween 80	^[57]
NP	gradual	bovine serum albumin, ovalbumin, and myoglobin	low molecular weight CS, Compound 48/80, MTT (3-[4, 5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide), albumin-fluorescein isothiocyanate conjugate (FITC-BSA), trehalose, Dulbecco’s modified Eagle medium (DMEM) and Roswell Park Memorial Institute (RPMI), Bicinchoninic acid (BCA) assay and micro BCA kits, Fetal bovine serum (FBS), wheat germ agglutinin Alexa Fluor^® 350 Conjugate and Lysotracker^® Red DND 99	^[58]
NPs	extended	PPE17 antigen (for tuberculosis)	CS, SA	^[59]
NP	burst release prevented	PR8 influenza virus	SA, CS, N,N,N-trimethyl CS, concanavalin A	^[60]
NPs	biphasic	inactivated influenza virus	SA powder, class B CpG ODN 2007 with a phosphorothioated backbone, 2,3-bis-(2-methoxy-4-nitro-5- sulfophenyl)-2H -tetra- zolium-5-carboxanilide, Tween 80 and Span 80	^[61]
NPs	prolonged	bovine serum albumin	Poly(D,L-lactide-co-glycolide), Bisphenol-A-ethoxylate di-acrylate, ethylenediamine, tetrahydrofuran, poly(vinyl alcohol)	^[62]
nanogel	gradually	surface protein A fusion antigens	pullulan with 1.3% cholesterol and 23% amino residues	^[63]
nanogels	complete release in 6 h	Ovalbumin	squalane oil, cyclohexane, surfactant sucrose laurate (L-195)	^[64]
nanodispersion	prolonged	Ovalbumin	Epsiliseen^®-H (ϵ-polylysine), dextran sulfate sodium salt, hydrogen chloride, sodium hydroxide	^[65]

* Drug release rate as stated by the author(s); CS: chitosan, NPs: nanoparticles, SA: sodium alginate.

This entry is adapted from the peer-reviewed paper 10.3390/ma15196547

References

Sadeghi, S.; Lee, W.K.; Kong, S.N.; Shetty, A.; Drum, C.L. Oral administration of protein nanoparticles: An emerging route to disease treatment. Pharmacol. Res. 2020, 158, 104685.
Anselmo, A.C.; Gokarn, Y.; Mitragotri, S. Non-invasive delivery strategies for biologics. Nat. Rev. Drug Discov. 2018, 18, 19–40.
Dubey, S.K.; Parab, S.; Dabholkar, N.; Agrawal, M.; Singhvi, G.; Alexander, A.; Bapat, R.A.; Kesharwani, P. Oral peptide delivery: Challenges and the way ahead. Drug Discov. Today 2021, 26, 931–950.
Leonard, A.K.; Sileno, A.P.; Brandt, G.C.; Foerder, C.A.; Quay, S.C.; Costantino, H.R. In vitro formulation optimization of intranasal galantamine leading to enhanced bioavailability and reduced emetic response in vivo. Int. J. Pharm. 2007, 335, 138–146.
Rapoport, A.; Winner, P. Nasal delivery of antimigraine drugs: Clinical rationale and evidence base. Headache 2006, 46, 192–201.
Laffleur, F.; Bauer, B. Progress in nasal drug delivery systems. Int. J. Pharm. 2021, 607, 120994.
Illum, L. Nasal drug delivery—Recent developments and future prospects. J. Control. Release 2012, 161, 254–263.
Deli, M.A. Potential use of tight junction modulators to reversibly open membranous barriers and improve drug delivery. Biochim. Biophys. Acta Biomembr. 2009, 1788, 892–910.
Wolburg, H.; Wolburg-Buchholz, K.; Sam, H.; Horvát, S.; Deli, M.A.; Mack, A.F. Epithelial and endothelial barriers in the olfactory region of the nasal cavity of the rat. Histochem. Cell Biol. 2008, 130, 127–140.
Illum, L. Nasal drug delivery—Possibilities, problems and solutions. J. Control. Release 2003, 87, 187–198.
Pires, A.; Fortuna, A.; Alves, G.; Falcão, A. Intranasal drug delivery: How, why and what for? J. Pharm. Pharm. Sci. 2009, 12, 288–311.
Xi, J.; Si, X.A.; Kim, J.; Zhang, Y.; Jacob, R.E.; Kabilan, S.; Corley, R.A. Anatomical Details of the Rabbit Nasal Passages and Their Implications in Breathing, Air Conditioning, and Olfaction. Anat. Rec. 2016, 299, 853–868.
Gizurarson, S. The effect of cilia and the mucociliary clearance on successful drug delivery. Biol. Pharm. Bull. 2015, 38, 497–506.
Ugwoke, M.I.; Verbeke, N.; Kinget, R. The biopharmaceutical aspects of nasal mucoadhesive drug delivery. J. Pharm. Pharmacol. 2010, 53, 3–21.
Lazovic, G.D.; Daniel, R.K.; Janosevic, L.B.; Kosanovic, R.M.; Colic, M.M.; Kosins, A.M. Rhinoplasty: The nasal bones-anatomy and analysis. Aesthetic Surg. J. 2015, 35, 255–263.
Kim, D.; Kim, Y.H.; Kwon, S. Enhanced nasal drug delivery efficiency by increasing mechanical loading using hypergravity. Sci. Rep. 2018, 8, 1–9.
Bitter, C.; Suter-Zimmermann, K.; Surber, C. Nasal drug delivery in humans. Curr. Probl. Dermatol. 2011, 40, 20–35.
Mujawar, N.; Ghatage, S.; Navale, S.; Sankpal, B.; Patil, S.; Patil, S. Nasal Drug Delivery: Problem Solution and Its Application. J. Curr. Pharma Res. 2014, 4, 1231–1245.
Gosau, M.; Rink, D.; Driemel, O.; Draenert, F.G. Maxillary sinus anatomy: A cadaveric study with clinical implications. Anat. Rec. 2009, 292, 352–354.
Inoue, D.; Tanaka, A.; Kimura, S.; Kiriyama, A.; Katsumi, H.; Yamamoto, A.; Ogawara, K.I.; Kimura, T.; Higaki, K.; Yutani, R.; et al. The relationship between in vivo nasal drug clearance and in vitro nasal mucociliary clearance: Application to the prediction of nasal drug absorption. Eur. J. Pharm. Sci. 2018, 117, 21–26.
Tomazic, P.V.; Darnhofer, B.; Birner-Gruenberger, R. Nasal mucus proteome and its involvement in allergic rhinitis. Expert Rev. Proteom. 2020, 17, 191–199.
Evans, C.M.; Koo, J.S. Airway mucus: The good, the bad, the sticky. Pharmacol. Ther. 2009, 121, 332–348.
Roger, D.F. Physiology of airway mucus secretion and pathophysiology of hypersecretion. Respir. Care 2007, 52, 1134–1146.
Charlton, S.; Jones, N.S.; Davis, S.S.; Illum, L. Distribution and clearance of bioadhesive formulations from the olfactory region in man: Effect of polymer type and nasal delivery device. Eur. J. Pharm. Sci. 2007, 30, 295–302.
Ali, A.; Wahlgren, M.; Rembratt-Svensson, B.; Daftani, A.; Falkman, P.; Wollmer, P.; Engblom, J. Dehydration affects drug transport over nasal mucosa. Drug Deliv. 2019, 26, 831–840.
Illum, L. Nasal drug delivery: New developments and strategies. Drug Discov. Today 2002, 7, 1184–1189.
Costa, C.; Moreira, J.N.; Amaral, M.H.; Sousa Lobo, J.M.; Silva, A.C. Nose-to-brain delivery of lipid-based nanosystems for epileptic seizures and anxiety crisis. J. Control. Release 2019, 295, 187–200.
Costantino, H.R.; Illum, L.; Brandt, G.; Johnson, P.H.; Quay, S.C. Intranasal delivery: Physicochemical and therapeutic aspects. Int. J. Pharm. 2007, 337, 1–24.
Tanaka, A.; Furubayashi, T.; Enomura, Y.; Hori, T.; Shimomura, R.; Maeda, C.; Kimura, S.; Inoue, D.; Kusamori, K.; Katsumi, H.; et al. Nasal drug absorption from powder formulations: Effect of fluid volume changes on the mucosal surface. Biol. Pharm. Bull. 2017, 40, 212–219.
Keller, L.A.; Merkel, O.; Popp, A. Intranasal drug delivery: Opportunities and toxicologic challenges during drug development. Drug Deliv. Transl. Res. 2022, 12, 735–757.
Ugwoke, M.I.; Agu, R.U.; Verbeke, N.; Kinget, R. Nasal mucoadhesive drug delivery: Background, applications, trends and future perspectives. Adv. Drug Deliv. Rev. 2005, 57, 1640–1665.
Chen, Y.; Cheng, G.; Hu, R.; Chen, S.; Lu, W.; Gao, S.; Xia, H.; Wang, B.; Sun, C.; Nie, X.; et al. A Nasal Temperature and pH Dual-Responsive In Situ Gel Delivery System Based on Microemulsion of Huperzine A: Formulation, Evaluation, and In Vivo Pharmacokinetic Study. AAPS PharmSciTech 2019, 20, 1–12.
Youssef, N.A.H.A.; Kassem, A.A.; Farid, R.M.; Ismail, F.A.; EL-Massik, M.A.E.; Boraie, N.A. A novel nasal almotriptan loaded solid lipid nanoparticles in mucoadhesive in situ gel formulation for brain targeting: Preparation, characterization and in vivo evaluation. Int. J. Pharm. 2018, 548, 609–624.
Omar, M.M.; Eleraky, N.E.; El Sisi, A.M.; Ali Hasan, O. Development and Evaluation of in-situ Nasal Gel Formulations of Nanosized Transferosomal Sumatriptan: Design, Optimization, in vitro and in vivo Evaluation. Drug Des. Dev. Ther. 2019, 13, 4413–4430.
Londhe, V.; Krishnan, S. Formulation, Evaluation, and Pharmacodynamic Investigation of Ziprasidone-b-cyclodextrin In-Situ Nasal Gel. Proceedings 2020, 78, 42.
Wang, Y.; Jiang, S.; Wang, H.; Bie, H. A mucoadhesive, thermoreversible in situ nasal gel of geniposide for neurodegenerative diseases. PLoS ONE 2017, 12, e0189478.
Salatin, S.; Barar, J.; Barzegar-Jalali, M.; Adibkia, K.; Jelvehgari, M. Thermosensitive in situ nanocomposite of rivastigmine hydrogen tartrate as an intranasal delivery system: Development, characterization, ex vivo permeation and cellular studies. Colloids Surf. B Biointerfaces 2017, 159, 629–638.
Altuntaş, E.; Yener, G. Formulation and Evaluation of Thermoreversible In Situ Nasal Gels Containing Mometasone Furoate for Allergic Rhinitis. AAPS PharmSciTech 2017, 18, 2673–2682.
Durgapal, S.; Rana, M.; Mukhopadhyay, S.; Rana, A.J.; Goswami, L.; Joshi, S. Formulation and Evaluation of in-Situ Nasal Gel of Montelukast Sodium for the Effective Treatment of Asthma. Int. J. Pharm. Sci. Res. 2018, 9, 2792.
Khandagale, P.M.; Rokade, M.M.; Phadtare, D.G. Formulation Development and Evaluation of Nasal In- Situ Gel of Hydrocortisone. Asian J. Pharm. Technol. 2018, 8, 92–102.
Raj, R.; Wairkar, S.; Sridhar, V.; Gaud, R. Pramipexole dihydrochloride loaded chitosan nanoparticles for nose to brain delivery: Development, characterization and in vivo anti-Parkinson activity. Int. J. Biol. Macromol. 2018, 109, 27–35.
Belgamwar, A.; Khan, S.; Yeole, P. Intranasal chitosan-g-HPβCD nanoparticles of efavirenz for the CNS targeting. Artif. Cells Nanomed. Biotechnol. 2018, 46, 374–386.
Wilson, B.; Mohamed Alobaid, B.N.; Geetha, K.M.; Jenita, J.L. Chitosan nanoparticles to enhance nasal absorption and brain targeting of sitagliptin to treat Alzheimer’s disease. J. Drug Deliv. Sci. Technol. 2021, 61, 102176.
Piazzini, V.; Landucci, E.; D’Ambrosio, M.; Tiozzo Fasiolo, L.; Cinci, L.; Colombo, G.; Pellegrini-Giampietro, D.E.; Bilia, A.R.; Luceri, C.; Bergonzi, M.C. Chitosan coated human serum albumin nanoparticles: A promising strategy for nose-to-brain drug delivery. Int. J. Biol. Macromol. 2019, 129, 267–280.
Ahmed, O.A.A.; Badr-Eldin, S.M. In situ misemgel as a multifunctional dual-absorption platform for nasal delivery of raloxifene hydrochloride: Formulation, characterization, and in vivo performance. Int. J. Nanomed. 2018, 13, 6325–6335.
Kammoun, A.K.; Khedr, A.; Hegazy, M.A.; Almalki, A.J.; Hosny, K.M.; Abualsunun, W.A.; Murshid, S.S.A.; Bakhaidar, R.B. Formulation, optimization, and nephrotoxicity evaluation of an antifungal in situ nasal gel loaded with voriconazole–clove oil transferosomal nanoparticles. Drug Deliv. 2021, 28, 2229–2240.
Boche, M.; Pokharkar, V. Quetiapine Nanoemulsion for Intranasal Drug Delivery: Evaluation of Brain-Targeting Efficiency. AAPS PharmSciTech 2017, 18, 686–696.
Belgamwar, A.V.; Khan, S.A.; Yeole, P.G. Intranasal dolutegravir sodium loaded nanoparticles of hydroxypropyl-beta-cyclodextrin for brain delivery in Neuro-AIDS. J. Drug Deliv. Sci. Technol. 2019, 52, 1008–1020.
Pashirova, T.N.; Zueva, I.V.; Petrov, K.A.; Lukashenko, S.S.; Nizameev, I.R.; Kulik, N.V.; Voloshina, A.D.; Almasy, L.; Kadirov, M.K.; Masson, P.; et al. Mixed cationic liposomes for brain delivery of drugs by the intranasal route: The acetylcholinesterase reactivator 2-PAM as encapsulated drug model. Colloids Surf. B Biointerfaces 2018, 171, 358–367.
Tai, J.; Han, M.; Lee, D.; Park, I.-H.; Lee, S.H.; Kim, T.H. Different Methods and Formulations of Drugs and Vaccines for Nasal Administration. Pharmaceutics 2022, 14, 1073.
Dumkliang, E.; Pamornpathomkul, B.; Patrojanasophon, P.; Ngawhirunpat, T.; Rojanarata, T.; Yoksan, S.; Opanasopit, P. Feasibility of chitosan-based nanoparticles approach for intranasal immunisation of live attenuated Japanese encephalitis vaccine. Int. J. Biol. Macromol. 2021, 183, 1096–1105.
Oliveira Gomes, D.C.; Lilian da Silva Costa Souza, B.; Schwedersky, R.P.; Covre, L.P.; Leonel de Matos Guedes, H.; Lopes, U.G.; Inês Ré, M.; Rossi-Bergmann, B. Intranasal immunization with chitosan microparticles enhances lack-dna vaccine protection and induces specific long-lasting immunity against visceral leishmaniasis. Microbes Infect. 2021, 24, 104884.
Sinani, G.; Sessevmez, M.; Gök, M.K.; Özgümüş, S.; Alpar, H.O.; Cevher, E. Modified chitosan-based nanoadjuvants enhance immunogenicity of protein antigens after mucosal vaccination. Int. J. Pharm. 2019, 569, 118592.
Bedford, J.G.; Caminschi, I.; Wakim, L.M. Intranasal delivery of a chitosan-hydrogel vaccine generates nasal tissue resident memory CD8+ T cells that are protective against influenza virus infection. Vaccines 2020, 8, 572.
Dabaghian, M.; Latifi, A.M.; Tebianian, M.; NajmiNejad, H.; Ebrahimi, S.M. Nasal vaccination with r4M2e.HSP70c antigen encapsulated into N-trimethyl chitosan (TMC) nanoparticulate systems: Preparation and immunogenicity in a mouse model. Vaccine 2018, 36, 2886–2895.
Pirouzmand, H.; Khameneh, B.; Tafaghodi, M. Immunoadjuvant potential of cross-linked dextran microspheres mixed with chitosan nanospheres encapsulated with tetanus toxoid. Pharm. Biol. 2017, 55, 212–217.
Kabiri, M.; Bolourian, H.; Dehghan, S.; Tafaghodi, M. The dry powder formulation of mixed cross-linked dextran microspheres and tetanus toxoid-loaded trimethyl chitosan nanospheres as a potent adjuvant for nasal delivery system. Iran. J. Basic Med. Sci. 2020, 24, 116–122.
Bento, D.; Jesus, S.; Lebre, F.; Gonçalves, T.; Borges, O. Chitosan plus compound 48/80: Formulation and preliminary evaluation as a hepatitis B vaccine adjuvant. Pharmaceutics 2019, 11, 72.
Najafi, A.; Ghazvini, K.; Sankian, M.; Gholami, L.; Amini, Y.; Zare, S.; Khademi, F.; Tafaghodi, M. T helper type 1 biased immune responses by PPE17 loaded core-shell alginate-chitosan nanoparticles after subcutaneous and intranasal administration. Life Sci. 2021, 282, 119806.
Mosafer, J.; Sabbaghi, A.H.; Badiee, A.; Dehghan, S.; Tafaghodi, M. Preparation, characterization and in vivo evaluation of alginate-coated chitosan and trimethylchitosan nanoparticles loaded with PR8 influenza virus for nasal immunization. Asian J. Pharm. Sci. 2019, 14, 216–221.
Dehghan, S.; Kheiri, M.T.; Abnous, K.; Eskandari, M.; Tafaghodi, M. Preparation, characterization and immunological evaluation of alginate nanoparticles loaded with whole inactivated influenza virus: Dry powder formulation for nasal immunization in rabbits. Microb. Pathog. 2018, 115, 74–85.
Sinani, G.; Sessevmez, M.; Koray Gök, M.; Özgümüş, S.; Okyar, A.; Oya Alpar, H.; Cevher, E. Nasal vaccination with poly(β-amino ester)-poly(D,L-lactide-co-glycolide) hybrid nanoparticles. Int. J. Pharm. 2017, 529, 1–14.
Yuki, Y.; Uchida, Y.; Sawada, S.I.; Nakahashi-Ouchida, R.; Sugiura, K.; Mori, H.; Yamanoue, T.; Machita, T.; Honma, A.; Kurokawa, S.; et al. Characterization and Specification of a Trivalent Protein-Based Pneumococcal Vaccine Formulation Using an Adjuvant-Free Nanogel Nasal Delivery System. Mol. Pharm. 2021, 18, 1582–1592.
Kong, Q.; Kitaoka, M.; Tahara, Y.; Wakabayashi, R.; Kamiya, N.; Goto, M. Solid-in-oil nanodispersions for intranasal vaccination: Enhancement of mucosal and systemic immune responses. Int. J. Pharm. 2019, 572, 118777.
Bonaccorso, A.; Carbone, C.; Tomasello, B.; Italiani, P.; Musumeci, T.; Puglisi, G.; Pignatello, R. Optimization of dextran sulfate/poly-L-lysine based nanogels polyelectrolyte complex for intranasal ovalbumin delivery. J. Drug Deliv. Sci. Technol. 2021, 65, 102678.

© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.