About Authors: Rajan Sharma Bhattarai*, D.Nagasamy Venkatesh**, Ayush Shrestha
*Final Year B.Pharmacy Student.
**For correspondence
Department of Pharmaceutics
JSS College of Pharmacy, (A constituent college of JSS University, Mysore)
Ooty – 643 001, Tamil Nadu.
Reference ID: PHARMATUTOR-ART-1065
Abstract:
Alginate and chitosan are commonly used polymers in modifying the drug release. These two polymers can be used together or separately to form drug loaded modified release beads. The ionotropic gelation method and a slight modification in various ways are used to prepare these beads of different characteristics. The bead characteristics like morphology, buoyancy, swelling nature, drug entrapment efficiency, adsorption, release behavior are of importance. Also the therapeutic uses of the different modifications of the beads can be immense for the drugs which have low water solubility, short biological half life, require organ specific targeting and are proteineous in nature.
Introduction:
Alginate is a naturally occurring biopolymer that finds increasing applications in various fields. It has been used successfully for many years in the food and beverage industry as a thickening agent, a gelling agent and a colloidal stabilizer. Alginate also has several unique properties that have enabled it to be used as a matrix for the entrapment and/or delivery of a variety of proteins, drugs and cells.
These properties include:
(i) a relatively inert aqueous environment within the matrix;
(ii) a mild room temperature encapsulation process free of organic solvents; (iii) a high gel porosity which allows for high diffusion rates of macromolecules;
(iv) the ability to control this porosity with simple coating procedures and (v) dissolution and biodegradation of the system under normal physiological conditions. [1]
Alginate is a water-soluble linear, polyanionic, polysaccharide extracted from brown seaweed and is composed of alternating blocks of 1–4 linked α-L-guluronic and β-D-mannuronic acid residues.[2] The gel beads are prepared through the sol-gel transformation of alginate, which is brought about by cross-linking the alginate with divalent cations like Ca2+, Zn2+. Guluronic acid is responsible for the formation of gel by the alginate with the cations. The alginate matrix which consists of an open lattice structure forms porous beads. They have low retention capacity for encapsulating low molecular weight and water soluble drugs. [3]
Chitosan is a biocompatible, biodegradable, nontoxic, linear co-polymer polysaccharide consisting of β (1–4)-linked 2-amino-2-deoxy-D-glucose (D-glucosamine) and 2-acetamido-2-deoxy-D-glucose (N-acetyl-D-glucosamine) units. The structure of chitosan is very similar to that of cellulose (made up of β (1–4)-linked D-glucose units). Chitosan is the N-deacetylated derivative of chitin, although this N-deacetylation is never complete, exposing a number of amino groups making it polycationic polysaccharide. Different grades of chitosan are found depending on the amount of deacetylation of the compounds. Due to its gel-forming property it has been used in the design of drug delivery system. [3]
The interaction between alginate and chitosan has been systematically investigated. Their polyelectrolyte complex has been widely used to obtain devices for the controlled release of drugs. [4] The interaction between the alginate and the chitosan forms the polyelectrolyte complex via the ionic interaction between the carboxyl residue of alginate and the amino residue of chitosan. The complexation of alginate with chitosan decreases the leakage of the encapsulated drug from the beads. Due to this reason the previously used chitosan-tripolyphosphate beads which had low mechanical strengths and the alginate beads are replaced by the alginate chitosan beads which can be prepared by various methods.
Methods of Preparation of beads:
Modification in Preparation of the beads (alginate and alginate chitosan) by Ionotropic gelation. [5]
i. Syringe or Dropper Method
ii. Extrusion Method
iii. Laminar jet break-up or Prilling method
(i) Ionotropic Gelation Method:[6-9]
This includes the formation of the hydrogel beads by treating the alginate solution with the solution containing polyvalent (mostly divalent) ions. The polyvalent ions help in the formation of the gel by forming a bond with the alginate. This is the commonest method employed and it can be modified in many different ways to bring about the desired shape, size and therapeutic effects.
(a) The solution of the sodium alginate is prepared (different concentration). To that, the drug (if required in suitable vehicle) in different concentrations is added. The mixture is stirred and allowed to stand for required time. The mixture is then dropped into the solution containing divalent ion (different concentration) and if required at different pH conditions. The beads thus formed are washed (different solutions) and dried (different conditions). The wet beads thus formed can then be coated with the polymers like chitosan and then dried to modify the release.
(b) The solution of sodium alginate is mixed with the drug solution and the polymer like chitosan is added to it. Then the mixture is gelled with divalent ion solution as above.
(c) Further modification can be the addition of the alginate solution into the mixture of divalent ion salt and the polymer (chitosan). Then the beads formed are passed through the same processes.
(ii) Extrusion Method: [3]
The solution of sodium alginate is mixed with the drug solution and is introduced drop wise into the solution of divalent metal salt by means of extrusion through a silicone tubing using a peristaltic pump.
Then following the steps as mentioned above.
(iii) Prilling Method: [10]
Thermostated sodium alginate solution is used for making beads by using a vibrating nozzle device pumping through the nozzle at different rates into the solution of divalent metal salts and following the afore mentioned steps.
Preparation of Chitosan beads:
General Method: [11-16]
Chitosan solution made in acetate buffered solution (pH 4.5) is mixed with the drug and is left to stand for 24 hours at room temperature for complete hydration of polymer. The solution is then covalently cross-linked with glutaraldehyde followed by precipitation in an aqueous medium by a change in pH (basic) by adding NaOH solution. The beads are separated and dried if required.
Modifications:
Cross-linking chitosan succinate with Iron (FeCl3) leads to further cross-linking and allows pH independent drug release. [13]
Chitosan gel beads can also be prepared by complexing chitosan with divalent metal ions such as Cu2+ which improve the stability and absorption of peptide and protein drugs(water soluble e.g. insulin) which cannot be obtained by employing cross-linking with glutaraldehyde. [14]
Tripolyphosphate cross-linked chitosan beads show a more homogenous structure as a result of more homogenous cross-linking process, hence beads are strengthened greatly and have increased drug loading efficiency. [15-16]
Characterization of Beads:
Buoyancy: [17]
The buoyancy of the stomach specific preparation is measured using standard pycnometer or electronic densimeter. The bead containing drug and the vegetable oil in it floated to provide the stomach specific delivery.
Morphological studies/particle size using scanning electron microscope (SEM):
Dried beads with low concentration of alginate lost the spherical shape when dried but beads with high concentration retained the shape. The beads from method (i) b showed increasing size but lost the spherical structure on drying. The beads from (i) a, the calcium alginate beads coated with the chitosan (polymer), showed the spherical structure in both the dry and wet conditions. [6] But at times the coating with higher concentration of polymer led to cracks and holes on the surface [18], and even ethanol drying decreased the surface roughness. [19] Some authors reported the spherical shape of beads when eudragit, a polymer, is used while preparing the calcium alginate beads and when the calcium alginate beads are coated with chitosan. [20]
Swelling studies:
Swelling behavior of the beads is studied by measuring the diameter of the beads by digital camera. The magnitude of swelling is presented by the ratio of the mean diameter of the swollen beads to the mean diameter of the dried beads before the test and the increase in diameter is determined. Chitosan coated beads swell less than the uncoated ones due to the formation of skin layer with chitosan. [6, 20] The swelling behavior is pH dependent. The beads swell slightly in stomach but swelling gradually increases in the intestinal pH, and maximum in the colon for the colon specific delivery. [19]
Entrapping Efficiency:
The entrapping efficiency of the water soluble drug is less as the medium used is mostly aqueous and the drug will be lost more in the medium. The longer the curing time, the lesser the entrapment. [18] The water insoluble drug have good trapping efficiency. [15] The more the concentration of the drug more will be the entrapment. The increase in the coating polymer concentration also increases the trapping efficiency. [8]
Uptake of Bile Acids: [8, 9]
The alginate chitosan beads showed increasing adsorption of bile acids with the increase in the concentration of the bile acids when the acidic drugs like ascorbic acid or nicotinic acids were used which formed the strong links with the amino groups of chitosan.
Release behavior:
Drug release is determined by introducing the beads into buffered simulated dissolution media at 37±0.5OC [21], 37±0.1OC [16], 37OC [11, 14] and stirred at 50 rpm. The XXIII USP basket apparatus [21], Japanese Pharmacopoeia 13th edition (JPXIII) paddle type dissolution test apparatus [11] are used. The samples are withdrawn at specific time interval and assayed spectrophotometrically at the wavelength of maximum absorbance. [21] The percentage of the drug release is calculated with respect to the drug content of the beads. The drug content is expressed as the percentage of drug encapsulated in a unit weight of beads. The experiments are carried out in triplicate and the results averaged. [22]
The undried beads showed decreased drug release with increased chitosan concentration but increased alginate showed decreased release at low concentration of chitosan and increased release with high concentration of chitosan. [6] The beads containing oils in it released the drugs gradually. [17]
For the dried beads, due to the destruction of the alginate chitosan film the drug release was more. The increased concentration of coated chitosan showed the decreased drug release. [6, 18, 23] Also the increased drug concentration increases the drug release. [16]
Therapeutic Uses:
The alginate, chitosan or alginate-chitosan beads can have various therapeutic uses depending upon the drug loaded into them.
1. NSAID like Diclofenac sodium can be made into beads, which show reduced release in the acidic environment of the stomach. This minimizes the adverse effects of oral administration and avoids direct contact between the drug and the gastric mucosa. [24] The other NSAID, Ibuprofen can also be the candidate for the prolonged and the controlled release drug because of its short half life and gastric irritation activity both of which can be easily overcomed with the use of the alginate beads. [25]
2. The beads loaded with the antibiotics (like ampicillin) can be useful for the oral delivery for the treatment of gastric and intestinal diseases. The sustained and the controlled release of ampicillin can be useful to overcome its short biological half-life of 0.75-1.5 hours. [26]
3. Antihypertensive drugs like Verapamil HCl, with low bioavailability due to first pass metabolism, can be formulated in the alginate chitosan beads so that their controlled release can be obtained for the prolonged therapeutic effect. [23] Another antihypertensive calcium channel blocker, Nicardipine, can be a candidate for the controlled release beads as it has a very short half life of 1 hour. [19]
4. The sustained release dosage form which delivers Melatonin in a circardian fashion over 8 hours is of clinical value , because of its short life, for those who have disordered circardian rhythm and that could be obtained through the use of polymer reinforced and coated alginate beads. [18]
5. Metronidazole, an antiulcer drug, can be designed in bead form in such a way that it will be retained in stomach for sufficient time to exert anti Helicobactor pylori effect. [17, 31] So, the gastro-retention of the drugs, especially antiulcer and antacid, by formulating them in the floating beads form, could open new doors for the treatment of gastric ulcer and acidity.
6. Sustained release of Prednisolone from chitosan gel beads allows minimum effective dose to be delivered locally(subcutaneous) and prolongs the duration of drug activity, thus improves the therapeutic efficacy and decreases side effects by minimizing the transportation of the drug to the systemic circulation against inflammation. [11]
7. Theophylline, a poorly water soluble bronchodilator and the targeted drug for sustained delivery, showed the retarded drug release under physiologically simulated pH conditions ( acidic and neutral). [13] So, it could be formulated into modified dosage form.
8. Ketoconazole, an antifungal drug, can be formulated into the polymeric beads to reduce the adverse effects like hepatic dysfunction and GI disturbances as observed with conventional oral dosage forms. [27]
9. Cefadroxil, an antibiotic used in the treatment of bacterial infections, has a biological half-life of 1.2-2.0 hours. Its short half-life can be enhanced by the use of the sodium alginate interpenetrating network beads. [28]
10. Insulin, an antidiabetic drug, and albumin are degraded in the acidic medium when given orally. Formulating them in the modified alginate beads can deliver them in the intestinal region without significant degradation in the stomach. [29]
11. Brilliant blue (poorly water soluble dye) showed the extended release and dextran (water soluble polysaccharide) showed a faster release indicating that the water insoluble drugs can be used for the controlled delivery. [15]
12. Nicotinic acid and ascorbic acid (a water soluble vitamin), drugs for hyperlipidemia, can be delivered in alginate beads containing chitosan in controlled release manner. The beads can also be useful in absorbing the bile acids which are responsible for the breakdown and the absorption of the fatty substances. So, they can be very valuable in treatment of hyperlipidemic patients. [8, 9]
13. 5-fluorouracil, an anticancer drug, shows unpredictable and incomplete drug absorption orally. So their local use in the treatment of breast cancer can be justified in polymeric bead forms. [30]
Conclusion
The drug loaded beads of alginate, chitosan and alginate coated or mixed with chitosan can be of immense importance in the drug delivery through the oral route as well as the other routes as sustained and controlled release dosage forms. The desired effects in the drug release and the therapeutic value can be obtained by modifying various materials and/or their concentration. As these beads are nontoxic, biodegradable, biocompatible, they have to be studied properly in detail so that they can be used in practical for the delivery of the drugs in controlled and sustained release manners.
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