REVIEW ON BETA- CYCLODEXTRIN INCLUSION COMPLEX: A MORDEN APPROACH FOR DRUG DELIVERY

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ABOUT AUTHORS:
Bhatt Anjali*, Goshwami Lakshmi,  Papola Vibhooti, Pathak Namita, Rawat Shuveksha
Shri Guru Ram Rai Institute of Technology and Science,
Dehradun 248001, Uttrakhand India
*anjali23mar@gmail.com

ABSTRACT
Cyclodextrins were first described by Villiers in 1891. Schardinger laid the foundation of the cyclodextrin chemistry in 1903 and identified cyclodextrin. In the 1930s, Freudenberg identified cyclodextrin and suggested that larger cyclodextrins could exist. Freudenberg and co-workers showed that cyclodextrins were cyclic oligosaccharides formed by glucose units and somewhat later Cramer and co-workers described their ability to form inclusion complexes. By the early 1950s the basic physicochemical characteristics of cyclodextrins had been discovered, including their ability to solubilize and stabilize drugs. The first cyclodextrin-related patent was issued in 1953 to Freudenberg, Cramer and Plieninger. However, pure cyclodextrins that were suitable for pharmaceutical applications did not come available until about 25 years later and at the same time the first cyclodextrin-containing pharmaceutical product was marketed in Japan. Later cyclodextrin-containing products appeared on the European market and in 1997 also in the US. This review aims to assess the use of cyclodextrin in newer drug delivery system such as nanosponges, nanoparticles, nanospheres, liposomes and other drug delivery system.

Reference Id: PHARMATUTOR-ART-1980

INTRODUCTION
Carbohydrates, such as cellulose, starch and sucrose, are probably the most abundant organic substances in nature and form very ancient time they have been used for shelter, clothing and food. For thousands of years humans have processed carbohydrates through fermentation and observed their enzymatic degradation 1. It is now known that these processes lead to formation of mixtures of monosaccharides, disaccharides and various oligosaccharides, such as linear and branched dextrins and that, under certain conditions, small amounts of cyclic dextrins or cyclodextrins are also being formed during these degradation processes. Cyclodextrins are cyclic (R-1,4)-linked oligosaccharides of R-D-glucopyranose containing a relatively hydrophobic central cavity and hydrophilic outer surface. Owing to lack of free rotation about the bonds connecting the glucopyranose units, the cyclodextrins are not perfectly cylindrical molecules but are toroidal or cone shaped. Based on this architecture, the primary hydroxyl groups are located on the narrow side of the torus while the secondary hydroxyl groups are located on the wider edge. The most common cyclodextrins are R-cyclodextrin, â-cyclodextrin, and ç-cyclodextrin, which consist of six, seven, and eight glucopyranose units, respectively.2

APPROACHES FOR MAKING INCLUSION COMPLEX 3,4,5

The methods generally preferred are:-
I. Kneading

The method involves the formation of paste of cyclodextrin with guest molecules by using small quantity of either water or ethanol to form kneaded mass. Kneaded mass can be dried at 45°C and pulverized.

II. Melting
Excess quantity of guest melted, mixed with powdered cyclodextrin, after cooling excess quantity of quest is removed by washing with weak complex forming solvent. The method restricted to sublimable guest like menthol.

III. Solution-enhanced dispersion by the Supercritical fluids (SEDS)
SEDS is novel, single step method, which can produce solid drug-cyclodextrin complexes. The optimization of processing conditions is essential in order to achieve the optimum complexation efficiency and to compare with drug-cyclodextrin complexation methods described earlier in the literature (e.g. kneading, freeze drying, spray drying etc). Advantages over other methods are (a) Preparation of solid-cyclodextrin complexes in single step process, (b) Achievement of high complexation efficiency (avoidance of excess cyclodextrin in powder). (c) Possibility to minimize the contact of drug with cyclodextrin during the process. (d) Achievement of enhanced dissolution rate of the drug (which is comparable to the dissolution behavior of micronized drug-cyclodextrin complex).depends on the temperature of guest and it must be optimized for every guest.

IV.Co-evaporation / Solvent evaporation method
To the alcoholic solution of guest, aqueous solution of host is added and stirred for sometimes and evaporated at room temp until dried mass obtained, pulverized and sieved and fraction is collected.

V. Microwave Irradiation
This method is developed for rapid organic synthesis and reactions, which require shorter reaction time and higher aim product.

VI. Freeze Drying / Lyophilisation technique
The required stoichiometric quantity of host and guest were added to aqueous solution of cyclodextrin and this suspension stirred magnetically for 24 hours, and resulting mixture is freeze dried at 60°C for 24 hours.

VII. Spray drying / Atomisation
In this method, host solution prepared generally in ethanol: water 50% v/v. To this guest is added and resulting mixture is stirred for 24 hr. at room temperature solution is spray dried by observing following conditions-air flow rate, atomizing air pressure, inlet temperature, outlet temperature, flow rate of solution etc. Product obtained by passing through 63-160 micrometer granulometric sieve.

CD APPLICATION IN DRUG DELIVERY

Oral Drug Delivery
Applications of CDs in oral drug delivery include improvement of drug bioavailability due to increased drug solubility, improvement of rate and extent of dissolution, and/ or stability of the drug at the absorption site, eg, the gastrointestinal tract (GIT) or in formulation, reduction of drug induced irritation, and taste masking). CDs enhance the mucosal drug permeability mainly by increasing the free drug availability at the absorptive surface. CD complexation can provide better and uniform absorption of low-soluble drugs with poor and erratic absorption and also enhance the drug activity on oral administration. CD complexation increased the anthelmentic activity of albendazole and provided a high plasma concentration of the active metabolite. CD complexation increased the absorption of poorly water-solubledrugs, delivered via buccal or sublingual mucosa. Complexation of miconazole, econazole, and clotrimazole with HP-β-CD and genuine CDs increased the toxicity of these drugs on a human buccal cell culture model (TR146) by causing drug supersaturation. Captisol or (SBE) 7m-beta-CD, a solubilizer with osmotic property, was used to design osmotic pump tablets of chlorpromazine and prednisolone. Complexation can also mask the undesirable taste of drugs. Complexation with CDs suppressed the bitter taste of oxyphenonium bromide. HP-β-CDs were shown to have a better oral safety profile than β-CD and other parent CDs, but only limited data are available on the oral safety of the methylated CDs. β-CD is the most cost-effective compound of all CDs, whereas HP-β- and SBE-β-CDs are more expensive( table no 1). 6

Parenteral Drug Delivery
CD derivatives such as amorphous HP-β- and SBE-β-CDs have been widely investigated for parenteral use on account of their high aqueous solubility and minimal toxicity. The solubilizing potentials of both SBE-β- and HP-β-CDs for the drugs melphalan and carmustine were qualitatively similar but the intrinsic reactivities were significantly less with SBE-β-CD.Applications of CDs in parenteral delivery are solubilization of drugs, reduction of drug irritation at the site of administration, and stabilization of drugsunstable in the aqueous environment. Singla et al discussed the use of CDs to enhance the solubility and stability of paclitaxel in formulations and mentioned that the approach needs further research to overcome the serious limitations of CD-based formulations.An IM dosage form of ziprasidone mesylate with targeted concentration of 20 to 40 mg/mL was developed by inclusion complexation of the drug with SBE-β-CD.7 Aqueous phenytoin parenteral formulations containing HP-β-CD exhibited reduced drug tissue irritation and precipitating tendency because their pH values were significantly closer to the physiological value (7.4). Effects of CDs on drug pharmacokinetics were discussed by Rajewski and Stella.8 The synergistic effect of CDs with acids like lactic acid was used to solubilize miconazole for safe parenteral delivery. In some cases complexation may affect drug pharmacokinetics, eg, complexation with sugar branched β-CDs altered the disposition of dexamethsone in mice. The binding values of diflunisal in plasma solutions containing HP-β-CD were found to be lower than the theoretical because of competitive displacement of the drug from the CD by plasma cholesterol. In rabbits, coadministration of M-β-CD with doxorubicin resulted in reduced distribution half-life and modified renal and hepatic distribution profiles of the drug, but the main pharmacokinetic parameters of the CD were unaltered.

Ocular Delivery
Applications of CDs in aqueous eye drop preparations include solubilization and chemical stabilization of drugs, reduction of ocular drug irritation, and enhancement of ocular drug permeability (table no 2). Vehicles used in ophthalmic preparations should be nonirritating to the ocular surface to prevent fast washout of the instilled drug by reflex tearing and blinking. Hydrophilic CDs, especially 2HP-β- and SBE-β- CDs, are shown to be nontoxic to the eye and are welltolerated in aqueous eye drop formulations, eg, increased ocular absorption and shelf life of pilocarpine in eye drop solutions by SBE-β-CD and decreased ocular irritation of a lipophilic pilocarpine prodrug by SBE-β- and HP-β-CDs. The cytotoxicity order of CDs on the human corneal cell line was found to be α-CD 9 DM-β-CD 9 SBE-β-CD = HP-β-CD 9 γ-CD. It was suggested that ocular toxicity with SBE-β-CD (100 mM) after 1 hour of its exposure could be possibly a result of its high osmotic pressure. However, the toxicity with negatively charged SBE-β-CD was greater than that with the control, a neutral hypertonic mannitol solution.CDs enhance drug permeability by making the drug available at the ocular surface. HP-β-CD enhanced the ocular permeability of dexamethasone acetate and also inhibited the conversion of acetate salt to less permeable dexamethasone9.  Since only the free drug can permeate biological membranes, ophthalmic delivery of drugs can be limited by the dissociation of drug/CD complexes in the precorneal area due to the limited dilution in this area. The dissociation of drug/CD complexes depends more on the binding of drugs to precorneal proteins, absorption by corneal tissue, and displacement of drugs from CD complexes by precorneal fluid components. Formulation with HP-β-CD, with and without HPMC, improved the bioavailability and maximal mydriatic response of tropicamide by enhancing the drug’s ocular permeability, but reduced the ocular drug irritation probably by maintaining the pH in physiologic range.10 HP-β-CD also enhanced the permeability and miotic response of pilocarpine nitrate without damaging the rabbit corneal tissue.

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