Exploring versatile applications of cyclodextrins: an overview

Figures & data

Figure 1. Parent and representative modified cyclodextrins of pharmaceutical interest [RAMEB: Randomly methylated β-cyclodextrin; HP-β-CD: Hydroxy propyl β-cyclodextrin; HE-β-CD: Hydroxy ethyl β-cyclodextrin; DIME-β-CD: Heptakis (2, 6-dimethyl)-β-cyclodextrin; TRIME-β-CD: Heptakis (2, 3, 6-trimethyl)-β-cyclodextrin].

Table 1. Chronological in development of cyclodextrins.

Year	Scientists	Advancements	References
1891	A. Villers	Crystalline substance isolated from bacterial digest of starch having resistance for acid hydrolysis and deficient in reducing property. Substance was found out to be dextrin and was termed as “cellulosine” by Villers.	Loftsson & Duchene (2007)
1903	Franz Schardinger	Fractionation of two more crystalline compounds, α-dextrin and β-dextrin, from bacterial digest of potato starch. Further, isolation of considerably more amount of β-dextrin, and recognized as Villers “cellulosine” was achieved. Later, these were better known as α-CD and β-CD.	Nitalikar et al. (2012)
1935	Freudenberg and Jacobi	γ-CD was discovered.	Nitalikar et al. (2012)
1935–1955	Freudenberg, Cramer and co-workers	Identification of the chemical structure of CDs, their physiochemical properties and their liability to form inclusion complexes.	Brewster & Loftsson (2007)
1938	Freudenberg and Cramer	CDs possess a ring structure containing glucose units, which are α (1 → 4)-linked and have a central cavity.	Loftsson & Duchene (2007)
1976		Prostaglandin E2/β-CD (Prostarmon E™ sublingual tablets), is the world’s first testified CD based pharmaceutical product sold in Japan.	Loftsson & Brewster (2010)
1997		The first US approved product was announced named as Itraconazole/2-hydroxypropyl-βCD oral solution (Sporanox®).	Kumar Das et al. (2013)
1998		The first European CD containing product Piroxicam/β-CD (Brexin® tablets) was introduced.	Brewster & Loftsson (2007)

Figure 2. Torus-like shape of cyclodextrin.

Table 2. Structural and chemical properties of parent cyclodextrins.

Features	α-CD	β-CD	γ-CD	References
Glucopyranose units	6	7	8	Szejtli (2004)
Molecular weight (g/mol)	972	1135	1297	Singh et al. (2010)
Height (nm)	0.78	0.78	0.78	Loftsson & Brewster (2010)
Cavity diameter (nm)	0.50	0.62	0.80	Loftsson & Brewster (2010)
Outer diameter of cavity (nm)	1.46	1.54	1.75	Loftsson & Brewster (2010)
Cavity volume (Å^3)	174	262	427	Cal & Centkowska (2008)
Aqueous solubility at 25 °C (mg/ml)	129.5 ± 0.7	18.4 ± 0.2	249.2 ± 0.2	Loftsson & Brewster (2010)
Aqueous solubility at 25 °C (%w/v)	14.5	1.85	23.2	Del Valle (2004)

Figure 3. Versatile applications of cyclodextrins.

Figure 4. Schematic representation of cyclodextrins–drug complexation, subsequent release and absorption of drug.

Figure 5. Process of inclusion complex formation of drug and cyclodextrin.

Table 3. Various reports on solubility enhancement of therapeutically important pharmaceuticals by CD complexation.

Drugs	pKa	Log P	Water solubility	Enhancement in solubility	Complexation method	C:D	CD type	Binding constant (M^−1)	References
Aceclofenac	4.7	2.17	0.058 µg/ml	–	KN	1:1	HPβCD	221.11	Kasliwal & Negi (2011)
Acyclovir	2.27	−1.56	1.62 mg/ml	–	KN	1:1, 2:1, 3:1, 4:1	HPβCD, βCD	–	Sachan et al. (2010)
Amisulpride	9.37	1.10	16.89 µg/ml	3.74 times	KN	1:1	γCD	1166.65	Negi & Singh (2013)
Artemether	4.8	3.02	–	1.8 times	FD	1:1	HPβCD	220	Yang et al. (2009)
Albendazole	10.26	2.7	1.37 µg/ml	53.4 times	PM	1:1	βCD	1266	Moriwaki et al. (2008)
Atorvastatin	11.82	5.7	20.4 µg/ml	–	FD, PM, KN, CE	1:1	βCD	–	Palem et al. (2009)
Amiodarone	8.47	7.57	0.2–0.5 mg/ml	–	FD, SD, CE, PM	1:1	βCD	1957	Riekes et al. (2010)
Cefdinir	3.2	−0.2	0.46 mg/ml	101% βCD, 23.4% HPβCD	KN	1:1	HPβCD, βCD	–	Aleem et al. (2008)
Darifenacin	9.2	4.5	2.98 mg/ml	8.24–20.57 mg/ml	CE	1:1	HPβCD	465.30	Jagdale et al. (2012)
Daidzein	7.39	2.51	0.15 mg/ml	5.7-fold (βCD),7.2-fold (MβCD), 9.4-fold (HPβCD)	FD	1:1	HPβCD, βCD, MβCD	–	Borghetti et al. (2011)
Etodolac	4.65	2.5	16 µg/ml	–	FD, PM	–	HPβCD	–	Cappello et al. (2009)
Fexofenadin	13.2	5.6	3.6 mg/ml	–	–	1:1	βCD, HPβCD	1139, 406	Al Omari et al. (2007)
Gliclazide	5.98	2.6	55 mg/ml	20.31 times	KN	2:1	βCD	691.45	Ozkan et al. (2000)
Isoquercitin		2.92	5.6 mg/ml	12.3 times	–	1:1	DMβCD	783	Wang et al. (2009)
Itraconazole	3.7	5.66	∼1 ng/ml	12 times	–	2:1	HPβCD	–	Miyake et al. (1999)
Josamycin	13.5	3.47	0.35 mg/ml	13.14 times	CP	1:1	γCD	3060	El Harti et al. (2012)
Meloxicam	4.08	1.9	8 µg/ml	–	–	1:1	βCD	–	Awasthi et al. (2011)
Naringenin	9.46	2.47	4.38 µg/ml	1272.31 µg/ml	–	1:16	HPβCD	–	Wen et al. (2010)
Omeprazole	4.77	2.23	82.3 µg/ml	–	FD, SD	1:1	MβCD	77.4	Figueiras et al. (2007)
Piroxicam	6.3	3	23 µg/ml	–	FD	2:1	βCD	–	Jug et al. (2005)
Repaglinide	4.01	3.97	34 µg/ml	–	–	1:1	HPβCD, βCD, RMβCD	377.4	Nicolescu et al. (2010)
Rapamycin	13.37	4.3	2.6 µg/ml	61 times	FD	1:1	MβCD	579	Rouf et al. (2011)
Rofecoxib	19.7	3.2	–	–	KN	1:1	βCD	769	Rawat & Jain (2003)
Rifampicin	8.25	2.7	1.4 mg/ml	22 times	–	1:1	RMβCD	73.4	Tewes et al. (2008)
Rutin	8.45	0.15	0.125 mg/ml	–	–	1:1	HPβCD	405.3	Miyake et al. (2000)
Raloxifene HCl	9.55	5.2	0.25 µg/ml	–	KN	1:1	HPβCD	4.59	Wempe et al. (2008)
Telmisartan	4.45	7.7	0.09 µg/ml	–	KN	2:1	βCD, HPβCD	644.56	Kane & Kuchekar (2010)
Vanillin	7.78	1.21	10 mg/ml	–	FD	1:1	βCD	5.3	Karathanos et al. (2007)
Valdecoxib	9.8	3.2	10 µg/ml	–	KN	2:1	HPβCD	1.63	Rajendrakumar et al. (2005)
Sulfamethoxazole	5.8	0.7	610 µg/ml	–	CP	1:1	βCD	122.3	Ozdemir & Erkin (2012)

KN, kneading; FD, freeze drying; PM, physical mixing; CE, co-evaporation; SD, spray drying; CP, co-precipitation.

Table 4. Use of cyclodextrin in promoting oral drug delivery.

Drugs	Cyclodextrin used	Work done	Conclusion	References
Furosemide (FS)	β-CD	β-CD complexes with the solid forms of FS.	Suitability for development of drug delivery system.	Garnero et al. (2014)
Econazole nitrate (ECN)	SBE-β-CD, HP-β-CD	Ternary complexes using β-CD derivatives and compounds (l-AAs, CA, hydrophilic polymers) for synergistic effect.	Effective in better treatment of oral candidosis.	Jug et al. (2014)
Tacrolimus (TL)	β-CD	Pluronic F127-modified liposome-containing CD inclusion complex.	Improved drug solubility and intestinal mucous membrane penetration.	Zhu et al. (2013)
Docetaxel (DTX)	SBE-β-CD	DTX–chitosan nanoparticles having CDs complexes.	Better candidates for oral administration in comparison to existing DTX formulations.	Wu et al. (2013)
Dihydroartemisinin (DHA)	HP-β-CD	Inclusion complexes	Improved pharmacokinetic parameters along with better oral delivery.	Ansari et al. (2011)
Praziquantel (PZQ)	α-, β-, γ-CD	Inclusion complexes	Enhanced solubility, bioavailability through oral route.	Becket et al. (1999)

Table 5. Representative work done in enhancing the rectal drug delivery using cyclodextrins.

Drugs	Cyclodextrin used	Work done	Conclusion	References
Diazepam and Flubiprofen	TM-β-CD	Inclusion complexes	Better drug release and permeability.	Lakshmi et al. (2012)
Ethyl 4-biphenylylacetate (EBA)	β-CD, HP-β-CD, DM-β-CD	Inclusion complexes	Better stability, release rate and hence improved rectal absorption.	Arima et al. (1992)
Morphine	α-CD	Pharmacokinetic studies of morphine and its glucuronides in rabbit plasma upon rectal administration from hollow type suppositories with xanthan gum.	Improved rectal bioavailability of morphine.	Kondo et al. (1996)

Table 6. Role of cyclodextrins in nasal drug delivery.

Drugs	Cyclodextrin used	Work done	Conclusion	References
Dihydroergotamine (DHE)	RM-β-CD	Development of nasal formulation containing inclusion complex.	Better stability with enhanced concentration and improved nasal drug delivery.	Rasheed et al. (2008)
Estradiol (ES)	DM-β-CD	Inclusion complex formation.	Better absorption hence enhanced bioavailability.	Ali et al. (2012)
Melatonin (MT)	HP-β-CD, RM-β-CD	Inclusion complexes.	HP-β-CD as well as RM-β-CD increased the nasal permeability of MT.	Babu et al. (2008)
Pirodavir	HP-β-CD	Formulation development for nasal delivery	Improved efficacy.	Rasheed et al. (2008)

Table 7. Application of cyclodextrins in ophthalmic drug delivery.

Drugs	Cyclodextrin used	Work done	Conclusion	References
Dexamethasone	CDs	Inclusion complex.	More patient compliance in comparison to un-complexed drug-based eye drops.	Loftsson & Stefansson (2002)
Econazole	SBE-β-CD	Chitosan nanoparticles containing complex CD were prepared and monitored.	Chitosan/SBE-β-CD nanoparticles developed had the tendency to act as a carrier for controlled delivery of drug to eyes.	Mahmoud et al. (2011)
Methazolamide	2-HP-β-CD	Effect on intra ocular pressure estimated in a double-blind randomized trial in humans.	Better lowering of intraocular pressure due to CD complexation.	Gudmundsdottir et al. (2000)
Zinc diethyldithiocarbamate (Zn-DDC)	HP-β-CD	Formulation optimization and anti-cataract effects of aqueous eye drop having high concentration of Zn-DDC.	Drug solubility and permeability were increased through the rabbit cornea.	Wang et al. (2004)

Table 8. Applications of CDs for improving dermal and transdermal drug delivery.

Drugs	Cyclodextrin used	Work done	Conclusion	References
Bupranolol (BPL)	HPβ-CD, PM β-CD	Inclusion complexes.	Improved solubility and penetration.	Babu & Pandit (2004)
Glipizide (GPZ)	β-CD, DM-β-CD, HP-β-CD and HP-γ-CD.	Percutaneous formulations of the drug complex in different bases (o/w emulsion, PEG, CMC and Carbopol).	Effective means for transdermal delivery in management of type 2 diabetes.	Ammar et al. (2006)
Gliquidone	HP-β-CD	Effect of pH and complexation on drug delivery.	Higher transdermal delivery of gliquidone was achieved due to improved solubility and permeability of the drug.	Sridevi & Diwan (2002)
Isotretinoin	HP-β-CD	Elastic liposomes loaded with complexes.	Possibility for skin targeting, extended drug release, less photo degradation and least possibility of skin irritation with better topical delivery.	Kaur et al. (2010)

Table 9. Recent reports of cyclodextrins in cosmetics.

Drugs	Cyclodextrin used	Work done	Conclusion	References
Eusolex® 4360 (Avobenzone), Eusolex® 9020 (Oxybenzone) and Eusolex® 232 (Ensulizole)	β-CD	Effects of β-CD complexation on transdermal penetration of sun blocking agents.	Reduction of systemic absorption of UV filters followed by toxicity and allergic reactions.	Shokri et al. (2013)
Lemongrass volatile oil	β-CD and HP-β-CD	Microparticles formed.	Efficacy improvement.	Weisheimer et al. (2010)
Octyl p-methoxycinnamate (OMC)	β-CD	Sunscreen preparations.	The lipo/OMC system proved as most beneficial release system.	Monteiro et al. (2011)
Phenylenediamine isomers (PDI)	β-CD	Detection of PDI in hair dyes.	Suitable method was developed.	Wu et al. (2011)

Table 10. Studies on use of cyclodextrins in food and flavors.

Food products	Cyclodextrin used	Work done	Conclusion	References
Cholesterol	β-CD	Study of inclusion properties and the factors affecting encapsulation and stability.	Successful elimination of cholesterol in the new food products.	Dos Santos et al. (2011)
Fat containing meal	α-CD	Effect of α-CD on the acute post-prandial responses in healthy adults.	Significant reduction of acute post-prandial blood triglyceride levels.	Jarosz et al. (2013)
Ginseng solution	β-, γ-CDs	Studies on taste masking and improvement of sensory properties of ginseng.	CDs in water and model energy drink base solutions containing ginseng, help in the formation of beverages suitable for consumers.	Tamamoto et al. (2010)
Goat milk and its yogurt	α-, β-, γ-CDs	Effect of CDs on the flavor of goat milk and its yogurt.	β-CD most effectively masked goaty flavor in yogurt with retention of nutritional benefits.	Young et al. (2012)
Mandarin juices enriched with pomegranate extract and goji berries juice	β-CD, HP-β-CD	Antioxidant efficacy of tested compounds was examined upon addition of β-CD or HP-β-CD.	Juices containing HP-β-CD showed more intense color, greater vitamin C content, retinol equivalents and antioxidant activity.	Navarro et al. (2011)

Table 11. Cyclodextrins applicability in textile industry.

Cyclodextrins	Work done	Conclusion	References
HP-γ-CDs	Use of CDs as a finishing agent of polyamide fibers in order to obtain inguinal meshes with enhanced antibiotic delivery properties. Polymerization between citric acid and CDs produced a cross-linked polymer that physically adhered to the surface of PA fibers.	CDs as efficient drug delivery systems for multiple applications in the fields of biomaterials and medical textiles.	El Ghoul et al. (2008)
MCT-βCD	Making of reactive cotton/wool and viscose/wool prints with outstanding UV-protection functions through inclusion of definite UV-absorbers/blockers like as a reactive additive, in the printing paste formulation with sodium alginate as a thickening agent.	Outstanding UV-protection efficacy even after 15 washing cycles.	Ibrahim et al. (2013b)
MCT-β-CD	Alteration in wool fabric structure.	Superior post-printing, using different dyestuffs and outstanding antibacterial activities.	Ibrahim et al. (2013a)
Monochlorotriazinyl-β-CD (MCT-β-CD)	The cotton grafted with an inclusion compound with natural anti-allergic active principles.	Anti-allergic knitted fabric/therapeutic pajamas were obtained.	Radu et al. (2013)

Table 12. Role of cyclodextrins in separation process.

Drugs	Cyclodextrin used	Work done	Conclusion	References
Racemic trans-δ-viniferin (TVN)	HP-β-CD	Preparative chiral high-speed counter-current chromatography method, based on which induced circular dichroism spectrum was developed.	Effective separation of TVN enantiomers.	Han et al. (2014)
Iodiconazole (IA)	HP-γ-CD	Chiral separation of IA and 12 new structurally related triadimenol analogs using capillary electrophoresis by HP-γ-CD.	Development of proper strategy for chiral separation.	Li et al. (2012)
Resibufogenin and cinobufagin	γ-CD	RP-HPLC using CDs as mobile phase additives.	Effective separation.	Xing et al. (2012)

Table 13. Cyclodextrin as anti-infectives.

Drugs	Cyclodextrin used	Work done	Conclusion	References
Artemisinin (AN)	β-CD	Agglomerated powder dosage form for oral administration based on primary microparticles containing AN/β-CD complex.	Enhancement in drug bioavailability.	Balducci et al. (2013)
Norfloxacin	β-CD	The solid-state properties of complexes of β-CD and norfloxacin at the molecular level.	Better understandings of the molecular fragments.	Chattah et al. (2013)
Voriconazole (VA)	HP-β-CD, 2-O-methyl-β-CD	The influence of CD complexation on VA solubility, dissolution rate and chemical stability was studied.	2-O-methyl-β-CD was found as more efficient solubilizer.	Miletic et al. (2013)
Zaltoprofen (ZP)	2-HP-β-CD	Development of gel formulation using carbomer complexed drug and other excipients.	No dermal irritation.	Baek et al. (2013)

Table 14. Use of cyclodextrins in non-viral gene delivery.

Cyclodextrin used	Work done	Conclusion	References
Polycationic amphiphilic CDs (paCDs)	A novel targeted gene delivery system was developed and assessed.	Suitability for cost effective production at large scale.	Aranda et al. (2013)
α-CD	Investigation of in vitro and in vivo gene delivery efficiency of polyamidoamine starburst dendrimer conjugates with α-CD.	Establishment of Lac-α-CDE as a non-viral vector for gene delivery toward hepatocytes.	Arima et al. (2010)
β-CDs	Nanoparticles coated with β-CD coupled to amino acids with different surface charges through direct ligand-exchange reactions were synthesized and used to deliver siRNA.	New insights into the mechanisms of amino acid mediated delivery and monitoring of gene silencing studies.	Zhao et al. (2011)

Table 15. Use of cyclodextrins in bioconversion process.

Cell culture	Substrate	Product	Inference	References
Saccharomyces cerevisiae	Androstenedione	Testosterone	Bioconversion increased in the presence of HP-β-CD from 27% to 78%.	Singer et al. (1991)
Mucuna pruriens	17-β-estradiol	4-hydroxyestradiol	The solubility of steroid and bioconversion efficiency was enhanced.	Woerdenbag et al. (1990)
Lactobacillus bulgaricus	Cholesterol	Testosterone	Increase in rate of bioconversion.	Singh et al. (2002)

Table 16. Cyclodextrins in plant cell technology.

Cell culture	Precursor	Product	Inference	References
Catharanthus roseus suspension culture	Methyl jasomate	Ajmalicine	Improvement in ajmalicine production	Almagro et al. (2011)
Artemisia annua suspension culture	Methyl jasomate	Artemisinin (AN)	300-fold enhancement in AN content.	Durante et al. (2011)
Vitis vinifera suspension culture	Methyl jasomate	Trans-Resveratrol	Increment in productivity was achieved.	Belchi Navarro et al., (2012)
Linum album suspension culture	Coniferyl alcohol	Podophyllotoxin, 6-methoxypodophyllotoxin	Increase in product content due to CDs by many folds.	Baldi (2008)

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