Formulation and Evaluation of a Novel Multiparticulate Drug Delivery System for Poorely Water Soluble Drug-Ziprasidone Hydrochloride Monohydrate

Research in pharmaceutical Formulation development revolves around increasing therapeutic efficacy, patient safety, patient compliance and reducing dosing frequency, side effects, toxicity etc. Formulating a novel delivery system, an existing drug molecule can get a new life. Formulation scientists develop new drug delivery systems; new dosage forms by studying physicochemical properties, therapeutic properties, pharmacokinetic parameters, pharmacodynamics properties of drug, limitations and side effects of existing drug delivery systems and dosage forms of the drug under consideration. Drugs with poor water solubility are real challenge for formulation scientists to enhance their solubility which ultimately helps in improvement of all solubility dependent pharmacokinetic parameters of drug, hence it’s in vivo performance and therapeutic efficacy.

Reduction in particle size of drug results in improvement in aqueous solubility of a drug. Many methods are explored by formulators for alteration of physicochemical properties of drugs, improvement of solubility profile, drug release pattern and bioavailability of drugs. Recent trends indicate that multiparticulate drug delivery systems are especially suitable for achieving controlled or delayed release oral formulations with low risk of dose dumping, flexibility of blending to attain different release patterns as well as reproducible and short gastric residence time. Multi-particulate drug delivery systems are mainly oral dosage forms consisting of a multiplicity of small discrete units, each exhibiting some desired characteristics.

In these systems, the dosage of the drug substances is divided on a plurality of subunit, typically consisting of thousands of spherical particles. Thus multiparticulate dosage forms are pharmaceutical formulations in which the active substance is present as a number of small independent subunits. To deliver the recommended total dose, these subunits are filled into a sachet and encapsulated or compressed into a tablet.

Evolution of an existing drug molecule from a conventional form to a novel delivery system can significantly improve its performance in terms of patient compliance, safety and efficacy. An appropriately designed Novel Drug Delivery System can be a major advance for solving the problems related to the release of the drug at specific site with specific rate.

Lack of safe polymers and solvents with regulatory approval and their high cost have limited the applications of polymeric nanoparticles. To avoid the disadvantages of polymeric nanoparticles, lipids have been put forward as an alternative carrier, particularly for lipophilic pharmaceuticals. These lipid nanoparticles are known as Solid Lipid Nanoparticles (SLNs) and Nanostructured Lipid Carriers (NLCs) which are attracting wide attention of formulators worldwide. NLCs offer many advantages, refer figure 1.Nanostructured lipid carriers (NLCs) are drug-delivery systems composed of both solid and liquid lipids as a core matrix. To obtain the blends for the particle matrix, solid lipids are mixed with liquid lipids, preferably in a ratio of 70/30 up to a ratio of 99.9/0.1.

Chemical name:

5-[2-[4-(1, 2-benzothiazol-3-yl) piperazin-1-yl] ethyl]-6 chloro-1, 3-dihydroindol-2-one hydrochloride ZHM is an atypical antipsychotic with very poor water solubility. ZHM’s antipsychotic activity is likely due to a combination of its antagonistic function at D2 receptors in the mesolimbic pathways and at 5HT2A receptors in the frontal cortex.

ZHM is a BCS Class II drug which is poorly water soluble and also undergoes extensive first pass metabolism, so a novel formulation is required to overcome it. It has short biological half-life of 4-7 hours.

The bioavailability of ZHM is 60%. It is extensively metabolised. Its absorption increases 2 folds when administered orally with food. Since, most of the patients with schizophrenia often eat a poorer diet and do not necessarily take their medicines as instructed. In order to achieve sustained or controlled release of ZHM with enhanced bioavailability and no food effect, conventional matrix or coating-based delivery systems may be proposed, but poor water solubility of drug limits their use, hence the current formulation development work is undertaken to develop Nanostructured Lipid Carrier (NLC) of ZHM with an aim to enhance its solubility, dissolution profile which will ultimately improve oral bioavailability and overcome the food effect of ZHM.