Encyclopedia of Biomedical Polymers and Polymeric Biomaterials DOI: 10.1081/E-EBPP-120050015Copyright © 2014 by Taylor & Francis. All rights reserved. 1

Psyllium, Natural and Grafted

Ranvijay KumarKaushlendra SharmaRakesh KumarBirla Institute of Technology, Mesra, Patna, India

AbstractPsyllium (commonly referred to as Isabgol in India), abundantly present in nature, is a renewable raw material and has been used to treat certain stomach-related diseases such as constipation, irritable bowel syndrome, diarrhea, and colon cancer. Psyllium has certain drawbacks, like uncontrolled rate of hydration, thickening, and drop in viscosity, on storage and microbial contamination. To overcome these drawbacks, these materials need some functionalization or modifi cation. In the last 10 years, psyllium has been grafted with several synthetic polymers such as polymethacrylic acid, N-hydroxymethylacrylamide, or acrylamide. The grafted products have been explored in drug delivery systems for drugs such as salicylic acid, acetyl salicylic acid, and tetracycline hydrochloride.

INTRODUCTION

Psyllium is a common name used for several members of the plant genus Plantago. It has more than 200 species in which Plantago psyllium and Plantago ovata are produced commercially. Psyllium, commonly referred to as Isabgol in India, was basically a native of Persia. India is the largest producer as well exporter of psyllium and psyllium husk in the world. The description of the psyllium plant is given below:

● Genus: Plantago ● Species: P. psyllium ● Type: Herb ● Height: 30–46 cm ● Flower: Small and white in color ● Life duration: 90 days

Though this plant is cultivated all over the world, Tables 1, 2, and 3 give an idea to the readers about the species cultivated in a particular region. There are about 50 species of psyllium for which the places of cultivation are not mentioned.

GRAFTING/MODIFICATION ON NATURAL PSYLLIUM

Psyllium has certain drawbacks, like uncontrolled rate of hydration, thickening, and drop in viscosity on storage and microbial contamination. To overcome these drawbacks,

these materials need some functionalization or modifi cation. Figure 1 shows the morphological structure of the cross-section of psyllium. The native psyllium is quite homoge-neous in appearance as observed from Fig. 1.

Grafting and cross-linking of vinyl monomers are the common techniques to modify and to improve the func-tional properties of polysaccharides and to make them advanced materials for drug delivery applications. Graft copolymerization of binary mixtures has more signifi cance in comparison to single monomers. It provides properties of both monomers to the grafted material. It also adds grafted chains with tailor-made properties to the backbone for biomedical applications. The mutual effect of mono-mers in the reaction mixture controls the fraction of indi-vidual monomers in the grafted chains. This synergistic effect of the comonomers enhances the fraction of the monomers in the graft yield. Hence, this technique pro-vides an opportunity to prepare tailor-made grafted chains of desired properties by using suitable monomers.[1]

Modifi cation of the psyllium structure is needed to improve its functionality like gelling capacities, water uptake capacities, swelling capacities, and bile acid-binding capacities as it is not carried out alone with HCl but takes place in the presence of ethanol.[2]

The general scheme of grafting as reported in the litera-ture is given in Fig. 2. The mechanism involves the genera-tion of psyllium free radical (Psy-O.), which interacts with an acrylic monomer (M) in the initiation process. Another monomer adds on Psy-OM. in the propagation step of the grafting process.

2 Psyllium, Natural and Grafted

MONOMER/POLYMER USED FOR GRAFTING

Microwave-assisted synthesis of polymethacrylic acid-grafted psyllium (Psy-g-PMA) has been done in our research laboratory using silver sulfate as a free radical ini-tiator keeping the temperature below 70°C. After the graft-ing process, morphology of the cross-sections showed heterogeneous structure, which confi rmed the grafting of the polymer on the psyllium (Fig. 3).[3]

The grafting of N-hydroxymethylacrylamide (NHMAAm) on psyllium backbone using ammonium persulfate as a reaction initiator has been reported. The reaction was car-ried out at a defi nite concentration of monomer and cross-linker in the aqueous reaction system at 65°C for 2 hr. Polymers thus formed were stirred for 2 hours in distilled water and for 2 hr in ethanol to remove the soluble fraction and then were dried in an air oven at 40°C. Figure 4 shows the surface morphology of NHMAAm-grafted polymer on psyllium with structural heterogeneity.[4]

As reported, the polymer psy-cl-poly(AAm-co-AMPS) hydrogels were also prepared by free radical graft/cross-linked copolymerization of acrylamide (AAm) and acrylamido-2-methylpropane sulfonic acid (AMPS) onto psyllium in the presence of a cross-linker and initiator in a test tube at 65°C for 2 hr. In addition to structural heterogeneity, cross-linked networks were observed in the scanning electron microscope (SEM) images of the hydrogels taken (Fig. 5).[1]

Recently psyllium was synthesized with AAm by microwave radiation technique keeping the temperature below boiling point (65°C) to minimize the competing homopolymer formation and also to prevent formation of unwanted vapors, which may be toxic/carcinogenic due to the presence of AAm. This microwave irradiation–cooling cycle was continued until a jelly-like mass was obtained or up to 3 minutes of irradiation time. Then, the reaction mix-ture was cooled and kept undisturbed for 12 hr to complete the grafting reaction. Figure 6 shows the SEM morphology of the grafted polymer on psyllium.[5]

Table 1 Details of the species of psyllium cultivated in the Mediterranean region

1. Plantago afra 8. Plantago bigelovii

2. Plantago amplexicaulis 9. Plantago coronopus: Buckshorn plantain

3. Plantago arborescens 10. Plantago cretica

4. Plantago arenaria: Branched plantain

11. Plantago lagopus

5. Plantago asiatica 12. Plantago subulata (Carinata)

6. Plantago atrata 13. Plantago subspathulata

7. Plantago bellardi 14. Plantago webbii

Table 2 Details of the species of psyllium cultivated in the European region

1. Plantago alpina 9. Plantago major/greater/common plantain

2. Plantago alistssima 10. Plantago maritime: Sea plantain

3. Plantago argentea 11. Plantago media: Hoary plantain

4. Plantago atrata 12. Plantago nivalis

5. Plantago aucklandica 13. Plantago reniformis

6. Plantago coronopus: Buckshorn plantain

14. Plantago sempervirens (P. cynops)

7. Plantago cornuti 15. Plantago unifl ora (Littorella unifl ora)

8. Plantago lanceolata: Ribwort plantain

16. Plantago cynops

Table 3 Details of the species of psyllium cultivated in the US region

1. Plantago aristata 11. Plantago cordata

2. Plantago australis 12. Plantago elongate

3. Plantago hookeriana 13. Plantago erecta

4. Plantago lundborgii 14. Plantago eriopoda/red-wool plantain

5. Plantago myosuros 15. Plantago hawaiensis

6. Plantago ovate: Blond psyllium

16. Plantago moorei: Moore’s plantain

7. Plantago patagonica 17. Plantago nubicola/Bougueria nubicola

8. Plantago rhodosperma 18. Plantago cordata

9. Plantago stauntonii 19. Plantago princeps

10. Plantago rugelii: Blackseed plantain

20. Plantago subnuda

Fig. 1 Morpholgical structure of the cross section of psyllium.

Psyllium, Natural and Grafted 3

THERAPEUTIC USE OF NATURAL PSYLLIUM

There are several diseases in which psyllium can be used for treatment. They are listed in the following text.

Constipation and Irritable Bowel Syndrome

In the digestion process, the stomach churns and mixes food to near-liquid food form; it then enters the small intes-tine and passes to the rectum, crossing the colon where soft stool is formed. The condition in which the colon fails to move the stool to the rectum is called constipation. Psyllium has the paradoxical property of both improving constipa-tion by increasing stool weight and ameliorating chronic diarrhea, as compared with sodium docusate.[6–12] When psyllium seeds are soaked in water, the size is increased from 8 to 14 times as compared to their original size. The gelatinous mass of psyllium promotes peristalsis, hydration of feces, provides a laxative exertion, relieves chronic con-stipation, and produces a soft stool as it lubricates, softens, and increases fecal volume and viscosity.[9,13–15] It was

reported that the gel fraction isolated from stool contained 75% carbohydrate; most of this carbohydrate was xylose (64%) and arabinose (27%), the same two sugars that account for the majority (79%) of the carbohydrate in psyl-lium.[16] When a patient uses psyllium for the treatment of constipation, it is essential to drink plenty of water, so that the psyllium is able to swell by absorbing water to develop mucilage action.

It is also reported that psyllium increased stool fre-quency and weight and decreased stool consistency in con-stipated patients, and clinical parameters were not signifi cantly affected by treatment with psyllium although there was a signifi cant decrease in transit time.[17–20]

Large amounts of benefi cial fi ber can be obtained by psyllium mucilloid. Multiple studies have examined the use of psyllium for irritable bowel syndrome (IBS).[21–24] The easing of bowel dissatisfaction appears to be a major reason for the therapeutic success of psyllium in IBS.[25] Prior and coworkers found the optimum dose of psyllium in IBS as 20 g per day.[26] However, personality factors infl uence the magnitude of the therapeutic response of psyllium.[24]

Fig. 2 General reaction scheme for grafting of synthetic polymer on psyllium.Source: Reprinted from Sen et al.,[5] with permission from Elsevier.

4 Psyllium, Natural and Grafted

(ETEC)-induced diarrhea and prevents the enhanced secre-tory responses to calcium-mediated agonists that occur in ETEC-infected piglet jejunum.[29]

Inflammatory Bowel Disease–Ulcerative Colitis (Crohn’s Disease)

Crohn’s disease is a chronic, recurrent infl ammatory dis-ease of the intestinal tract. The intestinal tract has four major parts: the esophagus or food tube; the stomach, where food is churned and digested; the long, small bowel, where nutrients, calories, and vitamins are absorbed; and the colon and rectum, where water is absorbed and stool is stored. The two primary sites for Crohn’s disease are the

Diarrhea

Diarrhea has a signifi cant impact on the quality of life and can contribute to malnutrition, weight loss, immune sup-pression, and mortality. Several studies suggest that psyl-lium may provide benefi ts for people with diarrhea. There is a scientifi c basis, and evidence suggests that psyllium increases the number of normal stools and decreases the number of liquid stools.[27] Stool looseness in diarrhea is determined by the ratio of fecal water-to-water-holding capacity of insoluble solids. In patients with diarrhea with normal stool weight, loose stools are due to low output of insoluble solids without the concomitant reduction in water output that occurs in normal subjects when insoluble solids are low.[28] Psyllium can be a cheap and effective alterna-tive to conventional treatment of chronic diarrhea.[21] Psyllium ameliorates enterotoxigenic Escherichia coli

Fig. 3 Morpholgical structure of the surface of polymethacrylic acid-grafted psyllium.

Fig. 4 Morpholgical structure of the surface of N-hydroxymethylacrylamide-grafted psyllium.Source: Reprinted from Singh et al.,[4] with permission from Elsevier.

Fig. 5 Morpholgical structure of the surface of acrylamide (AAm) and acrylamido-2- methylpropane sulfonic acid (AMPS)-grafted psyllium.Source: Reprinted from Sen et al.,[5] with permission from Elsevier.

Fig. 6 Morpholgical structure of the surface of acrylamide by microwave-assisted method.Source: Reprinted from Singh & Bala,[1] with permission from Elsevier.

Psyllium, Natural and Grafted 5

ileum, which is the last portion of the small bowel (ileitis, regional enteritis), and the colon (Crohn’s colitis). The condition begins as small, microscopic nests of infl amma-tion, which persist and smolder. The lining of the bowel can then become ulcerated and the bowel wall thickened. Eventually, the bowel may become narrowed or obstructed and surgery would be needed. A small number of studies have examined the ability of psyllium to maintain remis-sion in ulcerative colitis.[30–34] Colonic fermentation of psyllium yields n-butyrate; a signifi cant increase in fecal n-butyrate levels was observed after administration of P. ovata seeds. Hence, psyllium might be as effective as mesalamine to maintain remission in ulcerative colitis.[33]

The effi ciency of psyllium in relieving gastrointestinal symptoms in patients with ulcerative colitis in remission was studied in a placebo-controlled trial running for 4 months. Grading of symptoms judged psyllium consis-tently superior to placebo and associated with a signifi cantly higher rate of improvement (69%) than placebo (24%).[32]

Colon Cancer

Cancer of the colon is a major health problem, and it ranks as a leading form of cancer, along with lung and breast cancer. Importantly, colon cancer is also one of the most curable forms of cancer. When detected early, more than 90% of patients can be cured. This disease begins in the cells that line the colon. Colon cancer also can develop with other conditions, such as ulcerative colitis, a chronic infl ammation in the colon (as discussed in the preceding section).

Psyllium delays the fermentation rate of high-amylose cornstarch in the cecum and shifts the fermentation site of starch toward the distal colon, leading to the higher n-butyrate concentration in the distal colon and feces.[35] The presence of n-butyrate in the distal colon may be important in the prevention of colon cancer because the majority of tumors in both humans and experimentally induced rodent cancer models occur in the distal colon.[35,36] The end products of microbial carbohydrate fermentation in the large bowel include short-chain fatty acids (SCFAs), among which acetate, propionate, and n-butyrate are quan-titatively the most important. SCFAs have a range of effects that may be relevant to colonic health.[37,38] Of these, n-butyrate is of particular interest because it exerts a con-centration-dependent slowing of the rate of cancer cell proliferation and promotes expression of differentiation markers in vitro, leading to the reversion of cells from a neoplastic to a non-neoplastic phenotype.[39–41] Physical exercise and the use of psyllium and aspirin reduced the risk of colon cancer.[42] Psyllium strongly reduced the tumorigenicity of 1,2-dimethylhydrazine, and psyllium-fed rats had the highest fecal aerobic counts, lowest β-glucuronidase, and highest 7-α-dehydroxylase activi-ties.[43] Psyllium fi ber provided colonocytes some protec-tion from deoxycholic acid-induced lysis. Propionic acid,

a product of fi ber breakdown, was a potent colonocyte mitogen, suggesting that fi ber could indirectly protect the colon by providing colonocyte nutrients.[44]

Diabetes

The human body needs blood glucose to be maintained in a very narrow range. Insulin and glucagons are the hor-mones produced by the pancreas, which ultimately deter-mines diabetes, hypoglycemia, or some other sugar problem in patients. Psyllium has been proposed as a pos-sible treatment for high blood sugar levels, suggesting moderate reductions in blood sugar levels after a single dose of psyllium, with unclear long-term effects.[45–51] Water-soluble dietary fi bers decrease postprandial glucose concentrations and decrease serum cholesterol concentra-tions in men with type 2 diabetes.[52,53] Early or uncon-trolled studies suggested that psyllium improved glycemic and lipid control in individuals with type 2 diabetes.[54] In a carefully controlled crossover study of the effects of psyl-lium taken immediately before breakfast and dinner com-pared with the effects of cellulose placebo supplementation in individuals with type 2 diabetes, postprandial serum glucose values were 14% lower after breakfast, 31% lower after lunch, and 20% lower after dinner with psyllium.[55] Psyllium has also been shown to signifi cantly reduce post-prandial serum glucose and insulin concentrations in non-diabetic individuals.[56] Several studies indicate that high-fi ber diets or diets supplemented with soluble fi bers such as guar gum, soy, or pectin improve metabolic control in many individuals with type 2 diabetes.[57–63] In children and adolescents from developed countries, obesity preva-lence has strongly increased in the last decades, and insulin resistance and impaired glucose tolerance are frequently observed. Some dietary components such as foods with a low glycemic index and dietary fi ber could be used to improve glucose homeostasis in these children.[64] After psyllium supplementation, the percentage change in post-prandial glucose in type 2 diabetes patients ranged from −12.2 to −20.2.[65]

Cholesterol Lowering

Psyllium intake has consistently shown signifi cant reduc-tions in plasma low-density lipoprotein (LDL) cholesterol levels ranging from 10% to 24%.[66–70] Psyllium, in hyper-cholesterolemic men, lowered serum cholesterol as a result of the binding of bile acids in the intestinal lumen and reduced the risk of coronary heart disease.[71] Psyllium was shown to stimulate bile acid synthesis by increasing the 7-hydroxylase activity in animal and human models.[72,73] It is proposed that intake of psyllium causes greater viscosity in the intestine, thus preventing absorption of bile acids and neutral steroids, a phenomenon that has been observed for other viscous sources of dietary fi ber.[74–76]

6 Psyllium, Natural and Grafted

So far, no synthesized psyllium has been found to be used for therapeutic use directly or with composition.

NATURAL AND GRAFTED PSYLLIUM IN DRUG DELIVERY SYSTEM

Psyllium as Drug Delivery Agent

A number of drug delivery devices have been proposed to deliver drugs for effi cient therapy.[77] Among them, hydro-gels, specially based on polysaccharides, have attracted considerable attention as excellent candidates for con-trolled release devices or targetable devices of therapeutic agents.[78] The release rate of drugs from hydrogels was primarily determined by the swelling extent, which was further enhanced by the addition of enzymes in the buffer solutions,[79] whereas swelling of polymeric networks depended on the composition of copolymers and pH of the surrounding medium.[80] Modifi cation of psyllium to develop hydrogels is not much reported in the literature. Singh and coworkers modifi ed psyllium to prepare hydro-gels for specialty applications.[81]

Grafted Psyllium as Drug Delivery Agent

Grafted psyllium such as Psy-g-PMA releases medicines (acetyl salicylic acid) in acidic (4), neutral (7), and basic (9) pH, having a release percentage of approximately 85%, 82%, and 59%, respectively.[3] It releases 80% medicine in the fi rst hour and 84.65% within 3 hours. In neutral medium, it releases 55.12% in the fi rst hour and 82.04% within 11 hours, showing Fickian type of diffusion. In basic medium, it gives excellent results, releasing 27.51% in the fi rst hour (initially slow release), 59% up to 7 hours, and then becomes constant. The theory behind this is given in the next paragraph.

A faster Fickian diffusion mechanism occurs in large pores. At small duration of time and low pressure (before the onset of pore fi lling), total diffusion seems to be domi-nated by slower diffusion. In the case of acidic medium, the drug release is much faster than the other two mediums. The reason behind this is that acetyl salicylic acid is also acidic in nature; this increases the solubility of the drug in acidic medium on the basis of the concept “Like dissolves like.” Also in acidic medium, the pore size becomes large due to fast swelling of the matrix, and by Fickian law, fast diffusion takes place in the larger pores.[82]

The release dynamics of model drugs (salicylic acid and tetracycline hydrochloride) from Psy-g-NHMAAm on psyllium hydrogels has also been discussed, for the evalua-tion of the release mechanism and diffusion coeffi cients. In release medium of pH 7.4 buffer, the release pattern of tet-racycline drastically changed to the extent that the mecha-nism of drug diffusion shifted from non-Fickian diffusion to Fickian diffusion. It has been observed that diffusion

exponent ‘n’ has 0.71, 0.67, and 0.52 values, and gel char-acteristic constant ‘k’ has 1.552 × 10−2, 2.291 × 10−2, and 5.309 × 10−2 values in distilled water, pH 2.2 buffer, and pH 7.4 buffer, respectively, for tetracycline release. In a solu-tion of pH 7.4 buffer, the rate of polymer chain relaxation was more as compared to the rate of drug diffusion from these hydrogels, and it followed Fick’s law of diffusion. The value of the initial diffusion coeffi cient for the release of tetracycline hydrochloride was higher than the value of late time diffusion coeffi cient in each release medium, indi-cating that at the start, the diffusion of drug from the poly-meric matrix was fast as compared to the later stages.[4]

Synthesized psyllium and poly(AAm)-based hydrogels are used for in vitro release studies of drugs at 37°C. The release of water-soluble drugs, entrapped in a hydrogels, occurs only after water penetrates the polymeric networks to swell and dissolve the drug, followed by diffusion along the aqueous pathways to the surface of the device. The release of the drug is closely related to the swelling charac-teristics of the hydrogels, which in turn, is a key function of chemical architecture of the hydrogels. The amount of drug release in pH 7.4 buffer was higher than the release medium of 2.2 pH buffer and distilled water. The swelling of hydro-gels increased when the pH of the medium changed from acidic to basic. At lower pH values, the –CONH

2 groups do

not get ionized and keep the polymeric networks in the col-lapsed state. At high pH values, they get partially ionized, and the charged –COO groups repel each other, leading to higher swelling of the polymer and resulting in more drug release. The release of drug was observed to be faster in pH 7.4. From the percent cumulative release studies of salicylic acid, it was observed that the fi rst 50% of the total release occurred in 150 minutes, whereas in the case of tetracy-cline, 50% of the total release of the drug occurred in 90, 120, and 135 minutes in releasing mediums of pH 7.4 buffer, pH 2.2 buffer, and distilled water, respectively.[83]

CONCLUSIONS AND FUTURE PROSPECTS

Natural and modifi ed psyllium has various existing appli-cations in human life. Some of them are in constipation and IBS, diarrhea, infl ammatory bowel disease–ulcerative coli-tis (Crohn’s disease), colon cancer, diabetes, and choles-terol lowering. Modifi ed/grafted psyllium uses various monomers like polymethacrylic acid, N-hydroxymethyl-acrylamide, etc., that are used for drug delivery and fl oc-culation purpose. The inert nature of synthetic polymers has forced industries and researchers to look for eco-friendly grafting materials for psyllium. At present, acry-late-based monomers are polymerized for grafting on psyllium backbone but the research can be extended to polylactic acid (PLA) or polyhydroxyalkanoate (PHA)-based material for grafting on psyllium backbone. The applications of PLA or PHA as biopolymeric materials have become an attractive area of research due to their

Psyllium, Natural and Grafted 7

environmental friendliness. The thermal performances of biopolymeric materials are comparable with synthetic ones, but there is about 2–3% of water uptake. Because psyllium also has high water uptake, the grafting of another polymer with around 2% water uptake during immersion will not cause any problem with respect to applications. Investigations of PLA nanoparticles or polyhydroxy butyr-ate as drug delivery systems have already been reported. Hence, future work can be the combined use of psyllium and biopolymers in drug delivery systems.

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