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Development of Capsules Filled with Phenytoin and Berberine Loaded Nanoparticles- a New Approach to Improve Anticonvulsant Efficacy

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Development of Capsules Filled with Phenytoin and Berberine Loaded Nanoparticles- a New Approach to Improve Anticonvulsant Efficacy Original Article Development of Capsules Filled with Phenytoin and Berberine Loaded Nanoparticles- A New Approach to Improve Anticonvulsant Efficacy Chitra Karthikeyini Senthilvel, Kavitha Karuppaiyan*, Muthu Mohammed Jamal Moideen Department of Pharmaceutical Technology, BIT campus, Anna University, Tiruchirappalli, Tamil Nadu, INDIA. ABSTRACT Introduction: Currently used anticonvulsant drugs are not totally effective to control seizures. Phenytoin is a classic instance where its efficiency is inhibited through high metabolization (90%-95%) and back transport through cytochrome P450 and P-glycoprotein, respectively. To explore and attain improved anticonvulsant efficacy combination therapy with nanotechnology has been adopted in this research. Objective: development of nanotechnology-based drug delivery system by filling berberine and phenytoin nanoparticles in capsules. Method: phenytoin and berberine nanoparticles were formulated individually by utilising a solvent evaporation technique and later the mixture is filled in the hard gelatine capsule to create a single-unit dosage. Results: The formulated nanoparticles were evaluated in terms of FTIR and DSC studies, mean particle diameter and zeta-potential, entrapment efficiency and in vitro release. FTIR and DSC studies had proved that formulation components are compatible. SEM report revealed that all the nanoparticles were smooth, spherical in shape and within the size range of 100-500nm. Zeta-potential of phenytoin and berberine nanoparticles was negative (-2.61 and -35.9mV, respectively). In vitro release kinetics was in the accordance with the Higuchi model. The improved efficacy was proved by MES and Histopathological studies. Conclusion: The successfully developed Capsules filled with the Nanoparticles (Combination therapy) exhibited improved efficacy than that of single phenytoin therapy. Key words: Status epilepticus (SE), Phenytoin, Berberine, Nanoparticles, Cytochrome P-450, P-Gp efflux transporters. INTRODUCTION Submission Date: 07-10-2018; Status epilepticus is a serious neurological WHOs report stated that, around 50 million Revision Date: 28-12-2018; disorder that results from abnormal/exces- people are affected.4 Since termination of Accepted Date: 21-03-2019 sive or synchronous neuronal activity of seizure activities and control of brain dam- DOI: 10.5530/ijper.53.3.79 Correspondence: the brain. Normally a raised concentration age are quite difficult to attain, prompt and Dr. Kavitha Karuppaiyan, of calcium ion in neuronal tissue triggers a safer efficacious therapy is needed to pre- Department of Pharma- ceutical technology, Anna cascade of biochemical responses that leads vent loss of cerebral auto regulation and University, Thiruchirappalli– to the death of neuronal cell following sta- neuronal damage. 620024, Tamil Nadu, INDIA. Phone: +91 9841954918 1 tus epilepticus and subsequently leads to More than 20-40% epileptic patients are E-mail: kavithaaut@gmail. cellular damage, disruptions and eventu- being restricted to anti-epileptic drugs.5 The com ally to cell death.2 The mortality and mor- significant issue in the most anticonvulsant bidity rate of the status epileptics is higher drugs has been identified as the efficacy. due to the epileptic focal point of cerebral Phenytoin is the most widely used drug in neurons that frequently fires and thus had tonic clonic seizure and status epileptics6,7 raised metabolic demands. It has been This drug is a hydantoin derivative under found that global occurrence of active epi- barbiturates group and its efficacy is less due lepsy has extended to 4-5 per 1003 whereas to the metabolisation of more than 90% of www.ijper.org 468 Indian Journal of Pharmaceutical Education and Research | Vol 53 | Issue 3 | Jul-Sep, 2019 Senthilvel, et al.: Phenytoin and Berberine Loaded Nanoparticles the drug into inactive 5-(p-hydroxyphenyl)-5-phenylhy- Sampling 8 dantoinby cytochrome P450 and back transportation • The components Phenytoin and Hydroxyl Propyl by P-glycoprotein (P-gp) efflux transporter.9 Methyl Cellulose E15were obtained from Medo- The aim of this research is to explore and attain pharm, Chennai (India), at free of cost. improved anticonvulsant efficiency of combination • Sodium Caprate and berberine chloride were pur- therapy through the development of nanotechnology- chased from Sigma Chemical Co., USA. based drug delivery system incorporating berberine and • PEG 6000 was procured as a sample-gift from phenytoin. Berberineis anisoquinoline alkaloid, natu- Matrix, India. ral COX-2 inhibitor,10 P-Gp inhibitor,11 cytochrome P450 inhibitor and potent inhibitor of CYP1A and • Methanol and Ethanol were purchased from Merck CYP3A12,13 and therefore it has the potentialto maximize (India). the free drug concentration by reducing the metaboliza- • Other reagents (Analytical grade) were purchased tion and back transportation of phenytoin. It also exerts from SD Fine chem. (Bangalore). other activities such as anti-inflammatory, anti-diabetic, The obtained samples were subjected to several studies, lipid per-oxidation, neuro-protective activity and most such as: SEM study, DSC Study and histopathological importantly anticonvulsant activity.14,15 Subsequently the study, towards attaining the research objectives. next strategy was ‘adaptation of nanotechnology which Pre-Formulation Study positively impacts the efficacy improvement since nano- technology is a powerful platform and most promising The pre-formulation study in this research makes use strategy to CNS drug delivery, by which the drugs are of groups of studies like solubility study in which the efficiently delivered to the brain, by crossing the blood enhancers’ solubility would be studied at equilibrium; brain barrier.16 similarly, the permeability test was conducted to check By utilising both the strategies, the phenytoin and ber- the permeability enhancer’s concentration optimization; berine nanoparticles were formulated (Individually) etc. through solvent evaporation and sonication methods Solubility Study and they were loaded in the 1” sized hard gelatine cap- Three solubility enhancers were taken as variables for sules designed as a single unit dosage and later on the the test that has been adapted from the study of Higu- nanoparticles were optimized by in vitro release and chi and Connors.21 With an excess of drug (200mg), entrapment efficiency. Since, phenytoin has low solu- Phenytoin was added to 10mL of distilled water that has bility, high permeability and of a class II category as different concentration of solubility enhancers: PEG per BCS classification17 the PEG 600018 (solubility 6000, Tween 80 and SLS (0.5%, 1.0%, 1.5% and 2.0%). enhancer) and HPMC E1519 carrier were used to for- The shake-flask method was utilised for separation of mulate phenytoin nanoparticles. Similarly, berberine has phases, for 24 h. When equilibrium was achieved, super- low solubility, low permeability and of class IV category natant liquid was removed and filtered through 0.22µm and hence to enhance the permeability and solubility, filter paper, which was later analyzed spectrophotomet- sodium caprate20 and PEG 6000 were used respectively. Likewise, HPMC E15 was used as an effective controll- rically at 205nm, by Shimadzu UV -1800 visible spectro- release carrier which has excellent biocompatibility and photometer. The same solubility test was repeated thrice biodegradability to provide hydrophilic environment in and the same techniques were carried out for berberine drugs with intermolecular hydrogen bonding and semi except it was spectrophotometrically analysed at 345nm. inter penetrating network in the formulation. Permeability Study Egg membrane preparation MATERIALS AND METHODS The permeability study was carried out to optimize the Methodology concentration of permeability enhancer in the formula- Research Design tion. Egg membrane was prepared by soaking the egg in 0.1N HCl overnight after which the egg membrane was Since the current research is based on analysing and 21 exploring the effects of drugs in laboratory experimen- peeled off and utilized for permeability test. tal research design has been adapted by the researcher. This experiment was carried out in Franz diffusion cells at 37°C. The egg membrane subsequently increased Research Approach among donor as well as receptor cells after it has been The research approach adapted by the researcher would equilibrated with phosphate buffer 6.8. Donor cell ber- be quantitative approach. berine and sodium caprate in different ratios (1:0, 1:0.2, Indian Journal of Pharmaceutical Education and Research | Vol 53 | Issue 3 | Jul-Sep, 2019 469 Senthilvel, et al.: Phenytoin and Berberine Loaded Nanoparticles 1:0.4, 1:0.8 and 1:1) were taken separately with 6.8 phos- Table 1: Preparation of Phenytoin Nanoparticles. phate buffer 2 mL and the receptor sections were filled by phosphate buffer and mixed with a layered magnetic FORMULATION CODE DRUG: HPMC PEG6000 bar. Samples were extracted from receptor sections at E15 pre-determined time intervals and then replaced by PNANO1 1:0.25 1.25 the same quantity of phosphate buffer. The amount PNANO2 1:0.5 1.25 of permeated drug calculated according to the drug PNANO3 1:0.75 1.25 concentration in receptor medium determined spectro- PNANO4 1:1.0 1.25 photometrically at 345nm (Shimadzu UV-1800 visible PNANO5 1:1.25 1.25 Spectrophotometer). PNANO6 1:1.5 1.25 Preparation of Nanoparticles Preparation of Phenytoin-Loaded Nanoparticles Table 2: Preparation of Berberine Nanoparticles. Phenytoin
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