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Indian Journal of Chemistry

Vol. 52A, October 2013, pp. 1269-1274

Controlled-release performance of chitosan-polyuronic acid adducts

Mahesh U Chhatbara, Ramavatar Meenaa, b, Chirag B Godiyaa & A K Siddhantaa, b, *

aMarine Biotechnology and Ecology Discipline, CSIR-Central Salt & Marine Chemicals Research Institute, GB Marg, Bhavnagar 364 002, Gujarat, India

bAcademy of Scientific & Innovative Research, Anusandhan Bhavan, 2 Rafi Marg, New Delhi 110 001, India Email: aks@csmcri.org

Received 20 June 2013; revised and accepted 17 September 2013

Controlled release performance of chitosan-polyuronic acid (polymannuronic and polyguluronic acid) adducts, has been evaluated using five structurally different drugs, i.e., paracetamol (PCT), indomethacine (IND), isoniazid (INH), atenolol (ATN) and pravastatin (PST). The release rates of PCT, INH and ATN, all containing -NH-CO-moieties, show an inverse correlation with the change in pH, i.e., highest at pH 1.2 and lowest at pH 7.4. A reversed trend is noted with IND and PST, having no -NH-CO-moieties; the release rates are highest at pH 7.4 and lowest at pH 1.2. This appears to have a correlation with the structural features of the adducts and the drugs alike, containing -NH-CO-groups, manifesting pH-dependent preferential interactions of -NH-CO-groups through intermolecular hydrogen bonding facilitated at a higher pH. This study presents an array of biopolymer-based materials, which can be harnessed for delivering specific dosage schedules and would be of potential utility in pharmaceutical formulations.

Keywords: Polyuronic acid, Chitosan, Drug release studies, Polymannuronic acid, Polyguluronic acid, X-ray diffraction

The need for safe, therapeutically effective and patient-compliant drug delivery systems has continuously motivated researchers to design novel materials and strategies. Hydrogels play a very crucial role in modulating drug delivery. The development of controlled release systems has introduced a new concept in release administration. Controlled release technology has been employed in biomedical, food, agriculture and pharmaceutical industries to deliver active substances such as drugs, pesticides, herbicides and fertilizers.1-3

Biomaterials for tissue engineering and drug delivery have witnessed numerous advances in recent years. As an important class of biomaterials, hydrogels, have received a great deal of attention, in particular as site specific or controlled-release drug delivery systems,4,5 because of their soft tissue biocompatibility, the ease with which the drugs get dispersed in the matrix, and, the high degree of control achieved by selecting the physical and chemical properties of the polymer network.6 Sriamornsak et al.7 prepared chitosan-reinforced calcium pectinate beads by ionotropic gelation method and release behavior of indomethacin (IND) from the beads were investigated. An extended release osmotic dosage form was designed and the

effect of β-cyclodextrin inclusion complexation on the solubility of lovastatin in aqueous media was investigated by Mahramizi and coworkers.8 Various synthetic or natural polymeric hydrogels have been employed as the controlled release systems for drug delivery.9-13 Among these, chitosan is one of the commonly used material. It is reported that chitosan is a potentially useful pharmaceutical material owing to its good biocompatibility and low toxicity.10,14 For drug delivery applications, chitosan needs to be chemicaly modified due to its hydrophilicity. The adducts of chitosan with the poly-uronic acid components of alginate, e.g., poly-mannuronic acid (PMA) and poly-guluronic acid (PGA), were synthesized and reported by Meena et al.15 The chitosan-polyuronic acid adducts (CH-PMA and CH-PGA), as a pH-sensitive hydrogel, swells in all pH media, i.e. pH 1.2, 7.0 and 12.0.15 We report herein, the controlled release properties of the adducts (CH-PMA and CH-PGA) using five different types of drugs, viz., the antipyretic paracetamol (PCT), anti-inflammatory indomethacin (IND), anti-tuberculesis isoniazid (INH), anti-hypertensive atenolol (ATN) and cardiovascular pravastatin (PST) in simulated gastric pH 1.2 and intestinal pH 7.4 dissolution media.

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Materials and Methods

Paracetamol (PCT), Indomethacine (IND), Isoniazid (INH), Atenolol (ATN) and Pravastatin (PST) were purchased from Sigma–Aldrich, USA.

The structures of these drugs are depicted in Fig. 1. Chitosan-polyuronic acid adducts, viz., CH-PMA and CH-PGA (Fig. 2) were prepared as reported in the literature.15 KCl, KH2PO4, NaCl, and NaOH were purchased from S. D. Fine Chemicals, Mumbai, India and were used as received.

UV–vis absorbance of drug solutions were measured using UV–vis spectrophotometer (Cary 500, Varian) equipped with a quartz cell having a path length of 1 cm. Release experiments were performed using USP standard Veego tablet dissolution test apparatus, prograssive instruments, Mumbai, India.

Synthesis of chitosan polyuronic acid adducts

Chitosan-polyuronic acid adducts viz., CH-PMA and CH-PGA (Fig. 2) were synthesised by microwave as reported in the literature.15 These materials were pH responsive, water insoluble and highly swellable. The greatest swelling, 3000 ± 50%, and 2700 ± 25%, of CH–PMA and CH–PGA respectively occured in pH 1.2.15 The controlled release properties of these adducts (CH-PMA and CH-PGA) were studied using five different types of drugs, the antipyretic paracetamol (PCT), anti-inflammatory indomethacin (IND), anti-tuberculesis isoniazid (INH),

Fig. 2—Chitosan adducts (CH-PMA and CH-PGA) and schematic representation of stabilization of adduct-drug formulation through -NH-CO- interactions forming an eight membered ring at pH 7.4.

anti-hypertensive atenolol (ATN) and cardiovascular pravastatin (PST) in simulated gastric pH 1.2 and intestinal pH 7.4 dissolution media.

Initial drug concentration and drug uptake

The adducts exhibited greatest swelling in aqueous medium (pH 6.0) over 1.5 h, which was used for drug uptake experiments using PCT, IND, INH, ATN and PST. The absorbencies were determined at

Fig. 1—Structures of paracetamol (PCT), indomethacine (IND), isoniazid (INH), atenolol (ATN) and pravastatin (PST).

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CHHATBAR et al.: CONTROLLED-RELEASE PERFORMANCE OF CHITOSAN-POLYURONIC ACID ADDUCTS 1271 different initial concentrations of drugs (PCT, IND,

INH, ATN and PST) at a constant temperature, time and pH. Separate sets of aqueous solutions (10 mL) containing varying amounts of PCT, IND, INH, ATN and PST (e.g. 10, 30, 40, 50, and 75 mg) were treated with 100 mg of CH-PMA and CH-PGA adducts for 1.5 h at pH 6.0 at 30 °C in a 25 mL conical flask with continuous stirring. These concentrations translate into 1000 mg/L, 3000 mg/L and so on. The above experimental mixtures were filtered on sterilized filter papers and concentration of remaining unabsorbed drug in the filtrate was determined by UV–vis spectroscopy at λmax 243 nm (PCT), 267 nm (IND), 263 nm (INH), 224 nm (ATN) and 240 nm (PST).

Drug loading kinetics

Experiments were performed to optimize the time required for maximum absorbency of drugs into the CH-PMA and CH-PGA. To separate sets of aqueous solutions (10 mL) containing optimum quantities of drug uptake i.e., PCT (50 mg), IND (40 mg), INH (50 mg), ATN (50 mg) or PST (40 mg) in 25 mL conical flasks, were added 100 mg each of CH-PMA or CH-PGA adducts. The mixtures were allowed to stand for 1, 1.5, 2 and 2.5 h at 30 °C with continuous stirring. At the end of each designated time duration, the mixture was filtered through a sterilized filter paper and the concentration of remaining unabsorbed drug in the filtrate was determined by UV–vis spectroscopy at the λmax of the drug, on the basis of which the amount of loaded drugs were calculated. Drug loaded adducts were dried at 30 °C for 24 h.

In vitro drugs release from CH-PMA and CH-PGA

Two sets of buffer solutions (pH 1.2 and 7.4) were prepared. Buffer solution of pH 1.2 (simulated gastric fluid) was prepared by mixing 250 mL of 0.2 M HCl and 147 mL of 0.2 M KCl, While buffer solution of pH 7.4 (simulated intestinal fluid) was prepared by mixing 250 mL of 0.1 M KH2PO4 and 195.5 mL of 0.1 M NaOH. In vitro release studies were carried out in these two buffer solutions, employing the dialysis bag technique as described in the literature.16-18 Dialysis bags were equilibrated with the appropriate dissolution medium for a few hours prior to the experiments. The dry drug loaded adduct material (100 mg) was placed in 5 mL buffer solution, which was then placed in the dialysis bag. The dialysis bag was then dipped into a receptor compartment containing 300 mL of the respective dissolution

pH medium, which was shaken at 37±0.5 °C on a Veego tablet dissolution test apparatus. The receptor compartment was closed to prevent evaporation losses from the dissolution medium. An aliquot (5 mL) was withdrawn from the receptor compartment at regular time intervals and the same volume was replenished with fresh dissolution medium. The amount of drug released from the adducts was measured by UV spectrophotometry at the respective λmax. These studies were performed in triplicate for each sample and the average values were used in data analysis.

Data were analyzed using analysis of variance (ANOVA). Results were considered statistically significant when p<0.05. Calculations were performed using Origin Software, Version 6 (Microcal Software Inc. MA, USA).

Powder X-ray diffractometry

Powder X-ray diffractions were recorded on a Philips X’pert MPD system in the 2θ range 10–60°

for vacuum dried powdered samples of CH-PMA drug hybrids, CH-PGA drugs hybrids, drugs (PCT, IND, INH, ATN and PST) as well as the physical mixture of polyuronic acid adducts and drugs. Physical mixture was made by grinding each drug with the solid hydrogel material.

Results and Discussion

Initial drug concentration and drug uptake

The uptake of drugs (PCT, IND, INH, ATN and PST) in CH-PMA and CH-PGA is affected by the initial drug concentration in the dissolution medium (Supplementary Data, Table S1). As the initial concentration of drugs in the solution increases, the absorbency increases, which may be due to greater concentration gradient at the initial stage. However, it reached equilibrium when absorbances reached the levels of 170.5 mg of PCT/g of CH-PMA and 148.6 mg of PCT/g of CH-PGA while for IND the values were 150.6 mg/g of CH-PMA and 135.2 mg/g of CH-PGA. For INH it was 143.2 mg/g of CH-PMA and 132.7 mg/g of CH-PGA, for ATN it was 145.8 mg/g of CH-PMA and 128.6 mg/g of CH-PGA and for PST, the values were 135.7 mg/g of CH-PMA and 125.5 mg/g of CH-PGA. Initially, the uptake of IND and PST was faster than that of PCT, INH and ATN under the same set of conditions, while the maximum absorbancy of PCT was relatively higher. It may be noted that level of drug uptake was greater with CH-PMA than CH-PGA in all cases.

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Drug loading kinetics

Optimal absorbency of drugs in CH-PMA and CH-PGA is a relatively rapid process involving a 1.5 h timespan, when the uptake of PCT, IND, INH, ATN and PST reached maximum levels of 34%, 37.5%, 28.6%, 29% and 34% with CH-PMA respectively. The respective levels were 29.6%, 33.8%, 26.5%, 25.7% and 31.4% with CH-PGA.

The percent uptake was calculated with respect to the initial concentration of the drug in the dissolution medium (Supplementary Data, Table S2), which remained constant up to 15 h.

Drug release profile

The permeability or release ability of PCT, IND, INH, ATN and PST were measured in CH-PMA and CH-PGA by dissolution experiments. The release

rates of PCT, IND, INH, ATN and PST were dependent on the pH of the dissolution media. The release rates of PCT, INH and ATN increased when pH of the dissolution media decreased, and it was the greatest at pH 1.2. The greatest amounts 95% (PCT), 86% (INH) and 74% (ATN) of drugs that were released ~ 1200 min from the adducts (Fig. 3(a&b)).

On the other hand, the release of the same set of drugs were significantly low in pH 7.4 media (Fig. 4(a&b)), which were presumably due to the intermolecular hydrogen bonding between the -NH-CO- groups of the drugs and the adducts probably forming an eight membered ring (Fig. 2). CH-PMA showed 55%, 38%

and 43% release of PCT, INH and ATN till 2000 min respectively, while the corresponding releases with CH-PGA were 35%, 40% and 38% till 2000 min (Fig. 4(a&b)). It may thus be conclude that the

Fig. 3—Release profiles of drugs from the (a) CH-PMA adducts in simulated gastric fluid (pH 1.2) at 37±0.5 °C [1 = PCT, 2 = INH, 3 = ATN, 4 = PST, 5 = IND], and, (b) CH-PGA adduct in simulated gastric fluid (pH 1.2) at 37±0.5 °C [1 = PCT, 2 = INH, 3 = ATN, 4 = IND, 5 = PST].

Fig. 4—Release profiles of drugs from the (a) CH-PMA adduct in simulated intestinal fluid (pH 7.4) at 37±0.5 °C [1 = PCT, 2 = IND, 3 = INH, 4 = ATN, 5 = PST], and, (b) CH-PGA adducts in simulated intestinal fluid (pH 7.4) at 37±0.5 °C [1 = PCT, 2 = IND, 3 = INH, 4 = ATN, 5 = PST].

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CHHATBAR et al.: CONTROLLED-RELEASE PERFORMANCE OF CHITOSAN-POLYURONIC ACID ADDUCTS 1273 release of PCT, INH and ATN is favored in acidic pH

media. This can be positively correlated to the swelling ability of different adducts, as a result of protonation of the free -NH2 groups present in these drugs inhibiting the hydrogen bonding interactions with the adducts.19 Furthermore, the overall release rate of PCT was significantly higher among the other drugs in all pH media from the CH-PMA adduct than from CH-PGA adduct (Figs 3 & 4). In all the cases, the release of drug initially occurred at a faster rate reaching a plateau, and then the remainder drug was delivered rather slowly, which would be desirable in certain release administrations.

The release of IND and PST from CH-PMA and CH-PGA as studied at a physiological temperature of 37 °C exhibited a strong pH-dependent release behavior, offering minimum release at pH 1.2 and maximum at pH 7.4. The maximum release of IND was observed from CH-PMA and CH-PGA (~99%

and ~65%, respectively) in pH 7.4 (Fig. 4(a&b)). On the other hand, its minimum release (43% and 46.7%

respectively), was registered in pH 1.2 (Fig. 3(a&b)).

The maximum release of PST was observed from the adducts (~88% and ~76% respectively), at pH 7.4 (Fig. 4(a&b)), and its minimum release (42% and 38% respectively) was observed at pH 1.2 (Fig. 3(a&b)). The equilibrium percentage of release of IND and PST at pH 1.2 was relatively low (~40%), apparently due to the electrostatic interaction between -COOH of IND/PST and the adducts.20-22

X-ray diffraction analysis

The XRD patterns of drug loaded formulations were examined and compared with those of the pure drugs, chitosan-polyuronic acid adducts as well as their physical mixtures. The absence of diffraction peaks indicated the amorphous structure of the chitosan- polyuronic acid adducts (CH-PMA and CH-PGA).15 The sharp diffraction peaks corresponding to PCT, IND, INH, ATN and PST were observed and were similar to those of the pure drugs in the XRD patterns of all the physical mixture samples (Supplementary Data, Figs S1-S5). On the other hand, the XRD patterns of all the drug loaded formulations exhibited peaks of low intensity and an irregular baseline indicating typical peaks of PCT, IND, INH, ATN and PST. However the profiles were not as sharp as those of the pure drugs. These results suggest that the crystallinity of the drugs was maintained in the formulation matrices of chitosan-polyuronic acid adducts, and drugs crystals were apparently physically

absorbed into the pores of the chitosan-polyuronic acid adduct hydrogels (Supplementary Data, Figs S1-S5) as described by Cavallari et al.23 Further, two new sharp diffraction peaks were observed in PCT loaded formulation at θ = 31o and 40o while, a new sharp diffraction peak was observed in each of the IND and PST loaded formulations at θ = 36o and 32o, respectively (Supplementary Data, Figs S1-S5).

The profiles of the physical mixture of the drugs and the adducts as well as the drug loaded formulations indicate that in the latter the drugs were probably attached to the adduct matrices by hydrogen bonds as well as van der Waals’ forces as opposed their respective physical mixtures.

Conclusions

The controlled-release performance of the biopolymer based super swellable material, viz., chitosan-polyuronic acid adducts, were evaluated using five structurally different drugs paracetamol, indomethacine, isoniazid, atenolol and pravastatin.

The delivery profile presented a staggered pattern, i.e., initially the drug was released at a fast rate reaching a plateau, and thereafter there was a gradual release. This study presents a new set of biopolymer based materials, which could be developed into controlled release formulations for delivering specific dosage schedules.

Supplementary Data

Supplementary Data associated with this article i.e;

Tables S1 and S2, and Figs S1-S5, are available in the electronic form at http://www.niscair.res.in/jinfo/

ijca/IJCA_52A(10)1269-1274_SupplData.pdf.

Acknowledgement

Grateful thanks are accorded to Council of Scientific and Industrial Research, New Delhi, for generous support towards infrastructure and core competency development under Analytical Discipline and Centralized Instrument Facility.

MUC thanks CSIR, New Delhi, for the award of a senior research fellowship. CBG gratefully acknowledges the Ministry of Earth Sciences, New Delhi, for a fellowship (MoES/9-DS/6/2007-PC-IV).

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References

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