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Smart materials: in situ gel-forming systems for nasal delivery Christina Karavasili and Dimitrios G. Fatouros Q1 Department of Pharmaceutical Technology, School of Pharmacy, Aristotle University of Thessaloniki, 54124, Greece
In the last decade in situ gelling systems have emerged as a novel approach in intranasal delivery of therapeutics, capturing the interest of scientific community. Considerable advances have been currently made in the development of novel formulations containing both natural and synthetic polymers. In this paper we present recent developments on in situ gelling systems for nasal delivery, highlighting the mechanisms that govern their formation. Introduction Q2 Nasal drug delivery has been attracting significant research interest in the last years, as route of multi-variant targeting, employing topical drug administration, systemic drug delivery, as well as brain drug targeting. The nasal cavity has been emerged as an attractive route of administration, from drug molecules to peptides and protein drugs and vaccines, resulting to the successful launch of a plethora of marketed nasal formulations [1]. Oral drug delivery, the most common route of administration, is simpler, improves patient compliance and comfort. Nevertheless, many pharmaceutically active compounds, especially macromolecules, commonly confront the drawback of low bioavailability, ascribed to extended first-pass hepatic metabolism, low permeability across gastrointestinal tract and chemical/ proteolytic degradation [2]. The nasal route has been considered as a viable and efficacious alternative route to tackle these obstacles. Circumvention of the extended first pass metabolism, avoidance of the harsh environment of the gastrointestinal tract, enhanced pharmacokinetic profiles for the lipophilic molecules deriving from the favorable anatomical characteristics of nasal epithelium, brain targeting through the olfactory region and patient compliance can be considered the main advantages of this route of administration [3]. However, the limited capacity of the nasal cavity, the low membrane permeability of hydrophilic molecules, along with the rapid mucociliary clearance effect, constitute the main rate-limiting factors for nasal drug absorption. For that reason, research majorly Corresponding author: Fatouros, D.G. ([email protected]) 1359-6446/ß 2015 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.drudis.2015.10.016
oriented toward the exploitation of bioadhesive agents and/or permeation enhancers for the development of delivery systems able to extend formulation’s residency in the nasal cavity, further improving drug absorption and bioavailability of polar compounds [3], with the recent focus on smart stimulus-responsive systems. Intelligent drug delivery systems responding mainly to physiological stimuli have emerged as an innovative approach for the delivery of therapeutic agents. Owing to their properties, in situ gelling formulations have the ability to undergo a phase transition; a solution to gel formation, triggered either by physiological factors upon intranasal administration (e.g. temperature, ion concentration, water content). As a result, in actual usage these dosage forms can be easily administered as solutions, assuring accuracy in the administered dose, whereas gel formation upon contact with the nasal epithelium is of utter importance to ascertain sufficient contact time and thus improved bioavailability.
Thermo-responsive systems The concept involves the development of mucoadhesive formulations comprising of polymers which exhibit temperature-triggered sol-to gel transitions in the range of 25–37 8C. Below or above this temperature range, early or late gelation might occur, either hindering ease of handling or inducing liquid formulation’s leakage in the outer region of the nostrils.
Synthetic thermo-responsive polymers A commonly used mucoadhesive polymer is Poloxamer 407, which is known to bear thermosensitive properties. Poloxamer 407 undergoes micellization in a concentration and temperature-dependent
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Increasing temperature
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Block copolymer solution
Micellization
Gel formation Drug Discovery Today
FIGURE 1
Schematic illustration of the mechanism of in situ gelation of a thermo-responsive polymer as a function of temperature. Upon temperature rise, polymer desolvation accompanied with side chain conformational changes, result in displacement of the hydrating water molecules, modifications of micelles orientation and consequently gel formation.
manner, shifting to gel formation by micellar packing (Fig. 1). The underlying mechanism of gel formation, as a function of temperature, suggests polymer desolvation accompanied with side chain conformational changes, resulting in displacement of the hydrating water molecules and modifications of micelles orientation [4]. The thermo-responsive properties of Poloxamer 407 have been extensively exploited in the development of in situ nasal gels in combination with mucoadhesives, essential for the prolongation of formulation’s residency in the nasal cavity. Driven by the low oral bioavailability of sumatriptan (15%), used in the treatment of migraine, Majithiya et al. [5] developed an in situ gel by utilizing Poloxamer 407 and Carbopol 934P. The gel exhibited a Tsol–gel temperature ranging from 23.9 8C to 29 8C with decreasing Carbopol’s concentration, with the suppression effect on gelation temperature as a function of polymer’s concentration, partly associated to the subsequent increase in viscosity after polymer dissolution. The gel formulation containing 0.3% Carbopol exhibited favorable mucoadhesive properties and significantly enhanced the in vitro drug permeability, compared to the solution form, inducing no structural defects on nasal membrane. In an attempt to confront the extreme variations in the oral bioavailability of metoclopramide hydrochloride (ranging from 32% to 98%), the patient incompliance of parenteral and rectal drug administration and drug’s bitter taste perception, Zaki et al. [6] co-formulated the antiemetic compound with Poloxamer 407, polyethylene glycol (PEG) and an array of mucoadhesive polymers. The results demonstrated that the presence of mucoadhesives increased the viscosity of the gels, thus shifting Tsol–gel temperature toward lower values and delayed metoclopramide release rate. In vivo mucociliary transport time (MTT) measurements indicated prolonged retention of the carbopol containing in situ gel in the rat nasal cavity. Optimized formulation, comprising 0.5% Carbopol, achieved higher serum drug levels and a shorter Tmax, compared to the oral drug solution, also retaining mucosal integrity for extended periods of time after in vivo administration. The limitations in the brain uptake of hydrophilic molecules, compelled Gabal et al. to formulate the anti-parkinsonian ropinirole hydrochloride in nanostructured lipid carriers (anionic and 2
cationic), integrated in Poloxamer 188 in situ gels [7]. The lack of any toxic histopathological findings confirmed the safety of the systems. Both gels (anionic Tsol–gel: 34 8C, cationic Tsol–gel: 33.4 8C) exhibited exceptionally enhanced absolute bioavailability values, when compared to plain ropinirole solution, achieving drug targeting to the brain mainly via the olfactory route. An array of in situ gels of Poloxamer 407 and Poloxamer 188 coformulated with Carbopol 934, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, chitosan and diphtheria toxoid were evaluated for their adjuvanticity after intranasal administration [8]. The intranasal administration of selective formulations, based on their mucoadhesive and in vitro release properties, was found to be inadequate to produce systemic immune response. On the other hand, subcutaneous vaccination accompanied by intranasal administration of the chitosan containing in situ gel, resulted in increased neutralizing antibody titers, facilitating partial protection against diphtheria toxoid. The neuronal uptake for the nose-to-brain delivery of 32P-siRNA dendriplexes was evaluated by Perez et al. [9], in order to circumvent the blood brain barrier. Thermally triggered in situ gels comprised of Poloxamer 407 and two mucoadhesives, namely Carbopol 934P and chitosan, were developed. The results demonstrated that the Carbopol containing formulations displayed optimum rheological properties, exhibiting a Tsol–gel at 23 8C, compared to their congener with chitosan, with the later hindering the release of the siRNA dendriplexes. Histological studies revealed the absence of any epithelial toxicity upon application of the gel formulation, achieving higher levels of radioactivity to the brain, compared to intravenous and intranasal-in-buffer administration. Further studies are also mandatory to substantiate the silencing effect of dendriplexes in vivo. In an effort to regulate the Tsol–gel of an in situ gel at 33.5 8C, Poloxamer 407 was co-formulated with different amounts of Poloxamer 188 and PEG 6000 and paenolol, extracted from the root bark of Paeonia suffruticosa bearing analgesic, antioxidant and anti-inflammatory properties [10]. Authors reported an optimum composition of 22% Poloxamer 407, to enable increased micellar entanglement, 2% Poloxamer 188 and 2% PEG 6000, as Tsol–gel
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regulators and 2% paenolol. Preliminary studies revealed the efficacy of these gels for the treatment of allergic rhinitis by effectively reducing IgE and LTE4 levels, whereas no apparent toxicity was reported after application. Rationalized by the insufficient intranasal residence of ketorolac tromethamine nasal spray, Li et al. [11] developed a hydrogel comprised of Poloxamer 407 and Carrageenan. They observed a concentration-dependant increase of gelation temperature upon inclusion of the non-steroidal, anti-inflammatory drug. Further evaluation of the formulation in vivo, reported a 3-fold increase in bioavailability, compared to its solution congener, and prolonged nasal residency up to 8.8 3.5 h. Nasal ciliotoxicity studies further confirmed the safety and efficacy of the sustained drug release hydrogel for nasal administration. Prompted by the observation that rizatriptan benzoate, an antimigraine agent, undergoes extensive hepatic metabolism upon oral administration, Kempwade and Taranalli [12] explored nasal mucosa as an alternative administration route. They used the cold method to prepare in situ thermo-reversible gels comprised of Poloxamer 407 and Carbopol. A decrease in Tsol–gel was observed upon increase of Carbopol’s concentration from 0.1% to 0.5%. Sufficient mucoadhesiveness was achieved in the presence of 0.3% carbopol, a substantial parameter in order to avoid early formulation drainage from the nasal cavity. Permeation and histopathological studies indicated that this gel might be a promising drug carrier for nasal administration. A dual active postoperative/cancer therapeutic approach was demonstrated recently by El-Setouhy et al. [13] using a Pluronic F127 thermo-responsive gel. Gelation temperature was found to be modulated by both drug (granisetron and ketorolac tromethamine) and mucoadhesive polymers. Carbopol and Pemulen TR2 containing mucoadhesive gels were found to retard drug release and increase in vivo mucociliary transit time (MTT). Prolonged nasal residency accompanied with the induction of significant analgesia after intranasal administration, outranked oral administration, in terms of both first pass metabolism and gastrointestinal adverse effects avoidance. Qian and colleagues [14] developed Pluronic F-127 (20%, w/v) in situ gels for the intranasal delivery of tacrine, incited by its low oral bioavailability (17–24%) and dose-dependent hepatotoxicity. Optimized Tsol–gel was achieved upon addition of Pluronic F-68 and PEG 8000 in concentrations varying from 1–2% to 0.5–1%, respectively. Inclusion of 0.5% chitosan as mucoadhesive and penetration enhancer did not induce any alteration of Tsol–gel. A 2–3 fold higher peak plasma concentration (Cmax), a 3-fold higher tacrine exposure in the brain and a reduction of drug’s metabolites were observed after the in vivo intranasal administration of the gel, compared to the oral solution. The bioadhesive properties of xyloglucan, were evaluated by Kumar et al. [15] in an effort to extent residency in the nasal cavity of a Pluronic F127 in situ gel containing zolmitriptan, an antimigraine drug and ketorolac tromethamine, an anti-inflammatory drug,. Results pointed to a significant increase in drugs’ bioavailability (21% for zolmitriptan and 16% for ketorolac tromethamine) after intranasal administration, compared to the oral route. An almost 10-fold longer mucociliary transport time, was reported in a study by Chen et al. [16], when curcumin was incorporated into a thermosensitive in situ gel comprised of
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Pluronic F127 and Poloxamer 188, resulting in extended drug retention in the nasal cavity, compared to plain curcumin solution. Optimized formulation demonstrated increased brain tissue distribution of curcumin after intranasal administration and similar AUCplasma, when compared to i.v. injection, while at the same time mucosal integrity maintenance was kept for 14 consecutive days after in vivo application. A direct nose-to-brain lorazepam delivery was attempted by Jose et al. [17] using Pluronics as the thermo-responsive gelling agents, so as to eliminate non-specific drug distribution and limited brain uptake, after oral and intravenous administration. The authors reported a sustained release of lorazepam from chitosan microspheres, when dispersed in a gel carrier comprised of 21% Pluronic F 127 and 1% Pluronic F 68. Histopathological examination further confirmed the safety of the delivery system for nasal application. Poloxamer 407 based thermo-reversible gelling systems were developed by Ved and Kim [18] for the intranasal administration of zidovudine, since the drug’s transport across the BBB is limited, also undergoing extended hepatic metabolism after oral administration. Optimal permeation enhancing effects were observed in the presence of 0.1% n-tridecyl-b-d-maltoside. Increased bioavailability values and cerebrospinal fluid accumulation were obtained after intranasal administration of the optimized formulation, compared to intravenous administration of drug’s solution. Results clearly indicated the direct nose-to-brain transport of almost total drug content via the olfactory route, while on the other hand only 0.7% of the systematically administered drug accumulated in the brain tissue. The hydrophilic antidepressant agent venlafaxine hydrochloride, encounters limited BBB permeability, short half-life, extensive hepatic effect and low oral bioavailability (45%). Therefore, the nasal route was validated as an alternative to oral administration and venlafaxine was co-formulated with the thermo-responsive polymer Lutrol F127 and an array of mucoadhesive polymers (Carbopol 934P, HPMC K4M, PVP K30, sodium alginate, Tamarind seed gum and Carrageenan) [19]. For the optimum Lutrol F127 concentration (18%), gel properties were further reformed by adjusting mucoadhesives’ concentration. Results demonstrated decrease in Tsol–gel and increase in mucoadhesive strength of the produced gels, upon rising mucoadhesives’ concentration. Optimized formulations with Tsol–gel temperature at 30–33 8C, exhibited an almost total permeation of the drug across sheep nasal mucosa at the time scale of 150 min. In vivo pharmacodynamic studies demonstrated the superiority of the nasal formulation, exhibiting optimum antidepressant effectiveness compared to its oral congener. The same compound was incorporated into gels comprised of Poloxamer 407 and methyl cellulose [20]. Gelation temperature was determined at 33.4 8C and methyl cellulose was found to both enhance adhesion strength of the gels, a crucial parameter for prolonged residence in the nasal cavity and decelerate drug release rate. Ex vivo permeation studies pointed at a total amount of 87.3% of the initial drug concentration permeated across sheep nasal mucosa, while histopathological evaluation did not reveal any tissue impairment. Rationalized by the principle that cyclodextrins can increase the aqueous solubility of poorly soluble compounds, Singh et al. [21]
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have incorporated loratadine-b-CD complexes into Poloxamer 407 and Carbopol 934P nasal gels, in an attempt to circumvent drug’s rapid first-pass hepatic metabolism and its low oral bioavailability (40%). In situ gel formulations reported a gelling temperature range between 27.3 8C and 35.3 8C. Increase in the amount of polymers fortified molecular entanglement via hydrogen bonding, promoted micellar association, which in turn decreased Tsol–gel temperature. Increased viscosity values were recorded as a function of carbopol 934P concentration, in an attempt to retard mucociliary clearance rate. Transport studies across sheep nasal mucosa revealed that more than 90% of the drug could be permeated at the time scale of 6 h, without inducing changes in epithelium physiology. Toward the same direction, Balakrishnan et al. [22] utilized the mucoadhesive properties of Carbopol 934P (0.1%, w/v) and the solubilization capacity of hydroxypropyl-b-cyclodextrin (10%, w/v), to increase the intranasal absorption and the aqueous solubility of fexofenadine, a non-sedating, non-anticholinergic H1-receptor, used for allergic rhinitis with low oral bioavailability (13–16%). The resulting in situ gel comprising Poloxamer 407 (17%, w/v) reported a Tsol–gel temperature at 29.7 0.1 8C and an 11.3-fold increase in fexofenadine’s relative bioavailability over drug solution.
Natural thermo-responsive polymers In a study aiming to assess the effectiveness of a natural mucoadhesive polymer extracted from F. carica, compared to synthetic congeners (hydroxypropylmethyl cellulose and Carbopol 934), the anti-epileptic agent midazolam hydrochloride was co-formulated with these polymers at different ratios and was further evaluated [23]. The results demonstrated higher adhesive strength values for the mucilage based gels, which in turn proved to be safe for the nasal administration of midazolam, achieving higher absolute bioavailability values of the drug. These naturally occurring mucilage gels were proposed by the authors as a cost-effective and efficient system for the nasal administration of midazolam. Xyloglucans constitute another group of thermosensitive materials, naturally occurring in plants, able to transform from sol to gel structures upon temperature rising. On this basis, Mahajan et al. [24] developed xyloglucan in situ gels containing ondansetron hydrochloride as a model drug. Ondansetron exhibits low (i.e. 45%), inconsistent bioavailability, potentially due to high hepatic first-pass metabolism and high P-gp efflux, therefore thermo-responsive gels could serve well to increase the residence time of the drug. The gel formulations containing 2.5% (w/w) xyloglucan, reported favorable gel strength values and almost total drug permeation after the 4 h ex vivo study across sheep nasal mucosa. The intranasal administration of the in situ gel in rabbits demonstrated significantly higher bioavailability values, compared to the per oral administered drug solution, suggesting the potential of this formulation. The same authors [25] further assessed the improvement of mucoadhesive properties of the xyloglucan gels, after thiolation. The modified xyloglucan gels containing ondansetron showed a Tsol–gel in the range of 25–30 8C and improved bioadhesiveness, as compared to that of xyloglucan congener, possibly ascribed to disulfide bond interactions developed between the mucus and the thiolated polymer. Ex vivo studies across sheep nasal mucosa 4
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revealed significantly higher permeability coefficient values of ondansetron for the thiolated derivative, with no toxic effect observed after exposure of nasal epithelium to these gels. Chitosan, a natural polysaccharide derived by N-deacetylation of chitin, is considered as a biocompatible and biodegradable polymer bearing mucoadhesive properties [26]. These properties prompted Cho and his co-workers [27] to integrate chitosan into thermo-reversible gels comprising of Poloxamer 407, hydroxypropyl-b-cyclodextrin (Hp-b-CD) and fexofenadine hydrochloride. The slight increase observed in the Tsol– gel of the formulation from 29.9 to 30.5 8C was attributed to the presence of acetic acid, a chitosan solubilizer, which can cause a weakening to hydrogen bonding, affecting the physicochemical properties of the formulation [28]. A critical enhancement in drug’s permeation across cell monolayers was attributed to the synergistic effect of both chitosan and Hp-b-CD. In vivo studies in rabbits revealed the superiority of the thermo-responsive formulation, which exhibited a 18-fold higher bioavailability, compared to the control (nasal solution). Naik and Nair [29] in their effort to design a system for the delivery of the antidepressant doxepin prepared thermosensitive gels comprising chitosan (2%, w/v) and glycerophosphate in the presence and absence of polyethylene glycol. Although PEG addition did not affect gelation temperature, it significantly increased drug retardation. Both formulations proved to be effective on their anti-depressant activity, showing at the same time proper compatibility with the nasal epithelium. Since the oral administration of doxepin is accompanied by poor and variable bioavailability (13–45%), the nasal delivery of the drug is featured as a promising alternative. Despite the intensive use of chitosan in pharmaceutics its low aqueous solubility in neutral and basic pH values has limited its effectiveness as absorption enhancer. To tackle this problem, chitosan derivatives [e.g. trimethylchitosan (TMC)] readily soluble at these conditions have been synthesized [30].
Synthetic thermo-responsive derivatives from natural polymers Chitosan derivatives (TMC) with different average molecular weight and degree of quaternisation demonstrated thermosensitive behavior when co-formulated with polyethylene glycol and glycerophosphate. The gels containing TMC of medium average molecular weight and low degree of quaternisation with a Tsol–gel at 32.5 8C, exhibited exceptional mucoadhesive behavior and rheological properties, holding promise for nasal delivery [31]. In a subsequent study from the same workers, these formulations containing insulin were administered in vivo in a diabetic rat model, demonstrating a reduction in blood glucose over ca.24 hours [32]. A marked decrease in transepithelial resistance of Calu3 cell monolayers was observed after the application of the hydrogel formulation, interpreted as tight junction opening for the paracellular transport of insulin. The in situ TMC gels revealed prolonged residency in the nasal cavity, due to retardation of the mucociliary clearance, effect mainly attributed to the viscous nature of the hydrogels and the bioadhesiveness of TMC. Overall, results signify the potential of the thermosensitive system as a once-a-day dosage form for the nasal delivery of insulin. In an earlier study, a thermosensitive hydrogel comprised of N[(2-hydroxy-3-trimethylammonium) propyl] chitosan chloride,
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poly (ethylene glycol), a-b-glycerophosphate and insulin was evaluated for the effectiveness of its hypoglycemic activity. Enhanced insulin uptake was observed for the hydrogel formulation, with concurrent maintenance of cell integrity. In vivo nasal application in rodents, resulted in a decrease of blood glucose concentration (40–50% of initial blood glucose concentration) ca. 5 h after administration, further corroborating toward the exploitation of chitosan derivatives in the effective intranasal administration of hydrophilic macromolecules [33].
Ion responsive systems An approach toward the formation of in situ gels involves the presence of ion responsive agents. Gellan gum, an anionic polysaccharide, undergoes gelation under physiological ion concentration. The cation-induced gelling process is ascribed to double helical junction zones formation and inter-helical interaction, resulting in a three-dimensional network via cations complexation. The abundance of cations, especially Ca2+, naturally occurring in nasal fluids, enables in situ gelation of gellan gum formulations upon contact with nasal mucosa, sustaining their residency in nasal cavity, thereby improving drug absorption [34]. The variable and poor bioavailability (10–48%) of orally administered scopolamine, motivated Cao et al. [35] to formulate a nasal dosage form, examining the significance of a gellan gum composition within the process of gelation. Increased viscosity values were recorded as a function of polymer’s concentration, followed by retardation of drug release rate from the gels. In vivo studies were conducted in an experimental rat model with gels comprising of the optimum gellan gum concentration (0.5%, w/v), achieving therapeutic levels of the anti-muscarinic agent, without being toxic on nasal epithelium. The same workers, in an effort to achieve better nasal absorption efficacy of mometasone furoate, than the marketed nasal spray in suspension form, developed a new system, co-formulating xanthan gum and gellan gum at a concentration of 0.5% (w/v), thus improving the physicochemical properties (viscosity and redispersion) of the formulation [36]. Gelation was visually inspected after mixing the in situ gel and artificial nasal fluid. The authors reported that the formulation exhibited considerable stability during storage for a long period and effectiveness in suppressing the symptoms of allergic rhinitis in rats in vivo. Histopathological evaluation of the nasal epithelium further documented the safety of the formulation. Data generated by Cai et al. [37], further support the efficiency of 0.5% (w/v) in situ gels of gellan gum, when tested for the nasal administration of gastrodin. Formulations demonstrated favorable rheological properties; immediate gelling when mixed with artificial nasal fluid, prolonged stability, no obvious ciliotoxicity and enhanced pharmacodynamic action, compared to the oral formulation. An analogous approach was adopted by Saindane et al. [38], who have reported the co-formulation of carvedilol, a b2-adrenergic receptor antagonist, with gellan gum at the same concentration as previously reported (0.5%, w/v) for the development of an in situ gelling nasal spray. Formulations gelated rapidly upon contact with simulated nasal fluid, achieving sustained in vitro drug release and higher bioavailability values, when compared to the orally administered formulation of the drug.
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Rivastigmine’s hydrophilicity and short half-life necessitated the development of more efficient dosage forms and routes of administration. Nanostructured lipid carriers of rivastigmine were integrated in an in situ gelling system comprised of 0.8% gellan gum and 15% Lutrol F 127 [39]. In situ gels of favorable organoleptic properties namely; elasticity, rheology and mucoadhesiveness reported a 1.6-fold increase of drug’s permeation across nasal mucosa, compared to plain drug solution and a 3-fold increase in enzyme inhibition efficacy. Saindane et al. [38] utilized a nanosuspension of carvedilol incorporated in an ion-responsive gelling phase, to formulate an in situ gelling nasal spray, since drug suffers from low oral bioavailability (25–35%) and a short plasma half-life (6 h). A modified ultrasonication-precipitation method was adopted for the preparation of the stable drug nanosuspension, which was thereafter integrated in the in situ gelling phase. Optimized formulations containing 0.5% (w/v) gellan gum, demonstrated favorable rheological properties prior and after contact with nasal fluids and retardation in the release profile of carvedilol. Further in vivo evaluation in rabbits, demonstrated a 2.7-fold higher bioavailability of the nasal spray, compared to the orally administered formulation. Hosny et al. [40] formulated a nanosized microemulsion of saquinavir mesylate (SM) in a 0.5% (w/v) deacetylated gellan gum in situ gel, in order to confront drug’s poor oral bioavailability. Optimized formulation of appropriate gel strength was subjected to ex vivo permeation studies across goat nasal mucosa, exhibiting a 6.5-fold enhancement in drug’s permeation for the in situ gel, than for drug’s suspension. In vivo pharmacokinetic studies demonstrated the superiority of the ion responsive formulation, compared to the marketed oral tablet product, reporting a 12-fold increase in drug’s bioavailability. In an attempt to overcome the extensive hepatic metabolism of sumatriptan succinate (SS) after oral administration, Galgatte et al. [41] employed deacetylated gellan gum as the ion-responsive gelling agent for the intranasal administration of sumatriptan. Formulation of optimal properties, with regard to viscosity and mucoadhesive strength, consisted of 0.2% (w/v) gellan gum and exhibited complete in vitro drug release and enhanced permeation across sheep nasal mucosa. Pharmacokinetic studies confirmed the superiority of the intranasal in situ gel of the SS, which achieved 1.44 times higher AUC value in the brain tissue, over the oral SS solution. The drug targeting index, as calculated after the intranasal administration of the in situ gel in rats, suggested a possible direct transport of sumatriptan succinate through the olfactory pathway. The synergistic in situ response of a thermally triggered and an ion responsive hydrogel was exploited by Xin et al. [42] for the development of a smart delivery system of ketorocal tromethamine, since the already marketed nasal spray encounters short resident times in the nasal cavity. Deacetylated gellan gum (3%, w/v) and Poloxamer 407 (18%, w/v) as the ion- and thermoresponsive polymers, along with azone, sulfobutyl ether-b-cyclodextrin (2.5%, w/v) and chlorobutanol (0.5%, w/v) as permeation enhancers and the bacterial inhibitor, respectively, were combined to formulate these gels. In situ gels exhibited superior pseudoplastic behavior, longer retention on nasal mucosa over drug solution, hence favoring drug absorption, negligible ciliotoxicity, sustained drug release and good analgesia effect.
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Ca2+
O OH
OH
O
O
Polysaccharide chains
O
HO
O O –
– O O O HO
O
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FIGURE 2
Ion induced in situ gelation of anionic polysaccharides (e.g. pectin) in the presence of divalent cations. Ionic interactions developed between divalent cations and the functional groups of pectin chains, lead to the formation of an ordered three-dimensional network in the gel structure.
Wang et al. [43] evaluated the intranasal administration of curcumin in the form of a micro-emulsion based ion-responsive hydrogel. On that basis, Capryol 90, Solutol HS15 and Transcutol HP were added as the oil phase and the surfactants, respectively, whereas deacetylated gellan gum (DGG) was introduced at a concentration of 0.3% in the water phase. The selected concentration of DGG was a compromise between formulation’s prolonged residency in the nasal cavity and mucosal tolerability. The apparent safety of the system was confirmed by the absence of any histopathological tissue alterations after intranasal administration in rats. Absolute bioavailability values of curcumin after intranasal administration of the in situ gel were found to be significantly higher, compared to the respective values after per oral administration. Brain targeting index, calculated after nasal administration of the in situ gel, pointed toward a direct nose-to-brain curcumin transport. In vitro experiments by Krauland et al. [44] have shown that thiolation of deacetylated gellan gum via cysteine conjugation improved the viscoelastic properties of the formulation, as a result of the additional inter- and intra-molecular cross linking between the polymer and the amino acid. The in situ gelling properties of the modified polymer were significantly enhanced, even at physiological cations concentrations, enabling the extension of formulation’s residency on mucosal surfaces. Owing to its properties to form hydrogels in the presence of divalent cations abundantly found in physiological nasal secretions, pectin, a natural polysaccharide, is a commonly used excipient for nasal drug delivery systems. The underlying mechanism includes ionic interactions developed between cations and functional groups of pectin chains, 6
leading to the formation of an ordered three-dimensional network in the gel structure (Fig. 2). This approach has been exemplified by Castile et al. [45] who investigated the deposition and gelling characteristics of PecSys, low methoxy pectin. For this reason, an anatomical nasal cast model treated with adequate Ca2+ concentration was employed, demonstrating a significant reduction in dripping of the PecSys in situ gel from the site of deposition, compared to a non-gelling control. The practical utility of pectin in situ gel has been evaluated in clinical trials for the nasal administration of fentanyl, used in the management of cancer pain and further corroborated by the findings of the in vitro models developed by Castile et al. Pectin extracted from Aloe Vera plant has been investigated as a component for the development of in situ gels [46]. The authors demonstrated the ability of the polysaccharide to form gels even at polymer and Ca2+ concentrations as low as 0.2% (w/v) and 10 mM respectively, claiming their technological functionality for the nasal route of administration. In a subsequent study [47], the same authors investigated the mechanism of in situ gelation between Aloe vera and Ca2+ via crosslinking, as a function of molecular weight, ionic strength, and molar ratio of Ca2+ to COO by means of dynamic oscillatory rheology and pulsed field gradient NMR (PFG-NMR) determinations. Diffusion rates of model macromolecules from the hydrogels were discussed in light of hydrogels morphology, highlighting the importance of polymers’ concentration and electrolyte ionic strength. An overview of the temperature- and ion-responsive in situ gelling systems and their application in drug delivery is presented in Table 1.
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TABLE 1
Stimulus responsive agent
Triggering factor
Concentration (%, w/v)
Formulation excipients
Tsol–gel (8C, optimized formulation)
Active
Ref.
Poloxamer 407
Temperature
18
Carbopol 934P
25.9
Sumatriptan
[5]
Poloxamer 407
Temperature
18
Chitosan, hydroxypropyl cellulose, PEG (400 and 6000), Carbopol 934P, PVA
31 0.5
Metoclopramide HCl
[6]
Poloxamer 407
Temperature
23
Chitosan, Carbopol 974P
23.0
siRNA
[9]
Poloxamer 407
Temperature
20
Carrageenan
35.0
Ketorolac Tromethamine
[11]
Poloxamer 407
Temperature
18
Carbopol 934P
31–32
Rizatriptan Benzoate
[12]
Poloxamer 407
Temperature
17
Carbopol 974P, PemulenTM TR-2, HPMC
30.83 0.29
Granisetron HCl, Ketorolac Tromethamine
[13]
Poloxamer 407
Temperature
20
Chitosan, Pluronic F-68, PEG-8000
28.5 0.2
Tacrine
[14]
Poloxamer 407
Temperature
20
Xyloglucan, Sodium alginate, PEG (4000 and 6000)
27.4 0.2
Zolmitriptan, Ketorolac Tromethamine
[15]
Poloxamer 407
Temperature
20
n-Tridecyl-b-dmaltoside, Carbopol 934P, HPC and HPMC
27–30
Zidovudine
[18]
Poloxamer 407
Temperature
18
Carbopol 934, PVP K30, HPMC K4M, sodium alginate, tamarind seed gum, Carrageenan
31.17 0.30
Venlafaxine HCl
[19]
Poloxamer 407
Temperature
17
Methocel A4M
33.40 1.63
Venlafaxine HCl
[20]
Poloxamer 407
Temperature
20
Carbopol 934 P, bcyclodextrin
28.6 0.47
Loratadine
[21]
Poloxamer 407
Temperature
17
Carbopol 934P, hydroxypropyl-bcyclodextrin
29.70 0.1
Fexofenadine HCl
[22]
Poloxamer 407
Temperature
16
Ficus carica Mucilage, HPMC, Carbopol 934, sodium taurocholate
27.20 0.33
Midazolam
[23]
Poloxamer 407/188
Temperature
15/12 or 12/12
HPMC, anionic and cationic nanostructured lipid carriers
34 or 33.2
Ropinirole HCl
[7]
Poloxamer 407/188
Temperature
18/10
Carbopol 934, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, chitosan
29
Diphtheria toxoid
[8]
Poloxamer 407/188
Temperature
22/2
b-CD, PEG6000
33.5 0.29
Paeonol
[10]
Poloxamer 407/188
Temperature
20/2
–
32 0.5
Curcumin
[16]
Poloxamer 407/188
Temperature
21/1
Chitosan microspheres
37.0
Lorazepam
[17]
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Temperature and ion responsive in situ gelling systems.
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Drug Discovery Today Volume 00, Number 00 November 2015
TABLE 1 (Continued )
Reviews POST SCREEN
Stimulus responsive agent
Triggering factor
Concentration (%, w/v)
Formulation excipients
Tsol–gel (8C, optimized formulation)
Active
Ref.
Poloxamer 407
Temperature
17
Hydroxypropyl bcyclodextrin, chitosan
30.5 0.15
Fexofenadine hydrochloride
[27]
Poloxamer 407/deacetylated gellan gum
Temperature/ion
15/0.8
Nanostructured lipid carriers
Proper viscosity at 37 8C
Rivastigmine
[39]
Poloxamer 407/deacetylated gellan gum
Temperature/ion
18/3
Sulfobutyl etherb-cyclodextrin, chlorobutanol, HP-b-CD, azone
Proper viscosity at 37 8C
Ketorolac Tromethamine
[43]
Chitosan/glycerophosphate
Temperature
2/10
PEG 4000
37 0.4
Doxepin
[29]
Trimethylchitosan/glycerophosphate
Temperature
3.6
PEG 4000
32.5 0.4
–
[31]
Trimethylchitosan/glycerophosphate
Temperature
4.5
PEG 4000
35
Insulin
[32]
N-[(2-Hydroxy-3-trimethylammonium) propyl] chitosan chloride/ glycerophosphate
Temperature
3.6 (w/w)
PEG 4000
37
Insulin
[33]
Xyloglucan
Temperature
2.5 (w/w)
–
27–28
Ondansetron
[24]
Thiolated xyloglucan
Temperature
2.5 (w/w)
–
25–30
Ondansetron
[25]
Gellan gum
Ion
0.5
–
–
Scopolamine hydrobromide
[35]
Gellan gum
Ion
0.5
Xanthan gum
–
Mometasone furoate
[36]
Gellan gum
Ion
0.5
Poloxamer 407 and Oleic acid nanosuspension
–
Carvedilol
[38]
Deacetylated gellan gum
Ion
0.5
–
–
Gastrodin
[37]
Deacetylated gellan gum
Ion
0.5
Labrafac PG, Labrasol, Transcutol HP (nanosized microemulsion)
–
Saquinavir mesylate
[40]
Deacetylated gellan gum
Ion
0.2
PEG 400
–
Sumatriptan succinate
[41]
Deacetylated gellan gum
Ion
0.3
Solutol HS, Transcutol HP, Capryol 90 (nanosized microemulsion)
–
Curcumin
[43]
Other strategies of in situ gelation In situ gelling nasal inserts Another strategy toward the intranasal drug delivery involves the development of in situ gelling nasal inserts based on bioadhesive polymers, able to form gels upon contact with nasal mucosa (Fig. 3) [48]. Freeze-drying technique has been utilized to produce solid insert materials with porous structures to ensure water penetration for gel formation (Fig. 3). The mechanism proposed to explain the mucoadhesive behavior of the inserts considers the interactions between the bioadhesive polymers and mucin, which in turn enables the sustained release of the active in a controlled manner governed by the polymer’s properties. Gradual decomposition of the gel combined with the mucociliary clearance effect enables the removal of the insert from the nasal cavity. Driven by this demand, Bertram et al. [49] evaluated the effectiveness of rapidly in situ gelling inserts for nasal administration. A 8
series of hydrophilic mucoadhesive polymers were co-formulated with oxymetazoline as the model drug, molded and frozen to produce the inserts via lyophilization. Freeze drying procedure resulted in highly porous sponge-like inserts, a prerequisite to assure rapid hydration and gelation upon contact with nasal mucosa. Based on the physical properties of the selected polymers, it was outlined that a molecular weight of 100,000 is required for proper bioadhesion to be achieved. Increase in polymer’s MW resulted in gels of higher viscosity, lower dissolution rate and hence longer retention times in the nasal cavity, with the same effect also provoked by high polymer concentrations. Water uptake, the crucial step for gelation of the inserts, was determined to affect drug’s release rate, correlating low water uptake with slower drug release rates. Carrageenan, xanthan gum and carboxymethylcellulose sodium (NaCMC) assembled optimal characteristics as main matrix components of the nasal inserts, necessitating further evaluation of these extended drug release systems.
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In situ gelling solid insert
REVIEWS
Water uptake
Drug elution and formulation dissolution
Cilia
Nasal mucosa Reviews POST SCREEN
Drug Discovery Today
FIGURE 3
In situ gelation of solid nasal inserts upon contact with the nasal mucosa. Water uptake results in hydration of the polymer matrix and rapid gelation.
A subsequent investigation from the same group [50] evaluated nasal inserts for influenza vaccine delivery, composed of varying polymers, as well as permeation enhancing agents. Nasal inserts of sponge-like form consisting of bioadhesive polymers were the most effective, in regard to the induction of IgG serum response, as a result of their ability to prolong nasal residency. Xanthan gum, as matrix component of the inserts and cationic lipid, as adjuvant, were found to generate comparable IgG levels as the plain nasal liquid vaccine formulation, highlighting the potential of the inserts, also as storage containers for the stability enhancement of the antigens. The film casting method was introduced by Farid et al. [51] for the preparation of in situ gelling nasal inserts containing an array of mucoadhesive polymers, namely; sodium alginate (SA), chitosan, hydroxypropylmethylcellulose and carboxymethylcellulose sodium (CMC Na) co-formulated with salbutamol sulphate (1.4%, w/w), as the model drug. Higher water uptake values were reported for the SA and CMC Na polymers, as a result of their ionic nature. The same polymers demonstrated a positive mucoadhesion effect, despite their negative charge, possibly due to their hydrogen bonding capacity and expanded structural conformation, and a retardation in the release rate of salbutamol sulfate from the hydrogels. Nasal inserts demonstrated favorable water uptake, mucoadhesive and drug release properties, accredited to the presence of AL and CMC Na polymers.
Marketed products and clinical studies Considerable effort has been directed toward the development of in situ gelling systems using the natural polysaccharides pectins. Alterations to the gelation properties of pectin can be fine-tuned by the degree of esterification of the galacturonic acids [52]. As a result, a pectin-based system co-formulated with the opioid analgesic fentanyl, PecFent1 was approved for marketing in Europe in 2009 and in the USA in 2011 [53–55]. An inactivated H5N1 influenza vaccine based on the GelVac1 nasal powder formulation has been approved for human testing by the FDA, and a phase I clinical study is underway. GelVac1 is comprised of GelSite1, an
Q4
Aloe vera L.-derived polysaccharide polymer with mucoadhesive properties [55,56].
Conclusion and future directions In situ gelling formulations have risen as emerging drug delivery systems for nasal drug administration, comprising of polymeric materials able to undergo a sol–gel conversion, when exposed to biological stimuli. Integration of mucoadhesive polymers in in situ gelling systems has been proved to amplify drug absorption by prolonging residency in the nasal cavity. The mucociliary clearance (MCC; ca. 4–6 mm/min), the nose-specific enzymatic activity and the high rate of mucus turnover (resting-state daily production, 75–150 mL) are additional barriers to nasal drug delivery [57]. Consequently, the development of longer acting bioadhesive formulations regulating bioadhesive performance is pressing issue. Nasal cavity is capable of eliciting strong systemic and local immune responses. The encapsulation of the antigen into bioadhesive in situ gels is a promising approach toward successful nasal vaccine delivery [58]. Additionally, an increasing number of studies [7,9,16–18,29,39] have shown that nose-to-brain drug transport offers an attractive alternative to formulation strategies attempting to enhance drug penetration into the CNS. Finally, the complexity of nasal cavity combined with the different properties of the actives (small drugs, peptides, proteins, vaccines) delivered via the nasal route is leading to emerging nasal delivery devices and dispersing technologies, in an attempt to maximize the clinical performance of the formulations [58]. The use of smart polymers can significantly improve the transport of actives across nasal mucosa, counterbalancing the limitations posed by nasal epithelium. Therefore, in situ gel-forming nasal systems show considerable promise in delivery of therapeutics and rapid onset of action. Although at its infancy, in situ gelling formulations are very promising as a new platform in the field of drug discovery and delivery.
Uncited reference [59].
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Q3
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5 Majithiya, R.J. et al. (2006) Thermoreversible-mucoadhesive gel for nasal delivery of sumatriptan. AAPS Pharm. Sci. Tech. 7, 67 6 Zaki, N.M. et al. (2007) Enhanced bioavailability of metoclopramide HCl by intranasal administration of a mucoadhesive in situ gel with modulated rheological and mucociliary transport properties. Eur. J. Pharm. Sci. 32, 296–307 7 Gabal, Y.M. et al. (2014) Effect of surface charge on the brain delivery of nanostructured lipid carriers in situ gels via the nasal route. Int. J. Pharm. 473, 442–457 8 Ozbılgın, N.D. et al. (2014) Preparation and in vitro/in vivo evaluation of mucosal adjuvant in situ forming gels with diphtheria toxoid. Drug Deliv. 21, 140–147 9 Perez, A.P. et al. (2012) Increased brain radioactivity by intranasal P-labeled siRNA dendriplexes within in situ-forming mucoadhesive gels. Int. J. Nanomed. 7, 1373–1385 10 Chu, K. et al. (2013) Preparation of a paeonol-containing temperature-sensitive in situ gel and its preliminary efficacy on allergic rhinitis. Int. J. Mol. Sci. 14, 6499–6515 11 Li, C. et al. (2014) Enhancement in bioavailability of ketorolac tromethamine via intranasal in situ hydrogel based on Poloxamer 407 and carrageenan. Int. J. Pharm. 474, 123–133 12 Kempwade, A. and Taranalli, A. (2014) Formulation and evaluation of thermoreversible, mucoadhesive in situ intranasal gel of rizatriptan benzoate. J. SolGel Sci. Technol. 72, 43–48 13 El-Setouhy, D.A. et al. (2015) Preclinical evaluation of dual action intranasal formulation intended for postoperative/cancer associated therapies. Eur. J. Pharm. Sci. 76, 48–56 14 Qian, S. et al. (2014) Development, characterization and application of in situ gel systems for intranasal delivery of tacrine. Int. J. Pharm. 468, 272–282 15 Kumar, A. et al. (2015) Optimization of combinational intranasal drug delivery system for the management of migraine by using statistical design. Eur. J. Pharm. Sci. 70, 140–151 16 Chen, X. et al. (2013) Enhanced brain targeting of curcumin by intranasal administration of a thermosensitive poloxamer hydrogel. J. Pharm. Pharmacol. 65, 807–816 17 Jose, S. et al. (2013) Thermo-sensitive gels containing lorazepam microspheres for intranasal brain targeting. Int. J. Pharm. 441, 516–526 18 Ved, P.M. and Kim, K. (2011) Poly (ethylene oxide/propylene oxide) copolymer thermo-reversible gelling system for the enhancement of intranasal zidovudine delivery to the brain. Int. J. Pharm. 411, 1–9 19 Bhandwalkar, M.J. and Avachat, A.M. (2013) Thermoreversible nasal in situ gel of venlafaxine hydrochloride: formulation, characterization, and pharmacodynamic evaluation. AAPS Pharm. Sci. Tech. 14, 101–110 20 Pund, S. et al. (2013) Ex vivo permeation characteristics of venlafaxine through sheep nasal mucosa. Eur. J. Pharm. Sci. 48, 195–201 21 Singh, R.M. et al. (2013) Thermally triggered mucoadhesive in situ gel of loratadine: b-cyclodextrin complex for nasal delivery. AAPS Pharm. Sci. Tech. 14, 412–424 22 Balakrishnan, P. et al. (2015) Carbopol-incorporated thermoreversible gel for intranasal drug delivery. Molecules 20, 4124–4135 23 Basu, S. and Bandyopadhyay, A.K. (2010) Development and characterization of mucoadhesive in situ nasal gel of midazolam prepared with Ficus carica mucilage. AAPS Pharm. Sci. Tech. 11, 1223–1231 24 Mahajan, H.S. et al. (2012) Thermally reversible xyloglucan gels as vehicles for nasal drug delivery. Drug Deliv. 19, 270–276 25 Mahajan, H.S. et al. (2013) Thiolated xyloglucan: synthesis, characterization and evaluation as mucoadhesive in situ gelling agent. Carbohydr. Polym. 91, 618–625 ¨ rch, A. and Du ¨ nnhaupt, S. (2012) Chitosan-based drug delivery 26 Bernkop-Schnu systems. Eur. J. Pharm. Biopharm. 81, 463–469 27 Cho, H.J. et al. (2011) Poloxamer/cyclodextrin/chitosan-based thermoreversible gel for intranasal delivery of fexofenadine hydrochloride. J. Pharm. Sci. 100, 681–691 28 Choi, H.K. et al. (1999) Effect of additives on the physicochemical properties of liquid suppository bases. Int. J. Pharm. 190, 13–19 29 Naik, A. and Nair, H. (2014) Formulation and evaluation of thermosensitive biogels for nose to brain delivery of doxepin. Biomed. Res. Int. Article ID 847547 30 van der Lubben, I.M. et al. (2001) Chitosan and its derivatives in mucosal drug and vaccine delivery. Eur. J. Pharm. Sci. 14, 201–207 31 Nazar, H. et al. (2011) Thermosensitive hydrogels for nasal drug delivery: the formulation and characterization of systems based on N-trimethyl chitosan chloride. Eur. J. Pharm. Biopharm. 77, 225–232
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32 Nazar, H. et al. (2013) A simple, once-a-day dosage form for the delivery of insulin through the nasal route: in vitro assessment and in vivo evaluation. Biomater. Sci. 1, 306–314 33 Wu, J. et al. (2007) A thermosensitive hydrogel based on quaternized chitosan and poly(ethylene glycol) for nasal drug delivery system. Biomaterials 28, 2220–2232 34 Grasdalen, H. and Smidsroed, O. (1987) Gelation of gellan gum. Carbohydr. Polym. 7, 371–393 35 Cao, S.L. et al. (2007) Preparation of ion-activated in situ gel systems of scopolamine hydrobromide and evaluation of its antimotion sickness efficacy. Acta Pharmacol. Sin. 28, 584–590 36 Cao, S.L. et al. (2009) In situ gel based on gellan gum as new carrier for nasal administration of mometasone furoate. Int. J. Pharm. 365, 109–115 37 Cai, Z. et al. (2011) Formulation and evaluation of in situ gelling systems for intranasal administration of gastrodin. AAPS Pharm. Sci. Tech. 12, 1102–1109 38 Saindane, N.S. et al. (2013) Nanosuspension based in situ gelling nasal spray of carvedilol: development, in vitro and in vivo characterization. AAPS Pharm. Sci. Tech. 14, 189–199 39 Wavikar, P.R. and Vavia, P.R. (2014) Rivastigmine-loaded in situ gelling nanostructured lipid carriers for nose to brain delivery. J. Liposome Res. 9, 1–9 40 Hosny, K.M. and Hassan, A.H. (2014) Intranasal in situ gel loaded with saquinavir mesylate nanosized microemulsion: Preparation, characterization, and in vivo evaluation. Int. J. Pharm. 475, 191–197 41 Galgatte, U.C. et al. (2014) Development of in situ gel for nasal delivery: design, optimization, in vitro and in vivo evaluation. Drug Deliv. 21, 62–73 42 Li, X. et al. (2015) Nasal delivery of analgesic ketorolac tromethamine thermo- and ion-sensitive in situ hydrogels. Int. J. Pharm. 489, 252–260 43 Wang, S. et al. (2012) Formulation and evaluation of microemulsion-based in situ ion-sensitive gelling systems for intranasal administration of curcumin. J. Drug Target. 20, 831–840 44 Krauland, A.H. et al. (2003) Improvement in the in situ gelling properties of deacetylated gellan gum by the immobilization of thiol groups. J. Pharm. Sci. 92, 1234–1241 45 Castile, J. et al. (2013) Development of in vitro models to demonstrate the ability of PecSys1, an in situ nasal gelling technology, to reduce nasal run-off and drip. Drug Dev. Ind. Pharm. 39, 816–824 46 McConaughy, S.D. et al. (2008) Structural characterization and solution properties of a galacturonate polysaccharide derived from Aloe vera capable of in situ gelation. Biomacromolecules 9, 472–480 47 McConaughy, S.D. et al. (2008) Tailoring the network properties of Ca2+ crosslinked Aloe vera polysaccharide hydrogels for in-situ release of therapeutic agents. Biomacromolecules 9, 3277–3287 48 Bertram, U. and Bodmeier, R. (2012) Effect of polymer molecular weight and of polymer blends on the properties of rapidly gelling nasal inserts. Drug Dev. Ind. Pharm. 38, 659–669 49 Bertram, U. and Bodmeier, R. (2006) In situ gelling, bioadhesive nasal inserts for extended drug delivery: in vitro characterization of a new nasal dosage form. Eur. J. Pharm. Sci. 27, 62–71 50 Bertram, U. et al. (2010) In situ gelling nasal inserts for influenza vaccine delivery. Drug Dev. Ind. Pharm. 36, 581–593 51 Farid, R.M. et al. (2013) Formulation and in vitro evaluation of salbutamol sulphate in situ gelling nasal inserts. AAPS Pharm. Sci. Tech. 14, 712–718 52 Watts, P.J. and Illum L. (2007) Pectin compositions and methods of use for improved delivery of drugs to mucosal surfaces. US Patent 6432440 B1 53 Watts, P. and Smith, A. (2009) Pecsys: in situ gelling system for optimized nasal delivery. Expert Opin. Drug Deliv. 6, 543–552 54 Lyseng-Williamson, K.A. (2011) Fentanyl pectin nasal spray: in breakthrough pain in opioid-tolerant adults with cancer. CNS Drugs 25, 511–522 55 Illum, L. (2012) Nasal drug delivery – recent developments and future prospects. J. Control. Release 161, 254–263 56 Velasquez, L.S. et al. (2011) Intranasal delivery of norwalk virus-like particles formulated in an in situ gelling, dry powder vaccine. Vaccine 29, 5221–5231 57 Nazar, H. et al. (2012) Hydrogels in mucosal delivery. Ther. Del. 3, 535–555 58 Smart, J.D. (2012) Nasal and buccal drug delivery: management forum conference. Ther. Deliv. 3, 819–822 59 Djupesland, P.G. (2013) Nasal drug delivery devices: characteristics and performance in a clinical perspective – a review. Drug Deliv. Transl. Res. 3, 42–62
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Smart materials: in situ gel-forming systems for nasal delivery Christina Karavasili and Dimitrios G. Fatouros Q1 Department of Pharmaceutical Technology, School of Pharmacy, Aristotle University of Thessaloniki, 54124, Greece
In the last decade in situ gelling systems have emerged as a novel approach in intranasal delivery of therapeutics, capturing the interest of scientific community. Considerable advances have been currently made in the development of novel formulations containing both natural and synthetic polymers. In this paper we present recent developments on in situ gelling systems for nasal delivery, highlighting the mechanisms that govern their formation. Introduction Q2 Nasal drug delivery has been attracting significant research interest in the last years, as route of multi-variant targeting, employing topical drug administration, systemic drug delivery, as well as brain drug targeting. The nasal cavity has been emerged as an attractive route of administration, from drug molecules to peptides and protein drugs and vaccines, resulting to the successful launch of a plethora of marketed nasal formulations [1]. Oral drug delivery, the most common route of administration, is simpler, improves patient compliance and comfort. Nevertheless, many pharmaceutically active compounds, especially macromolecules, commonly confront the drawback of low bioavailability, ascribed to extended first-pass hepatic metabolism, low permeability across gastrointestinal tract and chemical/ proteolytic degradation [2]. The nasal route has been considered as a viable and efficacious alternative route to tackle these obstacles. Circumvention of the extended first pass metabolism, avoidance of the harsh environment of the gastrointestinal tract, enhanced pharmacokinetic profiles for the lipophilic molecules deriving from the favorable anatomical characteristics of nasal epithelium, brain targeting through the olfactory region and patient compliance can be considered the main advantages of this route of administration [3]. However, the limited capacity of the nasal cavity, the low membrane permeability of hydrophilic molecules, along with the rapid mucociliary clearance effect, constitute the main rate-limiting factors for nasal drug absorption. For that reason, research majorly Corresponding author: Fatouros, D.G. ([email protected]) 1359-6446/ß 2015 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.drudis.2015.10.016
oriented toward the exploitation of bioadhesive agents and/or permeation enhancers for the development of delivery systems able to extend formulation’s residency in the nasal cavity, further improving drug absorption and bioavailability of polar compounds [3], with the recent focus on smart stimulus-responsive systems. Intelligent drug delivery systems responding mainly to physiological stimuli have emerged as an innovative approach for the delivery of therapeutic agents. Owing to their properties, in situ gelling formulations have the ability to undergo a phase transition; a solution to gel formation, triggered either by physiological factors upon intranasal administration (e.g. temperature, ion concentration, water content). As a result, in actual usage these dosage forms can be easily administered as solutions, assuring accuracy in the administered dose, whereas gel formation upon contact with the nasal epithelium is of utter importance to ascertain sufficient contact time and thus improved bioavailability.
Thermo-responsive systems The concept involves the development of mucoadhesive formulations comprising of polymers which exhibit temperature-triggered sol-to gel transitions in the range of 25–37 8C. Below or above this temperature range, early or late gelation might occur, either hindering ease of handling or inducing liquid formulation’s leakage in the outer region of the nostrils.
Synthetic thermo-responsive polymers A commonly used mucoadhesive polymer is Poloxamer 407, which is known to bear thermosensitive properties. Poloxamer 407 undergoes micellization in a concentration and temperature-dependent
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Increasing temperature
Reviews POST SCREEN
Block copolymer solution
Micellization
Gel formation Drug Discovery Today
FIGURE 1
Schematic illustration of the mechanism of in situ gelation of a thermo-responsive polymer as a function of temperature. Upon temperature rise, polymer desolvation accompanied with side chain conformational changes, result in displacement of the hydrating water molecules, modifications of micelles orientation and consequently gel formation.
manner, shifting to gel formation by micellar packing (Fig. 1). The underlying mechanism of gel formation, as a function of temperature, suggests polymer desolvation accompanied with side chain conformational changes, resulting in displacement of the hydrating water molecules and modifications of micelles orientation [4]. The thermo-responsive properties of Poloxamer 407 have been extensively exploited in the development of in situ nasal gels in combination with mucoadhesives, essential for the prolongation of formulation’s residency in the nasal cavity. Driven by the low oral bioavailability of sumatriptan (15%), used in the treatment of migraine, Majithiya et al. [5] developed an in situ gel by utilizing Poloxamer 407 and Carbopol 934P. The gel exhibited a Tsol–gel temperature ranging from 23.9 8C to 29 8C with decreasing Carbopol’s concentration, with the suppression effect on gelation temperature as a function of polymer’s concentration, partly associated to the subsequent increase in viscosity after polymer dissolution. The gel formulation containing 0.3% Carbopol exhibited favorable mucoadhesive properties and significantly enhanced the in vitro drug permeability, compared to the solution form, inducing no structural defects on nasal membrane. In an attempt to confront the extreme variations in the oral bioavailability of metoclopramide hydrochloride (ranging from 32% to 98%), the patient incompliance of parenteral and rectal drug administration and drug’s bitter taste perception, Zaki et al. [6] co-formulated the antiemetic compound with Poloxamer 407, polyethylene glycol (PEG) and an array of mucoadhesive polymers. The results demonstrated that the presence of mucoadhesives increased the viscosity of the gels, thus shifting Tsol–gel temperature toward lower values and delayed metoclopramide release rate. In vivo mucociliary transport time (MTT) measurements indicated prolonged retention of the carbopol containing in situ gel in the rat nasal cavity. Optimized formulation, comprising 0.5% Carbopol, achieved higher serum drug levels and a shorter Tmax, compared to the oral drug solution, also retaining mucosal integrity for extended periods of time after in vivo administration. The limitations in the brain uptake of hydrophilic molecules, compelled Gabal et al. to formulate the anti-parkinsonian ropinirole hydrochloride in nanostructured lipid carriers (anionic and 2
cationic), integrated in Poloxamer 188 in situ gels [7]. The lack of any toxic histopathological findings confirmed the safety of the systems. Both gels (anionic Tsol–gel: 34 8C, cationic Tsol–gel: 33.4 8C) exhibited exceptionally enhanced absolute bioavailability values, when compared to plain ropinirole solution, achieving drug targeting to the brain mainly via the olfactory route. An array of in situ gels of Poloxamer 407 and Poloxamer 188 coformulated with Carbopol 934, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, chitosan and diphtheria toxoid were evaluated for their adjuvanticity after intranasal administration [8]. The intranasal administration of selective formulations, based on their mucoadhesive and in vitro release properties, was found to be inadequate to produce systemic immune response. On the other hand, subcutaneous vaccination accompanied by intranasal administration of the chitosan containing in situ gel, resulted in increased neutralizing antibody titers, facilitating partial protection against diphtheria toxoid. The neuronal uptake for the nose-to-brain delivery of 32P-siRNA dendriplexes was evaluated by Perez et al. [9], in order to circumvent the blood brain barrier. Thermally triggered in situ gels comprised of Poloxamer 407 and two mucoadhesives, namely Carbopol 934P and chitosan, were developed. The results demonstrated that the Carbopol containing formulations displayed optimum rheological properties, exhibiting a Tsol–gel at 23 8C, compared to their congener with chitosan, with the later hindering the release of the siRNA dendriplexes. Histological studies revealed the absence of any epithelial toxicity upon application of the gel formulation, achieving higher levels of radioactivity to the brain, compared to intravenous and intranasal-in-buffer administration. Further studies are also mandatory to substantiate the silencing effect of dendriplexes in vivo. In an effort to regulate the Tsol–gel of an in situ gel at 33.5 8C, Poloxamer 407 was co-formulated with different amounts of Poloxamer 188 and PEG 6000 and paenolol, extracted from the root bark of Paeonia suffruticosa bearing analgesic, antioxidant and anti-inflammatory properties [10]. Authors reported an optimum composition of 22% Poloxamer 407, to enable increased micellar entanglement, 2% Poloxamer 188 and 2% PEG 6000, as Tsol–gel
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regulators and 2% paenolol. Preliminary studies revealed the efficacy of these gels for the treatment of allergic rhinitis by effectively reducing IgE and LTE4 levels, whereas no apparent toxicity was reported after application. Rationalized by the insufficient intranasal residence of ketorolac tromethamine nasal spray, Li et al. [11] developed a hydrogel comprised of Poloxamer 407 and Carrageenan. They observed a concentration-dependant increase of gelation temperature upon inclusion of the non-steroidal, anti-inflammatory drug. Further evaluation of the formulation in vivo, reported a 3-fold increase in bioavailability, compared to its solution congener, and prolonged nasal residency up to 8.8 3.5 h. Nasal ciliotoxicity studies further confirmed the safety and efficacy of the sustained drug release hydrogel for nasal administration. Prompted by the observation that rizatriptan benzoate, an antimigraine agent, undergoes extensive hepatic metabolism upon oral administration, Kempwade and Taranalli [12] explored nasal mucosa as an alternative administration route. They used the cold method to prepare in situ thermo-reversible gels comprised of Poloxamer 407 and Carbopol. A decrease in Tsol–gel was observed upon increase of Carbopol’s concentration from 0.1% to 0.5%. Sufficient mucoadhesiveness was achieved in the presence of 0.3% carbopol, a substantial parameter in order to avoid early formulation drainage from the nasal cavity. Permeation and histopathological studies indicated that this gel might be a promising drug carrier for nasal administration. A dual active postoperative/cancer therapeutic approach was demonstrated recently by El-Setouhy et al. [13] using a Pluronic F127 thermo-responsive gel. Gelation temperature was found to be modulated by both drug (granisetron and ketorolac tromethamine) and mucoadhesive polymers. Carbopol and Pemulen TR2 containing mucoadhesive gels were found to retard drug release and increase in vivo mucociliary transit time (MTT). Prolonged nasal residency accompanied with the induction of significant analgesia after intranasal administration, outranked oral administration, in terms of both first pass metabolism and gastrointestinal adverse effects avoidance. Qian and colleagues [14] developed Pluronic F-127 (20%, w/v) in situ gels for the intranasal delivery of tacrine, incited by its low oral bioavailability (17–24%) and dose-dependent hepatotoxicity. Optimized Tsol–gel was achieved upon addition of Pluronic F-68 and PEG 8000 in concentrations varying from 1–2% to 0.5–1%, respectively. Inclusion of 0.5% chitosan as mucoadhesive and penetration enhancer did not induce any alteration of Tsol–gel. A 2–3 fold higher peak plasma concentration (Cmax), a 3-fold higher tacrine exposure in the brain and a reduction of drug’s metabolites were observed after the in vivo intranasal administration of the gel, compared to the oral solution. The bioadhesive properties of xyloglucan, were evaluated by Kumar et al. [15] in an effort to extent residency in the nasal cavity of a Pluronic F127 in situ gel containing zolmitriptan, an antimigraine drug and ketorolac tromethamine, an anti-inflammatory drug,. Results pointed to a significant increase in drugs’ bioavailability (21% for zolmitriptan and 16% for ketorolac tromethamine) after intranasal administration, compared to the oral route. An almost 10-fold longer mucociliary transport time, was reported in a study by Chen et al. [16], when curcumin was incorporated into a thermosensitive in situ gel comprised of
REVIEWS
Pluronic F127 and Poloxamer 188, resulting in extended drug retention in the nasal cavity, compared to plain curcumin solution. Optimized formulation demonstrated increased brain tissue distribution of curcumin after intranasal administration and similar AUCplasma, when compared to i.v. injection, while at the same time mucosal integrity maintenance was kept for 14 consecutive days after in vivo application. A direct nose-to-brain lorazepam delivery was attempted by Jose et al. [17] using Pluronics as the thermo-responsive gelling agents, so as to eliminate non-specific drug distribution and limited brain uptake, after oral and intravenous administration. The authors reported a sustained release of lorazepam from chitosan microspheres, when dispersed in a gel carrier comprised of 21% Pluronic F 127 and 1% Pluronic F 68. Histopathological examination further confirmed the safety of the delivery system for nasal application. Poloxamer 407 based thermo-reversible gelling systems were developed by Ved and Kim [18] for the intranasal administration of zidovudine, since the drug’s transport across the BBB is limited, also undergoing extended hepatic metabolism after oral administration. Optimal permeation enhancing effects were observed in the presence of 0.1% n-tridecyl-b-d-maltoside. Increased bioavailability values and cerebrospinal fluid accumulation were obtained after intranasal administration of the optimized formulation, compared to intravenous administration of drug’s solution. Results clearly indicated the direct nose-to-brain transport of almost total drug content via the olfactory route, while on the other hand only 0.7% of the systematically administered drug accumulated in the brain tissue. The hydrophilic antidepressant agent venlafaxine hydrochloride, encounters limited BBB permeability, short half-life, extensive hepatic effect and low oral bioavailability (45%). Therefore, the nasal route was validated as an alternative to oral administration and venlafaxine was co-formulated with the thermo-responsive polymer Lutrol F127 and an array of mucoadhesive polymers (Carbopol 934P, HPMC K4M, PVP K30, sodium alginate, Tamarind seed gum and Carrageenan) [19]. For the optimum Lutrol F127 concentration (18%), gel properties were further reformed by adjusting mucoadhesives’ concentration. Results demonstrated decrease in Tsol–gel and increase in mucoadhesive strength of the produced gels, upon rising mucoadhesives’ concentration. Optimized formulations with Tsol–gel temperature at 30–33 8C, exhibited an almost total permeation of the drug across sheep nasal mucosa at the time scale of 150 min. In vivo pharmacodynamic studies demonstrated the superiority of the nasal formulation, exhibiting optimum antidepressant effectiveness compared to its oral congener. The same compound was incorporated into gels comprised of Poloxamer 407 and methyl cellulose [20]. Gelation temperature was determined at 33.4 8C and methyl cellulose was found to both enhance adhesion strength of the gels, a crucial parameter for prolonged residence in the nasal cavity and decelerate drug release rate. Ex vivo permeation studies pointed at a total amount of 87.3% of the initial drug concentration permeated across sheep nasal mucosa, while histopathological evaluation did not reveal any tissue impairment. Rationalized by the principle that cyclodextrins can increase the aqueous solubility of poorly soluble compounds, Singh et al. [21]
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have incorporated loratadine-b-CD complexes into Poloxamer 407 and Carbopol 934P nasal gels, in an attempt to circumvent drug’s rapid first-pass hepatic metabolism and its low oral bioavailability (40%). In situ gel formulations reported a gelling temperature range between 27.3 8C and 35.3 8C. Increase in the amount of polymers fortified molecular entanglement via hydrogen bonding, promoted micellar association, which in turn decreased Tsol–gel temperature. Increased viscosity values were recorded as a function of carbopol 934P concentration, in an attempt to retard mucociliary clearance rate. Transport studies across sheep nasal mucosa revealed that more than 90% of the drug could be permeated at the time scale of 6 h, without inducing changes in epithelium physiology. Toward the same direction, Balakrishnan et al. [22] utilized the mucoadhesive properties of Carbopol 934P (0.1%, w/v) and the solubilization capacity of hydroxypropyl-b-cyclodextrin (10%, w/v), to increase the intranasal absorption and the aqueous solubility of fexofenadine, a non-sedating, non-anticholinergic H1-receptor, used for allergic rhinitis with low oral bioavailability (13–16%). The resulting in situ gel comprising Poloxamer 407 (17%, w/v) reported a Tsol–gel temperature at 29.7 0.1 8C and an 11.3-fold increase in fexofenadine’s relative bioavailability over drug solution.
Natural thermo-responsive polymers In a study aiming to assess the effectiveness of a natural mucoadhesive polymer extracted from F. carica, compared to synthetic congeners (hydroxypropylmethyl cellulose and Carbopol 934), the anti-epileptic agent midazolam hydrochloride was co-formulated with these polymers at different ratios and was further evaluated [23]. The results demonstrated higher adhesive strength values for the mucilage based gels, which in turn proved to be safe for the nasal administration of midazolam, achieving higher absolute bioavailability values of the drug. These naturally occurring mucilage gels were proposed by the authors as a cost-effective and efficient system for the nasal administration of midazolam. Xyloglucans constitute another group of thermosensitive materials, naturally occurring in plants, able to transform from sol to gel structures upon temperature rising. On this basis, Mahajan et al. [24] developed xyloglucan in situ gels containing ondansetron hydrochloride as a model drug. Ondansetron exhibits low (i.e. 45%), inconsistent bioavailability, potentially due to high hepatic first-pass metabolism and high P-gp efflux, therefore thermo-responsive gels could serve well to increase the residence time of the drug. The gel formulations containing 2.5% (w/w) xyloglucan, reported favorable gel strength values and almost total drug permeation after the 4 h ex vivo study across sheep nasal mucosa. The intranasal administration of the in situ gel in rabbits demonstrated significantly higher bioavailability values, compared to the per oral administered drug solution, suggesting the potential of this formulation. The same authors [25] further assessed the improvement of mucoadhesive properties of the xyloglucan gels, after thiolation. The modified xyloglucan gels containing ondansetron showed a Tsol–gel in the range of 25–30 8C and improved bioadhesiveness, as compared to that of xyloglucan congener, possibly ascribed to disulfide bond interactions developed between the mucus and the thiolated polymer. Ex vivo studies across sheep nasal mucosa 4
Drug Discovery Today Volume 00, Number 00 November 2015
revealed significantly higher permeability coefficient values of ondansetron for the thiolated derivative, with no toxic effect observed after exposure of nasal epithelium to these gels. Chitosan, a natural polysaccharide derived by N-deacetylation of chitin, is considered as a biocompatible and biodegradable polymer bearing mucoadhesive properties [26]. These properties prompted Cho and his co-workers [27] to integrate chitosan into thermo-reversible gels comprising of Poloxamer 407, hydroxypropyl-b-cyclodextrin (Hp-b-CD) and fexofenadine hydrochloride. The slight increase observed in the Tsol– gel of the formulation from 29.9 to 30.5 8C was attributed to the presence of acetic acid, a chitosan solubilizer, which can cause a weakening to hydrogen bonding, affecting the physicochemical properties of the formulation [28]. A critical enhancement in drug’s permeation across cell monolayers was attributed to the synergistic effect of both chitosan and Hp-b-CD. In vivo studies in rabbits revealed the superiority of the thermo-responsive formulation, which exhibited a 18-fold higher bioavailability, compared to the control (nasal solution). Naik and Nair [29] in their effort to design a system for the delivery of the antidepressant doxepin prepared thermosensitive gels comprising chitosan (2%, w/v) and glycerophosphate in the presence and absence of polyethylene glycol. Although PEG addition did not affect gelation temperature, it significantly increased drug retardation. Both formulations proved to be effective on their anti-depressant activity, showing at the same time proper compatibility with the nasal epithelium. Since the oral administration of doxepin is accompanied by poor and variable bioavailability (13–45%), the nasal delivery of the drug is featured as a promising alternative. Despite the intensive use of chitosan in pharmaceutics its low aqueous solubility in neutral and basic pH values has limited its effectiveness as absorption enhancer. To tackle this problem, chitosan derivatives [e.g. trimethylchitosan (TMC)] readily soluble at these conditions have been synthesized [30].
Synthetic thermo-responsive derivatives from natural polymers Chitosan derivatives (TMC) with different average molecular weight and degree of quaternisation demonstrated thermosensitive behavior when co-formulated with polyethylene glycol and glycerophosphate. The gels containing TMC of medium average molecular weight and low degree of quaternisation with a Tsol–gel at 32.5 8C, exhibited exceptional mucoadhesive behavior and rheological properties, holding promise for nasal delivery [31]. In a subsequent study from the same workers, these formulations containing insulin were administered in vivo in a diabetic rat model, demonstrating a reduction in blood glucose over ca.24 hours [32]. A marked decrease in transepithelial resistance of Calu3 cell monolayers was observed after the application of the hydrogel formulation, interpreted as tight junction opening for the paracellular transport of insulin. The in situ TMC gels revealed prolonged residency in the nasal cavity, due to retardation of the mucociliary clearance, effect mainly attributed to the viscous nature of the hydrogels and the bioadhesiveness of TMC. Overall, results signify the potential of the thermosensitive system as a once-a-day dosage form for the nasal delivery of insulin. In an earlier study, a thermosensitive hydrogel comprised of N[(2-hydroxy-3-trimethylammonium) propyl] chitosan chloride,
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poly (ethylene glycol), a-b-glycerophosphate and insulin was evaluated for the effectiveness of its hypoglycemic activity. Enhanced insulin uptake was observed for the hydrogel formulation, with concurrent maintenance of cell integrity. In vivo nasal application in rodents, resulted in a decrease of blood glucose concentration (40–50% of initial blood glucose concentration) ca. 5 h after administration, further corroborating toward the exploitation of chitosan derivatives in the effective intranasal administration of hydrophilic macromolecules [33].
Ion responsive systems An approach toward the formation of in situ gels involves the presence of ion responsive agents. Gellan gum, an anionic polysaccharide, undergoes gelation under physiological ion concentration. The cation-induced gelling process is ascribed to double helical junction zones formation and inter-helical interaction, resulting in a three-dimensional network via cations complexation. The abundance of cations, especially Ca2+, naturally occurring in nasal fluids, enables in situ gelation of gellan gum formulations upon contact with nasal mucosa, sustaining their residency in nasal cavity, thereby improving drug absorption [34]. The variable and poor bioavailability (10–48%) of orally administered scopolamine, motivated Cao et al. [35] to formulate a nasal dosage form, examining the significance of a gellan gum composition within the process of gelation. Increased viscosity values were recorded as a function of polymer’s concentration, followed by retardation of drug release rate from the gels. In vivo studies were conducted in an experimental rat model with gels comprising of the optimum gellan gum concentration (0.5%, w/v), achieving therapeutic levels of the anti-muscarinic agent, without being toxic on nasal epithelium. The same workers, in an effort to achieve better nasal absorption efficacy of mometasone furoate, than the marketed nasal spray in suspension form, developed a new system, co-formulating xanthan gum and gellan gum at a concentration of 0.5% (w/v), thus improving the physicochemical properties (viscosity and redispersion) of the formulation [36]. Gelation was visually inspected after mixing the in situ gel and artificial nasal fluid. The authors reported that the formulation exhibited considerable stability during storage for a long period and effectiveness in suppressing the symptoms of allergic rhinitis in rats in vivo. Histopathological evaluation of the nasal epithelium further documented the safety of the formulation. Data generated by Cai et al. [37], further support the efficiency of 0.5% (w/v) in situ gels of gellan gum, when tested for the nasal administration of gastrodin. Formulations demonstrated favorable rheological properties; immediate gelling when mixed with artificial nasal fluid, prolonged stability, no obvious ciliotoxicity and enhanced pharmacodynamic action, compared to the oral formulation. An analogous approach was adopted by Saindane et al. [38], who have reported the co-formulation of carvedilol, a b2-adrenergic receptor antagonist, with gellan gum at the same concentration as previously reported (0.5%, w/v) for the development of an in situ gelling nasal spray. Formulations gelated rapidly upon contact with simulated nasal fluid, achieving sustained in vitro drug release and higher bioavailability values, when compared to the orally administered formulation of the drug.
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Rivastigmine’s hydrophilicity and short half-life necessitated the development of more efficient dosage forms and routes of administration. Nanostructured lipid carriers of rivastigmine were integrated in an in situ gelling system comprised of 0.8% gellan gum and 15% Lutrol F 127 [39]. In situ gels of favorable organoleptic properties namely; elasticity, rheology and mucoadhesiveness reported a 1.6-fold increase of drug’s permeation across nasal mucosa, compared to plain drug solution and a 3-fold increase in enzyme inhibition efficacy. Saindane et al. [38] utilized a nanosuspension of carvedilol incorporated in an ion-responsive gelling phase, to formulate an in situ gelling nasal spray, since drug suffers from low oral bioavailability (25–35%) and a short plasma half-life (6 h). A modified ultrasonication-precipitation method was adopted for the preparation of the stable drug nanosuspension, which was thereafter integrated in the in situ gelling phase. Optimized formulations containing 0.5% (w/v) gellan gum, demonstrated favorable rheological properties prior and after contact with nasal fluids and retardation in the release profile of carvedilol. Further in vivo evaluation in rabbits, demonstrated a 2.7-fold higher bioavailability of the nasal spray, compared to the orally administered formulation. Hosny et al. [40] formulated a nanosized microemulsion of saquinavir mesylate (SM) in a 0.5% (w/v) deacetylated gellan gum in situ gel, in order to confront drug’s poor oral bioavailability. Optimized formulation of appropriate gel strength was subjected to ex vivo permeation studies across goat nasal mucosa, exhibiting a 6.5-fold enhancement in drug’s permeation for the in situ gel, than for drug’s suspension. In vivo pharmacokinetic studies demonstrated the superiority of the ion responsive formulation, compared to the marketed oral tablet product, reporting a 12-fold increase in drug’s bioavailability. In an attempt to overcome the extensive hepatic metabolism of sumatriptan succinate (SS) after oral administration, Galgatte et al. [41] employed deacetylated gellan gum as the ion-responsive gelling agent for the intranasal administration of sumatriptan. Formulation of optimal properties, with regard to viscosity and mucoadhesive strength, consisted of 0.2% (w/v) gellan gum and exhibited complete in vitro drug release and enhanced permeation across sheep nasal mucosa. Pharmacokinetic studies confirmed the superiority of the intranasal in situ gel of the SS, which achieved 1.44 times higher AUC value in the brain tissue, over the oral SS solution. The drug targeting index, as calculated after the intranasal administration of the in situ gel in rats, suggested a possible direct transport of sumatriptan succinate through the olfactory pathway. The synergistic in situ response of a thermally triggered and an ion responsive hydrogel was exploited by Xin et al. [42] for the development of a smart delivery system of ketorocal tromethamine, since the already marketed nasal spray encounters short resident times in the nasal cavity. Deacetylated gellan gum (3%, w/v) and Poloxamer 407 (18%, w/v) as the ion- and thermoresponsive polymers, along with azone, sulfobutyl ether-b-cyclodextrin (2.5%, w/v) and chlorobutanol (0.5%, w/v) as permeation enhancers and the bacterial inhibitor, respectively, were combined to formulate these gels. In situ gels exhibited superior pseudoplastic behavior, longer retention on nasal mucosa over drug solution, hence favoring drug absorption, negligible ciliotoxicity, sustained drug release and good analgesia effect.
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Ca2+
O OH
OH
O
O
Polysaccharide chains
O
HO
O O –
– O O O HO
O
Drug Discovery Today
FIGURE 2
Ion induced in situ gelation of anionic polysaccharides (e.g. pectin) in the presence of divalent cations. Ionic interactions developed between divalent cations and the functional groups of pectin chains, lead to the formation of an ordered three-dimensional network in the gel structure.
Wang et al. [43] evaluated the intranasal administration of curcumin in the form of a micro-emulsion based ion-responsive hydrogel. On that basis, Capryol 90, Solutol HS15 and Transcutol HP were added as the oil phase and the surfactants, respectively, whereas deacetylated gellan gum (DGG) was introduced at a concentration of 0.3% in the water phase. The selected concentration of DGG was a compromise between formulation’s prolonged residency in the nasal cavity and mucosal tolerability. The apparent safety of the system was confirmed by the absence of any histopathological tissue alterations after intranasal administration in rats. Absolute bioavailability values of curcumin after intranasal administration of the in situ gel were found to be significantly higher, compared to the respective values after per oral administration. Brain targeting index, calculated after nasal administration of the in situ gel, pointed toward a direct nose-to-brain curcumin transport. In vitro experiments by Krauland et al. [44] have shown that thiolation of deacetylated gellan gum via cysteine conjugation improved the viscoelastic properties of the formulation, as a result of the additional inter- and intra-molecular cross linking between the polymer and the amino acid. The in situ gelling properties of the modified polymer were significantly enhanced, even at physiological cations concentrations, enabling the extension of formulation’s residency on mucosal surfaces. Owing to its properties to form hydrogels in the presence of divalent cations abundantly found in physiological nasal secretions, pectin, a natural polysaccharide, is a commonly used excipient for nasal drug delivery systems. The underlying mechanism includes ionic interactions developed between cations and functional groups of pectin chains, 6
leading to the formation of an ordered three-dimensional network in the gel structure (Fig. 2). This approach has been exemplified by Castile et al. [45] who investigated the deposition and gelling characteristics of PecSys, low methoxy pectin. For this reason, an anatomical nasal cast model treated with adequate Ca2+ concentration was employed, demonstrating a significant reduction in dripping of the PecSys in situ gel from the site of deposition, compared to a non-gelling control. The practical utility of pectin in situ gel has been evaluated in clinical trials for the nasal administration of fentanyl, used in the management of cancer pain and further corroborated by the findings of the in vitro models developed by Castile et al. Pectin extracted from Aloe Vera plant has been investigated as a component for the development of in situ gels [46]. The authors demonstrated the ability of the polysaccharide to form gels even at polymer and Ca2+ concentrations as low as 0.2% (w/v) and 10 mM respectively, claiming their technological functionality for the nasal route of administration. In a subsequent study [47], the same authors investigated the mechanism of in situ gelation between Aloe vera and Ca2+ via crosslinking, as a function of molecular weight, ionic strength, and molar ratio of Ca2+ to COO by means of dynamic oscillatory rheology and pulsed field gradient NMR (PFG-NMR) determinations. Diffusion rates of model macromolecules from the hydrogels were discussed in light of hydrogels morphology, highlighting the importance of polymers’ concentration and electrolyte ionic strength. An overview of the temperature- and ion-responsive in situ gelling systems and their application in drug delivery is presented in Table 1.
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TABLE 1
Stimulus responsive agent
Triggering factor
Concentration (%, w/v)
Formulation excipients
Tsol–gel (8C, optimized formulation)
Active
Ref.
Poloxamer 407
Temperature
18
Carbopol 934P
25.9
Sumatriptan
[5]
Poloxamer 407
Temperature
18
Chitosan, hydroxypropyl cellulose, PEG (400 and 6000), Carbopol 934P, PVA
31 0.5
Metoclopramide HCl
[6]
Poloxamer 407
Temperature
23
Chitosan, Carbopol 974P
23.0
siRNA
[9]
Poloxamer 407
Temperature
20
Carrageenan
35.0
Ketorolac Tromethamine
[11]
Poloxamer 407
Temperature
18
Carbopol 934P
31–32
Rizatriptan Benzoate
[12]
Poloxamer 407
Temperature
17
Carbopol 974P, PemulenTM TR-2, HPMC
30.83 0.29
Granisetron HCl, Ketorolac Tromethamine
[13]
Poloxamer 407
Temperature
20
Chitosan, Pluronic F-68, PEG-8000
28.5 0.2
Tacrine
[14]
Poloxamer 407
Temperature
20
Xyloglucan, Sodium alginate, PEG (4000 and 6000)
27.4 0.2
Zolmitriptan, Ketorolac Tromethamine
[15]
Poloxamer 407
Temperature
20
n-Tridecyl-b-dmaltoside, Carbopol 934P, HPC and HPMC
27–30
Zidovudine
[18]
Poloxamer 407
Temperature
18
Carbopol 934, PVP K30, HPMC K4M, sodium alginate, tamarind seed gum, Carrageenan
31.17 0.30
Venlafaxine HCl
[19]
Poloxamer 407
Temperature
17
Methocel A4M
33.40 1.63
Venlafaxine HCl
[20]
Poloxamer 407
Temperature
20
Carbopol 934 P, bcyclodextrin
28.6 0.47
Loratadine
[21]
Poloxamer 407
Temperature
17
Carbopol 934P, hydroxypropyl-bcyclodextrin
29.70 0.1
Fexofenadine HCl
[22]
Poloxamer 407
Temperature
16
Ficus carica Mucilage, HPMC, Carbopol 934, sodium taurocholate
27.20 0.33
Midazolam
[23]
Poloxamer 407/188
Temperature
15/12 or 12/12
HPMC, anionic and cationic nanostructured lipid carriers
34 or 33.2
Ropinirole HCl
[7]
Poloxamer 407/188
Temperature
18/10
Carbopol 934, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, chitosan
29
Diphtheria toxoid
[8]
Poloxamer 407/188
Temperature
22/2
b-CD, PEG6000
33.5 0.29
Paeonol
[10]
Poloxamer 407/188
Temperature
20/2
–
32 0.5
Curcumin
[16]
Poloxamer 407/188
Temperature
21/1
Chitosan microspheres
37.0
Lorazepam
[17]
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Temperature and ion responsive in situ gelling systems.
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TABLE 1 (Continued )
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Stimulus responsive agent
Triggering factor
Concentration (%, w/v)
Formulation excipients
Tsol–gel (8C, optimized formulation)
Active
Ref.
Poloxamer 407
Temperature
17
Hydroxypropyl bcyclodextrin, chitosan
30.5 0.15
Fexofenadine hydrochloride
[27]
Poloxamer 407/deacetylated gellan gum
Temperature/ion
15/0.8
Nanostructured lipid carriers
Proper viscosity at 37 8C
Rivastigmine
[39]
Poloxamer 407/deacetylated gellan gum
Temperature/ion
18/3
Sulfobutyl etherb-cyclodextrin, chlorobutanol, HP-b-CD, azone
Proper viscosity at 37 8C
Ketorolac Tromethamine
[43]
Chitosan/glycerophosphate
Temperature
2/10
PEG 4000
37 0.4
Doxepin
[29]
Trimethylchitosan/glycerophosphate
Temperature
3.6
PEG 4000
32.5 0.4
–
[31]
Trimethylchitosan/glycerophosphate
Temperature
4.5
PEG 4000
35
Insulin
[32]
N-[(2-Hydroxy-3-trimethylammonium) propyl] chitosan chloride/ glycerophosphate
Temperature
3.6 (w/w)
PEG 4000
37
Insulin
[33]
Xyloglucan
Temperature
2.5 (w/w)
–
27–28
Ondansetron
[24]
Thiolated xyloglucan
Temperature
2.5 (w/w)
–
25–30
Ondansetron
[25]
Gellan gum
Ion
0.5
–
–
Scopolamine hydrobromide
[35]
Gellan gum
Ion
0.5
Xanthan gum
–
Mometasone furoate
[36]
Gellan gum
Ion
0.5
Poloxamer 407 and Oleic acid nanosuspension
–
Carvedilol
[38]
Deacetylated gellan gum
Ion
0.5
–
–
Gastrodin
[37]
Deacetylated gellan gum
Ion
0.5
Labrafac PG, Labrasol, Transcutol HP (nanosized microemulsion)
–
Saquinavir mesylate
[40]
Deacetylated gellan gum
Ion
0.2
PEG 400
–
Sumatriptan succinate
[41]
Deacetylated gellan gum
Ion
0.3
Solutol HS, Transcutol HP, Capryol 90 (nanosized microemulsion)
–
Curcumin
[43]
Other strategies of in situ gelation In situ gelling nasal inserts Another strategy toward the intranasal drug delivery involves the development of in situ gelling nasal inserts based on bioadhesive polymers, able to form gels upon contact with nasal mucosa (Fig. 3) [48]. Freeze-drying technique has been utilized to produce solid insert materials with porous structures to ensure water penetration for gel formation (Fig. 3). The mechanism proposed to explain the mucoadhesive behavior of the inserts considers the interactions between the bioadhesive polymers and mucin, which in turn enables the sustained release of the active in a controlled manner governed by the polymer’s properties. Gradual decomposition of the gel combined with the mucociliary clearance effect enables the removal of the insert from the nasal cavity. Driven by this demand, Bertram et al. [49] evaluated the effectiveness of rapidly in situ gelling inserts for nasal administration. A 8
series of hydrophilic mucoadhesive polymers were co-formulated with oxymetazoline as the model drug, molded and frozen to produce the inserts via lyophilization. Freeze drying procedure resulted in highly porous sponge-like inserts, a prerequisite to assure rapid hydration and gelation upon contact with nasal mucosa. Based on the physical properties of the selected polymers, it was outlined that a molecular weight of 100,000 is required for proper bioadhesion to be achieved. Increase in polymer’s MW resulted in gels of higher viscosity, lower dissolution rate and hence longer retention times in the nasal cavity, with the same effect also provoked by high polymer concentrations. Water uptake, the crucial step for gelation of the inserts, was determined to affect drug’s release rate, correlating low water uptake with slower drug release rates. Carrageenan, xanthan gum and carboxymethylcellulose sodium (NaCMC) assembled optimal characteristics as main matrix components of the nasal inserts, necessitating further evaluation of these extended drug release systems.
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FIGURE 3
In situ gelation of solid nasal inserts upon contact with the nasal mucosa. Water uptake results in hydration of the polymer matrix and rapid gelation.
A subsequent investigation from the same group [50] evaluated nasal inserts for influenza vaccine delivery, composed of varying polymers, as well as permeation enhancing agents. Nasal inserts of sponge-like form consisting of bioadhesive polymers were the most effective, in regard to the induction of IgG serum response, as a result of their ability to prolong nasal residency. Xanthan gum, as matrix component of the inserts and cationic lipid, as adjuvant, were found to generate comparable IgG levels as the plain nasal liquid vaccine formulation, highlighting the potential of the inserts, also as storage containers for the stability enhancement of the antigens. The film casting method was introduced by Farid et al. [51] for the preparation of in situ gelling nasal inserts containing an array of mucoadhesive polymers, namely; sodium alginate (SA), chitosan, hydroxypropylmethylcellulose and carboxymethylcellulose sodium (CMC Na) co-formulated with salbutamol sulphate (1.4%, w/w), as the model drug. Higher water uptake values were reported for the SA and CMC Na polymers, as a result of their ionic nature. The same polymers demonstrated a positive mucoadhesion effect, despite their negative charge, possibly due to their hydrogen bonding capacity and expanded structural conformation, and a retardation in the release rate of salbutamol sulfate from the hydrogels. Nasal inserts demonstrated favorable water uptake, mucoadhesive and drug release properties, accredited to the presence of AL and CMC Na polymers.
Marketed products and clinical studies Considerable effort has been directed toward the development of in situ gelling systems using the natural polysaccharides pectins. Alterations to the gelation properties of pectin can be fine-tuned by the degree of esterification of the galacturonic acids [52]. As a result, a pectin-based system co-formulated with the opioid analgesic fentanyl, PecFent1 was approved for marketing in Europe in 2009 and in the USA in 2011 [53–55]. An inactivated H5N1 influenza vaccine based on the GelVac1 nasal powder formulation has been approved for human testing by the FDA, and a phase I clinical study is underway. GelVac1 is comprised of GelSite1, an
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Aloe vera L.-derived polysaccharide polymer with mucoadhesive properties [55,56].
Conclusion and future directions In situ gelling formulations have risen as emerging drug delivery systems for nasal drug administration, comprising of polymeric materials able to undergo a sol–gel conversion, when exposed to biological stimuli. Integration of mucoadhesive polymers in in situ gelling systems has been proved to amplify drug absorption by prolonging residency in the nasal cavity. The mucociliary clearance (MCC; ca. 4–6 mm/min), the nose-specific enzymatic activity and the high rate of mucus turnover (resting-state daily production, 75–150 mL) are additional barriers to nasal drug delivery [57]. Consequently, the development of longer acting bioadhesive formulations regulating bioadhesive performance is pressing issue. Nasal cavity is capable of eliciting strong systemic and local immune responses. The encapsulation of the antigen into bioadhesive in situ gels is a promising approach toward successful nasal vaccine delivery [58]. Additionally, an increasing number of studies [7,9,16–18,29,39] have shown that nose-to-brain drug transport offers an attractive alternative to formulation strategies attempting to enhance drug penetration into the CNS. Finally, the complexity of nasal cavity combined with the different properties of the actives (small drugs, peptides, proteins, vaccines) delivered via the nasal route is leading to emerging nasal delivery devices and dispersing technologies, in an attempt to maximize the clinical performance of the formulations [58]. The use of smart polymers can significantly improve the transport of actives across nasal mucosa, counterbalancing the limitations posed by nasal epithelium. Therefore, in situ gel-forming nasal systems show considerable promise in delivery of therapeutics and rapid onset of action. Although at its infancy, in situ gelling formulations are very promising as a new platform in the field of drug discovery and delivery.
Uncited reference [59].
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