Prospective of guar gum and its derivatives as controlled drug delivery systems

International Journal of Biological Macromolecules 49 (2011) 117–124

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International Journal of Biological Macromolecules journal homepage: www.elsevier.com/locate/ijbiomac

Review

Prospective of guar gum and its derivatives as controlled drug delivery systems M. Prabaharan ∗ Department of Chemistry, Faculty of Engineering and Technology, SRM University, Kattankulathur 603 203, India

a r t i c l e

i n f o

Article history: Received 5 April 2011 Received in revised form 25 April 2011 Accepted 30 April 2011 Available online 7 May 2011 Keywords: Guar gum Galactomannan Colon targeting Drug delivery Hydrogels

a b s t r a c t Guar gum is a non-ionic polysaccharide that is found abundantly in nature and has many properties desirable for drug delivery applications. However, due to its high swelling characteristics in aqueous solution, the use of guar gum as delivery carriers is limited. Guar gum can be modified by derivatization, grafting and network formation to improve its property profile for a wide spectrum of biomedical applications. This review article is aimed at focusing the recent efforts and developments on guar gum and its derivatives as colon-specific, antihypertensive, protein and transdermal drug delivery systems. Based on the literatures reviewed, it is concluded that guar gum and its derivatives in the various forms such as coatings, matrix tablets, hydrogels and nano/microparticles can be exploited as potential carriers for targeted drug delivery. © 2011 Elsevier B.V. All rights reserved.

Contents 1. 2.

3.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Drug delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Colon-specific drug delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Antihypertensive drug delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Protein delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Transdermal drug delivery systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Polysaccharides are the polymers of monosaccharides. In nature, polysaccharides have various resources from algal origin (e.g. alginate), plant origin (e.g. pectin and guar gum), microbial origin (e.g. dextran and xanthan gum), and animal origin (chitosan and chondroitin) [1]. Polysaccharides have a large number of reactive groups, a wide range of molecular weight, varying chemical composition, which contribute to their diversity in structure and in property. Due to the presence of various derivable groups on molecular chains, polysaccharides can be easily modified chemically and biochemically, resulting in many kinds of polysaccharide derivatives [2,3]. As natural biomaterials, polysaccharides are highly stable, safe, nontoxic, hydrophilic and biodegradable. In addition, polysaccharides have abundant resources in nature and low cost in their process-

∗ Tel.: +91 9500013036; fax: +91 4427452343. E-mail address: [email protected] 0141-8130/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.ijbiomac.2011.04.022

117 118 118 121 123 123 124 124

ing. Particularly, most of natural polysaccharides have hydrophilic groups such as hydroxyl, carboxyl and amino groups, which could form non-covalent bonds with biological tissues (mainly epithelia and mucous membranes), forming bioadhesion [4]. For the application of naturally occurring polysaccharides for drug carriers, issues of safety, toxicity and availability are greatly simplified. In recent years, a large number of studies have been conducted on polysaccharides and their derivatives for their potential application as drug delivery systems [5–7]. In recent years, considerable attention has been focused on hydrophilic polysaccharides in the design of oral controlled drug delivery systems because of their flexibility to obtain a desirable drug release profile, cost-effectiveness and broad regulatory acceptance. Among the hydrophilic polysaccharides, guar gum (GG) is generally considered as a potential candidate for colon-specific drug delivery application due to its drug release retarding property and susceptibility to microbial degradation in the large intestine [8,9]. GG is also a prospective hydrophilic matrix carrier for oral controlled delivery of drugs with varying solubility and therefore

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M. Prabaharan / International Journal of Biological Macromolecules 49 (2011) 117–124

HO

OH O

HO OH

O HO O

H

O

OH O OH

O OH HO

OH

n

Fig. 1. Structure of GG.

many reports have been published on the use of GG for oral delivery of drugs [10]. GG is a water soluble polysaccharide derived from the seeds of Cyamopsis tetragonolobus, family Leguminosae. It consists of linear chains of (1 → 4)-␤-d-mannopyranosyl units with ␣-dgalactopyranosyl units attached by (1 → 6) linkages (Fig. 1) [11]. GG contains about 80% galactomannan, 12% water, 5% protein, 2% acidic insoluble ash, 0.7% ash and 0.7% fat. In pharmaceutical formulations, GG is used as a binder, disintegrant, suspending agent, thickening agent and stabilizing agent. GG is soluble in cold water, hydrating quickly to produce viscous pseudo plastic solutions that although shear-thinning generally have greater low-shear viscosity than other hydrocolloids [12,13]. This gelling property retards release of the drug from the dosage form, and it is susceptible to degradation in the colonic environment [14–16]. Over the past few years, many review articles have been published on natural based polysaccharides as controlled drug delivery carriers [17,18]. However, there is no specific review reported on GG-based materials for drug delivery applications till date. In this paper, the recent developments on GG and its derivatives as drug delivery carriers are discussed in detail. Special emphasis has been given to the application of these materials as colon specific, antihypertensive, protein and transdermal drug delivery systems. Moreover, different methods of preparation, properties and applications of the chemically modified GG designed for the association and delivery of drugs were also discussed. 2. Drug delivery 2.1. Colon-specific drug delivery Site-specific drug delivery to the colon has attracted considerable attention for the past few years in order to develop drug delivery systems that are able to release drugs specifically in the colon in a predictable and reproducible manner. The site specific drug delivery to colon is important for the treatment of diseases associated with the colon, reducing the side effects of the drug and reducing the administered dose. GG could potentially be used as a biodegradable material for the preparation of colon specific delivery systems of drugs by either compressing native guar into matrix tablets or chemical modification to reduce its swelling properties. GG based matrix tablets of dexamethasone and other antiinflammatory agents have shown very encouraging results as colon-carriers. Matrix tablets of dexamethasone and budesonide were prepared using 60.5% (w/w) of GG in the tablet [19]. The study showed negligible drug release in simulated gastric and intestinal fluid whereas in simulated colonic fluid significant increase in drug release was observed. The study demonstrated that the

galactomannanase (∼0.1%) accelerated dissolution of dexamethasone and budesonide from GG matrix tablet. The extent of drug dissolution depended on the concentration of galactomannanase. Delivery of dexamethasone to the colon using GG was tried in healthy human volunteers [20]. One formulation was designed for rapid release while the other three were designed for delayed release of the drug. Formulations were labeled with radioactive 153 Sm. Scintigraphs in human volunteers were taken from time to time after the oral administration of dosage form. Serum concentration profiles and scintigraphs showed that the rapid release-tablet disintegrated in the stomach. One of the delayed delivery dosage forms began to disintegrate in the small intestine. While the other two tablets showed disintegration times of 5.8 ± 2.3 and 3.6 ± 1.6 h, respectively. All three formulations disintegrated completely in the colon releasing 72–82% of drug, thereby showing suitability to deliver drug to colon. GG was also evaluated in healthy human male volunteers with gamma scintigraphic study using technetium 99m-DTPA as tracer [21,22]. It was seen that some amount of tracer present on the surface of the tablets was released in stomach and small intestine and the bulk of the tracer present in the tablet mass was delivered to the colon. The colonic arrival time of the tablets was 2–4 h. On entering the colon, the tablets were found to degrade. Further investigations were also conducted to evaluate the suitability of GG as a carrier in colonic drug delivery. Rama Prasad et al. prepared matrix tablet of indomethacin with GG [16]. These tablets were found to retain their integrity in 0.1 M HCl for 2 h and in Sorensen’s phosphate buffer (pH 7.4) for 3 h releasing only 21% of the drug in these 5 h. However, in the presence of 2% rat cecal contents the drug release increased and further increased with 4% concentration of cecal contents. The drug release improved to about 91% in 4% cecal content medium after the enzyme induction of rats. This study suggests the specificity of these matrices for enzyme trigger in the colon to release the drug. In the absence of enzyme system the GG swells to form a viscous layer that slows down the seeping of the dissolution fluid into the core. The initial 21% release can be attributed to the dissolution of indomethacin present on the surface of the tablet. GG has also been evaluated as a compression coating to protect the drug core of 5-amino salicylic acid (a drug used for the treatment of ulcerative colitis) in upper gastrointestinal track (GIT) [23]. The tablets coated with 300, 200 and 150 mg of GG showed cumulative mean drug release percentages of 5.98 ± 0.70, 8.67 ± 0.35 and 12.09 ± 0.29, respectively, after 26 h while tablets coated with 125 mg GG disintegrated within 5 min in simulated gastric fluid. Cores with GG coat as high as 300 and 200 mg could not successfully release the drug in the presence of rat cecal contents even in 26 h as drug release was 23.85 ± 3.13 and 63.43 ± 6.30%, respectively. However, the formulation with 150 mg of GG as a coating showed 95.51 ± 1.50% of 5-ASA release in the presence of rat cecal contents after 26 h. Percent drug release from tablet increased considerably from 11th hour and the tablets were completely disintegrated in 26 h. The results of drug release studies on compression coated tablets suggested that the thickness of GG coating in the range of 0.61–0.91 mm was sufficient to deliver the drugs selectively to the colon. Compression coated tablets of 5-ASA and matrix tablets of mebendazole have been prepared using GG as a carrier [24]. Matrix tablets containing various proportions of GG were prepared by wet granulation technique using starch paste as a binder. The tablets were evaluated for drug content uniformity, and were subjected to in vitro drug release studies. The results of the studies showed that matrix tablets containing either 20% or 30% of GG is most likely to provide targeting of mebendazole for local action in the colon. Recently, poly(acrylamide)-graft-GG was synthesized by microwave initiated free radical grafting method as matrix for controlled release of 5-amino salicylic acid (Fig. 2) [25]. The applicability of this matrix for sustained drug release has been

M. Prabaharan / International Journal of Biological Macromolecules 49 (2011) 117–124 HO

OH

HO

119

OH

O

O

HO

HO OH

O

O

H

O

OH

O HO O

H

OH O OH

O

O

OH O OH

O

n

OH

HO

OH

Microwave

HO

O

n

O

O

Guar gum NH2

Acrylamide O

HO

OH O HO

OH

O HO

O

H

O OH O

O

OH O O

O

n

CH2 CH2

CH-CONH2

CH CH2 CONH2

Initiation

CH-CONH2

Propagation

CH2 CH-CONH2 CH2 CH-CONH2 CH2 CH-CONH2 CH = CH-CONH2

Termination Fig. 2. Schematic representation for the synthesis of GG-graft-poly(acrylamide).

investigated by United States Pharmacopeia (USP) drug dissolution method, under different pH environments. It has been found that higher the percentage grafting, lower is the rate of drug release. Further, it has been observed that the rate of release of the enclosed drug from grafted GG matrix is low in acidic environment and is higher in neutral and alkaline environment, thus raising the possibility of further optimization of grafted GG matrix as a potential candidate for lower GIT targeted drug delivery. The pharmacokinetic evaluation of mebendazole containing GG matrix tablets against an immediate release tablet was carried out in human volunteers [26]. Six healthy volunteers participated in the study and a crossover design was followed. Mebendazole was administered at a dose of 50 mg both in immediate release tablet and colon-targeted tablets. On oral administration of colontargeted tablets, mebendazole started appearing in the plasma at 5 h, and reached the peak concentration (Cmax of 25.7 ± 2.6 ng/ml)

at 9.4 ± 1.7 h (Tmax ) whereas the immediate release tablets produced peak plasma concentration (Cmax of 37.2 ± 6.8 ng/ml) at 3.4 ± 0.9 h (Tmax ). Colon-targeted tablets showed delayed Tmax and absorption time, and decreased Cmax and absorption rate constant when compared to the immediate release tablets. The results of the study indicated that the GG-based colon-targeted tablets of mebendazole did not release the drug in stomach and small intestine, but delivered the drug to the colon resulting in a slow absorption of the drug and making the drug available for local action in the colon. The influence of concomitant administration of metronidazole/tinidazole (having antibacterial activity against anaerobic bacteria) on the usefulness of GG as a carrier for colon-specific drug delivery using GG matrix tablets of albendazole as a model formulation was investigated [27]. The results showed that the release of albendazole from GG matrix tablets decreased with an increase in the dose of metronidazole and tinidazole administrated.

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M. Prabaharan / International Journal of Biological Macromolecules 49 (2011) 117–124

From this study, it was observed that for successful design of colon targeted delivery systems for drugs having antimicrobial activity against anaerobic bacteria using GG as a carrier, it requires a tight control of drug release until the swollen GG formulation is acted upon by colonic bacteria. In another study, matrix, multilayer and compression coated tablets of metronidazole containing various proportions of GG were prepared for colon targeted drug delivery [28]. Release studies showed that matrix tablets and multilayer tablets of metronidazole released 43–52% and 25–44% of the metronidazole, respectively, in the physiological environment of stomach and small intestine depending on the proportion of GG used in the formulation. It was observed that both the formulations failed to control the drug release within 5 h of the dissolution study in the physiological environment of stomach and small intestine. The compression coated formulations released less than 1% of metronidazole in the physiological environment of stomach and small intestine. When the dissolution study was continued in simulated colonic fluids, the compression coated tablet with 275 mg of GG coat released another 61% of metronidazole after degradation by colonic bacteria at the end of 24 h of the dissolution study. The compression coated tablets with 350 and 435 mg of GG coat released about 45 and 20% of metronidazole, respectively, in simulated colonic fluids indicating the susceptibility of the GG formulations to the rat caecal contents. The results of the study showed that compression coated metronidazole tablets with either 275 or 350 mg of GG coat are most likely to provide targeting of metronidazole for local action in the colon owing to its minimal release of the drug in the first 5 h. Sinha et al. designed a formulation with a considerably reduced coat weight and gum concentration for colonic delivery of 5fluorouracil for the treatment of colorectal cancer [29]. In this study, rapidly disintegrating 5-fluorouracil-loaded tablets coated with 175 mg of granules containing a mixture of xanthan gum and GG in varying proportions were prepared. With this coat weight, a highly retarded drug release was observed. After 24 h of dissolution the mean percent drug release from the compression coated xanthan gum:GG 20:20, 20:10 and 10:20 tablets was found to be around 18 ± 1.23%, 20 ± 1.54% and 30 ± 1.77%, respectively. To study the effect of coat weight on drug release profile, the coat weight on the tablets was further reduced to 150 mg. It was observed that the reduction of coat weight did not affect the initial drug release rate in simulated upper gastrointestinal tract (GIT) conditions. At the end of 24 h of dissolution the amount of drug released increased to 25 ± 1.22%, 36.6 ± 1.89% and 42.6 ± 2.22%, respectively, in xanthan gum:GG 20:20, 20:10 and 10:20 tablets. Studies of xanthan gum:GG (10:20) tablets in the presence of colonic contents showed an increased cumulative percent drug release of 67.2 ± 5.23% in the presence of 2% cecal content and 80.34 ± 3.89% in the presence of 4% cecal content after 19 h of incubation. Intravenous administration of 5-fluorouracil for colon cancer therapy could produce severe systemic side-effects due to its cytotoxic effect on normal cells. To avoid such problems, recently GG tablet formulations were developed for site-specific delivery of 5fluorouracil to the colon without the drug being released in the stomach or small intestine [30]. In this study, fast disintegrating 5-fluorouracil core tablets were compression coated with 60%, 70% and 80% of GG, and were subjected to in vitro drug release studies. The amount of 5-fluorouracil released from the compressioncoated tablets in the dissolution medium at different time intervals was estimated by a HPLC method. GG compression-coated tablets released only 2.5–4% of the 5-fluorouracil in simulated GI fluids. When the dissolution study was continued in simulated colonic fluids (4%, w/v, rat caecal content medium) the compression-coated with 60%, 70% and 80% GG tablets released another 70, 55 and 41% of the 5-fluorouracil, respectively. The results of the study show that compression-coated tablets containing 80% of GG are most

O

NaO

OH

O

+ OH

Guar gum

O

ONa

P

P ONa

O O

P

ONa P

O O

O

Guar gum

O Guar gum

Trisodium trimetaphosphate Fig. 3. A schematic representation of the reaction between trisodium trimetaphosphate and GG.

likely to provide targeting of 5-fluorouracil for local action in the colon, since they released only 2.38% of the drug in the physiological environment of the stomach and small intestine. Since a major restriction in the design of GG matrices for drug delivery is its high swelling characteristics (a property which requires high compression forces at production to avoid premature burst release), a chemical modification of GG to reduce its enormous swelling properties is a practical alternative solution, especially for orally administered colon-specific drug delivery systems. Earlier, it was shown [31] that when GG is cross-linked with borax, a decrease in viscosity is observed in the presence of enzymes, suggesting that GG retains its degradation properties even after cross-linking. However, the borax cross-linked GG was not very successful due to its high swelling in the presence of gastric and intestinal fluids. In another study, methotrexateloaded GG microspheres were prepared by the emulsification method using glutaraldehyde as a cross-linking agent for colonspecific drug delivery [32]. It was found that particle size, shape, and surface morphology were significantly affected by GG concentration, glutaraldehyde concentration, emulsifier concentration (Span 80), stirring rate, stirring time, and operating temperature. Methotrexate-loaded microspheres demonstrated high entrapment efficiency (75.7%). The in vitro drug release was investigated using a US Pharmacopeia paddle type (type II) dissolution rate test apparatus in different media (phosphate-buffered saline [PBS], gastrointestinal fluid of different pH, and rat cecal content release medium), which was found to be affected by a change to the GG concentration and glutaraldehyde concentration. The drug release in PBS (pH 7.4) and simulated gastric fluids followed a similar pattern and had a similar release rate, while a significant increase in percent cumulative drug release (91.0%) was observed in the medium containing rat cecal content. In in vivo studies, GG microspheres delivered most of their drug load (79.0%) to the colon, whereas plain drug suspensions could deliver only 23% of their total dose to the target site. The cross-linked hydrogels are gaining much importance in a wide variety of applications as superabsorbents in wound dressings, as drug carriers, as artificial organs, etc. Phosphated cross-linked low swelling GG hydrogels were prepared (Fig. 3) and analysed in vitro and in vivo for their potential as colon drug carriers [33,34]. These hydrogels were loaded with hydrocortisone and were able to resist the release of 80% of the drug for 6 h in phosphate buffer pH 6.4. The addition of ␣-galactosidase and ␤-mannanase (enzymes which act upon GG) in the buffer solution increased the drug release. In vivo studies in rat showed that modified GG was degraded by enzymes in concentration dependent manner showing the suitability of the phosphated cross-linked GG for colon drug delivery. Using similar approach, Rubinstein et al. have reported GG cross-linked with glutaraldehyde (GA) for applications in colon targeting [35]. Li et al. synthesized thermo-responsive GG/poly(Nisopropylacrylamide) hydrogels with interpenetrating polymer networks (IPN) [36]. The synthesis schemes of poly(Nisopropylacrylamide) polymerization, cross-linking, and GG

M. Prabaharan / International Journal of Biological Macromolecules 49 (2011) 117–124 CH

H2C

CH2=CH-CONH NH

(A) O

CH2

+

N,N,N',N'-tetramethylethylene diamine

CH2=CH-CONH

CH H3C

APS

CH3

N,N'-methybisacrylamide

N-isopropylacrylamide

CH2-CH

n

CH2

CH

m

OC

NH

NH

O

CH H3C

CH3

CH2 NH OC

CH2-CH

n

CH2

CH

m

NH O

CH H3C

(B)

O

+

OH

O

OH

+

OH

+ 2H+

OH

OH

OH

O

+ OH

HC-(CH2)3CH + +

OH

HC-(CH2)3CH + +

HC-(CH2)3CH

HC-(CH2)3CH

CH3

OH

H H C (CH2)3-C OH

OH

O HO

Guar gum -2H2O

O O

H H C (CH2)3-C

O O

Fig. 4. Synthesis of poly(N-isopropylacrylamide) hydrogel (A) and the schemes of isomerization of glutaric dialdehyde at acid environment and the cross-linking reaction of two adjacent hydroxyl groups on GG (B).

cross-linking are shown in Fig. 4. The introduction of GG component with IPN technology could improve the temperature sensitivity and permeability of GG/poly(N-isopropylacrylamide) IPN hydrogels which could be expected as good candidates for the controlled drug delivery system with both thermo-responsive and specific-colonic drug release behaviors. In this study, the temperature responsive GG/poly(N-isopropylacrylamide) IPN hydrogels with different response rates were prepared by modifying the proportion of GG to poly(N-isopropylacrylamide). The results showed that compared with pure poly(N-isopropylacrylamide) hydrogels, GG/poly(N-isopropylacrylamide) hydrogels with reversible thermo-responsive characteristics exhibited faster deswelling rates and much lower water retentions at low GG content (below 15 wt%). Thus, the authors suggested that the introduction of GG component with IPN technology could improve the temperature sensitivity and permeability of GG/poly(Nisopropylacrylamide) IPN hydrogels. Using the similar approach, GG/poly(acrylic acid) IPN hydrogels have also been reported [37]. Here, kinetics of swelling and the water transport mechanism were studied as a function of the composition of the hydrogels and the pH of the swelling medium. Hydrogels showed enormous swelling in aqueous medium and displayed swelling characteristics, which were found to be highly dependent on the chemical composition of the hydrogels and pH of the medium.

121

Cationic GG/poly(acrylic acid) polyelectrolyte hydrogels was prepared through free radical solution polymerization as colonspecific drug delivery carrier [38]. In this work, the quaternized GG was prepared by the reaction of GG with 3-chloro-2hydroxypropyltrimethylammonium chloride in the presence of sodium hydroxide as shown in Fig. 5. The results indicated that the strong electrostatic interaction existed in the hydrogels, which resulted in the formation of the polyelectrolyte complexes. In this work, the swelling ratios were studied as a function of poly(acrylic acid) content and pH. The result indicated that the polyelectrolyte hydrogels were highly sensitive to the pH environment. The ketoprofen-loaded GG/poly(acrylic acid) matrices were prepared as hydrogels and directly compressed tablets for drug release applications. The release studies showed that the compositions of the hydrogel had an important effect on ketoprofen release. The increase of poly(acrylic acid) content conduced to the rapid release of ketoprofen from the polyelectrolyte hydrogels. It was found that the ketoprofen release followed non-Fickian mechanism. Furthermore, it was observed that the polymer erosion is a dominating factor in the release process of the tablet prepared by compression. The pH of the dissolution medium appeared to have a strong effect on the drug transport mechanism. At more basic pH values, a drug release mechanism highly influenced by macromolecular chain relaxation. In this study, the ketoprofen release was also tested under the conditions chosen to simulate the pH and time interval likely to be encountered during transit from stomach to colon. The results implied that the polyelectrolyte hydrogels can be exploited as potential carriers for colon-specific drug delivery. Recently, amphiphilic GG grafted with poly(ε-caprolactone) (PCL) was fabricated as a ketoprofen drug-delivery carrier using microwave irradiation [39]. In this study, GG-g-PCL with high grafting percentage (>200%) was obtained in a short reaction time. The GG-g-PCL co-polymer was found to be capable of self-assembling into nanosized spherical micelles in aqueous solution with the diameter of around 75–135 nm and 60–100 nm. The critical micelle concentration (CMC) of GG-g-PCL was found to be approx. 0.56 mg/l in a phosphate buffer solution. The drug-release profile showed that the GG-g-PCL micelles provided an initial burst release followed by a sustained release of the entrapped drug over a period of 10–68 h. Under physiological conditions, the GG-g-PCL co-polymer hydrolytically degraded into lower-molecular-weight fragments within a 7-week period. These results suggested that the GG-g-PCL micelles could be used as a nanocarrier for in vitro controlled drug delivery. 2.2. Antihypertensive drug delivery The potential advantages of GG as a sustained release excipient are its high viscosity, low cost, and commercial availability. GG’s potential in sustaining the release of antihypertensive water soluble drugs is presented in many reports. The use of GG as controlled release matrix for antihypertensive drugs such as ketoprofen, nifedipine and diltiazem hydrochloride has been reported [40,41]. From these studies, it was observed that the dissolution of hydrophilic drugs from GG formulations is nearly independent of stir speed under normal dissolution conditions. In these studies, the stability of guar based formulations under stressed conditions was also established. All the prepared formulations provided prolonged drug release under both in vitro and in vivo conditions. In another study, matrix tablets of diltiazem hydrochloride, using various viscosity grades of GG in two proportions, were prepared by wet granulation method for oral controlled release [42]. Diltiazem hydrochloride matrix tablets containing 30% (w/w) low viscosity, 40% (w/w) medium viscosity or 50% (w/w) high viscosity GG showed controlled release. The drug release from all the GG matrix tablets followed the first order kinetics via Fickian-

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M. Prabaharan / International Journal of Biological Macromolecules 49 (2011) 117–124 H 3C

CH3Cl N

HO

OH

+

O

-

RO CH3

O

OR O

RO

HO OR OH

RO

HO O

H

O

OH

O

H

O OH

O HO

O

Aq. NaOH

O

OH

O

OR

RO

OH

O OR

O

OH

n

O

CH3

n

N

Guar gum

OH

CH3 N

R= OH

+

CH3Cl

-

+

CH3Cl

-

CH3

or H, according to DS

CH3

Fig. 5. Reaction scheme for the quaternization of GG with 3-chloro-2-hydroxypropyltrimethylammonium chloride.

diffusion mechanism. Further, the results of in vitro drug release studies in simulated gastrointestinal and colonic fluids showed that high viscosity tablets provided controlled release comparable with commercial diltiazem hydrochloride tablets (D-SR tablets). When subjected to in vivo pharmacokinetic evaluation in healthy volunteers, the high viscosity tablets provided a slow and prolonged drug release when compared to D-SR tablets. Based on the results of in vitro and in vivo studies it was concluded that that GG matrix tablets provided oral controlled release of diltiazem hydrochloride drug. Oral controlled delivery systems for antihypertensive drug trimetazidine dihydrochloride using GG as a carrier were also reported [43]. In this study, three layer matrix tablets with 200 mg of release retardant layer containing 65%, 75% or 85% of GG over matrix formulation containing various proportions of GG were prepared. The three layer matrix tablet with 200 mg of 85% of GG layers over matrix formulation containing 50% of GG was found to provide the required release rate matching with the theoretical release rates. Based on differential scanning calorimetric (DSC) studies, it was found that there is no possible interaction between trimetazidine dihydrochloride and GG/other excipients used in the matrix tablets. The results clearly indicate that GG in the form of a threelayer matrix system is a potential hydrophilic carrier in the design of oral controlled drug delivery systems for highly soluble drugs. Stimuli-responsive nano/microgels can respond to external stimuli such as pH, ionic strength, temperature, and electric current. Such polymeric systems are useful as stimulus responsive drug carriers for several classes of drugs such as anticancer agents, antihypertensive agents, immunomodulators, hormones and macromolecules such as nucleic acids, proteins, peptides and antibodies [44–46]. Recently, Soppimath et al. have reported the glutaraldehyde cross-linked poly(acrylamide)-graft-GG hydrogel microspheres for the controlled release of calcium channel blockers like verapamil hydrochloride and nifedipine (Fig. 6) [47–49]. In these studies, the drugs were incorporated either during crosslinking by dissolving it in the reaction medium or after cross-linking by the soaking technique. Dynamic swelling experiments indicated that with an increase in cross-linking, water transport deviates from Fickian to non-Fickian mechanism. The in vitro drug release showed a dependence on the extent of cross-linking, amount of drug loading, nature of drug molecule and method of drug loading. The hydrogel microspheres showed a swelling followed by diffusion controlled drug release mechanism. Spherical shaped cross-linked microgels of poly(acrylamide)graft-GG possessing weakly anionic groups were prepared by the emulsification method [50]. Due to the presence of ionizable carboxylic functional groups, the microgels formed were found to

OH

OH

OH

OH

H

CH2 = CH-CONH2 +

O O

Acrylamide

O

H

Ce (IV), 60 0C

O

Guar gum CONH2 OH

OH

OH

O-CH2-CH

H

n +

O H

O

OHC-(CH2)3-CHO Glutaraldehyde

O

Cross-linking reaction

O

poly(acrylamide)-graft-guar gum

O

O CH (CH2)3 CONH2

CH O

O

OH

O-CH2-CH

H O O

H

n

O

O

Cross-linked poly(acrylamide)-graft-guar gum Fig. 6. Formation of cross-linked poly(acrylamide)-graft-GG.

be sensitive to pH and ionic strength of the external media. The pH-sensitivity of the microgels was evaluated by monitoring their dimensional changes with time by light microscopy. The solvent front velocity and diffusion coefficients have been calculated, and these data indicated that the rate of solvent diffusion increases considerably at higher pH, i.e. above the pKa of the anionic microgels. The mechanism of swelling was explained in terms of the relaxation-controlled phenomenon in both acidic and basic pH conditions as well as in ionic solution (1.0 M NaCl). The release of both diltiazem hydrochloride and nifedipine followed the relaxationcontrolled process, which was found to be closely related to the swelling of the microgels in response to the pH changes. Poly(acrylamide)-graft-GG was also prepared by taking three different ratios of GG to acrylamide (1:2, 1:3.5 and 1:5) [51]. In this work, amide groups of these grafted copolymers were converted into carboxylic functional groups as shown in Fig. 7. These modified

M. Prabaharan / International Journal of Biological Macromolecules 49 (2011) 117–124

CONH2 OH

OH

OH

O-CH2-CH

H O

O

H

O

n

O

Poly(acrylamide)-graft-guar gum

Aq. NaOH, 40 oC COOH OH

OH

OH

O-CH2-CH

H

n +

O O

H

NH3

O

O

Hydrolyzed poly(acrylamide)-graft-guar gum Fig. 7. Reaction scheme for conversion of amide group into carboxylic group.

polymers were used as the matrix tablet for the controlled release of diltiazem hydrochloride. For poly(acrylamide)-graft-GG matrix, the release was found to be continued up to 8 h. In case of hydrolyzed poly(acrylamide)-graft-GG matrix, release time increased with increasing grafting ratio of the grafted copolymer, which continued up to 12 h. Parameters of Kopcha equation revealed the predominance of diffusion on drug release for both the types of matrices. Hydrolyzed poly(acrylamide)-graft-GG matrices released only 27% of the total drug in gastric pH, while rest of the drug was released in the intestinal pH conditions. Hence, the systems of this study can be good candidates for intestinal drug delivery. In another study, lipase functionalized GG nanoparticles in the size range 19–32 nm were prepared by nano precipitation and cross-linking method for drug delivery applications [52]. In this work, the efficacy of the drug release on the GG nanocarrier was demonstrated indirectly by the release of crystal violet. The release kinetics indicated that the release was faster till 24 h and thereafter the release was very slow. This result suggests that GG based nanosized materials could be potentially used as a drug delivery carrier. 2.3. Protein delivery The most challenging task in the development of protein pharmaceuticals is to deal with physical and chemical instabilities of proteins. Protein instability is one of the major reasons by which protein pharmaceuticals are administered traditionally through injection rather than taken orally like most small chemical drugs [53]. Peptide and protein drugs are readily degraded by the low pH of the gastric medium in the stomach. In order to achieve the successful oral delivery of protein drugs, they need to be protected from the harsh environment in the stomach. For designing oral dosage forms, the formulator must consider that the natural pH environment of GI tract varies from acidic (pH ∼ 1.2) in the stomach to slightly alkaline in the intestine (pH ∼ 7.4) [54]. In the design of oral delivery of peptide or protein drugs, pH sensitive hydrogels have attracted increasing attention. Swelling

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of such hydrogels in the stomach is minimal and thus the drug release is also minimal. Due to increase in pH, the extent of swelling increases as the hydrogels pass down the intestinal tract. A variety of synthetic or natural polymers with acidic or basic pendant groups have been employed to fabricate pH sensitive hydrogels for getting the desired controlled release of protein drugs [55]. Recently, George and Abraham designed a pH sensitive alginate–GG hydrogel cross-linked with glutaraldehyde for the controlled delivery of protein drugs [56]. Alginate is a non-toxic polysaccharide with favorable pH sensitive properties for intestinal delivery of protein drugs. Drug leaching during hydrogel preparation and rapid dissolution of alginate at higher pH are major limitations, as it results in very low entrapment efficiency and burst release of entrapped protein drug, once it enters the intestine. To overcome these limitations, in this study, GG was included in the alginate matrix along with a cross linking agent to ensure maximum encapsulation efficiency and controlled drug release. The release profiles of a model protein drug (BSA) from alginate–GG hydrogels were studied under simulated gastric and intestinal media. The beads having an alginate to GG percentage combination of 3:1 showed desirable characters like better encapsulation efficiency and bead forming properties. The glutaraldehyde concentration giving maximum (100%) encapsulation efficiency and the most appropriate swelling characteristics was found to be 0.5% (w/v). Freeze-dried samples showed swelling ratios most suitable for drug release in simulated intestinal media (∼8.5). Protein release from alginate–GG hydrogels was minimal at pH 1.2 (∼20%), and it was found to be significantly higher (∼90%) at pH 7.4. The results of this study clearly showed that the presence of GG and glutaraldehyde cross-linking increases entrapment efficiency and prevents the rapid dissolution of alginate in higher pH of the intestine, which ensures a controlled release of the entrapped drug. 2.4. Transdermal drug delivery systems A transdermal drug delivery device, which may be of an active or a passive design, is a device which provides an alternative route for administering medication. These devices allow for pharmaceuticals to be delivered across the skin barrier [57]. In theory, transdermal patches work very simply. A drug is applied in a relatively high dosage to the inside of a patch, which is worn on the skin for an extended period of time. Through a diffusion process, the drug enters the bloodstream directly through the skin. Since there is high concentration on the patch and low concentration in the blood, the drug will keep diffusing into the blood for a long period of time, maintaining the constant concentration of drug in the blood flow. Recently, Murthy et al. evaluated carboxymethyl GG for its suitability of use in transdermal drug delivery systems [58]. The polymer exhibited good film forming ability and therefore used to prepare films possessing desired properties by varying the composition of the casting solution. In this study, terbutaline sulfate was used as a model drug. The results of this study showed that the diffusion of terbutaline sulfate from carboxymethyl GG solution was relatively slower at pH 5 than at pH 10. This observation might be due to the static interaction between carboxymethyl GG and terbutaline sulfate at pH 5. It was observed that the ionized/unionized state of drug is an important factor to be considered while preparing the casting solution to induce or minimize the interaction between the polymer and the drug. Release study showed that the release was exponential at pH 5 whereas the release rate followed zero or Higuchian order at pH 10. Thakur et al. also synthesized various types of acryloyl GG hydrogels by the reaction of GG with acrylic acid, methacrylic acid, 2-hydroxyethyl methacrylate and 2-hydroxypropyl methacrylate [59]. These hydrogels were used as transdermal drug delivery devices for l-tyrosine and 3,4-dihydroxy phenylalanine

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(l-DOPA) as the model pro-drugs. l-Tyrosine is involved in the synthesis of neurotransmitters in brain. It is a precursor to lDOPA, nor-epinephrine and epinephrine. The results showed that these hydrogel materials exhibited unique swelling behavior and responded well to the physiological stimuli such as pH and the ionic strength. The high loading of l-tyrosine and l-DOPA was achieved on these hydrogel materials. Release studies showed that the release behavior of these hydrogels was slow, especially, in the medium of pH 7.4. The hydrogel materials exhibited structure–property relationship in the release of both l-tyrosine and l-DOPA. The % cumulative release of l-tyrosine was found to be maximum from the acryloyl GG containing poly(methacrylic acid), while the maximum release of l-DOPA was observed from acryloyl GG containing poly(acrylic acid) in both the media. On the other hand, acryloyl GG based on 2-hydroxyethyl methacrylate and 2hydroxypropyl methacrylate showed a sustained release of both l-tyrosine and l-DOPA even after 12 h. These results indicate that acryloyl guar gum hydrogels could be used as pro-drug delivery carriers for transdermal applications. 3. Conclusions GG and its derivatives are stable, safe and biodegradable. Due to these favorable properties, they are widely considered as potential target-specific drug delivery carriers. GG can be used as a colonspecific drug carrier in the form of matrix and compression-coated tablets as well as microspheres due to its viscous colloidal dispersions in aqueous solution. To reduce the enormous swelling properties of GG that limits its application as drug delivery carriers; various approaches of chemical medications have been taken on GG. Among these, cross-linking GG polymer chains with crosslinking agents is quite promising. The viscosity of GG was found to be decreased even in the presence of enzymes by cross-linking with borax, glutaraldehyde and trisodium trimetaphosphate. These cross-linked GG formulations can be useful for the controlled release of several antihypertensive drugs. In order to achieve pH and temperature-responsive GG hydrogels, GG has been grafted with pH-responsive polymers such as poly(acrylamide) and poly(acrylic acid) and a temperature-responsive polymer, poly(N-isopropylacrylamide). These chemically modified stimuliresponsive GG hydrogels can be used in the area of the site-specific drug delivery to specific regions of the gastrointestinal tract, especially in the colon-specific delivery of low molecular weight protein drugs. Since GG and its derivatives have good film forming and controlled drug release abilities, they have potential to be used as transdermal drug delivery devices. From this review, it is obvious that a number of studies have been conducted on plain GG in the form of coatings and matrix tablets for colon-specific drug delivery. However, a substantial amount of research remains to be conducted on GG hydrogels, micro and nanoparticles in order to develop a target-specific drug delivery dosage form which is easier and simpler to formulate and is highly site-specific. References [1] L. Hovgaard, H. Brondsted, Crit. Rev. Ther. Drug Carrier Syst. 13 (1996) 185–223. [2] M. Prabaharan, R. Jayakumar, Int. J. Biol. Macromol. 44 (2009) 320–325. [3] M. Prabaharan, J. Biomater. Appl. 23 (2008) 5–36. [4] J.W. Lee, J.H. Park, J.R. Robinson, J. Pharm. Sci. 89 (2000) 850–866. [5] A. Rubinstein, Drug Dev. Res. 50 (2000) 435–439. [6] T.F. Vandamme, A. Lenourry, C. Charrueau, J. Chaumeil, Carbohydr. Polym. 48 (2002) 19–231. [7] C. Lemarchand, R. Gref, P. Couvreur, Eur. J. Pharm. Biopharm. 58 (2004) 327–341. [8] C.E. Bayliss, A.P. Houston, Appl. Environ. Microbiol. 48 (1986) 626–632. [9] J. Tomolin, J.S. Taylor, N.W. Read, Nutr. Rep. Int. 39 (1989) 121–135.

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