Alginate-chitosan combinations in controlled drug delivery

C H A P T E R 15

Alginate-chitosan combinations in controlled drug delivery Gamal M. El Maghraby, Mona F. Arafa Department of Pharmaceutical Technology, College of Pharmacy, University of Tanta, Tanta, Egypt

Chapter Outline List of abbreviations 339 1. Introduction 340 2. Oral controlled drug delivery

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2.1 Liquid oral sustained release preparations (in situ gelling systems) 341 2.2 Particulate carriers 344

3. Transdermal controlled drug delivery 348 4. Ocular controlled drug delivery 350 5. Nasal controlled drug delivery 352 6. Vaginal controlled drug delivery 353 7. Implantable drug delivery system 354 8. Tissue engineering and wound dressing 355 9. Concluding remarks 356 References 356

List of abbreviations 5-FU BSA BCG CD GIT Hb H. pylori PRRSV SGF SIF

5-fluorouracil Bovine serum albumin Bovis bacilli calmette-gue´rin cyclodextrins Gastrointestinal tract Hemoglobin Helicobacter pylori Porcine reproductive and respiratory syndrome virus Simulated gastric fluid Simulated intestinal fluid

Natural Polysaccharides in Drug Delivery and Biomedical Applications. https://doi.org/10.1016/B978-0-12-817055-7.00015-7 Copyright © 2019 Elsevier Inc. All rights reserved.

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340 Chapter 15

1. Introduction Alginate and chitosan are biopolymers which are derived from natural sources. These biopolymers have extended application in food and pharmaceutical industries. Alginates are obtained by treatment of alginic acid which is obtained naturally from brown seaweed (Phaeophyceae). The isolation process involves extraction of seaweed with dilute alkaline solution to solubilize alginic acid forming viscous mass. This mass is then treated with mineral acids to liberate the free alginic acid [1]. Alginates are linear polysaccharides with chemical backbone comprising varying ratios of b-d mannuronic acid (M) and a-L-guluronic acid (G) residues. These residues are 1,4-linked by glycosidic bonds to produce homopolymeric MM or GG blocks. These blocks are intercalated with heteropolymeric MG or GM blocks [2]. Based on the chemical backbone, alginates can be prepared with wide range of viscosities. Alginates disperse easily in water forming viscous liquid which allow them to be employed in food and pharmaceutical industries as thickening and emulsion stabilizing agents [3e5]. The application of alginates in pharmaceutical formulations was extended to enhance tablet disintegration in addition to its application as gelling agent in semisolid formulations [5]. The biocompatibility, biodegradability, and lack of antigenicity of alginates extended their application to the biomedical fields. These biomedical applications included tissue engineering and formulation of controlled drug delivery systems. The alginates have been shown to provide gastroprotective effect preventing the aggravation of gastric ulcer [3,5]. Chitosan is derived from chitin which is abundant in crab and shrimp shells and cell walls of bacteria and mushrooms. The chemical backbone of chitosan is in the form of Dglucosamine and N-acetyl-D-glucosamine copolymers. These units are linked by b(1e4) glycosidic linkages [1,6]. The use of chitosan in medical and pharmaceutical fields is gaining much interest due to its biocompatibility, nontoxicity, gel forming properties, and biodegradability, in addition to its effect on membrane permeability [7e10]. Chitosan can be devised into various pharmaceutical formulations including films, beads, microparticles, and nanoparticles [3]. Combinations of alginate and chitosan extended their pharmaceutical applications due to their ability to form polyelectrolyte complex which can modulate the characteristics of the product. This provides the drug delivery specialists with a more versatile delivery system for controlling drug release [6,11e13]. The expected outcomes of such combination are summarized in Table 15.1. The proceeding sections summarize the applications of alginate-chitosan combinations in controlled drug delivery via different routes of administration. The applications will be categorized according to the route of drug administration.

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Table 15.1: The expected outcomes of alginate-chitosan combination in formulation of controlled drug delivery systems. Route of administration Oral

Transdermal Ocular

Physical form Liquid in situ gelling system Particulate drug carriers Transdermal patches or films Nanoparticles Ocular film

Nasal

Microspheres Contact lenses Microparticles

Vaginal

Nanoparticles Microcapsules

Vaginal insert Implantable

Implants

Outcomes of combination • Increased gelling capacity and sustained release in gastric and intestinal conditions • Site specific release • Enhanced bioadhesive strength and sustained drug release • Initial burst release of the drug followed by gradual release • Enhanced bioadhesion and sustained drug release • Sustained drug release and prolonged effect • Extended drug release profile • Enhanced mucoadhesive properties and controlled drug release • Enhanced systemic availability • Enhanced mucoadhesive properties, localized drug within the vagina, and sustained release rate • Enhanced mucoadhesion and controlled drug release rate • Sustained drug release after implantation

2. Oral controlled drug delivery Oral route is the most widespread route for drug administration. It allows the administration of liquid, semisolid, and solid formulations. Accordingly, authors utilized alginate-chitosan to prepare controlled drug delivery from liquids, solid particulates, and hydrogel forming systems.

2.1 Liquid oral sustained release preparations (in situ gelling systems) Liquid oral formulations are preferred especially for children and those who had swallowing problems. Unfortunately, liquid systems have short residence time in stomach making it difficult to control the rate of drug release and absorption. Accordingly, authors employed alternative strategies to develop liquid oral controlled drug delivery systems. These include preparation of controlled release drug particles which are dispensed as suspension [14,15]. However, this technique requires sophisticated method to prepare the particulate system and may suffer from dose variability due to sedimentation upon storage. Other technique employed ion exchange resin which sequesters the drug and liberates the

342 Chapter 15 drug at controlled rate after administration depending on the exchange with endogenous ions in the gastrointestinal tract [16,17]. This system depends on the availability of endogenous ions which are variable from one person to another and may be affected by food. In situ gelling strategy provided another promising alternative for preparation of liquid oral sustained release preparations. This tactic produces a formulation which is dispensed as liquid that undergoes gelation after oral administration. The in situ gel formation can take place owing to pH change, temperature modification, and ion-induced cross-linking [18e22]. The ion-induced cross-linking employs sodium alginate as the principle polymer which must be administered simultaneously with calcium ions which induce cross-linking after administration. To prevent premature cross-linking during storage, calcium ions are complexed with citrate buffer before mixing with the alginate salt. This prevents the gelation in the container and maintains the fluidity of the formulation. Immediately after administration calcium ions are liberated in the acidic environment of the stomach with subsequent in situ gelation [23e26]. Miyazaki and coworkers recorded sustained release of theophylline after incorporation in sodium alginate-based in situ gelling liquid. This system increased the bioavailability of the drug by 1.3e2-fold compared to commercial sustained release microparticles suspended in syrup (Theo-Dur Dry Syrup) [27]. A sodium alginate-based system was able to undergo in situ gelation in the rat and rabbit stomach. This formulation was suggested to create a stomach reservoir which liberates paracetamol over a period of 6 h. However, this system delivered paracetamol with a bioavailability comparable to drug suspension and the author recommended the in situ gelling system as homogenous liquid free from the problems of suspension [24]. The same principle has been adopted to formulate in situ gelling system which floats after mixing with the acidic environment. This system was able to liberate metformin over extended period of time. However, the authors did not support this work with in vivo data [28]. The abovementioned alginate-based systems overlooked the possibility of dose dumping after gastric emptying due to breakdown of the gel structure in response to pH increase in the intestinal environment. This will be associated with liberation of most of the drug. The time at which dose dumping may take place depends on the gastric emptying rate which is variable. This can add to the problems of using alginate only systems. Taking this into consideration, El Maghraby and coworkers developed a liquid oral in situ gelling sustained release system in which chitosan was combined with sodium alginate in presence of calcium citrate. This system was optimized using dextromethorphan as a model drug. The authors monitored the gelling capacity, gelling strength, and the rate of drug release both in absence and presence of chitosan. The gelling capacity and gelling strength were assessed at simulated gastric conditions. The release pattern was monitored in simulated gastrointestinal conditions with the pH of the dissolution medium changing from gastric to

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intestinal pH to mimic the in vivo situation. The study was extended to compare the release of dextromethorphan from the developed systems to that from the marketed product which employs ion exchange resin to control the rate of drug release. Chitosanfree alginate solutions produced very soft gel at low concentrations of alginate with the developed gel becoming relatively firmer in formulation containing alginate at a 2% w/v. Combination of chitosan with alginate enhanced the gelling capacity and produced a more firm gel indicating stronger degree of cross-linking (Fig. 15.1). This was explained on the basis that chitosan can synergistically enhance the cross-linking process via polyelectrolyte complexation resulting from electrostatic interactions between alginate and chitosan. The benefit of chitosan was expressed further in the release pattern of drug. Chitosan-free alginate-based in situ gelling system was able to sustain the release of dextromethorphan in the gastric phase with immediate liberation of the loaded drug in the intestinal phase. Combination of chitosan with alginate reduced the rate of drug release in the gastric phase and maintained the sustained release pattern in the intestinal phase even at pH of 7.4. The release pattern of alginate-chitosan system was comparable to that of the marketed product with respect to the amount released but the latter

Figure 15.1 Effect of alginate-chitosan combination on the gelling strength of liquid in situ gelling system.

344 Chapter 15 liberated the drug in a zero order mode [25]. However, question remained about the possibility of eliminating calcium from alginate-chitosanebased system. In a more recent study El Maghraby et al. [29], investigated the possibility of elimination of calcium ion from alginate-chitosan in situ gelling liquids. This work was done to develop a system which can avoid the potential interaction of calcium with drugs as well as to avoid the deleterious effects of calcium on patients with hypercalcemia or osteolysis. The authors monitored the gelling capacity and release pattern of nateglinide (oral hypoglycemic agent) from alginate-chitosan in situ gelling liquid both in presence and absence of calcium ion. The results reflected the possibility of eliminating calcium ions from the formulation without significant modulation of the gelling capacity and drug release pattern particularly in presence of chitosan. This study was extended to in vivo evaluate calcium free formulation in presence and absence of chitosan. This was conducted by monitoring the hypoglycemic effect of nateglinide after oral administration of the formulations to diabetic rats. Both formulations were able to provide gradual reduction in blood glucose level which lasted for longer duration compared to the unprocessed drug. There was a trend of increased efficacy after using chitosan containing system compared to the corresponding chitosan-free system [29]. Similar calcium-free alginate-chitosan liquid oral sustained release system was successfully employed to control the release of ranitidine hydrochloride [30]. Those articles highlighted the promising potential of alginate-chitosan in situ gelling system as a liquid oral sustained release formulation and the future will disclose the possibility of their application in pharmaceutical industry.

2.2 Particulate carriers Drugs encapsulation within a particulate carrier is widely employed for oral delivery. Alternative terminologies have been used to describe these particulate carriers. These terminologies are based on the structure and the size of the carriers. According to the size, they can be classified as beads, microparticulate carriers, and nanocarriers. Beads are multiparticulate systems with diameter up to a few millimeters [31]. When the diameter is in the micrometer range (typically 1e1000 mm), the particulate carriers can be termed as microspheres (sometimes referred as microparticles) or microcapsules [32]. They are called nanoparticulate carriers when the size of the particles is less than 1 mm. It is obvious that the term capsule is used if there is clear evidence that the drug is encapsulated forming the core of particles with the polymeric materials forming a coatlike structure. All these multiparticulate carriers are considered to be advantageous over single unit dosage forms for oral drug administration. Owing to their smaller particle size, they can minimize inter and intrasubject variations, providing a more uniform distribution throughout the gastrointestinal tract with greater chance to eliminate the effect of gastric

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emptying rate on drug release in case of enteric-coated systems. The retention and residence could be controlled better if the components had bioadhesive properties. All these factors account for the expected greater bioavailability from particulate carriers compared to single unit solid dosage form [33]. Different types of polymeric materials were employed in the fabrication of these particulate carriers. These polymeric materials include chitosan, alginate, cellulose, dextran, poly (D,L-lactide-coglycolide), carrageenan, and pectin. Among these polymers, chitosan and alginate were the most widely utilized. This can be attributed to their safety, biocompatibility, biodegradability, and mucoadhesive properties. In addition, chitosan can open epithelial tight junctions transiently and reversibly enhance paracellular drug absorption [34,35]. Unfortunately, rapid dissolution of chitosan or its derivatives at low pH limits their applications as single component of particles in oral drug delivery due to potential burst effect in the acidic condition of the stomach [36]. The same defect applies for particulate carriers utilizing alginate as the only polymer. This limitation is based on the porous nature of the resulting particle in addition to fast drug release at intestinal pH [5,37,38]. To overcome the limitations, alginatechitosan combinations were employed as polymeric material for development of particulate drug delivery systems. This can be achieved by formulation of the alginate particles which are subsequently coated by chitosan. Another approach depended on preparation of alginate-chitosan dispersion before devising the particle using such mixture. Coating of chitosan particles by alginate solution was also attempted in few studies [39]. Numerous studies are available on the use of alginate-chitosan beads for oral controlled drug release and delivery. The application of such beads included protection of insulin from degradation in the gastric environment with subsequent slow release in the intestine [40]. More recently, the application was extended to maximize the intestinal bioadhesion which allowed a prolonged interaction of the delivered insulin with the membrane epithelia. This is believed to provide greater chance for a more efficient absorption [41]. The same strategy was also tested using bovine serum albumin (BSA) as a model protein drug. One of these studies involved the preparation of multilayer chitosan-alginate beads by giving additional treatment either with chitosan or alginate or both. Multilayering resulted in a significant delay in the release of BSA compared to chitosan-alginate beads prepared in a single step [42]. Comparable results were recorded later after encapsulating BSA in beads comprising a blend of alginate with N,O-carboxymethyl chitosan (watersoluble derivative of chitosan). These beads underwent a pH-sensitive release pattern for BSA with the protein being liberated at pH 7.4 [43]. The same model protein has been employed by other authors, and it was concluded that encapsulation of protein in alginatechitosan beads can provide a promising carrier for safe delivery of proteins to the intestine with a high chance for colonic drug input [44e46]. In addition to controlled delivery of protein drug, traditional drug molecules were also included into alginate-chitosan beads with the goal of controlling their release after oral

346 Chapter 15 administration. For example, the oral hypoglycemic agent, nateglinide was encapsulated into alginate-chitosan beads which were formulated as simple beads of the mixture or as multilayered beads. Both types were able to sustain the rate of drug release with the multilayered beads showing lower swelling capacity with better control on the rate of drug release [47]. Alginate-chitosan based dual, ionic cross-linked multiparticulate system was investigated for targeted colon delivery of tinidazole and sustained its release for the treatment of amebiasis. The swelling behavior of the developed particles and the rate of drug release depended on the composition of the beads. The swelling capacity increased by increasing the proportion of sodium alginate in the polymer ratio. This was associated with an increase in the rate of tinidazole release. To reduce the swelling capacity and subsequently the rate of drug release, the degree of cross-linking was increased. This was achieved by increasing the concentration of chitosan and/or increasing the concentration of crosslinking agent in the formulation. The optimized formulation was shown to be susceptible for degradation and liberation of the drug in simulated in vitro colonic environment. These findings reflected the suitability of the developed system for colon targeting and were confirmed by gamma scintigraphy in vivo. The latter experiment showed minimal release in the stomach and small intestine with significant liberation in the colon [48]. Alginate-chitosan beads were also adopted to provide controlled local input of antibiotics to the upper part of the GIT for suppression of Helicobacter pylori. For example, ciprofloxacin was encapsulated into those beads to provide an initial burst effect in gastric and intestinal conditions with subsequent programmable slow liberation of the drug. Interestingly, the drug was liberated at constant rate in pH 7.4 (zero-order kinetics). Based on these findings, chitosan shell was considered as an effective barrier hindering drug release [49]. The benefit of these beads was extended to devise a floating formulation which undergoes gastric retention with controlled liberation of amoxicillin. The amoxicillin-loaded alginate beads which were coated with chitosan exhibited excellent floating ability (95%e100%). The beads were able to encapsulate significant amounts of the drug. The recorded release pattern was considered optimal for attacking the H. pylori [50]. In addition to beads alginate-chitosan system was utilized in preparation of microparticulate carriers (microspheres and microcapsules) as oral delivery systems. One of these studies evaluated alginate-chitosan microspheres as antitubercular drug carriers which were loaded simultaneously to prepare fixed dose combination. The microspheres which have a mean particle size of 70 mm were able to encapsulate rifampicin, isoniazid, and pyrazinamide with an encapsulation efficiency values ranging from 65% to 83% for the three drugs. The spheres delivered the drugs at controlled rate depending on the pH with less than 7% of the encapsulated drugs being released in simulated gastric fluid

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(SGF) throughout the 72 h study period. In the simulated intestinal fluid (SIF), the microspheres liberated less than 16% of rifampicin with 20.6% of isoniazid and 22.1% of pyrazinamide being released during the initial 6 h. The recorded control of drug release rate was reflected even after oral administration to guinea pigs. The recorded plasma concentrations versus time values reflected good correlation with the in vitro release pattern. The authors considered alginate-chitosan microspheres as effective system for controlled delivery of antiTB drugs [51]. Chitosan-coated alginate microspheres have been tried as carriers for oral protein delivery. Authors employed hemoglobin (Hb) as a model protein and prepared the microspheres by emulsification/internal gelation followed by chitosan coating. The naked alginate microspheres were less than 30 mm in diameter with the particle size increasing after chitosan coating. The loading efficiency of Hb was so high that it exceeded 90% of the initial drug with no significant loss being shown after surface coating. The release depended on the pH with the chitosan-coated microspheres retaining the drug even in simulated intestinal conditions [52]. Two years later, another research group employed bovine serum albumin as a model protein. The microspheres were prepared by layer-by-layer technology. Once again, alginate-coated chitosan microparticles extended the release of BSA with only about 40% of BSA being released during the first 8 h with the formulation retaining about 50% of BSA for 48 h. The authors also highlighted the potential of these microparticles to protect the drug against acid degradation for at least 2 h [11]. Similar microspheres were shown later to protect insulin from degradation in the gastric conditions even in presence of pepsin. This protection was confirmed in vivo by monitoring the hypoglycemic effect after oral administration of insulin-loaded and insulin-free alginate-chitosan microspheres to diabetic rats. The rats showed extended hypoglycemia after oral administration of the medicated microspheres [53]. Recent study employed chitosan-alginate microspheres (101 mm) loaded with icariin for colon targeting in the treatment of ulcerative colitis. The spheres liberated the drug slowly with only 10% being recovered in simulated gastric and intestinal fluids, indicating gastrointestinal protection. Subsequent release of about 65.6% icariin was recorded in colonic environment. In addition to controlled drug release, the spheres were able to reach the colon and remain intact for 12 h as indicated from the in vivo study [54]. The promising data on alginate-chitosan particulate systems encouraged the authors to extend the scope to nanotechnology with the researchers preparing nanoparticles and nanocapsules as drug delivery systems [55]. One of these studies evaluated alginatechitosan nanoparticle as a delivery system for nifedipine. Spherical nanoparticles were developed by ionotropic pregelation of the positively charged chitosan and the anionic alginate. The nanospheres liberated nifedipine in a pH dependent manner with the majority of the drug being released in the intestinal conditions. This release pattern was taken as an indication for the ability of nanoparticles to protect drug from loss in acidic

348 Chapter 15 environment followed by controlled output throughout the rest of GIT [56]. The nanoscale of alginate-chitosan particles was tested as a tool to enhance mucopenetrating potential of amoxicillin for complete eradication of H. pylori. The in vitro mucoadhesion studies revealed a decrease in the mucoadhesive power of the devised nanoparticle. The authors considered this as an advantage, as it can help the nanoparticles to infiltrate at faster rate into gastric mucosa which is a prerequisite for accumulation at the site of H. pylori which is located beneath mucosa. Fluorescent labeled alginate-chitosan nanoparticles showed high capacity to penetrate into the gastric mucosa of rats during 6 h study. It was thus concluded that alginate-chitosan nanoparticles can undergo initial weak mucoadhesion with subsequent infiltration into the gastric mucosa where it can attack the H. pylori. However, the experimental design in this work did not test the ability of such particles to attack bacteria after infiltration into the mucus membrane [57]. In 2015, Mukhopadhyay and coworkers presented very good piece of work in which insulin loaded alginate-chitosan nanoparticles were able to limit the degradation of insulin in the intestine while maintaining sustained delivery of the drug over extended time. This advantage was associated with measurable systemic input of insulin after oral administration which was indicated from the recorded hypoglycemic effect. Unlike subcutaneous administration of insulin solution which produced rapid action and returned to its basal level within 5e6 h, oral administration of insulin loaded nanoparticles produced hypoglycemic effect for 9 h. This was further reflected from the increase in insulin serum level which reached its maximum level 7 h after oral administration [58]. The potential of alginate-chitosan nanoparticles was extended further after fabrication of legend directed nanoparticles. In this study folate was used as the targeting moiety with paclitaxel being selected as the anticancer agent. The prepared particles were able to sustain drug release within a simulated extracellular environment. Folate directed nanoparticles showed better cellular uptake due to combination with folate receptors on the surface of the hepatoma G2 cells. Thus, the study highlighted the use of alginatechitosan nanoparticles as vehicle for anticancer drug targeted delivery system especially when it was fabricated with targeting moiety like folate [59]. With this large number of studies, future investigations should concentrate on the feasibility for developing alginate-chitosanebased oral drug delivery systems to the scaling up phase.

3. Transdermal controlled drug delivery Transdermal drug delivery has unique advantages over other routes of drug administration. Unfortunately, the invasion of skin strata is problematic and is controlled by the uppermost

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layer of the skin which is responsible for the main barrier function [60e62]. Alternative strategies have been adopted to enhance the transdermal drug delivery and the authors were able to optimize transdermal input of many valuable compounds [61,63e66]. The next challenge was to devise the optimized formulation in an acceptable transdermal therapeutic system. The development and standardization of skin patches was used as a tool to take skin penetration enhancing strategies to the clinical application. The composition of skin patches depends mainly on the type of polymer used which controls the drug release rate, the adhesive nature of the patch, and subsequently the bioavailability after topical application. The film forming capacity and elasticity are important parameters in selection of the polymer. The use of biopolymers like polysaccharides including alginate and chitosan has gained much interest in recent years. Alginates have been shown to form strong bioadhesive matrices allowing their application as carriers for site-specific transdermal delivery [67]. Chitosan-based hydrogels have been categorized as excellent film forming bioadhesive systems with high potential for application in development of transdermal therapeutic systems [68]. The main limitation of chitosan hydrogels depends on the rigidity of the developed film [69]. This attracted the attention of investigators to combine chitosan with other polymers. Alginates showed good potential with the resulting hybrid film having improved strength and elasticity while retaining the positive attributes of chitosan film. Alginate-chitosan combinations were used to develop cefixime trihydrate transdermal patches. The authors developed patches containing different ratios of alginate and chitosan. These patches were prepared in presence and absence of Span 80 as skin penetration enhancer. The patches were of acceptable physical properties with the drug release and permeation through skin depending on the relative proportions of alginate and chitosan. The optimum formulation was not an irritant and was able to deliver measurable amounts of the drug to the systemic circulation especially in presence of skin permeation enhancer. This formulation was even better than oral suspension with respect to the bioavailability [70]. In a more recent study a bioadhesive matrix of alginate and chitosan was employed as transdermal film for ketotifene fumarate. Propylene glycol was used as plasticizer with Tween 80 and Span 20 being utilized as permeation enhancers. The prepared films were of acceptable properties with maximum bioadhesion being recorded with formulations containing equal proportions of chitosan and alginate. This bioadhesive strength was associated with sustained release with incorporation of plasticizer and enhancer increasing the rate of drug release. A formulation containing equal proportions of alginate and chitosan in presence of Tween 80 as enhancer was considered optimum and was able to deliver the drug through rat abdominal skin at acceptable flux and lag time values. The developed system was considered as an advance to improve the patient compliance by eliminating the need for repeated dosing, enhancing bioavailability and sustaining the drug action [71].

350 Chapter 15 The work in this area is still premature and further investigations are required to test the effect of the suitability of such combination for transdermal therapeutic system irrespective to the nature of the drug and the presence of skin penetration enhancers.

4. Ocular controlled drug delivery Treatment of ophthalmic disorders after topical ocular application is beneficial for patients due to minimization of systemic side effects. Unfortunately, ocular availability of drugs is very poor after topical application. Overcoming such problem is tricky due to the difficulty of bypassing the efficient protective mechanisms [72,73]. These protective mechanisms include the unique corneal structure which is a sandwich of lipid barrier enclosing a hydrophilic layer that limits the entry of drug molecules to the targeted site of action. In addition, rapid precorneal loss, high rate of tear turnover, and reflex blinking also account for poor ocular drug bioavailability [74]. These factors limit both the residence time and the transmembrane permeability. The presence of enzymes like esterases, aldehyde and ketone reductase in the ocular milieu is another reason of poor ocular bioavailability. These enzymes can metabolize the drug reducing its concentration in cul-de-sac [75]. Accordingly, selection of suitable delivery system which can overcome all these barriers for ocular drug delivery will be worthy. Incorporation of the drug in a biocompatible and biodegradable polymer matrix is a suitable means for enhancing ocular bioavailability. This polymer matrix undergoes slow erosion with subsequent liberation of the loaded drug at controlled rate. This provides direct control on the residence time in the eye [76,77]. The benefit will become even greater if the principal polymer undergoes bioadhesion as well. Sodium alginate is one of the commonly used polymers for controlling ocular drug delivery due to its ion activated gelling ability [78,79]. Chitosan was also employed as a polymer for ocular drug delivery to improve the retention and distribution of drugs after topical application onto the eye due to its bioadhesion, permeability enhancing, and film forming properties [80]. Numerous studies had employed alginate-chitosan combinations as drug carriers for ocular delivery. The complex formed between alginate and chitosan gave better protection for the entrapped drug with greater control of the rate of drug release compared to either alginate or chitosan alone. The advantage of such combination is the feasibility for formulation into alternative carriers ranging from the nanoparticulate to ocular film or even incorporated in medicated contact lenses. One of these studies developed and evaluated mucoadhesive nanoparticulate formulation for ocular delivery of gatifloxacin. The alginate-chitosan nanoparticles were prepared by a modified coacervation method. Nanoparticles were spherical in shape with solid dense structure which was able to encapsulate significant amount of the drug. The size of the particles ranged from 205 to 572 nm depending on the concentration of the polymers. The optimized nanoparticle formulation was selected for the in vitro release study in an

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artificial tear fluid. The results indicated initial burst release of gatifloxacin (10%e12%) followed by gradual drug release for 24 h. The recorded controlled release pattern is advantageous compared to the immediate release behavior of the marketed product [4]. The same drug was utilized by other investigators to assess alginate-chitosan system for controlled ocular delivery, but the system was fabricated in the form of ocular film. Alginate-chitosan films were devised with and without calcium induced surface crosslinking. This employed solvent casting method. The prepared films were uniform, smooth in appearance with no visible cracks, and showed acceptable flexibility. Surface crosslinking of the films resulted in considerable increase in film’s hardness and reduced flexibility and the swelling index. The extent of bioadhesion increased at higher chitosan concentrations with further increase upon cross-linking. The developed films were able to sustain the drug release with cross-linking providing greater control of the drug release rate. The optimized system introduced a promising composition for ocular film with tailored release rate [81]. Alginate-chitosan nanoparticles were devised using ionic gelation for ocular delivery of 5-fluorouracil (5-FU) with the aim of enhancing its ocular bioavailability, minimizing systemic absorption, and reducing frequency of administration. The developed particles were in the nanoscale with good drug loading capacity and controlled in vitro release rate. In addition to the optimized release nanoparticles delivered the drug through excised rabbit cornea at significantly higher rate compared to 5-FU aqueous solution. This was reflected further in vivo as indicated from the recorded higher drug concentration in aqueous humor with this level being maintained for 8 h indicating sustained release effect. Interestingly, the enhanced ocular bioavailability from these nanoparticles was associated with negligible 5-FU plasma levels with formulation being tolerable by the eyes. The authors recommended alginate-chitosan nanoparticles as a promising carrier for ocular delivery [82]. This recommendation was strengthened after recording enhanced ocular availability of betamethasone for extended period of time after application in alginate-chitosan nanoparticles [83]. The efficiency of alginate-chitosan particulate system was retained even with microspheres which were able to sustain the release of azelastine hydrochloride. This was associated with prolonged antihistamic effects on rat ocular allergy model. These results suggest that the efficacy of alginate-chitosan system is not only driven by reduced particle size [84]. The application of alginate-chitosan was extended to control the rate of drug release from medicated contact lenses. This was achieved by fabrication of silicon-based contact lenses which were loaded with drug by soaking in drug solution. The medicated lenses were coated with successive layers of alginate/chitosan-alginate with the alginate layers being stabilized with calcium ions. Four model drugs (moxifloxacin, chlorhexidine, diclofenac, and ketorolac) were employed in this study. This coating process showed a promising

352 Chapter 15 potential for controlled drug release over extended period of time. The recorded data reflected a dependence of the drug release rate on the type of drug with only diclofenac showing extended release profile. These findings suggest the need for further investigations on such system before drawing a general conclusion [85]. Overall the use of alginate-chitosan combination in the field of ocular drug delivery is promising and scientists need to widen the scope of their research in this area.

5. Nasal controlled drug delivery Nasal route of drug administration offers attractive alternative for systemic drug delivery [86e88]. It has several advantages which include the ease of administration, absence of pain, and good patient compliance. Besides, the highly vascularized nasal mucosa and the large epithelial surface area give a chance for rapid drug absorption. The nasal route allows the avoidance of drugs presystemic metabolism enhancing their bioavailability. The landmark of this route is high potential for drug delivery to the central nervous system. Unfortunately, wide application of such a route is hampered by rapid mucociliary clearance which decreases the contact time of the drug at the site of absorption. This limitation has to be considered during the development of nasal drug delivery system. One of the commonly employed techniques which can overcome this problem is the use of bioadhesive polymeric materials which can be adsorbed to nasal mucosal surface increasing the contact time. Alginate and chitosan had been previously employed for this purpose with chitosan providing excellent membrane permeation enhancement which is believed to be due to widening of the tight junctions of the membrane. This can provide additional advantage for such system [89e91]. Microparticulate formulations comprising alginate-chitosan combinations were employed for nasal delivery of various pharmaceutically active agents. In 2005, Gavini and coinvestigators prepared mucoadhesive microspheres as a controlled nasal delivery system for metoclopramide hydrochloride which is an antiemetic drug. The microspheres comprising pure chitosan, pure alginate, or their combination were prepared by spraydrying technique. Pure chitosan microspheres underwent swelling within 30 min with the spheres eroding gradually after this time. Alginate microspheres showed weaker swelling behavior compared to chitosan microspheres. Alginate-chitosan microspheres showed rapid swelling (within 5 min) and retained the acquired size during the study period (60 min) due to lack of erosion which is imparted by polyelectrolyte complexation. In vitro mucoadhesion studies revealed that all drug loaded formulations had good mucoadhesive properties, but they were better in case of chitosan or alginate-chitosan microspheres compared with alginate alone. The in vitro release data highlighted the ability of the prepared microspheres to control the rate of drug liberation compared with the pure drug. Ex vivo permeation studies showed that microspheres comprising chitosan

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alone or alginate-chitosan had delivered the drug through the nasal mucosa at higher rate compared with microspheres based on alginate alone. Transmission electron microscopic analyses of the mucosa after exposure to the microspheres consisting of alginate/chitosan showed opened tight junctions. These results with the acceptable mucoadhesive properties made these microspheres suitable nasal delivery system for metoclopramide [92]. Another study aimed to prepare mucoadhesive microspheres for nasal delivery of cyclodextrins (CD) targeting the brain. Different formulations were prepared using alginate, chitosan, and their combinations in different ratios. The encapsulation efficiency of the prepared microspheres ranged from 86% to 100%. The ex vivo mucoadhesion behavior of the microspheres was evaluated and the results reflected good mucoadhesive properties of all systems with alginate microspheres being the best. In vitro release test showed that the free CDs exhibit a very rapid dissolution rate (100% dissolves in 5 min) but the total amount of CD was released from microspheres within 30 min indicating controlled release rate [93]. The application of such formulations has been extended to encapsulate Mycobacterium bovis bacilli Calmette-Gue´rin (BCG) in alginate-chitosan microparticles for intranasal vaccine delivery. The study was able to encapsulate the BCG into the microparticles while maintaining the viability of the attenuated organism. The prepared particles included various formulations with the positively charged system being considered as promising candidate for transnasal vaccination, but no immune response was assessed in this study [94]. In a more recent study, alginate-chitosan nanoparticles encapsulating bee venom were prepared and were assessed with respect to their ability to enhance systemic immune response and improve clearance of porcine reproductive and respiratory syndrome virus (PRRSV). The developed particles were able to trigger systemic immune response after nasal administration. Challenging these particles by PRRSV indicated their efficacy as reflected from the recorded significant reduction of the virus burden in the serum and various target organs. Based on these results, the authors considered alginate-chitosan loaded bee venom as a promising system for overcoming the disadvantages of classical PRRSV vaccination and can be used as prophylactic measure against PRRSV and other immune-suppressive viral diseases [95]. These positive reports can open the way for investigators to test alginate-chitosanebased systems in drug delivery to the central nervous system after nasal application.

6. Vaginal controlled drug delivery The natural vaginal environment offers healthy women natural protection. Unfortunately, this physiologic environment can be compromised by abnormal vaginal flora and local

354 Chapter 15 infection. The most common infectious organism is Candida with nearly 75% of women experiencing an acute candidiasis once in their lifetime [96]. Treatment of these infections requires high local drug concentration for extended period of time. The advantage can be enhanced further if this was achieved after single application. This requires development of controlled release drug delivery systems which have long retention time, optimum drug release, and proper spreading over the diseased epithelium while maintaining the ease of application and lack of irritating sensation [97e99]. Alginate-chitosanebased systems can help in this direction. However, few studies had been reported about their use as a vaginal controlled drug delivery system. The first attempt in this area developed nystatin alginate microcapsules which were coated with either chitosan or poloxamer 407. This was employed as vaginal drug delivery system, and the developed particles exhibited appropriate mucoadhesive properties. The developed formulations showed marked fungicidal activity against Candida albicans. The particles liberated the drug in two stages, the first was in the form of initial burst which originated from the surface adsorbed drug. The following stage delivered the drug at a slower sustained release. The alginatechitosanecoated microparticles were considered optimum with respect to their ability to sustain drug release with poloxamer coated ones being inferior in this respect. All particles were able to localize the drug within the vaginal mucosa with the recovered concentrations being enough to exert the antifungal activity. Overall the developed particles were considered suitable for vaginal administration due to their ability to adhere to the mucosa with subsequent input of therapeutic amounts of nystatin over extended period of time [100]. Another study employed alginate-chitosan complex as vaginal insert for the delivery of chlorhexidine digluconate (broad spectrum antibacterial and antifungal agent). Depending on the relative proportions of alginate and chitosan, the developed inserts had enough strength for safe removal from the package with subsequent insertion into the vaginal cavity. The developed inserts underwent mucoadhesion with this property decreasing with the reduction in chitosan concentration. The devised systems were able to liberate the drug at controlled release rate with the optimized vaginal insert showing strong antimicrobial activity against Escherichia coli and C. albicans [101]. These studies highlight the need for extending the scope of alginate-chitosanebased systems to cover vaginal drug delivery and scientists need to conduct more research in this promising area.

7. Implantable drug delivery system Implantable delivery systems are a promising strategy for controlled delivery of therapeutic agents. The feasibility of this strategy was enhanced by employing biodegradable components due to elimination of the need for surgical removal of the implant at the end of the therapy [102,103]. This opened the gates for application of alginate and chitosan as major components in implantable formulations due to their biocompatibility and biodegradability. The first application in this field employed

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implantable alginate-chitosan system for sustained delivery of norethisteron acetate to restore the hormonal balance in treatment of amenorrhea, endometriosis, and abnormal uterine bleeding. The optimum alginate-chitosan ratio was used to prepare various implantable formulations which included fixed ratio of alginate-chitosan with different excipients being included. The formulations were able to provide continuous input of norethisteron acetate over a period of 10e23 days depending on the composition of the formulations with that containing glyceryl monosterate providing the best control over drug release [104]. Similar systems were developed for sustained delivery of metoprolol tartrate for treatment of hypertension, strokes, heart attacks, and angina. The optimized system was able to sustain drug release over extended period of time with the drug being held for up to 15 days [105]. The work in this area is still immature, and the authors are encouraged to probe the effect of sterilization technique on the drug release pattern. Moreover, in vitro in vivo correlation is necessary.

8. Tissue engineering and wound dressing In addition to controlled systemic drug delivery, alginate-chitosan combinations have been employed for scaffolds in tissue engineering and wound dressing. The combined polymers were shown to have better mechanical properties compared to systems made of individual polymers. This combination was impregnated with smad3 antisense oligonucleotides and was tried for accelerated wound healing. This system enhanced the proliferation of cultured cells and developed large number of fibroblast cells compared to the untreated cells. This was taken as an indication for the suitability of the developed system for dressing application which was confirmed further by monitoring the transforming growth factor b1 levels and collagen contents in wounds in vivo [106]. Alginate-chitosan complexes were developed as sponge which was loaded with curcumin in wound healing. The developed sponges showed high water absorption power and liberated curcumin for extended period of time. The optimized curcumin loaded sponge showed high wound healing potential as indicated from significant reduction in wound area compared to the control [107]. Drug-free wound dressing was prepared by coacervation of alginate and chitosan followed by film casting. The prepared dressing was able to reduce the wound size significantly to reach 90 percent reduction after 6 days with the untreated group showing a maximum of 30 percent reduction. Interestingly, alginate-chitosan dressing allowed synthesis of thin collagen fibers and reduced the scar tissue. This is believed to be responsible for reduced healing time [108]. Beside their application in wound healing, various studies reported the use of alginate and chitosan as scaffold in tissue engineering [109]. For example, chitosan-alginate scaffolds were compared to a scaffold based on chitosan alone for cartilage tissue engineering. The prepared scaffolds provided the required porosity with homogenous pore distribution.

356 Chapter 15 This investigation highlighted the superiority of alginate-chitosan scaffolding compared to chitosan only system. This was evidenced by better biological and mechanical characteristics in addition to greater potential to hasten tissue growth while retaining the phenotype of chondrocytes [110]. As for cartilage tissue engineering chitosan-alginate hydrogel has been tried as scaffold for neural tissue engineering. Once again the developed scaffold was highly porous with hydrophilic surface which is suitable for cell attachment and proliferation. The neural stem cell proliferation behavior on the developed hydrogel was similar to that recorded on commercial gels but the ease of preparation and low cost of the chitosan-alginate hydrogel added to the feasibility of its application in this field [111]. This area requires further investigation and sterile wound healing and tissue engineering systems should be developed and optimized.

9. Concluding remarks Alginate-chitosan combinations are promising for controlling the drug delivery with high versatility for administration by various routes. In oral drug delivery, these systems were successfully developed as liquid oral formulation and as particulate delivery systems of varying particle size. They were able to control the drug delivery for both local and systemic effects. Future investigations in this area should be extended to probe the scaling up potential. Alginate-chitosan combination was effectively employed as carriers for transdermal drug delivery in a few studies which encourages further investigations. Alginatechitosan particulate systems were able to control the drug delivery after ocular application. Some success was recorded in the field of medicated contact lenses but the work in this area needs to be widened. Transnasal route is another important platform for these systems with promising data being reported which encourage further investigations to target drug delivery to the central nervous system. The bioadhesive nature of these systems allowed for development of vaginal drug delivery systems which can cover the mucosal surface. The versatility of alginate-chitosan combinations provided a chance for development of implantable drug delivery systems, formulation of medicated and nonmedicated dressing for wound healing, in addition to their application as scaffolds in tissue engineering and wound dressing. It is important to highlight that many of the developed systems need to be sterile but the effect of sterilization process on the characteristics of the developed systems was not tested and future work should take this direction.

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