Colloids and Surfaces B: Biointerfaces 114 (2014) 130–137

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Review

Synthesis, characterization and application of Epichlorohydrin-␤-cyclodextrin polymer Bina Gidwani, Amber Vyas ∗ University Institute of Pharmacy, Pt. Ravi Shankar Shukla University, Raipur, CG, India

a r t i c l e

i n f o

Article history: Received 25 June 2013 Received in revised form 8 September 2013 Accepted 18 September 2013 Available online xxx Keywords: Epichlorohydrin-␤-cyclodextrin Polymerized cyclodextrin Host–guest interaction Hydrophilic Drug delivery

a b s t r a c t Cyclodextrins, the macrocyclic compounds are renowned for their inclusion ability. Several chemical and polymerized derivatives of parent cyclodextrins are synthesized to improve the physicochemical/biopharmaceutical properties of drug and inclusion capacity of cyclodextrin. This review article recapitulates the potential aspects of polymerized water-soluble derivative of ␤-cyclodextrin viz. epichlorohydrin-␤-cyclodextrin polymer in different areas of drug delivery. Polymerized cyclodextrin combines the advantage of the properties of polymer (high molecular weight and higher solubility) with the formation of inclusion complex with cyclodextrin. This justifies the superiority of polymerized cyclodextrin over parent cyclodextrin and some other chemically modified and non-polymerized derivatives. The use of polymerized cyclodextrin in various fields like biomedical, pharmaceutical and gene delivery is increasing day-by-day. ␤-Cyclodextrin-epichlorohydrin polymer is a high molecular weight compound, which acts as an effective drug carrier for enhancing the solubility and oral bioavailability of drugs along with the increase in therapeutic efficiency. The future panorama of polymerized cyclodextrins is quite bright as they can serve as useful multifunctional tools for pharmaceutical scientists to develop and optimize drug delivery through various routes. Also, no information concerning the regulatory status and toxicity of polymerized cyclodextrins is available. So, there is a need to focus on these critical issues for resolving the problems associated with the development and commercialization of drug products. © 2013 Elsevier B.V. All rights reserved.

Contents 1. 2.

3.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cyclodextrin as carbohydrate polymer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Structure of cyclodextrin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Inclusion complex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Polymerized cyclodextrins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.1. Water-insoluble ␤-cyclodextrin-epichlorohydrin polymer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3.2. Water-soluble epichlorohydrin ␤-cyclodextrin (␤-CDEP)/(␤-CDP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Commercial availability of epichlorhydrin-␤-cyclodextrin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Applications of epichlorhydrin-␤-cyclodextrin in drug delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Effect on drug properties in formulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.1. Effect on solubility, bioavailability and dissolution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Applications of epichlorohydrin-␤-CD in formulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.1. Drug delivery in oral cavity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.2. Topical drug delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2.3. Parenteral drug delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Applications in designing of some novel carriers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

∗ Corresponding author. Tel.: +91 9926807999. E-mail addresses: [email protected] (B. Gidwani), [email protected] (A. Vyas). 0927-7765/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.colsurfb.2013.09.035

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4.

Conclusion and future prospects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Cyclodextrins (CDs) are valuable multifunctional tools that have been extensively used in pharmaceutical industry. They are classified into hydrophilic, hydrophobic and ionic derivatives. The bio-adaptability and versatility of cyclodextrins makes them capable of alleviating the undesirable properties of drug molecules in various areas of drug delivery through the formation of inclusion complexes. In fact, numerous derivatives of CDs are examined continuously to improve physicochemical properties of drug in order to obtain both higher solubility and stability. Cyclodextrin-based carriers can enhance the capability of encapsulating guest molecule, improve the stability of drug and efficiently regulate the drug release rate. The principal advantages of natural/parent cyclodextrins (␣, ␤ and ␥) are their low toxicity, low pharmacological activity and well-defined chemical structure [1]. ␤-Cyclodextrin (␤-CD) is most widely used because it is readily available and has suitable cavity size. Moreover, it provides pharmaceutically useful complexation characteristics for the widest range of drugs [2]. However, its use is limited in formulations due to low aqueous solubility and toxicity [3]. To reimburse this issue, hydrophilic derivatives of ␤-cyclodextrin like hydroxypropyl-␤-cyclodextrin (HP-␤-CD), sulfobutylether-␤cyclodextrin (SBE-␤-CD) and randomly methylated-␤-cyclodextrin (RM-␤-CD) have been investigated [4–12]. Still, the number of natural CDs currently available is limited and does not satisfy and fulfill all the necessary requirements that fundamental studies or commercial applications demand. To conquer this, several amorphous, non-crystalline derivatives were synthesized by chemical modification of native CDs [13]. 2. Cyclodextrin as carbohydrate polymer Enzymatic hydrolysis of starch results in formation of several sugars like glucose, maltose and a long range of linear and branched dextrins. However, the enzyme cyclodextrin glucosyltransferases (CGTs) degrade starch through an intramolecular chain splitting reaction, producing cyclodextrins. Of all the potentially useful polymers in drug delivery, naturally occurring polysaccharides appears as an attractive and alternative approach due to high biodegradability and biocompatibility. Cyclomaltooligosaccharides (cyclodextrins) represent a paradigmatic example of carbohydrate derivatives, exhibiting a close relationship between molecular status and supramolecular functional properties [14]. Thus, CDs are considered as a class of nano-biomaterial, susceptible of further manipulation to modulate their topology and recognition features with the environment. Coating inside a nanocavity with sugars or building up a glyconanocavity from carbohydrate building blocks is, however, much less evident. This is the reason that cyclodextrins are the only representatives of nanomaterials that allow both fundamental studies and commercial applications [15,16]. 2.1. Structure of cyclodextrin Cyclodextrins are toroidal molecules with a truncated cone structure having lipophilic inner cavities and hydrophilic outer surface. Their cylindrical structures with cavities of about 0.7 nm deep and 0.5–0.8 nm inside diameter yield various unique properties [17]. The attractive property of CDs is the presence of many

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hydroxyl groups on glucose units i.e. 18, 21 and 24 for ␣, ␤, and ␥-CD. Modification of hydroxyl groups is expected to affect the capability of molecular recognition. Methylation or hydroxyalkylation of hydroxyl groups improve the solubility and stability of inclusion complexes with guest molecules [18]. The secondary hydroxyl groups are on the wider side of the ring, whereas the primary hydroxyl groups are on the opposite narrower side of the torus. The CH groups having the H-1, H-2, and H-4 protons are mainly located on the exterior side of the molecule and the hydroxyl groups are oriented toward the exterior of cone, making the external portion of CDs hydrophilic in nature. At the interior of the torus, two rings of CH groups (H-3 and H-5) and a ring of glycosidic ether oxygen is present with H-6 located near the cavity. Fig. 1 shows the structure of cyclodextrin. This low polarity central void is able to encapsulate (partially or wholly) a wide variety of guest molecules of suitable size, shape, structure and dimensions, resulting in a stable association without the formation of covalent bond [3,19]. The hydroxyl groups allow direct substitution reactions and/or chemical modifications to different positions (primary face, secondary face or both faces) yielding various polymerized derivatives for specific domains of application. 2.2. Inclusion complex A complex in which one component (host) forms cavity/channels in which the molecular entity of second chemical species (guest) is located is Inclusion complex. The attraction between host and guest is due to vanderwaal forces. CD complexation is the most preferred technique for industrial, research and analytical purposes [20–23]. Due to the distinctive features and host like structure, CDs and their polymers can form supramolecular complexes in both solid state and solution with various organic molecules [24–27]. 2.3. Polymerized cyclodextrins Polymerized cyclodextrins are prepared by cross-linking the CD rings, polymerizing bi-functional substituent containing CDs or bonding CDs to other polymers. Due to the unique structure of molecules combined with their poly-functionality, ␤-CD molecules have the ability to form cross-linked networks. It can be cross-linked by direct reaction between its hydroxyl groups with a coupling agent to form water-soluble/insoluble polymeric structures [28]. Based on the method of synthesis, CD polymer can be linear or branched. Linear polymers are prepared by co-polymerization of CD vinyl derivatives [29–34] or by reaction of mono/bi-functionalized derivatives of CD with pre-existing polymer/bi-functional reactants [33–35]. Moreover, branched polymers are prepared by polycondensation of CD with bifunctional reactants [36–38] leading to formation of high molecular weight polymers. Soluble polymers are prepared by employing reaction for shorter time with smaller initial concentration of cyclodextrin [39]. Insoluble polymerized cyclodextrins are used as sorbents for removing the pollutants and dyes from wastewater and are for preparation of hydrogels due to their swelling property [40–43]. Polymerized cyclodextrins can be cationic, anionic or non-ionic in nature. Due to the presence of charge, these charged polymerized cyclodextrins posses special complexing and solubilizing ability.

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Fig. 1. (a) Shows the general structure of cyclodextrin and (b) shows the arrangement of OH and CH groups on the trauncated cone (left) and the number of atoms in glucopyranoside ring (right).

Table 1 Types of polymerized cyclodextrins. Parent cyclodextrin

Polymerized cyclodextrin

Charge

Solubility

Cross linking agent

␣

Epichlorohydrin-␣-cyclodextrin polymer

Non-ionic

Soluble

Epichlorohydrin

␤

Epichlorohydrin-␤-cyclodextrin polymer Carboxymethyl epichlorohydrin-␤-cyclodextrin Branched cationic-␤-cyclodextrin polymer Sulfated ␤-cyclodextrin polymer ␤-Cyclodextrin epichlorohydrin polymer

Non-ionic Anionic Cationic – –

Soluble Soluble Insoluble Soluble Insoluble

Epichlorohydrin Epichlorohydrin Epichlorohydrin and choline chloride Epichlorohydrin Epichlorohydrin

␥

Epichlorohydrin-␥-cyclodextrin

Non-ionic

Soluble

Epichlorohydrin

The ionic interactions outside the cavities and the hydrophobic interactions inside the cavities, contributes to the drug solubilization. They may form stronger complex with oppositely charged molecules and weaker complex with molecules of same charge [44]. From last few years, researchers are attracted toward the use of a special member of polymerized hydrophilic derivative of ␤cyclodextrin i.e. epichlorohydrin ␤-cyclodextrin polymer [45–47]. Epichlorohydrin cyclodextrin has been studied as early as 1960s but not been explored widely [48–50]. Table 1 enlist the examples of various polymerized cyclodextrin derived from parent cyclodextrin. 2.3.1. Water-insoluble ˇ-cyclodextrin-epichlorohydrin polymer Polymerized cyclodextrins are gaining much attention for separation and purification purpose, removal of impurities, pollutants and toxins from wastewater using chromatographic techniques like high performance liquid chromatography (HPLC) and gas chromatography (GC). They are used to increase stability, encapsulation ability and separation efficiency of contaminants. But, because of their water solubility, they cannot be used directly. Recently Crini and Crini (2013) synthesized water-insoluble ␤-cyclodextrinepichlorohydrin polymer and explored its utility for environmental applications [51]. 2.3.2. Water-soluble epichlorohydrin ˇ-cyclodextrin (ˇ-CDEP)/(ˇ-CDP) During 19th century, the use of water-soluble ␤-cyclodextrin polymer (␤-CDP) was limited [45,46]. Recently in the 21st century and coming decades, extensive use of this cyclodextrin is reported. Fig. 2 shows the structure of epichlorohydrin ␤-cyclodextrin.

Fig. 2. Chemical structure of epichlorohydrin-␤-cyclodextrins.

2.3.2.1. Epichlorohydrin. Chemical cross-linking with epichlorohydrin is the basic method to produce ␤-cyclodextrin-based polymer. This cross-linking agent is known from past 50 years and is relatively easy to use. EPI (1-chloro-2,3-epoxypropane) is the most common cross-linker used in polysaccharide chemistry [52]. It is a bi-functional agent containing two reactive functional groups, an epoxide group and a chloroalkyl moiety, which can form bonds with ␤-CD molecules (cross-linking step) and/or itself (polymerization step). The polymers prepared are purified before use and the presence of free/unreacted EP can be discarded [53]. 2.3.2.2. Synthesis of water-soluble ˇ-CDP. Epichlorohydrin-␤-CD is synthesized by single step condensation and polymerization reaction. Generally, it is prepared by reacting parent ␤-CD with epichlorohydrin in alkaline medium resulting in products that contains mixture of monomeric species and of polymeric fraction [46]. In a thermostatic reactor vessel, a mixture of ␤-CD (approx. 20 g) and 50% (w/w) NaOH solution (32 mL) is stirred for 24 h at 25 ◦ C. This mixture is then heated to 30 ◦ C and 24 mL of EP is added rapidly and stirred vigorously with a magnetic stirrer for 6 h at 30 ◦ C. Finally, the reaction is stopped by addition of acetone. After decantation, acetone is removed and the solution is kept at 50 ◦ C overnight. After cooling, the solution is neutralized with 6 N HCl and ultra filtrated (molecular weight cutoff 3500) in order to eliminate salt and low-molecular-weight compounds. The process is affected by change in the concentration and amount of NaOH, epichlorohydrin and cyclodextrin used. The solution obtained is evaporated and precipitated by adding dehydrated ethanol. The white product obtained is dried, crushed and finally granulated to particle size of 1–2 mm in diameter. Fig. 3 shows the schematic representation of different steps for the synthesis of epichlorohydrin ␤-cyclodextrin. 2.3.2.3. Properties of epichlorohydrin-ˇ-cyclodextrin. Epichlorohydrin-␤-cyclodextrin polymer remains within the cavity structure of ␤-CD, providing capability of forming inclusion complexes with a variety of guest molecules [48,49]. This cyclodextrin is proved to be more effective compared to parent ␤-CD [13,48,54,55].

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2.4. Commercial availability of epichlorhydrin-ˇ-cyclodextrin Natural cyclodextrins and chemically modified derivatives are available easily in bulk quantities as compared to the polymerized cyclodextrins. One of the largest suppliers of these polymerized cyclodextrins is the Cyclolab, Hungary. 3. Applications of epichlorhydrin-␤-cyclodextrin in drug delivery 3.1. Effect on drug properties in formulation Cyclodextrins and their derivatives encompass significant role in formulation and development. This part of review highlights superiority of epichlorohydrin ␤-cyclodextrin polymer over parent ␤-cyclodextrin with various examples.

Fig. 3. Synthesis of epichlorohydrin-␤-cyclodextrin.

Table 2 Properties of epichlorohydrin-␤-cyclodextrin. Properties of epichlorohydrin-␤-cyclodextrin Synonym Molecular weight Appearance Purity Solubility in water at 25 ◦ C pH Melting point Nature

Soluble ␤-cyclodextrin polymer cross linked with 1-chloro-2,3-epoxy propane 112 kDa/112,000 Da White or pale yellow amorphous powder >95% >50 g/100 mL 6.5 230–240 ◦ C Hydrophilic

After synthesis in laboratory, it is necessary to characterize the prepared epichlorohydrin-␤-cyclodextrin polymer. For characterization, the physical and chemical properties of epichlorohydrin-␤-cyclodextrin are listed in Table 2. Other important parameters of characterization are FTIR, XRD and DSC. 2.3.2.4. FTIR spectra of epichlorohydrin-ˇ-cyclodextrin. The IR spectrum of ␤-CDEP contains CH2 Cl wagging band and C Cl stretching at 1288.36, 1249.79 and 721.33, respectively, which are characteristic peaks for epichlorohydrin. The stretching vibrations of OH, CH2 and C O C are around 3452.34, 3411.84, 3271.05, 2933.53 and 1099.35, respectively conform the presence of ␤-cyclodextrin in the structure [56]. Fig. 4 shows the characteristics peaks of epichlorohydrin ␤-cyclodextrin.

Fig. 4. FTIR spectra of epichlorohydrin-␤-cyclodextrin.

3.1.1. Effect on solubility, bioavailability and dissolution Cyclodextrins enhance the bioavailability of insoluble drugs by increasing the solubility and permeability. They increase the permeability of hydrophobic drug by making them available at the surface of biological barrier (e.g. skin and mucosa) from where it partitions into the membrane without disrupting the lipid layers of the barrier. In case of water-soluble drugs, cyclodextrins increase the permeability by direct action on mucosal membrane and enhance the drug absorption and bioavailability [57]. The effect of EPI-␤-CD on solubility and bioavailability has been demonstrated [49] and confirmed in human volunteers [58]. Nie et al. (2011) evaluated the potential of EPI-␤-CD for enhancing the dissolution rate and oral bioavailability of glipizide [59]. It is a BCS class II, oral hypoglycemic agent used in type II diabetes mellitus. The low water solubility is rate-limiting step and contributing factor for its absorption in gastrointestinal tract [60,61]. To overcome this problem, cyclodextrin complexation was used as approach. Phase-solubility study [62] proved that ␤-CDP possesses better properties than HP-␤-CD. The apparent solubility of glipizide increased linearly with increasing concentration of ␤-CDP and showed AL -type profile with the formation of 1:1 complex. The glipizide/␤-CDP complex showed higher dissolution rate when compared to pure drug and physical mixture. The increase in solubility was 36.65 times with EPI-␤-CD and 20.87 times with HP-␤-CD. This proved that ␤-CDP exhibited 10–12 times better solubility compared to HP-␤-CD. Other drugs which have been complexed with epichlorohydrin-␤-cyclodextrin are butylparaben, hydrocortisone, cinnarizine, tolnaftate, acetohexamide and furosemide [13,48,54,55]. In another study, Deveswaran et al. (2012) investigated the feasibility of epichlorohydrin␤-cyclodextrin for same purpose (enhancing the dissolution rate and oral bioavailability) using aceclofenac. The inclusion complexes were prepared by physical mixture and kneading method. Results showed 90% yield, which revealed minimum loss of drug and polymer. Significant increase in solubility was observed with ␤-cyclodextrin-epichlorohydrin when compared to parent ␤-cyclodextrin. The dissolution rate of complex was faster with kneading than with physical mixture and pure drug. This may be due to the wetting effect of cyclodextrin at the initial stage of the dissolution process. The dissolution efficiency was maximum for epichlorhydrin ␤-CD and minimum for pure drug. The order was ␤-CDEP (kneading process) > ␤CDEP (physical mixing) > aceclofenac powder. Thus, complexation with ␤-CDEP was productive for improving the dissolution rate of aceclofenac [56]. Furthermore, Jug et al. in the year 2011 studied the interaction of triclosan (TR), a practically waterinsoluble antimicrobial agent with ␤-cd and EPI-␤-cd in both

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Table 3 Applications of hydrophilic polymerized ␤-cyclodextrin in drug delivery. S.N.

Drug

Category

Cyclodextrin

Purpose

Method

1.

Bupivacaine hydrochloride

Local anesthetic

Epichlorohydrin ␤-cyclodextrin

Mucoadhesive formulation

2.

Glipizide

Oral hypoglycemic agent

Epichlorohydrin ␤-cyclodextrin

3.

Ketoprofen

Non-steroidal antiinflammatory drug (NSAID)

4.

Indomethacin

5.

Insulin

Non-steroidal antiinflammatory drug (NSAID) –

Epichlorohydrin ␤-cyclodextrin (EPI-␤-CD) and carboxymethylathed␤-Cd-epichlorohydrin polymer (EPI-CM ␤ Cd) Branched cationic ␤-cyclodextrin polymers (CP-␤-CDs)

Enhancement of the dissolution rate and oral bioavailability Improve the therapeutic efficacy through NLC

Physical mixture, co-evaporation, ball milling and lyophilization Co-evaporation

6.

Triclosan

Antimicrobial Agent

Epichlorohydrin ␤-cyclodextrin

Cationic ␤-cyclodextrinepichlorohydrin polymer

Improve the drug loading capacity and achieve controlled release Protection from gastric degradation and controlled release Enhancement of solubility and dissolution

solid state and solution [63]. The poor aqueous solubility of triclosan can give rise to formulation problems and reduce its biological activity [64,65]. Phase-solubility studies showed higher solubilizing and complexing ability of EPI-␤-CD (Ks = 11,733 M−1 ) compared to parent ␤-CD (Ks = 2526 M−1 ). The solubility linearly increased with the concentration of EPI-␤-CD leading to formation of AL type curve. The stability constant of TR/EPI-␤CD complex was 4.6 times higher than with the native ␤-CD. All the above examples confirmed greater solubilizing and complexing ability of EPI-␤-CD toward different lipophilic molecules [13,66].

3.2. Applications of epichlorohydrin-ˇ-CD in formulations 3.2.1. Drug delivery in oral cavity Applications of CDs in oral delivery include improvement of drug’s bioavailability, mainly due to increased solubility, improvement of drug’s dissolution rate and/or stability. CD complexation decreases local drug irritation and modifies the time of drug release during GI transit [67]. Epichlorohydrin-␤-CD, finds budding applications in buccal drug delivery. Advantage of buccal delivery includes excellent accessibility, patient compliance, avoids first-pass metabolism and involves robust mucosa. Cyclodextrins enhance mucosal drug permeability by increasing availability of free drug at the absorption surface. No specific toxicity is reported with the use of EPI-␤-cyclodextrin polymer on buccal mucosa [49,58]. Jug et al. (2010) prepared solid binary product of bupivacaine hydrochloride (an amide type local anesthetic) for buccal delivery [57]. This drug is widely used in management of the pain associated with dental and oral surgery, but has several drawbacks like administered in injectable form, less effective and slow onset of reaction [68–70]. Results showed that EPI-␤-CD possessed more powerful interaction with BVP HCl than ␤-CD, leading to the stronger reduction in drug crystallinity and amorphous nature of the carrier. This formulation led to an improvement in effectiveness of regional administration of local anesthetics in the oral cavity, increasing the patient’s comfort. The drug dissolution rate was higher with EPI-␤-CD. This type of formulation can be used

Nanocarrier/ formulation

Delivery route

Reference

Buccal delivery

[57]

–

Oral delivery

[59]

Co-grinding and co-lyophilization

NLC

Topical delivery

[78]

Kneading

Hydrogel

Topical delivery

[89]

Physical mixing

Alginate/chitosan nanospheres and nanoparticles

Oral delivery

[90]

Co-grinding

–

Oral delivery

[63]

for treatment of radiation-induced oral mucositis that occurs during radiation therapy of the carcinoma in the oral cavity or as side effect of cytostatics administration. This polymerized cyclodextrin can overcome the obstacles of limited amount of dissolution medium in the mouth and the barrier properties of the oral mucosa [57,71].

3.2.2. Topical drug delivery Complexation of drug with hydrophilic polymerized cyclodextrin in suitable ratios can serve as potent delivery system with prolonged therapeutic effect and equitable bioavailability [72–74]. Lipid nanoparticles are particularly advantageous as carriers for topical administration of active pharmaceutical ingredients, allowing prolonged release and improved bioavailability of the drug at the site of action [75–77]. For example, Cirri et al. (2012) prepared topical delivery system for ketoprofen (a non-steroidal anti-inflammatory drug), based on dual approach of cyclodextrin complexation, to enhance drug solubility and dissolution properties and loading of complex into nanostructured lipid carriers, to improve drug delivery through the skin [78]. This system led to improvement in therapeutic efficacy. Although different approaches have been exploited for improving the non-optimal characteristic of ketoprofen, such as the use of prodrug [79,80], loading into liposomes [81] and lipid nanoparticles [77]. An improvement in bioavailability has already been reported by using these techniques as directly related to its improved solubility and dissolution rate obtained by complexation with natural and alkylated cyclodextrins [82–84] but the contribution of Cirri et al., proved to be superior of all. In the study, two polymeric CDs, i.e. ␤-CD-epichlorohydrin polymer and carboxymethylated␤-CD-epichlorohydrin polymer (EPI-CM-␤-CD) and two different techniques (co-grinding and co-lyophilization) were used to obtain solid complexes. EPI-␤-CD was more effective than EPI-CM-␤-CD in enhancing the solubility and dissolution properties of ketoprofen and co-grinding in dry conditions was best preparation technique, leading to homogeneous amorphous particles in nanometric range. Table 3 covers the applications of ␤-CD-epichlorohydrin polymer in drug delivery.

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Fig. 5. (a) Shows the comparative release profile of ketoprofen from drug aqueous suspension, from NLC loaded with drug alone or as physical mixture or as co-ground product with EPI-␤-Cd and EPI-CM-␤-Cd and (b) shows the comparative permeation profile of ketoprofen from hydrogel loaded with aqueous suspension of drug alone (Keto) or its co-ground product with EPI-␤-Cd (Keto-EPI-␤-Cd GR) or with NLC containing the drug alone (NLC Keto) or as physical mixture (P.M.) or co-ground product (GR) with EPI-␤-Cd.

3.2.3. Parenteral drug delivery Injectable formulation of drug consists of mixtures of water, organic co-solvents and surfactants. The use of organic solvents and surfactants can be replaced by isotonic aqueous cyclodextrin solutions. These aqueous cyclodextrin vehicles containing the active drug will cause no variation in the intrinsic pharmacokinetics of a drug [28,51]. After intravenous injection, the drug is released upon dilution, competitive replacement and binding of drug molecules to plasma proteins and tissue. ␤-CD cannot be administered parenterally, due to its poor solubility and ability to precipitate and form complex with cholesterol. This problem can be mitigated by use of functionalized and chemically modified cyclodextrin. Cyclodextrins suitable for parenteral delivery are the hydrophilic derivatives like 2-hydroxypropyl-␤-cyclodextrin and sulfobutylether ␤-cyclodextrin. Both these derivatives are relatively non-toxic and have minimal effect on the intrinsic pharmacokinetics of drugs. As epichlorohydrin-␤-cyclodextrin is also hydrophilic chemically modified polymerized derivative of ␤cyclodextrin, its use in parenteral/injectable delivery is not yet reported in literatures. Till date, it is used for research purposes only. So, in future it can be explored for application in parenteral delivery.

3.3. Applications in designing of some novel carriers In drug delivery, the concept of entrapping cyclodextrin–drug complexes into carriers combines the advantage of both cyclodextrins and the carriers into a single system and thus circumvents the problems associated with each system. The use of such delivery system can solubilize poorly water-soluble drug, provide prolonged release, improve bioavailability, decrease side effect, protect from degradation and modify the pharmacokinetic parameters [85]. Entrapment of cyclodextrin inclusion complexes in liposomes [86] increases the drug-to-lipid mass ratio and enlarges the number of insoluble drugs that can be incorporated. Solid lipid nanoparticles (SLN) have since been prepared as carriers of drug complexes of ␤cyclodextrin, and showed good loading capacity and slower drug release [87]. Epichlorhydrin-␤-cyclodextrin is also used to achieve controlled drug release [88]. An example in this regard is nanostructured lipid carriers of ketoprofen. NLC of the complexed system

was prepared by ultrasonication process. The (drug-CD)-loaded NLC system, was formulated into hydrogel, which exhibited drug permeation properties better than the plain drug suspension and plain drug-loaded NLC. Fig. 5 shows the comparative results of release profile and permeation study of ketoprofen. Apart from NLCs, several other micro/nanocarriers such as nanoparticles, nanospheres, solid lipid nanoparticles, liposomes, microspheres, microcapsules are rarely available in literature and thus can be explored in coming future. 4. Conclusion and future prospects Cyclodextrins and their derivatives have received considerable attention in pharmaceutical field from past several years. EPI␤-CD, the safer and superior complexing and solubilizing agent with multifunctional characteristics is a proficient tool for tailoring the poor biopharmaceutical/physico-chemical properties of drug. Phase-solubility study of several drugs proved that ␤-CDP is superior and possesses better properties compared to parent ␤-CD and some of its derivatives. Taking into account all the above facts and considerations, ␤-CDP possess great pharmaceutical potential as a alternate excipient for commercial ␤-CD and HP-␤-CD based on its important modifications on the physicochemical and biological properties of poorly water-soluble drugs. The tunable structure of polymerized hydrophilic cyclodextrins makes them endowed excipient or carrier through superior loading capacity and controlled drug release. In future, in vivo studies on human volunteers need to be explored in order to verify the superior therapeutic effectiveness of the formulations containing polymerized water-soluble cyclodextrin. ␤-CDP could be considered a useful excipient/carrier to deliver drugs in a pattern that will allow fast dissolution and better absorption. Also, this polymerized cyclodextrin needs to be studied with respect to its regulatory status and toxicity, as no documentary evidence is available in this regard. In future, this hydrophilic cyclodextrin might solve many problems associated with drug delivery through different routes. Till date, this cyclodextrin is utilized for oral and topical delivery only but in the future, it use in parenteral, ocular, nasal, rectal, colon-specific, brain, gene and peptides delivery can be explored. Thus, the functionality of this hydrophilic polymerized cyclodextrin will increase rapidly in the coming years.

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