CHAPTER 3. CHAPTER 3: Need, Aim, Objectives and Plan of Work

Transcription

1 39 CHAPTER 3 CHAPTER 3: Need, Aim, Objectives and Plan of Work S. No. Name of the Sub-Title Page. No. 3.1 Need of Study Aim Objectives Plan of Work 42-44

2 40 3. NEED, AIM, OBJECTIVES AND PLAN OF WORK 3.1. NEED OF THE STUDY Multiple Sclerosis (MS) is a progressive autoimmune disorder, characterized by inflammation, gliosis and demyelination of CNS. The international MS federation undertook a Delphi study. According to this study in the year 2013 accounted for 2 million cases were reported and the prevalence may rise to 5 million and 10 million by 2020 and 2040, respectively, worldwide. The treatment of MS with disease modifying drug formulations costs around $52,000/- per month hence there is a need to develop economic alternative formulations. Current research of nasal drug delivery system advised intranasal administration is a safe and suitable route for targeting the drugs to brain. Exclusively, centrally acting drugs and also which have the low permeability through BBB. Intranasal (Nose to brain) administration is now considered as the stable alternative to both oral and parenteral routes, it also offers fruitful advantages from the patient point of view includes circumvent of first pass metabolism, requires low therapeutic dose of drug, painless, rapid onset of action, non-invasiveness, rapid systemic absorption, easy to administer, high drug bioavailability, convenient to use and also economic in comparison with oral and parenteral formulations. The nose to brain path way i.e. olfactory epithelium located in the upper part of two nasal cavities is directly linked to CNS and is a favorable way to bypass the hindrances of blood brain barrier by directly allowing the drug molecules into CNS. Nanoparticles are manufactured either from polymer or lipid but due to scarcity of safe polymer from regulatory approval, high cost, rapid drug release, high toxicity has limited the application of polymeric nanoparticles in clinical practice. Apart from polymeric nanoparticles, lipid carriers are suitable for targeting of brain due to their low toxicity, biocompatibility, biodegradability, rapid up take by the brain, controlled release, improve stability in different ph environments, high encapsulation efficiency,

3 41 amenability to loading both hydrophilic and lipophilic drugs. It also enhances permeability of hydrophilic drugs through the biomembranes and long term stability profile. Hence in the current research solid lipid nanoparticles are selected for targeting of drug from nose to brain. Prednisolone acetate is a corticosteroid drug used in the treatment of multiple sclerosis. To overcome the drawbacks with current treatment for MS, it is necessary to develop the nose to brain drug delivery system with nanoparticles using prednisolone acetate AIM The main aim of present research investigation is to design and develop prednisolone acetate solid lipid nanoparticles using hot lipid microemulsion method to enhance the solubility and bioavailability and explore the possibility of brain targeting by nose-to-brain delivery in the treatment of multiple sclerosis OBJECTIVES 1. To develop the hot lipid microemulsions. 2. To formulate solid lipid nanoparticles from hot lipid microemulsions by probe sonication technique. 1. To study the effect of process and formulation variables on solid lipid nanoparticles formation using Box-Behnken design. 2. To evaluate the developed solid lipid nanoparticles for entrapment efficiency, size analysis, zeta potential and drug diffusion. 3. To study the influence of type of lipid, concentration of lipid and S mix on zeta size, entrapment efficiency, drug diffusion of SLNs. 4. To compare SLNs prepared by using different concentrations of lipids, surfactants and optimize the best formulation based on evaluation parameters 5. To estimate the kinetics and drug release mechanism from the optimized SLNs. 6. To accomplish accelerated stability studies for optimized formulation as per International Conference Harmonization (ICH) guidelines.

4 42 7. To target the stable solid lipid nanoparticles (SLNs) through intranasally and administer the tablet orally. 8. To study the brain and plasma pharmacokinetics of optimized formulation in C57BL/6 mice. 9. To compare the pharmacokinetics of tablet (orapred-marketed formulation) and SLNs after administration through oral and intranasal route, respectively. 10. To develop the in vitro-in vivo correlation data and determining valid level of correlation, interpretation of results PLAN OF WORK The objective of the present research task is to develop a nasal dosage form for prednisolone acetate by formulating them as solid lipid nanoparticles to enhance solubility, rate of dissolution followed by targeting from nose to brain to improve bioavailability. In order to achieve the above referral objectives the research work was planned in the following phases. Phase I 1. Literature survey 2. Acquirement of drug, solid lipids and other excipients 3. Physicochemical properties of prednisolone acetate A. Organoleptic properties B. Partition coefficient determination C. Melting point determination D. Loss on drying E. FTIR F. DSC G. UV H. HPLC 4. Pre formulation studies for drug A. Compatibility studies of lipids and surfactant mixtures

5 43 B. Solubility analysis in different lipids and surfactant mixtures C. To screen excipients for compatibility studies by FTIR and DSC D. To construct calibration curve for prednisolone acetate by UV-Vis spectroscopy Phase II Formulation and optimization of hot lipid microemulsions 1. To develop placebo hot lipid microemulsions using solid lipids, surfactants, co surfactants and hot water 2. To construct the pseudo-ternary phase diagram followed by determination of microemulsion zone area. 3. To develop the drug loaded microemulsions. 4. To optimize the formulation and process variables using Box-Behnken design. Surfactant type and concentration Lipid type and concentration Sonication time Phase III To develop the solid lipid nanoparticles with the hot lipid microemulsions by using probe sonicator as per the data obtained from Box-Behnken design. Phase IV Characterization of SLNs A. Particle size, PDI, Zeta potential Zeta sizer B. Morphology of particle surface and size Transmission electron microscopy (TEM) C. Crystallinity

6 44 DSC D. In vitro drug diffusion studies of optimized formulations. E. Release kinetics and mechanism of drug diffusion from the SLNs. Phase V A. To convert liquid form of solid lipid nanoparticles into free flowing powder. B. To evaluate powdered nanoparticles based on measurement of particle size. C. To perform stability studies for optimized formulation. Phase VI In vivo studies 1. To investigate the effect of drug loaded nanoparticles against cuprizone induced demyelination (multiple sclerosis) on experimental animals in comparison to PA SLNs intranasal and PA tablet oral route of administration. 2. Histopathology studies. 3. Quantification of prednisolone acetate in plasma and brain tissue homogenates using HPLC. 4. To develop the in vitro-in vivo correlation data and identifying the valid level of correlation and interpretation of results.