International Journal of Diabetes Mellitus
Volume 2, Issue 1 , Pages 32-37, April 2010

Dietary fiber psyllium based hydrogels for use in insulin delivery

Department of Chemistry, Himachal Pradesh University, Shimla 171 005, India

Received 27 August 2009; received in revised form 18 December 2009; accepted 20 December 2009. published online 22 January 2010.

Article Outline

Abstract 

The present article is related to the development of psyllium based oral insulin delivery systems that could release insulin in a controlled and sustained manner. Psyllium is a medicinally important gel, forming glucose lowering dietary fiber and drug delivery system developed by its functionalization will have the double potential of curing diabetes. Psyllium and acrylamide/methacrylamide based hydrogels were prepared, and the effect of pH on the release dynamics of insulin from drug loaded hydrogels has been studied to evaluate the drug release mechanism. Non-Fickian diffusion mechanism has been observed for the release of insulin in the pH 7.4 buffer.

Keywords: Drug delivery devices, Hydrogels, Insulin, Diabetes mellitus

 

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1. Introduction 

Diabetes mellitus is a common problem nowadays which is caused by decreased production of insulin or by decreased ability to use insulin. This leads to an increase in blood glucose level. Due to the inconvenience of the traditional treatment of diabetes by subcutaneous administration of insulin injection, various attempts have been made to develop an efficient method of insulin delivery [1], [2]. Usually, insulin is injected subcutaneously two to four times to the patients in a day, because they need a relatively constant basal level of insulin to achieve a near physiological pattern of insulin secretion. Therefore, there has been significant interest in the development of oral delivery systems for insulin that could release the drug in a constant level for longer periods; patients would be freed from the need to administer multiple doses. Hydrogels have been shown to be promising candidates for such a system [3], [4].

The goal of oral insulin delivery devices is to protect the sensitive drug from proteolytic degradation in the stomach and upper portion of the small intestine. The pH responsive hydrogels have been studied as potential drug carriers for the protection of insulin from the acidic environment of the stomach, before releasing in the small intestine. In one case, insulin was administered orally to healthy and diabetic Wistar rats through pH responsive hydrogels. In the acidic environment of the stomach, the gels remained un-swollen due to the formation of intermolecular polymer complexes and the insulin remained in the gel and was protected from proteolytic degradation. In the basic and neutral environments of the intestine, the complexes dissociated which resulted in rapid gel swelling and insulin release. Within 2h of administration of the insulin-containing polymers, strong dose-dependent hypoglycemic effects were observed in both healthy and diabetic rats. These effects lasted up to 8h following administration [5]. In another study, the ability of the insulin loaded hydrogels to influence the blood glucose levels of the diabetic rats was investigated. The blood glucose level has been reduced for animals that received the insulin loaded hydrogel and the effect lasted for 8–10h. It was also observed, two capsules per day of the hydrogel micro-particles containing 80 I.U./kg of insulin dose were sufficient to control the blood glucose level of fed diabetic rats between 100 and 300mg/dl [6].

Insulin-loaded polymer micro-particles composed of crosslinked poly(methacrylic acid) and poly(ethylene glycol) are multi-functional carriers, and have shown high insulin incorporation efficiency, a rapid insulin release in the intestine, enzyme-inhibiting effects and mucoadhesive characteristics. Thus, these are potential carriers for insulin delivery via an oral route. Drug release from the hydrogel is affected by several factors, such as pore size, degradability, size, hydrophobicity, the concentration of a drug and the presence of specific hydrogel-drug interactions. Initially, the release mechanism from a biodegradable hydrogel is limited by the drug’s diffusivity. Following this, a combination of diffusion and degradation processes controls the drug’s release from the polymeric matrix [7], [8].

Polysaccharides based hydrogels enhance the intestinal absorption of insulin and increase the relative pharmacological bioavailability of insulin; it has been investigated by monitoring the plasma glucose level of alloxan-induced diabetic rats after oral administration of various doses of insulin-loaded chitosan-nanoparticles [9]. On the other hand, the blood glucose level can also be controlled by the polysaccharides, based diet management therapy. According to a report by the American Diabetic Association, fiber improves the control of blood glucose, and delays glucose absorption and hyperinsulinaemia [10]. Viscous forms of dietary fiber have been shown to improve blood glucose control by trapping ingested carbohydrates inside the viscous gel formed after digestion. As a result, sugars are absorbed into the bloodstream more slowly, limiting the rise in blood glucose seen after a meal [11], [12]. It has been suggested that the benefits of increased fiber intake result principally from the greater consumption of soluble forms, due to effects on gastric emptying, macronutrient absorption, and reduced postprandial glucose responses [13], [14]. Insoluble fiber may reduce diabetes risk by the production of short chain fatty acids in the colon and their effect on hepatic insulin sensitivity [15], [16]. The advantages of high-fiber diets for diabetic patients have also been said to include the lowering of serum lipids, assisted weight reduction and maintenance, along with the lowering of blood glucose levels [17], [18]. Psyllium is one of the medicinally important gel forming glucose lowering dietary fiber. It reduces hyperglycemia in diabetes via inhibition of intestinal glucose absorption and enhancement of motility [19]. Since the glucose lowering effect of psyllium was clearly evident when simultaneously administered with glucose, inhibition of glucose absorption in the gut is a likely contributor to the mechanism of action [20]. Psyllium in the diet also improves glucose tolerance in diabetes [21], [22]. This effect may be due to retarded gastric emptying, increased intestinal transit, or a modification of the secretion and action of digestive enzymes [23]. During the last two decades, several studies have been carried out to investigate, whether psyllium interferes with normal intestinal absorption of carbohydrate in healthy volunteers [24] and in type 1 [25] and type 2 diabetic patients [26]. The improvement in glucose tolerance produced by consumption of viscous fiber is due to slower absorption of carbohydrates, rather than mal-absorption. Intimate mixing, allowing physical interaction between food and fiber, seems to be important in converting the carbohydrate to what might be termed a slow-release form [27]. The mechanism of action of gel forming fiber is related to the ability to increase the viscosity of the gastrointestinal contents, and thus, interfere with motility and absorption [28].

Psyllium mucilage obtained from the seed coat by mechanical milling/grinding of the outer layer of the seeds and yield amounts to approximately 25% of the total seeds yield. Mucilage is fibrous, hydrophilic and forms the clear colorless mucilaginous gel by absorbing water. The gel nature and composition of the polysaccharides extracted from the seeds of the Plantago ovata has been reported in literature. The gel forming fraction of the alkali-extractable polysaccharides is composed of arabinose, xylose and traces of other sugars. Beside its sugar lowering property, it has been reported for the treatment of constipation, diarrhea, inflammation bowel diseases-ulcerative colitis, obesity in children and adolescents and high cholesterol [29].

In view of the pharmacological importance of psyllium polysaccharides to reduce glucose absorption and drug delivery devices based on hydrogels, psyllium, if suitably tailored to prepare the hydrogels, can act as the double potential candidates to develop novel drug delivery systems. Therefore, the present study is an attempt to synthesize psyllium and poly(AAm) and poly(AAm-co-MAAm) based hydrogels by using N,N′-methylenebisacrylamide (N,N-MBAAm) as crosslinker and ammonium persulfate (APS) as initiator and thereafter use as drug delivery devices. It also discusses the in vitro release dynamics of insulin in a different release medium, for the evaluation of release mechanism and diffusion coefficients.

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2. Experimental 

2.1. Materials and method 

Plantago psyllium mucilage (Psy) was obtained from Sidpur Sat Isabgol factory (Gujrat, India), acrylamide (AAm) and methacrylamide (MAAm) were obtained from Merck-Schuchardt, Germany. Sodium hydroxide, Sodium potassium tartrate and Folin’s reagents was obtained from Merck Mumbai-India. Ammonium persulphate (APS), copper sulphate and N,N′-methylenebisacrylamide (N,N-MBAAm) was obtained from S.D. Fine, Mumbai-India and were used as received. Insulin was obtained from the Torrent Pharmaceuticals Ltd., Indrad, Mehsana, India. Sodium carbonate was obtained from Ranbaxy, SAS Nagar Punjab-India.

2.2. Synthesis of polymers/hydrogels 

Reaction was carried out with 1g of psyllium husk, definite concentration of monomer, initiator and crosslinker taken in the aqueous reaction system at 65°C temperature for 2h. Polymers were stirred for 2 h in distilled water and for 2 h in ethanol to remove the soluble fraction and then were dried in oven at 40°C. Two types of hydrogels were prepared by using AAm and mixture of AAm/MAAm. The hydrogels were named as psy-cl-poly(AAm) and psy-cl-poly(AAm-co-MAAm) hydrogels, respectively. For the synthesis of psy-cl-poly(AAm) hydrogels 7.03×10−1 mol/L of AAm and was used along with 1.095×10−2 mol/L of APS, 16.20×10−3 mol/L of N,N-MBAAm. On the other hand, the psy-cl-poly(AAm-co-MAAm) hydrogels was synthesized by taking 3.52×10−1 mol/L of AAm and 0.58×10−1 mol/L of MAAm simultaneously in the mixture containing 0.66×10−2 mol/L of APS and 9.73×10−3 mol/L of N,N-MBAAm. These hydrogels were used to study the release dynamics of the drug from the drug loaded hydrogels.

2.3. Release dynamics of insulin from drug loaded hydrogels 

2.3.1. Preparation calibration curves 

In this procedure, the absorbance of a number of standard solutions of the reference substance at concentrations encompassing the sample concentrations were measured on the UV Visible Spectrophotometer (Cary 100 Bio, Varian) and calibration graph was constructed. The concentration of the drug in the sample solution was read from the graph as the concentration corresponding to the absorbance of the solution. Three calibration graphs of insulin were made to determine the amount of drug release from the drug loaded polymeric matrix respectively for distilled water, pH 2.2 buffer and pH 7.4 buffer [29].

2.3.2. Drug loading to the polymer matrix 

The loading of a drug onto hydrogels was carried out by a swelling equilibrium method. The hydrogels were allowed to swell in the drug solution of known concentration for 24h at 37°C and then dried to obtain the release device.

2.3.3. Drug release from polymer matrix 

In vitro release studies of the drug were carried out by placing dried and loaded sample in definite volume of releasing medium at 37°C temperature. The amount of insulin released was assayed spectrophotometrically by Lowry method [30]. The absorbance of the solution was measured at wavelength 768.0nm, 753.0nm and 758.0nm, respectively, for release in distilled water, pH 2.2 buffer and pH 7.4 buffer after every 30min in each case. The procedure for the Lowry method is as follows.

2.3.3.1. Reagents used for Lowry method 

Reagent A: sodium carbonate (2% w/v) in 0.1N sodium hydroxide solution was prepared by dissolving 20g of sodium carbonate and 4g of sodium hydroxide in 1L of distilled water.

Reagent B: copper sulphate solution (1% w/v) was prepared by dissolving 1g of copper sulphate (AR) in 100mL of distilled water.

Reagent C: sodium potassium tartrate solution (2% w/v) was prepared by dissolving 2g of the salt in 100mL distilled water.

Reagent D: alkaline copper reagent: 1mL each of reagents B and C was mixed with 98mL of reagent A and vortexed. This reagent was prepared freshly.

2.3.3.2. Procedure for Lowry method 

To 1mL of the standard protein solution containing 10–100μg of protein or released insulin sample solution were added 4ml of reagent D and the contents were mixed. After 10min of incubation at room temperature, 0.4mL of Folin’s reagent was added and the contents were vortexed immediately. A reagent blank with 1mL of distilled water (or buffer solution of respective pH) was also processed in same manner as described above. After 30min of incubation at room temperature, the blue color developed was measured at λmax. The calibration curve was constructed and computed to calculate the concentration of the insulin released from the sample. While calculating the insulin concentration in the unknown sample, the dilution factor has been taken into account [30].

2.3.4. Preparation of buffer solution 

Buffer solution of pH 2.2 was prepared by taking 50mL of 0.2M KCl and 7.8ml of 0.2N HCl in volumetric flask to make volume 200ml with distilled water. Buffer solution of pH 7.4 was prepared by taking 50mL of 0.2M KH2PO4 and 39.1mL of 0.2N NaOH in volumetric flask to make volume 200ml with distilled water [31].

2.4. Mechanism of swelling and drug release from polymer matrix 

The mechanisms of swelling and drug release have been discussed in detail in our earlier study [29]. Swelling of polymers has been classified into three types of diffusion mechanisms, on the basis of relative rate of diffusion of water into polymer matrix and rate of polymer chain relaxation [32], [33], [34], [35]. The values of diffusion exponent ‘n’ and diffusion coefficients have been evaluated for the swelling of the polymers and for the release of the drug from the polymer. The values of diffusion coefficients have been evaluated for the release of the drug from the polymer, and the results are presented in Table 1.

Table 1. Results of diffusion exponent ‘n’, gel characteristic constant ‘k’ and various diffusion coefficients for the release of insulin from drug loaded polymers in different medium at 37°C.
Drug in releasing mediumDiffusion exponent ‘n’Gel characteristic constant ‘k’×102Diffusion coefficients (cm2/min)
Initial Di×104Average DA×104Late time DL×104
Psy-cl-poly(AAm)
Distilled water0.810.8718.016.952.25
pH 2.2 buffer0.388.397.4719.881.60
pH 7.4 buffer0.602.7319.6920.443.19

Psy-cl-poly(AAm-co-MAAm)
Distilled water0.603.298.337.611.69
pH 2.2 buffer0.4010.695.8212.752.01
pH 7.4 buffer0.573.467.837.961.34

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3. Results and discussion 

Polymeric networks were synthesized by chemically induced polymerization through free radical mechanism. APS has generated the reactive sites, both on the psyllium and monomer, leading to the propagation of the reaction. In the presence of crosslinker N,N-MBAAm (CH2CHCONHCH2 NHCOCHCH2) four reactive sites are generated and these sites can be linked both with the radical on the psyllium and the poly(AAm)/poly(MAAm) and formed a crosslinked three-dimensional networks, which have been used to study the in vitro release of the model drugs.

3.1. Characterization 

FTIR spectra of psyllium, psy-cl-poly(AAm) and psy-cl poly(AAm-co-MAAm) polymers were recorded in KBr pellets on Nicolet 5700 FTIR (THERMO) shown in (Fig. 1a–c). The broad absorption bands at 3421.6 and 3415.6cm−1 were observed due to –OH and NH stretching of –OH and NH groups present in psy-cl-poly(AAm), and psy-cl poly(AAm-co-MAAm) polymers and FTIR absorption bands due to CO stretching of amide has been prominently witnessed at 1664.3 and 1664.8cm−1 for respective polymer matrix. The bands at 1042.3 and 1041.9cm−1 were observed due to C–N stretching of amide present in all the three modified samples apart from usual peaks in psyllium.

3.2. Release dynamics of insulin from drug loaded hydrogels 

3.2.1. Release dynamics of insulin from psy-cl-poly(AAm) hydrogels 

In present studies, the release profile of insulin from per grams of the drug loaded hydrogels has been shown in the Fig. 2. The amount of insulin release in pH 7.4 buffer and distilled water was higher than the release medium of pH 2.2 buffer. After 24 h the total amount of drug release, (23.22±2.01) μg, (16.65±1.69) μg (33.21±1.82) μg per g of gel have been observed, respectively, in distilled water, pH 2.2 buffer and pH 7.4 buffer. The diffusion exponent ‘n’ has 0.81, 0.38 and 0.60 values and gel characteristic constant ‘k’ has 0.87×10−2, 8.39×10−2 and 2.73×10−2 values in distilled water, pH 2.2 buffer and pH 7.4 buffer, respectively. The values of ‘n’ indicate a non-Fickian diffusion mechanism for the release of drug in case of pH 7.4 buffer and distilled water. In this mechanism, the rate of polymer chain relaxation and the rate of drug diffusion from these hydrogels are comparable. On the other hand, a Fickian type of diffusion mechanism occurs in case of pH 2.2 buffer. The values of the initial diffusion coefficients for the release of insulin were observed to be higher than the values of average and late time diffusion coefficients in each release medium indicating that in the start, rate of diffusion of drug from the polymeric matrix was higher (Table 1).

3.2.2. Release dynamics of insulin from psy-cl-poly(AAm-co-MAAm) hydrogels 

The release of insulin, entrapped in a hydrogels, occurs only after water penetrates the network to swell the polymer and dissolve the drug, followed by diffusion along the aqueous pathways to the surface of the device. In the present studies, the release profile of insulin from per grams of the drug loaded hydrogels has been shown in the Fig. 3. The amount of insulin release in pH 7.4 buffer and distilled water was higher than the release medium of pH 2.2 buffer. After 24 h total amount of drug release, (52.66±1.29) μg, (28.68±0.88) μg and (53.90±0.77) μg per g of gel have been observed, respectively, in distilled water, pH 2.2 buffer and pH 7.4 buffer. The diffusion exponent ‘n’ have 0.60, 0.40 and 0.57 values and gel characteristic constant ‘k’ have 3.29×10−2, 10.69×10−2 and 3.46×10−2 values in distilled water, pH 2.2 buffer and pH 7.4 buffer, respectively. As the values of ‘n’ indicates a non-Fickian or anomalous diffusion mechanism for the release of drug in case of pH 7.4 buffer and distilled water. It means that the rate of polymer chain relaxation and the rate of drug diffusion from these hydrogels are comparable. On the other hand, Fickian type of diffusion mechanism occurs in case of pH 2.2 buffer. The values of the initial diffusion coefficient for the release of insulin was observed to be higher than the value of average and late time diffusion coefficient in each release medium indicating that in the start, rate of diffusion of drug from the polymeric matrix was higher.

The present drug delivery system will have the double potential to control the glucose level in the blood. This will release the insulin in the colon in a controlled and sustained manner, and polymer degradation in the colon will release the psyllium, which itself has been proposed as a glucose lowering agent. Since the glucose lowering effect of psyllium was clearly evident when simultaneously administered with glucose, the inhibition of glucose absorption in the gut is a likely contributor to the mechanism of action [20]. Psyllium in the diet also improves glucose tolerance in diabetes [21], [22] This effect may be due to retarded gastric emptying, increased intestinal transit or a modification of the secretion and action of digestive enzymes [23]. The human body needs blood glucose to be maintained in a very narrow range. Insulin and glucagons are the hormones which make this happen. It is the production of insulin and glucagons by the pancreas which ultimately determines if a patient has diabetes, hypoglycemia, or some other sugar problem. Psyllium has been proposed as a possible treatment for high blood sugar levels. Studies in humans suggest moderate reductions in blood sugar levels after a single dose of psyllium, with unclear long-term effects [36]. The brief discussion about the role of insulin in glucose lowering and in regulating glucose metabolism will be praiseworthy.

People who do not produce the necessary amount of insulin have diabetes. There are two general types of diabetes. Insulin is a hormone that regulates the amount of glucose (sugar) in the blood and is required for the body to function normally. Insulin is produced by cells in the pancreas, called the islets of Langerhans. These cells continuously release a small amount of insulin into the body, but they release surges of the hormone in response to a rise in the blood glucose level. Without insulin, the blood glucose builds up in the blood and the cells are starved of their energy source. The cells will begin to use fat, the energy source stored for emergencies. When this happens for too long a time, the body produces ketones, chemicals produced by the liver. Ketones can poison and kill cells if they build up in the body over an extended period of time. This can lead to serious illness and coma. In addition to its role in regulating glucose metabolism, insulin increases DNA replication and protein synthesis via control of amino acid uptake, modification of the activity of numerous enzymes, decreased proteolysis, forces reduction in conversion of fat cell lipid stores into blood fatty acids, decreased gluconeogenesis, increases amino acid uptake into cells, forces cells to absorb serum potassium, forces arterial wall muscle to relax, increasing blood flow, especially in micro arteries; lack of insulin reduces flow by allowing these muscles to contract. Although the specific treatments can vary greatly by subtype of disease, all diabetes treatments have the same goal; to adequately regulate blood glucose in order to prevent the primary and secondary effects of hyperglycemia.

Overall the hydrogels can act as double potential drug delivery systems for the delivery of insulin. These pH responsive hydrogels can make the site specific delivery of the proteins. Mahkam has investigated the protective ability of the hydrogel for insulin in the harsh environment of the stomach, insulin and insulin-incorporated polymer-bonded drug by treating with a simulated gastric solution that contained endopesidase pepsin [37]. The results of this study indicated that all insulin has been degraded immediately after contact with gastric fluid. The main cause of degradation was the proteolytic enzyme, pepsin. After being treated with gastric fluid, all of hydrogels demonstrated a protective effect on insulin and the biological activity remained after the treatment with gastric fluid of hydrogels [37]. In one case study it is reported by Wood and coworkers that hydrogels enhances insulin absorption and holds great promise as an oral insulin delivery system. The pH-sensitive complexation hydrogels composed of methacrylic acid and functionalized polyethylene glycol (PEG) tethers, referred to as P(MAA-g-EG) WGA, can be used for oral protein delivery system. The PEG tethers have been functionalized with wheatgerm agglutinin (WGA), a lectin that can bind to carbohydrates in the intestinal mucosa, to improve residence time of the carrier and absorption of the drug at the delivery site. The ability of P(MAA-g-EG) WGA to improve insulin absorption has been observed in two different intestinal epithelial models. In Caco-2 cells P(MAA-g-EG) WGA improved insulin permeability 9-fold as compared with an insulin only solution, which was similar to the improvement by P(MAA-g-EG). P(MAA-g-EG) and P(MAA-g-EG) WGA have also been evaluated in a mucus-secreting culture that contained Caco-2 and HT29–MTX cells. Insulin permeability has been increased 5-fold in the presence of P(MAA-g-EG) and P(MAA-g-EG) WGA. In addition, it was determined that both P(MAA-g-EG) and P(MAA-g-EG) WGA were cytocompatible with the Caco-2 and HT29–MTX cell lines [38].

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4. Conclusion 

Because of the therapeutic importance of psyllium in curing diabetes mellitus, hydrogels developing from it can act as double potential drug delivery devices, indicated from the drug release dynamics in different release medium. These hydrogels may be useful for the controlled delivery of peptides. It is concluded from the drug release dynamics that the drug released through the polymeric matrix follows non-Fickian diffusion mechanism pH 7.4 buffer solution, for which the rate of drug diffusion and rate of polymer chain relaxation are comparable. Therefore, drug release depends on two simultaneous rate processes, water migration into the device and drug diffusion through continuously swelling hydrogels. In each release medium, the earlier stage of the diffusion coefficient has been observed more than the late time diffusion coefficient.

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PII: S1877-5934(09)00071-X

doi:10.1016/j.ijdm.2009.12.014

International Journal of Diabetes Mellitus
Volume 2, Issue 1 , Pages 32-37, April 2010

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