Review
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Cyclodextrin-based nanosponges: a propitious platform for enhancing drug delivery 1.
Introduction
2.
Applications
3.
Conclusion
4.
Future scenario
5.
Expert opinion
Sai V Chilajwar†, Priti P Pednekar, Kisan R Jadhav, Gajendra JC Gupta & Vilasrao J Kadam University of Mumbai, Bharati Vidyapeeth’s College of Pharmacy, Department of Pharmaceutics, Navi-Mumbai, India
Introduction: Recently, Nanotechnology is receiving considerable acknowledgment due to its potential to combine features that are difficult to achieve by making use of a drug alone. Cyclodextrin-based nanosponges are yet another contemporary approach for highlighting the advancements which could be brought about in a drug delivery system. Statistical analyses have shown that around 40% of currently marketed drugs and about 90% of drugs in their developmental phase encounter solubility-related problems. Cyclodextrin-based nanosponges have the capacity to emerge as a productive approach over conventional cyclodextrins by overcoming the disadvantages associated with the latter. Areas covered: This review is intended to give an insight regarding cyclodextrin-based nanosponges such as their physical and chemical properties. In addition, methods of preparation and characterization are discussed along with biocompatibility, and how these nanomeric elements can be exploited in developing effective drug formulations. Expert opinion: This emerging technology of cyclodextrin-based nanosponges is expected to provide technical solutions to the formulation arena and to come up with some successful products in the pharmaceutical market. It also has an exciting future in the field of therapeutics wherein it can cater site-directed drug delivery and hence it possesses vibrant opportunities. Keywords: b-cyclodextrin, drug delivery, encapsulation, nanosponges, solubility Expert Opin. Drug Deliv. (2014) 11(1):111-120
1.
Introduction
The hunt for an efficient drug delivery system is an enigma in itself. Our medical researchers and formulation scientists are always surrounded by issues pertaining to drug targeting, drug release, overdosing, solubility, permeability, activity and bioavailability. Thus, creating or improving systems for drug delivery is an area of ongoing research. As soon as nanotechnology has turned up in the limelight, its bright prospects in medicine have been hailed enthusiastically. The advent of cyclodextrin-based nanosponges has paved the way to alleviate the above limitations and has gained a tremendous impetus in drug delivery. Scientists De Quan Li and Min Ma have coined the term ‘cyclodextrin nanosponges’. We have tried to explore the profound ability of these nanosponges in enlivening the domains of drug delivery. Cyclodextrins are cyclic oligomers of D-glucopyranose units linked by (a-1, 4) linkages. A cyclodextrin has a characteristic toroidal structure with primary hydroxyl groups extending from the narrow edge and secondary hydroxyl groups extending from the wider edge which impart to cyclodextrins their peculiar hydrophilic outer surface and a lipophilic cavity. This forms the basis for the delivery of both 10.1517/17425247.2014.865013 © 2014 Informa UK, Ltd. ISSN 1742-5247, e-ISSN 1744-7593 All rights reserved: reproduction in whole or in part not permitted
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Cyclodextrin-based nanosponges are a promising and an innovative form of a drug delivery system which comprises a nanostructured three-dimensional network of crosslinked cyclodextrin molecules with a porous structure capable of encapsulating hydrophilic as well as hydrophobic drug molecules. They are biocompatible, nontoxic and safe for use. The drug release from these nanosponges can be customized by tuning the type and degree of crosslinking. They possess numerous advantages ranging from improved solubility, stability, permeation, bioavailability, modulation of drug release to efficient drug targeting in case of anticancer therapeutics. In addition, delivery of proteins, enzymes and gases is possible. There is a scope for a vibrant future in research and development of cyclodextrin-based nanosponges.
This box summarizes key points contained in the article.
lipophilic as well as hydrophilic drug moieties. The three main native cyclodextrins are a, b and g, which comprise six, seven and eight glucopyranose units, respectively [1]. However, these native cyclodextrins have many drawbacks. They cannot form inclusion complexes with all drugs; moreover, b-cyclodextrins have poor water solubility and is reported to be toxic when injected intravenously [1-6]. Hence, many researchers are coming up with new strategies to improve the technological characteristics of cyclodextrins. In the present review, we describe an emerging approach to prepare multifunctional cyclodextrin derivatives by bringing about crosslinking of cyclodextrin polymers. Cyclodextrin-based nanosponges are tiny, mesh-like structures, resembling ‘sponges’ microscopically, 200 -- 500 nm in diameter that can be loaded with a wide array of drugs [7]. Cyclodextrin-based nanosponges are hypercrosslinked polymers of cyclodextrins which are prepared by crosslinking the native a-, b- and g-cyclodextrins with an appropriate crosslinking agent. There are various crosslinkers which could be employed. They include an active carbonyl compound, such as, carbonyldimiidazole, triphosgene, diphenyl carbonate, or organic dianhydrides [6]. Table 1 gives an account of the formulation of cyclodextrin-based nanosponges. The cyclodextrin-based nanosponges so obtained are spherical, basically, a scaffold structure possessing many cavities (or pockets) where drug molecules can be entrapped [8]. The terminology ‘cyclodextrin nanosponges’ was originally used by De Quan Li and Min Ma in 1998 to signify a b-cyclodextrin, crosslinked by diisocyanates which when observed microscopically showed a porous structure and had a very high inclusion constant with quite a lot of organic pollutants [6,9]. The crosslinking can be modulated according to the release rate requirements. It has been observed that more the cross linking, slower will be the drug release and vice versa. Hence, 112
the drug can be released on predictive manner by tuning the degree of crosslinking [10]. Cyclodextrin-based nanosponges can be prepared by two techniques namely solvent evaporation technique and ultrasound-assisted synthesis. General scheme for the preparation of cyclodextrin-based nanosponges is described in Figure 1. As the name ‘solvent evaporation’ suggests, cyclodextrins are refluxed with solvents such as ethanol, dimethylformamide, dimethylacetamide in the presence of an excess quantity of crosslinker preferably the ones with carbonyl group in it. Once the reaction gets over, the mixture is allowed to cool and is poured into excess of distilled water. The product is recovered by vacuum filtration. Purified product is obtained by Soxhlet extraction process which is followed by grinding in mill to get the powder form of the cyclodextrin-based nanosponges. Figure 2 summarizes the steps involved in the preparation of cyclodextrin-based nanosponges by the solvent evaporation technique [7,8]. Unlike the solvent evaporation technique, the ultrasound-assisted technique does not require solvents in the synthesis of cyclodextrin-based nanosponges. In addition, it has been reported that the nanosponges obtained by ultrasound technique are spherical and uniform in size. The mixture of cyclodextrin and the crosslinking agent are taken in a flask which is placed in an ultrasound bath filled with water under temperature conditions of 90 C, which is then subjected to sonication. The product, thereby, obtained is allowed to cool. It is washed with water to remove traces of any unreacted product. Purified nanosponges are obtained by carrying out Soxhlet extraction method using ethanol. Figure 3 outlines the events during the synthesis of cyclodextrin-based nanosponges by ultrasound-assisted synthesis [7,8].The drug is then loaded subsequently in these nanosponges which could be prepared by either of the two abovementioned methods. Figure 4 demonstrates the processes involved during the loading of drug molecule in cyclodextrin-based nanosponges. Importantly, some factors such as nature and type of cyclodextrin, temperature, degree of substitution, type of drug and the like affect the nanosponge formation [7,8]. A comprehensive characterization of cyclodextrin-based nanosponges, including Fourier transform infrared radiation (FTIR), nuclear magnetic resonance, X-ray diffraction, microscopy, thermal analyses, solubility studies, zeta potential and the like help in confirming the inclusion complexes formed [6-8]. It is noteworthy that they are safe because of biodegradable material with negligible toxicity on cell cultures and are found to be well tolerated after injection in mice. Both in vitro and in vivo toxicity studies have been carried out. The in vitro tests carried out on different cell lines, such as HELA, MCF7, COS, Vero, HT-29, HCPC-1, have proved that these cyclodextrin-based nanosponges were not cytotoxic and its incubation with the erythrocytes for around 90 min did not induce hemolytic reactions. The in vivo tests involved testing of acute systemic toxicity by injecting formulations of nanosponges in Swiss albino mice which were devoid of any toxic reactions. In addition, oral administration
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Cyclodextrin-based nanosponges: a propitious platform for enhancing drug delivery
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Table 1. Formulation of cyclodextrin-based nanosponges. Cyclodextrins and a-cyclodextrin, b-cyclodextrin, g-cyclodextrin, their derivatives hydroxypropyl cyclodextrin, methyl b-cyclodextrin, alkoxycarbonyl cyclodextrins [6,8] Crosslinkers Carbonyldimiidazole, triphosgene, dimethyl carbonates, diphenyl carbonate, organic dianhydrides (e.g., pyromellitic dianhydrides) and citric acid [5,6,8,37] Solvents Ethanol, dimethylformamide, dimethylacetamide, water [7,37]
does not show any untoward reactions [6,10]. Cyclodextrinbased nanosponges have limited water solubility [11], owing to a high degree of crosslinking between them, but they are found to form stable nanodispersions in water. In physiological fluids, they may swell in presence of water and have been found to release drug in a predictable manner wherein the release of the entrapped drug from the complex can be modulated depending on the crosslinking of the cyclodextrins. Moreover, the zeta potentials of these cyclodextrinbased nanosponges are found to be sufficiently high to render stable nanodispersions which do not undergo aggregation in physiological fluids [6]. 2.
Applications
Owing to their characteristic nanoporous structure and prospective to expediently carry both hydrophilic as well as lipophilic drugs, these cyclodextrin-based nanosponges have attracted much interest. These nanosponges hold a tremendous promise in enhancing various attributes that pose a problem for formulation scientists, including concerns pertaining to solubility, stability, bioavailability, activity, permeation and the like, which makes a formulation challenging. Improved solubility According to Biopharmaceutics Classification System (BCS), drugs are classified into four classes, namely, classes I, II, III and IV. BCS class II drugs are characterized by high permeability and low solubility. Examples of BCS class II drugs are amiodarone, carvedilol, ciprofloxacin, diclofenac, lansoprazole, tamoxifen and warfarin [7,8]. This problem of low solubility poses a severe hurdle in their formulation. The BCS class II drugs can be successfully incorporated in the cyclodextrin-based nanosponges for formulation efficacy. Low water solubility poses a great barrier in the development of pharmaceuticals. Cyclodextrin-based nanosponges improve the wetting and solubility of molecules in water and hence the apparent solubility of drug in water can be increased. The anticancer drug paclitaxel has poor water solubility of about < 0.3 µg/ml and hence renders a severe hurdle toward an effectual anticancer therapy. Mognetti et al. have developed Cremophor EL (polyethoxylated castor oil)-based 2.1
formulation of paclitaxel which later was found to have many adverse effects such as cardiotoxicity, nephrotoxicity and neurotoxicity. Cyclodextrin-based nanosponges encapsulating paclitaxel were found to be safe with mean diameter of 350 nm and monodisperse in nature. A water-stable colloidal system was formed without any need to carry out paclitaxel recrystallization. In addition, it has been observed in in-vitro release studies that within 2 h, there is a complete drug release without any initial burst effect. Additionally, the research concluded that the quantity of paclitaxel entering through these cyclodextrin-based nanosponges into the MCF-7 cells increased, lowering the IC50 values of paclitaxel and this complex has been found to be cytotoxic and more effective against this cell line. As a result, the activity of paclitaxel is found to be enhanced [6,12,13]. Itraconazole is a BCS class II antifungal drug, which at physiological pH has a solubility of just 1 ng/ml. To overcome this problem of dissolution rate-limited poor bioavailability, Swaminathan et al. loaded this drug in cyclodextrinbased nanosponges using solid dispersion technique. It has been observed that the solubility improved > 27-fold in the presence of cyclodextrin-based nanosponges. Swaminathan et al. made use of copolyvidonum as a ternary component and the outcome was 50-fold increase in solubility of the drug. The dissolution profiles of the drug--cylodextrin-based nanosponge and of drug--cyclodextrin-based nanosponge-copolyvidonum combinations were much faster than that of marketed formulations of itraconazole. Hence, the cyclodextrin-based nanosponges’ ability to improve the solubility and in turn the bioavailability is apparent [6,14]. Telmisartan is yet another BCS class II antihypertensive drug having problems similar to that of itraconazole in terms of poor solubility of 9.9 µg/ml in water leading to poor bioavailability. Poor bioavailability results in high cost, inefficient treatment and a higher risk of toxicity. To avoid this problem, Rao et al. investigated the influence of a ternary component NaHCO3 on carbonate crosslinked b-cyclodextrin-based nanosponges of telmisartan and have found that the solubility rose by 8.53-fold in distilled water, 3.35-fold in 0.1 N HCl and 4.66-fold in phosphate buffer pH 6.8 than simply making use of telmisartan. Thus, the loading of telmisartan with carbonate-linked cyclodextrin-based nanosponges in the presence of ternary component alkalizer NaHCO3 enhanced the dissolution rate of telmisartan. This property is mainly due to adjustment of microenvironmental pH and by bringing about variation in the amorphous properties of the drug [6,15]. Enhanced stability The consequence of interaction between cyclodextrin-based nanosponges and labile drugs is remarkable and is being broadly studied. Cyclodextrin-based nanosponges can retard degradation without itself getting involved in the reaction. This parameter can be attributed to the ability of the cyclodextrin-based nanosponges to guard, at least partly, the molecule from reactive environment and in this way, reduce or even prevent drug 2.2
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CH2OH O
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β-Cyclodextrins
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Figure 1. Schematic representation of preparation of cyclodextrin-based nanosponges using diphenyl carbonate as a crosslinking agent.
hydrolysis, oxidation, steric rearrangement, racemization, and other forms of isomerization, polymerization and even enzymatic decomposition of drugs [1,2]. Recently, ‘gamma oryzanol’ has received a great consideration, which is currently employed in stabilizing food and pharmaceuticals as well as a UV blocker in cosmeceutical formulations. The main obstacle in its utility is its fast photo degradation. Sapino et al. prepared the bcyclodextrin nanosponges of g-oryzanol in 1:1 ratio and they were characterized with the help of differential scanning 114
calorimetry (DSC), X-ray powder diffractometry (XRPD) and membrane diffusion runs. The UV-assisted photodegradation of g-oryzanol is found to be retarded when developed as cyclodextrin-based nanosponges. In addition, the in vitro evaluations conducted on porcine ear skin showed high skin accumulation of g-oryzanol, Hence, complexes of g-oryzanol with cyclodextrin-based nanosponge are effective as antioxidants [16]. The potent anticancer drug Camptothecin is of limited use in anticancer therapies due to high instability of its lactone
Expert Opin. Drug Deliv. (2014) 11(1)
Cyclodextrin-based nanosponges: a propitious platform for enhancing drug delivery
Solution of cyclodextrin in solvent
Add to
Reflux
Recover product by filtration under vacuum
Purify by soxhlet extraction with ethanol Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by UVA Universiteitsbibliotheek SZ on 04/06/14 For personal use only.
Excess quantity of crosslinker
Cool down to room temperature
Add to excess quantity of distilled water
Figure 2. Steps involved in the preparation of cyclodextrin-based nanosponges by solvent evaporation technique are shown.
Cyclodextrin
Cross linker
Ultrasonication at 90°C
Cool the product
Wash the product with water
Purify with soxhlet’s extraction
in vitro studies using dialysis-bag technique that release of drug was about 60% after 2 h at pH 7.4. Hence, cyclodextrin-based nanosponges can protect labile compounds from light-assisted degradation [6]. Darandale and Vavia found that the stability of curcumin was also found to be improved by reduction in its hydrolytic degradation and biotransformation and increased solubility following its inclusion in cyclodextrin-based nanosponges. Hence, complex of curcumin with cyclodextrin-based nanosponges can be effectively used in anticancer treatment [18]. Reduction in volatility of essential oils Linalool is an important essential oil in the cosmetic sector. Up to 8% w/w of linalool was incorporated within b-cyclodextrin ¼ nanosponges and entrapment was confirmed with DSC analysis. According to the in vitro release studies, the drug released from cyclodextrin-based nanosponges was 50%, as compared to only b-cyclodextrin complex, after 2 h. Hence, it is possible to induce protection of volatile components against loss by evaporation, thereby, in perfumes, we can have a long-lasting effect by slow release of the chief volatile components [6,19]. 2.3
Figure 3. Steps involved in the preparation of cyclodextrinbased nanosponges by ultrasound-assisted synthesis are shown.
ring which is prone to hydrolysis under physiological circumstances rendering it inactive and also due to low solubility of the drug. To solve this problem, three types of b-cyclodextrin nanosponges have been prepared by Swaminathan et al. with different crosslinking ratios namely 1:2, 1:4 and 1:8 on a molar basis with the crosslinker to prevent hydrolysis and prolonged drug release. The resultant formulation seemed to have particle size of 450 -- 600 nm with low polydispersity indices. In addition, the high zeta potential values (-20 to -25 mV) revealed that a stable nanosuspension is formed. Camptothecin was released slowly over a period of 24 h as per in vitro studies. Besides, the cytotoxic activity of drug-loaded cyclodextrin-based nanosponges was also found to be better than pure drug, when tested on HT-29 cell lines. Thus, we can achieve better stability and prolongation in the release of Camptothecin when developed as cyclodextrin-based nanosponges [6,17]. Appropriate photo protection can also be imparted to drug substances following their encapsulation in cyclodextrin-based nanosponges. The example of 5-fluorouracil can be illustrated. Up to 30% incorporation of 5-fluorouracil was possible in b-cyclodextrin-based nanosponges developed by Cavalli et al. It has been observed in the
Better permeation in topical drug delivery Efficient permeation is of absolute importance in a successful topical drug delivery system. Resveratrol is well known for its antioxidant properties and is hence used in the prevention and treatment of cardiovascular diseases, cancer, hyperlipidemia, inflammation, gonorrhea, dermatitis and fever. But its low permeability along with poor solubility and instability renders the therapy unproductive. Ansari et al. prepared the complexes of resveratrol with b-cyclodextrin nanosponges in different weight ratios and characterized with aid of DSC, FTIR and XRPD. The particle sizes were in range of 400 -- 500 nm. The polydispersity indices were found to be low, and a high zeta potential yielded a stable nanosuspension. Permeation studies carried out on porcine skin and rabbit mucosa revealed better permeation in case of resveratrol--cyclodextrin-based nanosponge formulation as compared to plain drug. In addition, the in vitro release and stability of resveratrol complex were noticeably increased compared with plain drug and cytotoxicity was 2.4
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Nanosponges are pretreated so that particle size is below 500 nm Cyclodextrin based nanosponges are suspended in water, sonicated, centrifuged and subjected to freeze drying
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Aqueous suspension of cyclodextrin based nanosponge is prepared, excess amount of drug is dispersed Any uncomplexed drug is separated by centrifugation Solid crystals of drug loaded cyclodextrin based nanosponges are obtained by solvent evaporation or freeze drying
Figure 4. Steps involved in the loading of drugs in the formed cyclodextrin-based nanosponges are shown.
more than resveratrol alone, when tested on HCPC-1 cell lines. From these outcomes, we can suggest that cyclodextrin-based nanosponges are favorable for topical and buccal deliveries [6,20]. The example of g-oryzanol, which is described in Section 2.2, is also applicable in this context. The g-oryzanol-based cyclodextrin-based nanosponges can be developed as a gel or oil-in-water emulsion for topical application [6,16]. Modulation of drug release The advantages of administering a single dose of a drug which can be released over an extended period of time, instead of numerous doses, have been evident to the pharmaceutical industry in recent era. This is due to reduction in frequency of administration, decreased side effects and the obvious patient compliance. Studies have been carried out on acyclovir incorporated in carboxylated cyclodextrin-based nanosponges by Lembo et al. A spherical shape and particle size of 400 nm was confirmed by transmission electron microscopy. It can be proposed that electrostatic interactions may occur between the amino group of acyclovir and the carboxylic groups present in the nanosponge structure, thus leading to inclusion phenomena. The release of acyclovir has been found to be prolonged in carboxylated cyclodextrin-based nanosponges, and drug release was 20% after 3 hours according to the in vitro release studies [6,21]. Slow release of the antiviral drug nelfinavir was obtained from nanosponges of b-cyclodextrin as compared to entrapment of drug with just b-cyclodextrin as per research carried out by Vavia et al. [6]. In addition, < 10% of flurbiprofen was found to be released from its complex with b-cyclodextrin nanosponge after around 2 h [6], and in the case of doxorubicin, the release of drug increased proportionately with increase in physiological pH values. At pH 1.2, the drug was released very slowly and at pH of 7.4, the doxorubicin release rate was around 29%, thereby proving that cyclodextrin-based nanosponges have the capability to guard 2.5
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the drug from gastric environment, permitting delivery in the intestinal region, that is, enteric delivery [6].
Oral drug delivery The oral route of drug delivery has been acknowledged for decades as the most widely utilized route of administration and has the highest patient compliance. But for an efficient oral delivery, it is of utmost importance that the drug is devoid of dissolution rate-limited bioavailability issues. Acetyl salicylic acid (ASA) is a BCS class III nonsteroidal anti-inflammatory drug (NSAID), and Shende et al. prepared it as cyclodextrin-based nanosponges linked via pyromellitic dianhydride (PMDA) as crosslinking agent. Interactions with cyclodextrin-based nanosponges were confirmed by carrying out DSC, FTIR and XRPD analyses. The release of ASA was slowed through in vitro studies. ASA developed in the form of cyclodextrinbased nanosponges were administered to edema rats, which were induced by carrageenan through oral gavage and the inflammation, was found to reduce appreciably in comparison to the control group and ASA alone group. Hence, cyclodextrin-based nanosponges can be exploited with e´lan for oral drug delivery as well [6,22]. According to Torne et al., when compared to the commercially available product Taxol (control) paclitaxel-loaded cyclodextrin-based nanosponges showed a threefold increase in bioavailability following its administration in rats by an oral gavage [6,23]. Torne et al. have developed tamoxifen for oral drug delivery by encapsulating it in b-cyclodextrin nanosponges crosslinked with carbonyldiimidazole. The pharmacokinetics of complexes of cyclodextrinbased nanosponges and tamoxifen has been found to be improved than the plain drug. In addition, a higher cytotoxic activity of drug--cyclodextrin-based nanosponge complex was seen compared to the tamoxifen monotherapy when studies were carried out on MCF cell lines [6,24]. Table 2 gives a synopsis 2.6
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Cyclodextrin-based nanosponges: a propitious platform for enhancing drug delivery
Table 2. A synopsis of drugs complexed with the help of cyclodextrin-based nanosponges. Drug
Therapeutic activity
Route of administration
Paclitaxel
Antineoplastic
Oral and parenteral
Itraconazole
Antifungal
Oral and topical
Telmisartan
Antihypertensive
Oral
Natural antioxidant
Topical
Camptothecin 5-Fluorouracil Curcumin Resveratrol Acyclovir
Antineoplastic Antineoplastic Antitumor Antioxidant Antiviral
Parenteral Parenteral and topical Oral Oral and topical Oral, topical and parenteral
Nelfinavir Flurbiprofen Doxorubicin ASA Tamoxifen
Antiviral Anti-inflammatory Antineoplastic NSAID, analgesic Antineoplastic
Oral Oral Parenteral and oral Parenteral and oral Oral
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g-oryzanol
of drugs complexed with cyclodextrin-based nanosponges reviewed in this article.
Delivery of gases Certain gases such as oxygen, carbon dioxide and 1-methylcyclopropene have significant biomedical and pharmaceutical applications. Oxygen therapy is prescribed in hypoxic conditions prevalent in many inflammatory diseases and 1-methylcyclopropene is used as an anti-ethylenic agent to enhance the longevity of cut ornamental flowers, which calls for their efficient delivery. Encapsulation of these gases in cyclodextrin-based nanosponges has now been made possible. Trotta et al. proved that cyclodextrin-based nanosponges can store and release these gases, by acting as reservoirs. Oxygen also has applications in topical delivery to heal wounds. To promote this application, Cavalli et al. developed oxygen as cyclodextrin-based nanosponges crosslinked with carbonyldiimidazole. Oxygen permeation studies have been conducted on an apparatus which comprises donor and acceptor compartments separated by a silicon membrane. It has been observed that, though cyclodextrinbased nanosponges could release oxygen in presence as well as in the absence of ultrasound, the presence of ultrasound has improved in vitro release and permeation of oxygen. Since a topical application was considered, cyclodextrinbased nanosponges of oxygen were formulated as a hydrogel which facilitated a slower, sustained release of oxygen. Hence, it could be stated that cyclodextrin-based nanosponges might be favorable oxygen carriers for topical delivery [6,25,26]. 2.7
Advantages Improved solubility and activity and can be prepared as oral dosage form [12,13,23] Improved solubility and bioavailability [14] Improved solubility and bioavailability [15] Improved stability and activity and has better permeation [16] Improved stability and activity [17] Protection from photodegradation [6] Improved solubility and stability [18] Better permeation [20] Prolongation of release and enhanced antiviral action [21] Prolongation of release [6] Prolongation of release [6] Prolongation of release [6] Preparation of oral formulation [22] Better activity and preparation of oral formulation [24]
Delivery of proteins and enzymes It is worth mentioning that protein and peptide delivery is receiving great attention in recent years. Still, there have been numerous potential hurdles in its therapy. What renders protein administration challenging is its tendency to undergo denaturation, aggregation and adsorption and properties, such as short half-life, immunogenicity, rapid enzymatic degradation, large molecular size and rapid clearance, poor absorption and bioavailability. To overcome these hindrances, the dose can be increased or use of absorption promoters can be employed, but it could lead to toxicity problems. Encapsulation into cyclodextrin-based nanosponges can improve the stability as well as the pharmacokinetic properties of proteins and peptides. Swaminathan et al. have made possible the encapsulation of bovine serum albumin into swellable cyclodextrin-based poly(amidoamine) nanosponges called as NS 10 and NS 11, which were synthesized by crosslinking b-cyclodextrins with either 2,2-bis(acrylamidoacetic acid) or a short polyamidoamine chain derived from 2,2-bis(acrylamidoacetic acid) and 2-methylpiperazine, respectively. A prolonged release of albumin was observed over a period of 24 h and it was also stabilized and protected [6,8,10]. Industries make use of enzymes to carry out myriad reactions which eliminate limitations such as low yields, requirements of high temperature and pressure, consumption of large amounts of energy and water. Enzymes are the preferred ‘biocatalysts’, owing to their remarkable properties such as high specificity, high-reaction speed, ability to operate under mild conditions and being environment-friendly. When such pharmaceutically important enzymes are loaded into cyclodextrin-based nanosponges, the conduct of continuous flow processes 2.8
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becomes possible, while maintaining their activity and efficiency over an extended pH and temperature range [8]. This can be best illustrated by Nardo et al. on catechol 1,2-dioxygenases from Acinetobacter radioresistens S13 immobilized on b-cyclodextrins crosslinked with carbonate nanosponges can be highlighted. These groups of enzymes are responsible for manufacturing adipic acid which is of industrial importance. Adipic acid is obtained by converting catechol into cis, cismuconate. The immobilization gave way to increased thermostability of the enzyme. The activity toward other substrates, such as 3-and 4 methylcatechol and 4-chlorocatechol, was retained by the enzyme immobilized on cyclodextrin-based nanosponges which demonstrates reaction specificity [6,27]. Various other applications of cyclodextrin-based nanosponges
2.9
Apart from its predominance in the sector of drug delivery, this multifaceted nanostructure has established its relevance in other realms as well. Cyclodextrin-based nanosponges have applications in the remediation technologies wherein they are employed in water treatment processes and are found to be efficient than activated carbon and can have a major advantage of being reused by environment-friendly solvents such as ethanol [6,28]. Cyclodextrin-based nanosponges can encapsulate some chemicals that are important in agricultural sector and can enable their slow release [6,29,30]. Cyclodextrinbased nanosponges can also be engaged in enantiodifferentiating photoisomerisation reactions [6,31], and in the polymer industry they act as novel green flame retardants that improve the flame-retardant properties of various polymeric compounds [6,32,33]; finally, they also possess potential to eliminate natural product contaminants such as ochratoxin-A from various food products and beverages [34]. 3.
Conclusion
Cyclodextrin-based nanosponges are an innovative class of materials which comprise hypercrosslinked polymers of cyclodextrins nanostructured in a three-dimensional network. Their super porous structure enables them to entrap a wide array of hydrophilic and lipophilic compounds. The biocompatibility of this scaffold structure makes it nontoxic, nonallergenic, nonirritant and it possesses several advantages over native cyclodextrins and even cyclodextrin derivatives such as ability to entrap hydrophilic, high molecular weight compounds, nontoxicity on parenteral administration and inability to dissociate from the drug on dilution. They can be formulated as tablets, capsules, aerosols, parenteral and topical dosage forms. These ground-breaking entities have significant applications in drug delivery. Apart from offering solutions to solubility problems, they enjoy widespread attention and use in improving stability, permeation, bioavailability and prolonging drug release. Delivery of proteins and pharmaceutically important gases has also been made possible through these cyclodextrin-based nanosponges. It is anticipated that 118
the cyclodextrin-based nanosponges have the aptitude to gain momentum in anticancer therapies by enabling sitedirecting of drugs. The manifold applications of this novel system extend beyond the territories of drug delivery to domains of cosmetics, biomedicine, agriculture and environment remediation. It is also worthwhile to mention that this technology is expensive and hence calls for it being made affordable to the pharmaceutical and healthcare sector to improve quality of life and appear as promising candidates in drug delivery technology. 4.
Future scenario
This nascent field of cyclodextrin-based nanosponges has stirred up enormous interest among physical and biological scientists and has already attracted hundreds of millions of dollars of research funding. The next 10 -- 15 years will see a lot of interesting work being done in this area and we will be able to see truly ‘transformational changes’. Because of their small and spherical shape, cyclodextrin-based nanosponges can be developed in various dosage forms, such as parenteral, topical, aerosols, tablets and capsules, and can be utilized for venous and pulmonary delivery of drugs [8]. It is intriguing to realize that cyclodextrin-based nanosponges can selectively trap certain biomarkers from blood and protect them from degradation by enzymes present in the blood to exploit them as diagnostic agents in cases of anticancer therapies. A study has highlighted that cyclodextrin-based nanosponges can harvest rare cancer marker, Bak (a protein), from blood for subsequent analysis of melanoma [8,35]. Harth et al. has come up with a splendid innovation wherein cyclodextrin-based nanosponges-loaded anticancer drugs when administered were found to be about 3 -- 5 times more effective than direct injection of the anti-cancer drug alone. This fact is highlighted by the observations that these drug-loaded cyclodextrin-based nanosponges circulate in the body and attach to only the timorous cells on account of the ‘linkers’ which are attached to these nanosponges, and release of drug is in a predictable, controlled fashion thus circumventing the destruction of healthy cells. The above facts propose that cyclodextrin-based nanosponges are envisaged to have a major impact on bringing about a transmutation and open newer vistas for better anticancer therapeutics [36]. For further successful development of this field, promising trends must be identified and exploited, albeit with a clear understanding of the limitations of these approaches. 5.
Expert opinion
Cyclodextrins are prominent for their ability to form inclusion complexes with various compounds and hence are employed in pharmaceutical field. But it is found that this technology mostly applies only to lipophilic drugs wherein their solubility is improved and less effective for hydrophilic and certain high molecular weight compounds. In addition,
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Cyclodextrin-based nanosponges: a propitious platform for enhancing drug delivery
cyclodextrins were found to be toxic and they easily dissociated from the drug molecule on dilution. To combat this barrier, crosslinked polymers, that is, cyclodextrin-based nanosponges present a potential strategy. Cyclodextrins-based nanosponges have emerged as a necessary tool in the formulation scientist’s as well as physician’s resources to improve formulation aspects as well as therapeutics in order to enable a proficient drug delivery system. The biodegradability and nontoxicity of this novel system is sufficient to rest assure the concerns pertaining to the health hazards associated with the advancement of the nanoscience era. With the possibilities for new therapies seeming endless, cyclodextrin-based nanosponges are yet another novel approach to revolutionize nanomedicine. ‘Nanosponges’ being first diligently used in 1998 by De Quan Li and Min Ma has started to kindle myriad curiosity in the nanoscience which is evident from manifold research being carried out in this field. During its developmental process, a drug has to suffer a lot of setbacks for it to get launched in the market which include issues for a formulation scientist such as poor solubility, stability, permeation and bioavailability. These nanostructures have challenged these pitfalls and have aimed to create better dosage forms. The concept of tailored release of drug can be enabled with the help of cyclodextrin-based nanosponges by bringing about modifications in the degree of crosslinking to facilitate release profile of drug in cases of modulated drug release. In therapeutics, delivery of proteins, peptides, enzymes and even gases such as oxygen have made their debut and cyclodextrin-based nanosponges do not lag behind in their delivery as well. Cyclodextrin-based nanosponges have a solid potential to undergo a breakthrough in anticancer therapies,
owing to their ability to render a targeted drug delivery with minimal adverse effects. This cutting-edge technology is not only restricted to diagnostic and therapeutic fields but also has carved a niche in allied sectors such as cosmetics, agrochemistry, biomedical sciences and bioremediation technologies. This provides an outlook of the multifaceted aspects of cyclodextrin-based nanosponges. As we investigate this new realm of nanotechnology, it becomes necessary to realize that this new field offers some loopholes as well. It has been observed that the drug loading is not applicable to very high molecular weight compounds, which causes only selective drugs to be candidates for this delivery system. Even though production is easy, its high cost can form a barrier to its effective therapy. Hence, researchers should find means to make it affordable to the consumers. The clinical use of cyclodextrin-based nanosponges is still in its infancy but it could be a perfect solution for effectively delivering obstinate drug molecules. It could be considered as an appropriate nanosystem for delivery of active molecules and its future in nanomedicine appears promising. We optimistically speculate that in a few years from now, more and more improved cyclodextrin-based nanosponge formulations would gain access in the market, thus paving way for a metamorphosis in nanoscience and, indeed, act as a propitious platform for drug delivery and therapeutics.
Declaration of interest The authors state no conflict of interest and have received no payment in preparation of this manuscript.
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Affiliation
Sai V Chilajwar†, Priti P Pednekar, Kisan R Jadhav, Gajendra JC Gupta & Vilasrao J Kadam † Author for correspondence University of Mumbai, Bharati Vidyapeeth’s College of Pharmacy, Department of Pharmaceutics, Sector 8, C B D Belapur, Navi Mumbai 400 614, India Tel: +91 022 27571122; Fax: +91 022 27574525; E-mail: [email protected]
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Cyclodextrin-based nanosponges: a propitious platform for enhancing drug delivery 1.
Introduction
2.
Applications
3.
Conclusion
4.
Future scenario
5.
Expert opinion
Sai V Chilajwar†, Priti P Pednekar, Kisan R Jadhav, Gajendra JC Gupta & Vilasrao J Kadam University of Mumbai, Bharati Vidyapeeth’s College of Pharmacy, Department of Pharmaceutics, Navi-Mumbai, India
Introduction: Recently, Nanotechnology is receiving considerable acknowledgment due to its potential to combine features that are difficult to achieve by making use of a drug alone. Cyclodextrin-based nanosponges are yet another contemporary approach for highlighting the advancements which could be brought about in a drug delivery system. Statistical analyses have shown that around 40% of currently marketed drugs and about 90% of drugs in their developmental phase encounter solubility-related problems. Cyclodextrin-based nanosponges have the capacity to emerge as a productive approach over conventional cyclodextrins by overcoming the disadvantages associated with the latter. Areas covered: This review is intended to give an insight regarding cyclodextrin-based nanosponges such as their physical and chemical properties. In addition, methods of preparation and characterization are discussed along with biocompatibility, and how these nanomeric elements can be exploited in developing effective drug formulations. Expert opinion: This emerging technology of cyclodextrin-based nanosponges is expected to provide technical solutions to the formulation arena and to come up with some successful products in the pharmaceutical market. It also has an exciting future in the field of therapeutics wherein it can cater site-directed drug delivery and hence it possesses vibrant opportunities. Keywords: b-cyclodextrin, drug delivery, encapsulation, nanosponges, solubility Expert Opin. Drug Deliv. (2014) 11(1):111-120
1.
Introduction
The hunt for an efficient drug delivery system is an enigma in itself. Our medical researchers and formulation scientists are always surrounded by issues pertaining to drug targeting, drug release, overdosing, solubility, permeability, activity and bioavailability. Thus, creating or improving systems for drug delivery is an area of ongoing research. As soon as nanotechnology has turned up in the limelight, its bright prospects in medicine have been hailed enthusiastically. The advent of cyclodextrin-based nanosponges has paved the way to alleviate the above limitations and has gained a tremendous impetus in drug delivery. Scientists De Quan Li and Min Ma have coined the term ‘cyclodextrin nanosponges’. We have tried to explore the profound ability of these nanosponges in enlivening the domains of drug delivery. Cyclodextrins are cyclic oligomers of D-glucopyranose units linked by (a-1, 4) linkages. A cyclodextrin has a characteristic toroidal structure with primary hydroxyl groups extending from the narrow edge and secondary hydroxyl groups extending from the wider edge which impart to cyclodextrins their peculiar hydrophilic outer surface and a lipophilic cavity. This forms the basis for the delivery of both 10.1517/17425247.2014.865013 © 2014 Informa UK, Ltd. ISSN 1742-5247, e-ISSN 1744-7593 All rights reserved: reproduction in whole or in part not permitted
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Cyclodextrin-based nanosponges are a promising and an innovative form of a drug delivery system which comprises a nanostructured three-dimensional network of crosslinked cyclodextrin molecules with a porous structure capable of encapsulating hydrophilic as well as hydrophobic drug molecules. They are biocompatible, nontoxic and safe for use. The drug release from these nanosponges can be customized by tuning the type and degree of crosslinking. They possess numerous advantages ranging from improved solubility, stability, permeation, bioavailability, modulation of drug release to efficient drug targeting in case of anticancer therapeutics. In addition, delivery of proteins, enzymes and gases is possible. There is a scope for a vibrant future in research and development of cyclodextrin-based nanosponges.
This box summarizes key points contained in the article.
lipophilic as well as hydrophilic drug moieties. The three main native cyclodextrins are a, b and g, which comprise six, seven and eight glucopyranose units, respectively [1]. However, these native cyclodextrins have many drawbacks. They cannot form inclusion complexes with all drugs; moreover, b-cyclodextrins have poor water solubility and is reported to be toxic when injected intravenously [1-6]. Hence, many researchers are coming up with new strategies to improve the technological characteristics of cyclodextrins. In the present review, we describe an emerging approach to prepare multifunctional cyclodextrin derivatives by bringing about crosslinking of cyclodextrin polymers. Cyclodextrin-based nanosponges are tiny, mesh-like structures, resembling ‘sponges’ microscopically, 200 -- 500 nm in diameter that can be loaded with a wide array of drugs [7]. Cyclodextrin-based nanosponges are hypercrosslinked polymers of cyclodextrins which are prepared by crosslinking the native a-, b- and g-cyclodextrins with an appropriate crosslinking agent. There are various crosslinkers which could be employed. They include an active carbonyl compound, such as, carbonyldimiidazole, triphosgene, diphenyl carbonate, or organic dianhydrides [6]. Table 1 gives an account of the formulation of cyclodextrin-based nanosponges. The cyclodextrin-based nanosponges so obtained are spherical, basically, a scaffold structure possessing many cavities (or pockets) where drug molecules can be entrapped [8]. The terminology ‘cyclodextrin nanosponges’ was originally used by De Quan Li and Min Ma in 1998 to signify a b-cyclodextrin, crosslinked by diisocyanates which when observed microscopically showed a porous structure and had a very high inclusion constant with quite a lot of organic pollutants [6,9]. The crosslinking can be modulated according to the release rate requirements. It has been observed that more the cross linking, slower will be the drug release and vice versa. Hence, 112
the drug can be released on predictive manner by tuning the degree of crosslinking [10]. Cyclodextrin-based nanosponges can be prepared by two techniques namely solvent evaporation technique and ultrasound-assisted synthesis. General scheme for the preparation of cyclodextrin-based nanosponges is described in Figure 1. As the name ‘solvent evaporation’ suggests, cyclodextrins are refluxed with solvents such as ethanol, dimethylformamide, dimethylacetamide in the presence of an excess quantity of crosslinker preferably the ones with carbonyl group in it. Once the reaction gets over, the mixture is allowed to cool and is poured into excess of distilled water. The product is recovered by vacuum filtration. Purified product is obtained by Soxhlet extraction process which is followed by grinding in mill to get the powder form of the cyclodextrin-based nanosponges. Figure 2 summarizes the steps involved in the preparation of cyclodextrin-based nanosponges by the solvent evaporation technique [7,8]. Unlike the solvent evaporation technique, the ultrasound-assisted technique does not require solvents in the synthesis of cyclodextrin-based nanosponges. In addition, it has been reported that the nanosponges obtained by ultrasound technique are spherical and uniform in size. The mixture of cyclodextrin and the crosslinking agent are taken in a flask which is placed in an ultrasound bath filled with water under temperature conditions of 90 C, which is then subjected to sonication. The product, thereby, obtained is allowed to cool. It is washed with water to remove traces of any unreacted product. Purified nanosponges are obtained by carrying out Soxhlet extraction method using ethanol. Figure 3 outlines the events during the synthesis of cyclodextrin-based nanosponges by ultrasound-assisted synthesis [7,8].The drug is then loaded subsequently in these nanosponges which could be prepared by either of the two abovementioned methods. Figure 4 demonstrates the processes involved during the loading of drug molecule in cyclodextrin-based nanosponges. Importantly, some factors such as nature and type of cyclodextrin, temperature, degree of substitution, type of drug and the like affect the nanosponge formation [7,8]. A comprehensive characterization of cyclodextrin-based nanosponges, including Fourier transform infrared radiation (FTIR), nuclear magnetic resonance, X-ray diffraction, microscopy, thermal analyses, solubility studies, zeta potential and the like help in confirming the inclusion complexes formed [6-8]. It is noteworthy that they are safe because of biodegradable material with negligible toxicity on cell cultures and are found to be well tolerated after injection in mice. Both in vitro and in vivo toxicity studies have been carried out. The in vitro tests carried out on different cell lines, such as HELA, MCF7, COS, Vero, HT-29, HCPC-1, have proved that these cyclodextrin-based nanosponges were not cytotoxic and its incubation with the erythrocytes for around 90 min did not induce hemolytic reactions. The in vivo tests involved testing of acute systemic toxicity by injecting formulations of nanosponges in Swiss albino mice which were devoid of any toxic reactions. In addition, oral administration
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Cyclodextrin-based nanosponges: a propitious platform for enhancing drug delivery
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Table 1. Formulation of cyclodextrin-based nanosponges. Cyclodextrins and a-cyclodextrin, b-cyclodextrin, g-cyclodextrin, their derivatives hydroxypropyl cyclodextrin, methyl b-cyclodextrin, alkoxycarbonyl cyclodextrins [6,8] Crosslinkers Carbonyldimiidazole, triphosgene, dimethyl carbonates, diphenyl carbonate, organic dianhydrides (e.g., pyromellitic dianhydrides) and citric acid [5,6,8,37] Solvents Ethanol, dimethylformamide, dimethylacetamide, water [7,37]
does not show any untoward reactions [6,10]. Cyclodextrinbased nanosponges have limited water solubility [11], owing to a high degree of crosslinking between them, but they are found to form stable nanodispersions in water. In physiological fluids, they may swell in presence of water and have been found to release drug in a predictable manner wherein the release of the entrapped drug from the complex can be modulated depending on the crosslinking of the cyclodextrins. Moreover, the zeta potentials of these cyclodextrinbased nanosponges are found to be sufficiently high to render stable nanodispersions which do not undergo aggregation in physiological fluids [6]. 2.
Applications
Owing to their characteristic nanoporous structure and prospective to expediently carry both hydrophilic as well as lipophilic drugs, these cyclodextrin-based nanosponges have attracted much interest. These nanosponges hold a tremendous promise in enhancing various attributes that pose a problem for formulation scientists, including concerns pertaining to solubility, stability, bioavailability, activity, permeation and the like, which makes a formulation challenging. Improved solubility According to Biopharmaceutics Classification System (BCS), drugs are classified into four classes, namely, classes I, II, III and IV. BCS class II drugs are characterized by high permeability and low solubility. Examples of BCS class II drugs are amiodarone, carvedilol, ciprofloxacin, diclofenac, lansoprazole, tamoxifen and warfarin [7,8]. This problem of low solubility poses a severe hurdle in their formulation. The BCS class II drugs can be successfully incorporated in the cyclodextrin-based nanosponges for formulation efficacy. Low water solubility poses a great barrier in the development of pharmaceuticals. Cyclodextrin-based nanosponges improve the wetting and solubility of molecules in water and hence the apparent solubility of drug in water can be increased. The anticancer drug paclitaxel has poor water solubility of about < 0.3 µg/ml and hence renders a severe hurdle toward an effectual anticancer therapy. Mognetti et al. have developed Cremophor EL (polyethoxylated castor oil)-based 2.1
formulation of paclitaxel which later was found to have many adverse effects such as cardiotoxicity, nephrotoxicity and neurotoxicity. Cyclodextrin-based nanosponges encapsulating paclitaxel were found to be safe with mean diameter of 350 nm and monodisperse in nature. A water-stable colloidal system was formed without any need to carry out paclitaxel recrystallization. In addition, it has been observed in in-vitro release studies that within 2 h, there is a complete drug release without any initial burst effect. Additionally, the research concluded that the quantity of paclitaxel entering through these cyclodextrin-based nanosponges into the MCF-7 cells increased, lowering the IC50 values of paclitaxel and this complex has been found to be cytotoxic and more effective against this cell line. As a result, the activity of paclitaxel is found to be enhanced [6,12,13]. Itraconazole is a BCS class II antifungal drug, which at physiological pH has a solubility of just 1 ng/ml. To overcome this problem of dissolution rate-limited poor bioavailability, Swaminathan et al. loaded this drug in cyclodextrinbased nanosponges using solid dispersion technique. It has been observed that the solubility improved > 27-fold in the presence of cyclodextrin-based nanosponges. Swaminathan et al. made use of copolyvidonum as a ternary component and the outcome was 50-fold increase in solubility of the drug. The dissolution profiles of the drug--cylodextrin-based nanosponge and of drug--cyclodextrin-based nanosponge-copolyvidonum combinations were much faster than that of marketed formulations of itraconazole. Hence, the cyclodextrin-based nanosponges’ ability to improve the solubility and in turn the bioavailability is apparent [6,14]. Telmisartan is yet another BCS class II antihypertensive drug having problems similar to that of itraconazole in terms of poor solubility of 9.9 µg/ml in water leading to poor bioavailability. Poor bioavailability results in high cost, inefficient treatment and a higher risk of toxicity. To avoid this problem, Rao et al. investigated the influence of a ternary component NaHCO3 on carbonate crosslinked b-cyclodextrin-based nanosponges of telmisartan and have found that the solubility rose by 8.53-fold in distilled water, 3.35-fold in 0.1 N HCl and 4.66-fold in phosphate buffer pH 6.8 than simply making use of telmisartan. Thus, the loading of telmisartan with carbonate-linked cyclodextrin-based nanosponges in the presence of ternary component alkalizer NaHCO3 enhanced the dissolution rate of telmisartan. This property is mainly due to adjustment of microenvironmental pH and by bringing about variation in the amorphous properties of the drug [6,15]. Enhanced stability The consequence of interaction between cyclodextrin-based nanosponges and labile drugs is remarkable and is being broadly studied. Cyclodextrin-based nanosponges can retard degradation without itself getting involved in the reaction. This parameter can be attributed to the ability of the cyclodextrin-based nanosponges to guard, at least partly, the molecule from reactive environment and in this way, reduce or even prevent drug 2.2
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CH2OH O
2
O
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β-Cyclodextrins
O CH2O C OCH2
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O CH O C OCH 2
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O CH O C OCH
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Nanosponges
Figure 1. Schematic representation of preparation of cyclodextrin-based nanosponges using diphenyl carbonate as a crosslinking agent.
hydrolysis, oxidation, steric rearrangement, racemization, and other forms of isomerization, polymerization and even enzymatic decomposition of drugs [1,2]. Recently, ‘gamma oryzanol’ has received a great consideration, which is currently employed in stabilizing food and pharmaceuticals as well as a UV blocker in cosmeceutical formulations. The main obstacle in its utility is its fast photo degradation. Sapino et al. prepared the bcyclodextrin nanosponges of g-oryzanol in 1:1 ratio and they were characterized with the help of differential scanning 114
calorimetry (DSC), X-ray powder diffractometry (XRPD) and membrane diffusion runs. The UV-assisted photodegradation of g-oryzanol is found to be retarded when developed as cyclodextrin-based nanosponges. In addition, the in vitro evaluations conducted on porcine ear skin showed high skin accumulation of g-oryzanol, Hence, complexes of g-oryzanol with cyclodextrin-based nanosponge are effective as antioxidants [16]. The potent anticancer drug Camptothecin is of limited use in anticancer therapies due to high instability of its lactone
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Cyclodextrin-based nanosponges: a propitious platform for enhancing drug delivery
Solution of cyclodextrin in solvent
Add to
Reflux
Recover product by filtration under vacuum
Purify by soxhlet extraction with ethanol Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by UVA Universiteitsbibliotheek SZ on 04/06/14 For personal use only.
Excess quantity of crosslinker
Cool down to room temperature
Add to excess quantity of distilled water
Figure 2. Steps involved in the preparation of cyclodextrin-based nanosponges by solvent evaporation technique are shown.
Cyclodextrin
Cross linker
Ultrasonication at 90°C
Cool the product
Wash the product with water
Purify with soxhlet’s extraction
in vitro studies using dialysis-bag technique that release of drug was about 60% after 2 h at pH 7.4. Hence, cyclodextrin-based nanosponges can protect labile compounds from light-assisted degradation [6]. Darandale and Vavia found that the stability of curcumin was also found to be improved by reduction in its hydrolytic degradation and biotransformation and increased solubility following its inclusion in cyclodextrin-based nanosponges. Hence, complex of curcumin with cyclodextrin-based nanosponges can be effectively used in anticancer treatment [18]. Reduction in volatility of essential oils Linalool is an important essential oil in the cosmetic sector. Up to 8% w/w of linalool was incorporated within b-cyclodextrin ¼ nanosponges and entrapment was confirmed with DSC analysis. According to the in vitro release studies, the drug released from cyclodextrin-based nanosponges was 50%, as compared to only b-cyclodextrin complex, after 2 h. Hence, it is possible to induce protection of volatile components against loss by evaporation, thereby, in perfumes, we can have a long-lasting effect by slow release of the chief volatile components [6,19]. 2.3
Figure 3. Steps involved in the preparation of cyclodextrinbased nanosponges by ultrasound-assisted synthesis are shown.
ring which is prone to hydrolysis under physiological circumstances rendering it inactive and also due to low solubility of the drug. To solve this problem, three types of b-cyclodextrin nanosponges have been prepared by Swaminathan et al. with different crosslinking ratios namely 1:2, 1:4 and 1:8 on a molar basis with the crosslinker to prevent hydrolysis and prolonged drug release. The resultant formulation seemed to have particle size of 450 -- 600 nm with low polydispersity indices. In addition, the high zeta potential values (-20 to -25 mV) revealed that a stable nanosuspension is formed. Camptothecin was released slowly over a period of 24 h as per in vitro studies. Besides, the cytotoxic activity of drug-loaded cyclodextrin-based nanosponges was also found to be better than pure drug, when tested on HT-29 cell lines. Thus, we can achieve better stability and prolongation in the release of Camptothecin when developed as cyclodextrin-based nanosponges [6,17]. Appropriate photo protection can also be imparted to drug substances following their encapsulation in cyclodextrin-based nanosponges. The example of 5-fluorouracil can be illustrated. Up to 30% incorporation of 5-fluorouracil was possible in b-cyclodextrin-based nanosponges developed by Cavalli et al. It has been observed in the
Better permeation in topical drug delivery Efficient permeation is of absolute importance in a successful topical drug delivery system. Resveratrol is well known for its antioxidant properties and is hence used in the prevention and treatment of cardiovascular diseases, cancer, hyperlipidemia, inflammation, gonorrhea, dermatitis and fever. But its low permeability along with poor solubility and instability renders the therapy unproductive. Ansari et al. prepared the complexes of resveratrol with b-cyclodextrin nanosponges in different weight ratios and characterized with aid of DSC, FTIR and XRPD. The particle sizes were in range of 400 -- 500 nm. The polydispersity indices were found to be low, and a high zeta potential yielded a stable nanosuspension. Permeation studies carried out on porcine skin and rabbit mucosa revealed better permeation in case of resveratrol--cyclodextrin-based nanosponge formulation as compared to plain drug. In addition, the in vitro release and stability of resveratrol complex were noticeably increased compared with plain drug and cytotoxicity was 2.4
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Nanosponges are pretreated so that particle size is below 500 nm Cyclodextrin based nanosponges are suspended in water, sonicated, centrifuged and subjected to freeze drying
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Aqueous suspension of cyclodextrin based nanosponge is prepared, excess amount of drug is dispersed Any uncomplexed drug is separated by centrifugation Solid crystals of drug loaded cyclodextrin based nanosponges are obtained by solvent evaporation or freeze drying
Figure 4. Steps involved in the loading of drugs in the formed cyclodextrin-based nanosponges are shown.
more than resveratrol alone, when tested on HCPC-1 cell lines. From these outcomes, we can suggest that cyclodextrin-based nanosponges are favorable for topical and buccal deliveries [6,20]. The example of g-oryzanol, which is described in Section 2.2, is also applicable in this context. The g-oryzanol-based cyclodextrin-based nanosponges can be developed as a gel or oil-in-water emulsion for topical application [6,16]. Modulation of drug release The advantages of administering a single dose of a drug which can be released over an extended period of time, instead of numerous doses, have been evident to the pharmaceutical industry in recent era. This is due to reduction in frequency of administration, decreased side effects and the obvious patient compliance. Studies have been carried out on acyclovir incorporated in carboxylated cyclodextrin-based nanosponges by Lembo et al. A spherical shape and particle size of 400 nm was confirmed by transmission electron microscopy. It can be proposed that electrostatic interactions may occur between the amino group of acyclovir and the carboxylic groups present in the nanosponge structure, thus leading to inclusion phenomena. The release of acyclovir has been found to be prolonged in carboxylated cyclodextrin-based nanosponges, and drug release was 20% after 3 hours according to the in vitro release studies [6,21]. Slow release of the antiviral drug nelfinavir was obtained from nanosponges of b-cyclodextrin as compared to entrapment of drug with just b-cyclodextrin as per research carried out by Vavia et al. [6]. In addition, < 10% of flurbiprofen was found to be released from its complex with b-cyclodextrin nanosponge after around 2 h [6], and in the case of doxorubicin, the release of drug increased proportionately with increase in physiological pH values. At pH 1.2, the drug was released very slowly and at pH of 7.4, the doxorubicin release rate was around 29%, thereby proving that cyclodextrin-based nanosponges have the capability to guard 2.5
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the drug from gastric environment, permitting delivery in the intestinal region, that is, enteric delivery [6].
Oral drug delivery The oral route of drug delivery has been acknowledged for decades as the most widely utilized route of administration and has the highest patient compliance. But for an efficient oral delivery, it is of utmost importance that the drug is devoid of dissolution rate-limited bioavailability issues. Acetyl salicylic acid (ASA) is a BCS class III nonsteroidal anti-inflammatory drug (NSAID), and Shende et al. prepared it as cyclodextrin-based nanosponges linked via pyromellitic dianhydride (PMDA) as crosslinking agent. Interactions with cyclodextrin-based nanosponges were confirmed by carrying out DSC, FTIR and XRPD analyses. The release of ASA was slowed through in vitro studies. ASA developed in the form of cyclodextrinbased nanosponges were administered to edema rats, which were induced by carrageenan through oral gavage and the inflammation, was found to reduce appreciably in comparison to the control group and ASA alone group. Hence, cyclodextrin-based nanosponges can be exploited with e´lan for oral drug delivery as well [6,22]. According to Torne et al., when compared to the commercially available product Taxol (control) paclitaxel-loaded cyclodextrin-based nanosponges showed a threefold increase in bioavailability following its administration in rats by an oral gavage [6,23]. Torne et al. have developed tamoxifen for oral drug delivery by encapsulating it in b-cyclodextrin nanosponges crosslinked with carbonyldiimidazole. The pharmacokinetics of complexes of cyclodextrinbased nanosponges and tamoxifen has been found to be improved than the plain drug. In addition, a higher cytotoxic activity of drug--cyclodextrin-based nanosponge complex was seen compared to the tamoxifen monotherapy when studies were carried out on MCF cell lines [6,24]. Table 2 gives a synopsis 2.6
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Cyclodextrin-based nanosponges: a propitious platform for enhancing drug delivery
Table 2. A synopsis of drugs complexed with the help of cyclodextrin-based nanosponges. Drug
Therapeutic activity
Route of administration
Paclitaxel
Antineoplastic
Oral and parenteral
Itraconazole
Antifungal
Oral and topical
Telmisartan
Antihypertensive
Oral
Natural antioxidant
Topical
Camptothecin 5-Fluorouracil Curcumin Resveratrol Acyclovir
Antineoplastic Antineoplastic Antitumor Antioxidant Antiviral
Parenteral Parenteral and topical Oral Oral and topical Oral, topical and parenteral
Nelfinavir Flurbiprofen Doxorubicin ASA Tamoxifen
Antiviral Anti-inflammatory Antineoplastic NSAID, analgesic Antineoplastic
Oral Oral Parenteral and oral Parenteral and oral Oral
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g-oryzanol
of drugs complexed with cyclodextrin-based nanosponges reviewed in this article.
Delivery of gases Certain gases such as oxygen, carbon dioxide and 1-methylcyclopropene have significant biomedical and pharmaceutical applications. Oxygen therapy is prescribed in hypoxic conditions prevalent in many inflammatory diseases and 1-methylcyclopropene is used as an anti-ethylenic agent to enhance the longevity of cut ornamental flowers, which calls for their efficient delivery. Encapsulation of these gases in cyclodextrin-based nanosponges has now been made possible. Trotta et al. proved that cyclodextrin-based nanosponges can store and release these gases, by acting as reservoirs. Oxygen also has applications in topical delivery to heal wounds. To promote this application, Cavalli et al. developed oxygen as cyclodextrin-based nanosponges crosslinked with carbonyldiimidazole. Oxygen permeation studies have been conducted on an apparatus which comprises donor and acceptor compartments separated by a silicon membrane. It has been observed that, though cyclodextrinbased nanosponges could release oxygen in presence as well as in the absence of ultrasound, the presence of ultrasound has improved in vitro release and permeation of oxygen. Since a topical application was considered, cyclodextrinbased nanosponges of oxygen were formulated as a hydrogel which facilitated a slower, sustained release of oxygen. Hence, it could be stated that cyclodextrin-based nanosponges might be favorable oxygen carriers for topical delivery [6,25,26]. 2.7
Advantages Improved solubility and activity and can be prepared as oral dosage form [12,13,23] Improved solubility and bioavailability [14] Improved solubility and bioavailability [15] Improved stability and activity and has better permeation [16] Improved stability and activity [17] Protection from photodegradation [6] Improved solubility and stability [18] Better permeation [20] Prolongation of release and enhanced antiviral action [21] Prolongation of release [6] Prolongation of release [6] Prolongation of release [6] Preparation of oral formulation [22] Better activity and preparation of oral formulation [24]
Delivery of proteins and enzymes It is worth mentioning that protein and peptide delivery is receiving great attention in recent years. Still, there have been numerous potential hurdles in its therapy. What renders protein administration challenging is its tendency to undergo denaturation, aggregation and adsorption and properties, such as short half-life, immunogenicity, rapid enzymatic degradation, large molecular size and rapid clearance, poor absorption and bioavailability. To overcome these hindrances, the dose can be increased or use of absorption promoters can be employed, but it could lead to toxicity problems. Encapsulation into cyclodextrin-based nanosponges can improve the stability as well as the pharmacokinetic properties of proteins and peptides. Swaminathan et al. have made possible the encapsulation of bovine serum albumin into swellable cyclodextrin-based poly(amidoamine) nanosponges called as NS 10 and NS 11, which were synthesized by crosslinking b-cyclodextrins with either 2,2-bis(acrylamidoacetic acid) or a short polyamidoamine chain derived from 2,2-bis(acrylamidoacetic acid) and 2-methylpiperazine, respectively. A prolonged release of albumin was observed over a period of 24 h and it was also stabilized and protected [6,8,10]. Industries make use of enzymes to carry out myriad reactions which eliminate limitations such as low yields, requirements of high temperature and pressure, consumption of large amounts of energy and water. Enzymes are the preferred ‘biocatalysts’, owing to their remarkable properties such as high specificity, high-reaction speed, ability to operate under mild conditions and being environment-friendly. When such pharmaceutically important enzymes are loaded into cyclodextrin-based nanosponges, the conduct of continuous flow processes 2.8
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becomes possible, while maintaining their activity and efficiency over an extended pH and temperature range [8]. This can be best illustrated by Nardo et al. on catechol 1,2-dioxygenases from Acinetobacter radioresistens S13 immobilized on b-cyclodextrins crosslinked with carbonate nanosponges can be highlighted. These groups of enzymes are responsible for manufacturing adipic acid which is of industrial importance. Adipic acid is obtained by converting catechol into cis, cismuconate. The immobilization gave way to increased thermostability of the enzyme. The activity toward other substrates, such as 3-and 4 methylcatechol and 4-chlorocatechol, was retained by the enzyme immobilized on cyclodextrin-based nanosponges which demonstrates reaction specificity [6,27]. Various other applications of cyclodextrin-based nanosponges
2.9
Apart from its predominance in the sector of drug delivery, this multifaceted nanostructure has established its relevance in other realms as well. Cyclodextrin-based nanosponges have applications in the remediation technologies wherein they are employed in water treatment processes and are found to be efficient than activated carbon and can have a major advantage of being reused by environment-friendly solvents such as ethanol [6,28]. Cyclodextrin-based nanosponges can encapsulate some chemicals that are important in agricultural sector and can enable their slow release [6,29,30]. Cyclodextrinbased nanosponges can also be engaged in enantiodifferentiating photoisomerisation reactions [6,31], and in the polymer industry they act as novel green flame retardants that improve the flame-retardant properties of various polymeric compounds [6,32,33]; finally, they also possess potential to eliminate natural product contaminants such as ochratoxin-A from various food products and beverages [34]. 3.
Conclusion
Cyclodextrin-based nanosponges are an innovative class of materials which comprise hypercrosslinked polymers of cyclodextrins nanostructured in a three-dimensional network. Their super porous structure enables them to entrap a wide array of hydrophilic and lipophilic compounds. The biocompatibility of this scaffold structure makes it nontoxic, nonallergenic, nonirritant and it possesses several advantages over native cyclodextrins and even cyclodextrin derivatives such as ability to entrap hydrophilic, high molecular weight compounds, nontoxicity on parenteral administration and inability to dissociate from the drug on dilution. They can be formulated as tablets, capsules, aerosols, parenteral and topical dosage forms. These ground-breaking entities have significant applications in drug delivery. Apart from offering solutions to solubility problems, they enjoy widespread attention and use in improving stability, permeation, bioavailability and prolonging drug release. Delivery of proteins and pharmaceutically important gases has also been made possible through these cyclodextrin-based nanosponges. It is anticipated that 118
the cyclodextrin-based nanosponges have the aptitude to gain momentum in anticancer therapies by enabling sitedirecting of drugs. The manifold applications of this novel system extend beyond the territories of drug delivery to domains of cosmetics, biomedicine, agriculture and environment remediation. It is also worthwhile to mention that this technology is expensive and hence calls for it being made affordable to the pharmaceutical and healthcare sector to improve quality of life and appear as promising candidates in drug delivery technology. 4.
Future scenario
This nascent field of cyclodextrin-based nanosponges has stirred up enormous interest among physical and biological scientists and has already attracted hundreds of millions of dollars of research funding. The next 10 -- 15 years will see a lot of interesting work being done in this area and we will be able to see truly ‘transformational changes’. Because of their small and spherical shape, cyclodextrin-based nanosponges can be developed in various dosage forms, such as parenteral, topical, aerosols, tablets and capsules, and can be utilized for venous and pulmonary delivery of drugs [8]. It is intriguing to realize that cyclodextrin-based nanosponges can selectively trap certain biomarkers from blood and protect them from degradation by enzymes present in the blood to exploit them as diagnostic agents in cases of anticancer therapies. A study has highlighted that cyclodextrin-based nanosponges can harvest rare cancer marker, Bak (a protein), from blood for subsequent analysis of melanoma [8,35]. Harth et al. has come up with a splendid innovation wherein cyclodextrin-based nanosponges-loaded anticancer drugs when administered were found to be about 3 -- 5 times more effective than direct injection of the anti-cancer drug alone. This fact is highlighted by the observations that these drug-loaded cyclodextrin-based nanosponges circulate in the body and attach to only the timorous cells on account of the ‘linkers’ which are attached to these nanosponges, and release of drug is in a predictable, controlled fashion thus circumventing the destruction of healthy cells. The above facts propose that cyclodextrin-based nanosponges are envisaged to have a major impact on bringing about a transmutation and open newer vistas for better anticancer therapeutics [36]. For further successful development of this field, promising trends must be identified and exploited, albeit with a clear understanding of the limitations of these approaches. 5.
Expert opinion
Cyclodextrins are prominent for their ability to form inclusion complexes with various compounds and hence are employed in pharmaceutical field. But it is found that this technology mostly applies only to lipophilic drugs wherein their solubility is improved and less effective for hydrophilic and certain high molecular weight compounds. In addition,
Expert Opin. Drug Deliv. (2014) 11(1)
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Cyclodextrin-based nanosponges: a propitious platform for enhancing drug delivery
cyclodextrins were found to be toxic and they easily dissociated from the drug molecule on dilution. To combat this barrier, crosslinked polymers, that is, cyclodextrin-based nanosponges present a potential strategy. Cyclodextrins-based nanosponges have emerged as a necessary tool in the formulation scientist’s as well as physician’s resources to improve formulation aspects as well as therapeutics in order to enable a proficient drug delivery system. The biodegradability and nontoxicity of this novel system is sufficient to rest assure the concerns pertaining to the health hazards associated with the advancement of the nanoscience era. With the possibilities for new therapies seeming endless, cyclodextrin-based nanosponges are yet another novel approach to revolutionize nanomedicine. ‘Nanosponges’ being first diligently used in 1998 by De Quan Li and Min Ma has started to kindle myriad curiosity in the nanoscience which is evident from manifold research being carried out in this field. During its developmental process, a drug has to suffer a lot of setbacks for it to get launched in the market which include issues for a formulation scientist such as poor solubility, stability, permeation and bioavailability. These nanostructures have challenged these pitfalls and have aimed to create better dosage forms. The concept of tailored release of drug can be enabled with the help of cyclodextrin-based nanosponges by bringing about modifications in the degree of crosslinking to facilitate release profile of drug in cases of modulated drug release. In therapeutics, delivery of proteins, peptides, enzymes and even gases such as oxygen have made their debut and cyclodextrin-based nanosponges do not lag behind in their delivery as well. Cyclodextrin-based nanosponges have a solid potential to undergo a breakthrough in anticancer therapies,
owing to their ability to render a targeted drug delivery with minimal adverse effects. This cutting-edge technology is not only restricted to diagnostic and therapeutic fields but also has carved a niche in allied sectors such as cosmetics, agrochemistry, biomedical sciences and bioremediation technologies. This provides an outlook of the multifaceted aspects of cyclodextrin-based nanosponges. As we investigate this new realm of nanotechnology, it becomes necessary to realize that this new field offers some loopholes as well. It has been observed that the drug loading is not applicable to very high molecular weight compounds, which causes only selective drugs to be candidates for this delivery system. Even though production is easy, its high cost can form a barrier to its effective therapy. Hence, researchers should find means to make it affordable to the consumers. The clinical use of cyclodextrin-based nanosponges is still in its infancy but it could be a perfect solution for effectively delivering obstinate drug molecules. It could be considered as an appropriate nanosystem for delivery of active molecules and its future in nanomedicine appears promising. We optimistically speculate that in a few years from now, more and more improved cyclodextrin-based nanosponge formulations would gain access in the market, thus paving way for a metamorphosis in nanoscience and, indeed, act as a propitious platform for drug delivery and therapeutics.
Declaration of interest The authors state no conflict of interest and have received no payment in preparation of this manuscript.
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Affiliation
Sai V Chilajwar†, Priti P Pednekar, Kisan R Jadhav, Gajendra JC Gupta & Vilasrao J Kadam † Author for correspondence University of Mumbai, Bharati Vidyapeeth’s College of Pharmacy, Department of Pharmaceutics, Sector 8, C B D Belapur, Navi Mumbai 400 614, India Tel: +91 022 27571122; Fax: +91 022 27574525; E-mail: [email protected]
