Pharma Voice

Pharma's best kept secret

Tagalpallewar A, Prabhakar B and Gaud R S discuss the importance of ion exchange resins for controlled release drug delivery systems.

In the recent years, focus on the development of controlled release drug delivery systems has increased. The basic rationale of controlled release drug delivery system optimises the biopharmaceutical, pharmacokinetic, and pharmacodynamic properties of a drug in such a way that its utility is maximised, side-effects are reduced and cure or control of the condition is achieved, in the shortest possible time by using smallest quantity of drug administered by the most suitable route. There are several advantages of sustained release drug delivery over conventional dosage forms like improved patient compliance due to less frequent drug administration, reduction of fluctuation in steady-state drug levels, maximum utilisation of the drug, increased safety margin of potent drug, reduction in healthcare costs through improved therapy, shorter treatment period and less frequency of dosing.

Ion exchange resins have received considerable attention from pharmaceutical scientists because of their versatile properties as drug delivery vehicles. During the past few years, ion exchange resins have been extensively studied in the development of novel drug delivery systems and other biomedical applications. Some drug delivery systems containing ion exchange resins have been introduced into the market.

Ion exchange resins are insoluble ionic materials possessing acidic or basic group covalently bound and placed in repeating positions on the resin chains. This charged group is associated with other ions of opposite charge. Depending on whether the mobile counter ion is a cation or an anion, it is possible to distinguish between cationic and anionic ion exchange resins. The matrix carrier ionic groups such as -SO3, -COO, PO3a are present in cationic exchanger and -NH2 +, NH3+ N- groups are seen in anionic exchanger.

Chemically, ion exchange resins are made up of two components, a structural component consisting of polymer matrix, and a functional component to which the counter ion is bound. The structural component of ion exchange resin consists of a stable acrylic polymer of styrene-divinylbenzene (DVB) co-polymer, whereas the functional components can be acidic (commonly sulfonic or carboxylic) or basic (amine). Ion exchange resins can be classified based on the nature of the structural and functional components and ion exchange process.

Sustained release preparation

Improved drug safety could often be achieved by controlling the rate of drug delivery from dosage form. The advantages of sustained release dosage forms are well known. Sustained release dosage forms are prepared by coating the tablets so that the rate of solubility is controlled or individually encapsulating micro particles of varying sizes so that the rate of dissolution can be controlled. With the development of modern synthetic ion exchange resins, pharmaceutical industry adapted the ion exchange technology to achieve sustained release of drug. Keating listed the following advantages of adsorbing basic nitrogen containing drug onto strong acid cation exchange resins and using them in dosage forms:

• Prolonged release of drug from the complex for 8-12 hours in the gastrointestinal tract
• Reduced toxicity by slowing drug absorption
• Improved palatability
• Availability of formulation in liquid and solid sustained release dosage forms
• Increased stability by protecting the drug from hydrolysis or other degradative changes in the gastrointestinal tract

Sustained release tablets

The rate of release of drug adsorbed onto various ion exchange resins can be controlled by varying particle size, matrix structure and chemistry of the resins. The release of drug from ion exchange resins depends upon a series of ionic reactions between various body fluids and the drug resin complex. The first two factors control the diffusion of active ingredient through the resin particles and third factor controls the equilibrium of drug resin complex and the electrolyte in body fluids. Schliching has done a complete and detailed study of an anti-histaminic drug carbinoxamine using weak acid and strong acid cation exchange resins to develop a sustained release tablet of carbinoxamine.

Wolf compared the duration of antitussive effect of Noscapine Hydrochloride in a commercial resinate of Noscapine and sulfonated cross-linked polystyrene resins. Another study showed that microencapsulated tramadol-resin complex gave slow release. Resinates of propanolol, chlorpheniramine maleate and phenyl propanolamine have been described to show sustained release. Manek and Kamat evaluated Indion CRP-244 and CRP-254 resins as sustained release and taste masking agents.

Drug stabilisation: In general, the principle of ion exchange resins can be applied for improving the stability. A component of the API is fixed onto the ion exchange resin. This prevents harmful interaction with other components. Vitamin B12 is an example of a pharmaceutical that can deteriorate on storage. Stability of vitamin B12 can be improved by complexing it onto a weak acid exchanging resin. This complex is as effective as free form of vitamin.

Taste masking: Taste masking in chewable tablets containing drugs with amino groups like dextromethorphine, ephedrine, pseudoephedrine was successfully carried out using weak acid cation exchange resins. Taste masking of sparfloxacin is carried out by Bhalekar. Saliva with average pH of 7.4 and cation concentration of about 40 meq/lit would only elute a limited percentage of drugs from polycarboxylic acid resins. However, quantitative elution would occur as soon as it is exposed to the low pH of stomach.

Tablet disintegration: The effectiveness of drug supplied as compressed tablet depends upon the ease or rate at which the tablet disintegrates in the gastrointestinal tract. It is essential that tablets posses sufficient mechanical strength to withstand the rigors of packaging, shipment and storage and at the same time disintegrate in the digestive juice and make the active constituent available for absorption during passage through gastrointestinal tract. Varieties of starches, cellulose derivative aliginic acid its salt and colloidal silicon dioxide are widely employed as tablet disintegrants in pharmaceutical formulations, due to their considerable swelling pressure as they get hydrated.

Cholesterol reducers: Cholesteramine resins when used as an active ingredient binds bile acid. This leads to the replenishment of bile acids through increased metabolism of serum cholesterol resulting in lowered serum cholesterol levels.

In commercial formulation

The commercial use of ion exchange resins in pharmaceutical formulation falls into two categories — active ingredient and excipient. The active ingredients include sodium polystyrene sulphonate USP, an active ingredient for the treatment of hypercalemia. It works by removing potassium ion by exchange (boehringer ingelheim and other companies). Cholesteramine USP, is an active ingredient for the treatment of hypercalemia. It works by sequestering bile acids, preventing their absorption into blood stream. Amongst multifunctional excipients, nicotine gums and lozenges for smoking cessation. Nicotine works by extending the release of nicotine. And for vitamin B12 stabilisation, vitamin B12 is loaded onto a resin which has greatly improved shelf life compared to pure B12. Others include Paxil, taste-masked paroxetine oral suspension (GSK); Voltaren, XR extended release diclofenac (Novartis); and Delsym-extended release dextromethophan (Celtech).

Drugs suitable for resinate preparation

Drugs to be used in prolonged action dosage forms and particularly in resinate formulation must meet certain conditions. They should have an acidic or basic group in their structure. Also, the biological half-life of the drug should be between 2-6 hours. Drugs with t1/2 < 1hr, or >8 hrs are difficult to formulate into this category. Drugs prepared using this technology should be absorbed from all regions of the gastrointestinal tract. In case of drugs with limited absorption zone, the bioavailability will be insufficient. Moreover, drugs should be sufficiently stable in the gastric juice, otherwise their therapeutic effect reduces drastically.

Certain factors such as competing ion, ionic strength and pH influence the rate of drug release from resinate. Proper choice of resin characteristics such as acid or base strength, porosity, degree of cross-linking, particle size can help to accomplish the intended purpose.

(The authors are from the School of Pharmacy and Technology Management Narsee Monjee Institute of Management & Higher Studies University in Mumbai)