RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, KARNATAKA
4th ‘T’ Block, Jayanagar, Bangalore - 560 041
ANNEXURE – II
PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION
1. / Name of the Candidateand Address: / MALANI FIROZ KARIMBHAI
21, Kwaja House, Opp. Shirali Society,
Behind 7Seas Mall, Fatehgunj,
Vadodara-390002.
2. / Name of the Institution: /
Al-Ameen College of Pharmacy,
Hosur Road, Bangalore – 560 027.
3.
4. / Course of Study and Subject:
Date of Admission: / M. Pharm – Pharmaceutics
5. / Title of project
“FORMULATION AND EVALUATION OF SELF- EMULSIFYING DRUG DELIVERY SYSTEM OF NIMODIPINE ”
6-Brief resume of the intended work:
6.1 – Need for the study
Cardiovascular diseases have emerged as an important health problem. Nearly 1 billon people worldwide have high blood pressure and this number is expected to increase to 1.56 billon people by the year 2025. The World Health Organisation attributes hypertension, as leading cause of cardiovascular mortality. High blood pressure (BP) is a major risk factor and if controlled, can lead to prevention of 300,000 of the 1.5 million annual deaths from cardiovascular diseases in India.1 The main characteristic of essential hypertension is increased peripheral resistance. High blood pressure comes from blood pushing too hard against blood vessels.2
Calcium antagonists of dihydropyridine class are suitable for the treatment of hypertension because of their potential peripheral arteriolar vasodilatation property, relaxes blood vessels, which lets blood flow more easily and helps to lower blood pressure. Drugs that lower blood pressure have lower risk of astrokeorheart attack. Among the calcium channel antagonists, nimodipine is used commonly for the treatment of essential hypertension.3
Nimodipine, a BCS class II drug, is selected as the model drug for the proposed work. It is an antihypertensive, calcium channel blocker, vasodilator having low solubility and high membrane permeability. It is chemically described as 3-(2-methoxyethyl) 5-propan-2-yl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate, used in treatment of various cardiovascular disorders such as angina pectoris, cardiac arrhythmia and hypertension. Nimodipine is rapidly absorbed from the GIT following oral administration and undergoes extensive first-pass metabolism in the liver. The oral bio-availability is reported to be about 13%. The terminal elimination half-life is about 9 hrs.4
The poor oral bioavailability of nimodipine presents a major challenge because of the poor aqueous solubility. Various approaches have been developed with a focus on enhancement of the solubility, dissolution rate, and oral bioavailability of poorly water-soluble drugs. Extensive research is going on to alleviate the solubility for poorly water-soluble drugs. This is supported by various strategies like crystal modification, micronization, amorphization, self-emulsification, cyclodextrin complexation, and pH modification.
Self-emulsifying drug delivery systems (SEDDS) are mixtures of oils and surfactants, ideally isotropic, sometimes including co-solvents, which emulsify under conditions of gentle agitation, similar to those which would be encountered in the gastro-intestinal tract. SEDDS are further classified into self-microemulsification drug delivery systems (SMEDDS) and self-nanoemulsification drug delivery systems (SNEDDS) according to the size range of their oil droplets. SMEDDS form microemulsions ranging in droplet size from 100 to 250 nm. Finer microemulsions of less than 100 nm can be obtained using SNEDDS.5 Hydrophobic drugs can often be dissolved in SEDDS which allows them to be encapsulated as unit dosage forms for oral administration. When such a formulation is released into the lumen of the gut, it disperses to form a fine emulsion, so that the drug remains in solution in the gut, which avoids the dissolution step and frequently limits the rate of absorption of hydrophobic drugs from the crystalline state. Generally this can lead to improved bioavailability, and/or a more consistent temporal absorption profile from the gut.6
Hence in the present work attempt will be made to develop and evaluate self-emulsifying drug delivery systems (SEDDS) of nimodipine to improve the solubility, which results in satisfactory treatment of cardiovascular diseases like hypertension.
6.2 REVIEW OF LITERATURE
· Atef E et al., (2008) developed and characterized a self-emulsifying drug delivery system (SEDDS) of phenytoin to compare its relative bioavailability to a commercially available suspension. Four phenytoin SEDDS were prepared and evaluated. After emulsification, the optimized formula was selected to have the smallest mean particle size and the highest absolute zeta potential, which should yield the formation of a stable emulsion. Its dissolution characteristics were superior to the other SEDDS formulas. In vivo and in vitro tests were done to compare the optimized formula, SEDDS II, to a commercially available Dilantin® suspension. The in vitro dissolution indicated a significant improvement in phenytoin release characteristics. The in vivo study using male rats showed an enhancement in phenytoin oral absorption from SEDDS compared to Dilantin® suspension. The area under the curve (AUC10 min→10 h) of phenytoin after SEDDS administration was increased by 2.3 times compared to Dilantin® (p < 0.05), and the rate of absorption of phenytoin was significantly faster from the SEDDS. The concentration after 30 min (C30 min) of SEDDS administration was found to be 4.9 times higher than C30 min after Dilantin® administration (p < 0.05). A sustained effect of phenytoin in plasma was also observed. After 12 weeks storage, SEDDS II was found to be physically and chemically stable under stressed conditions.7
· Balakrishnan P et al., (2009) prepared and evaluated a solid form of lipid-based self-emulsifying drug delivery system (SEDDS) by spray drying liquid SEDDS with an inert solid carrier Aerosil 200 was the carrier used to improve the oral bioavailability of poorly water-soluble drug dexibuprofen. The liquid SEDDS consisted of dexibuprofen, Labrasol, Capryol 90 and Labrafil M 1944 CS. The particle size analysis revealed no difference in the z-average particle diameter of the reconstituted emulsion between liquid and solid SEDDS. The solid SEDDS was characterized by SEM, DSC and XRD studies. In vivo results of solid SEDDS and dexibuprofen powder in rats at the dose of 10 mg/kg showed that the initial plasma concentrations of drug in solid SEDDS were significantly higher than those of dexibuprofen powder (P < 0.05). The solid SEDDS showed significantly higher AUC and Cmax than did dexibuprofen powder (P < 0.05). In particular, the AUC of solid SEDDS was about twofold higher than that of dexibuprofen powder. The results
suggested that the solid SEDDS could be used as an effective oral solid dosage form to improve the bioavailability of poorly water-soluble drug dexibuprofen.8
· Odeberg JM et al., (2003) used a rational formulation approach, to find the general characteristics for promising self-emulsifying drug delivery systems (SEDDS) based on natural lipid components, for the oral delivery of lipophilic drugs. Galactolipids, which are polar lipids commonly found in the chloroplast of green plants, and a natural part of the human diet, were the main surfactants in these formulations. The clinical studies were carried out in three stages viz., screening study followed by a prediction study and finally a confirmatory study. 17 experimental formulations were investigated. The clinical trials were performed in healthy volunteers. Cyclosporine, a well-known lipophilic peptide, was incorporated in different SEDDS and administered orally, followed by the measurement of the blood concentration of the drug over time. The pharmacokinetic parameters were estimated. It was found that fractionated oat oil (FOO) and medium chain monoglycerides (60:30:10 mono-, di- and tri-glycerides) promoted absorption, and resulted in a formulation with absorption characteristics nearly equal to the commercial formulation of cyclosporine, Sandimmun Neoral®.9
· Wei Y et al., (2012) formulated and evaluated a high payload supersaturatable self-emulsifying drug delivery system (S-SEDDS) to improve the oral bioavailability of silybin, a poorly water-soluble drug candidate, employing hydroxypropyl methylcellulose (HPMC) as a precipitation inhibitor. The S-SEDDS formulation consisted of silybin, Labrafac CC, Cremophor RH40, Labrasol, and 5% HPMC. The pseudo-ternary phase diagrams were constructed to identify the self-emulsifying regions. The droplet size characterization study showed that the mean droplet size of the optimized S-SEDDS formulation was smaller than the conventional SEDDS formulation upon dilution with 0.1 M HCl, largely because of the presence of the HPMC. In vitro dilution of the S-SEDDS formulation resulted in formation of a microemulsion, which is followed by a slow precipitation of silybin, while the conventional SEDDS formulation underwent rapid precipitation, yielding a low silybin solution concentration. The results showed that the presence of HPMC effectively sustained the supersaturated state by retarding the precipitation kinetics. The in vivo study indicated that the area under the concentration–time curve (AUC0→12h) of the silybin-S-SEDDS increased by nearly 3-fold than that of
the conventional SEDDS without the presence of HPMC at a drug dose of 533 mg/kg. This case shows that supersaturatable formulations are an effective delivery approach to improve the oral bioavailability of poorly soluble drugs.10
· Basalious EB et al., (2010) developed and optimized SNEDDS formulations containing surfactants for improvement of dissolution and oral absorption of lacidipine (LCDP). Preliminary screening was carried out to select proper components combination. D-optimal mixture experimental design was applied to optimize a SNEDDS that contains a minimum amount of surfactant, a maximum amount of lipid, and have enhanced emulsification and dissolution rates. Three formulation variables; the oil phase X1 (a mixture of Labrafil®/Capmul®), the surfactant X2 (a mixture of Cremophor®/Tween® 80) and the co-surfactant X3, were included in the design. The systems were assessed for droplet size, light absorbance, optical clarity, drug release and emulsification efficiency. Following optimization, the values of formulation components (X1, X2, and X3) were 34.20%, 40.41% and 25.39%, respectively. There was a good correlation between light absorbance and droplet size analysis of diluted SNEDDS (R2 = 0.883). Transmission electron microscopy demonstrated spherical droplet morphology. The stability of the optimized formulation was retained after storage at 40 ◦C/75% RH for three months. The optimized formulation of LCDP demonstrated a significant increase in dissolution rate compared to the drug suspension under the same conditions. The results proposed that the optimized SNEDDS formulation, containing bioenhancing surfactants, could be promising to improve oral absorption of LCDP.11
· Elnaggar YSR et al., (2009) designed and optimized tamoxifen citrate self-nanoemulsifying drug delivery systems (SNEDDS), which is used as an antiestrogen for peroral breast cancer treatment. Preliminary screening was carried out to select proper ingredient combinations. All surfactants screened were recognized for their bioactive aspects. Ternary phase diagrams were constructed and an optimum system was designated. Three tamoxifen SNEDDS were then compared for optimization. The systems were assessed for robustness to dilution, globule size, cloud point, surface morphology and drug release. An optimum system composed of tamoxifen citrate (1.6%), Maisine 35-1 (16.4%), Caproyl 90 (32.8%), Cremophor RH40 (32.8%) and propylene glycol (16.4%)
was selected. The system was robust to different dilution volumes and types. It possessed a mean globule size of 150 nm and a cloud point of 80 ◦C. Transmission electron microscopy showed spherical particle morphology. The drug release from the selected formulation was significantly higher than other SNEDDS and drug suspension, as well. Realizing drug incorporation into an optimized nano-sized SNEDD system that encompasses a bioactive surfactant, results proposed that the prepared system could be promising to improve oral efficacy of the tamoxifen citrate.12
· Thomas N et al., (2012) prepared Novel supersaturated self-nanoemulsifying drug delivery systems (super-SNEDDS) containing the poorly water-soluble drug halofantrine above equilibrium solubility (150% Seq) to compare in vitro and in vivo with conventional SNEDDS containing the drug below equilibrium solubility (75% Seq). Pre-concentrates which comprises of either medium chain lipids (Captex 300/Capmul MCM) or long chain lipids (soybean oil/ Maisine), Cremophor RH40 and ethanol were formulated maintaining the lipid-to-surfactant-to-cosolvent ratio constant (55:35:10, w/w %). The ability of super-SNEDDS to increase the absorption of halofantrine in dogs, as well as the predictivity of the dynamic in vitro lipolysis model was studied. In vitro lipolysis of SNEDDS and super-SNEDDS showed rapid drug precipitation from all formulations while the same drug concentrations in the digestion medium were found during digestion of equal amounts of SNEDDS and super-SNEDDS. Elevated halofantrine solubilisation during in vitro lipolysis was observed only when multiple capsules of conventional SNEDDS were subjected to in vitro digestion. After lipolysis the isolated super-SNEDDS pellets were characterised by XRPD revealing no crystalline halofantrine from any of the investigated formulations. Subsequent dissolution studies of the super-SNEDDS pellet in the lipolysis medium showed enhanced dissolution of halofantrine suggesting that halofantrine in the pellet was amorphous. The enhanced dissolution of the amorphous halofantrine was also seen in vivo since two capsules of conventional SNEDDS were needed to achieve similar AUC and Cmax as obtained after dosing of a single capsule of super-SNEDDS. The study demonstrated that the absorption of halofantrine was not hampered by drug precipitation. Super-SNEDDS lead to precipitation of halofantrine in an amorphous form, which can be the driving force for enhanced absorption. Since super-SNEDDS were also physically stable for at least 6 months they represent a potential novel oral lipid-based drug delivery system for low aqueous soluble compounds.13
· Wang L et al., (2009) designed and optimized self-nanoemulsifying drug delivery systems (SNEDDS) to improve the dissolution rate of ibuprofen, a model poorly water soluble drug. Various surfactants and oils were screened as candidates for SNEDDS on the basis of droplet size of the resulting emulsions. The influence of the constituent structure, concentration and the composition of SNEDDS formulations, and the emulsifier HLB value, on the properties of the resulting emulsions was investigated. Several SNEDDS formulations were employed to study the relationship between the emulsion droplet size and the dissolution rate of ibuprofen. The dissolution rate was increased by decreasing the nanoemulsion droplet size, and was significantly faster than that from a conventional tablet. The optimal SNEDDS formulation had a mean nanoemulsion droplet diameters of 58 nm in phosphate buffer, pH 6.8 (simulated intestinal fluid), and released ibuprofen more than 95% within 30 min. Therefore, these novel SNEDDS carriers appear to be useful for controlling the release rate of poorly water soluble drugs.14
· Zadeh BSM et al., (2010) formulated SEDDS containing a lipophilic drug, loratadine, and explored the potential of carriers for such system. To perfect the formulation, full factorial design with three variables; surfactant/oil, surfactant/co-surfactant proportion and percentage of drug in two levels were used. The effects of variables on formulation characters; emulsifying efficiency, particle size, drug release and rat intestine permeability were evaluated. The results demonstrated liquid paraffin and labrafil as oil with span 20 as surfactant and capriol as co-surfactant prepared stable emulsions with refractive index higher than acidic medium and water. The particle sizes of formulations were influenced by type of oil, in the manner that liquid paraffin induced lower particle size in the range of 0.28- 1.8 micron. The percentage of release of drug after 6 hrs for labrafil and liquid paraffin were 30.87-54.26% and 31.99-61.34 respectively. Formulations prepared with liquid paraffin and labrafil showed drug permeability through rat intestine 2.72 and 2.25 folds compared to control. Comparison between drug release and in vitro permeability indicated that drug release from formulation after mixing with acidic condition is rate limiting for gastric absorption. Thus, SEDDS prepared with liquid paraffin provided perfect solubility in acidic condition and increased intestinal permeability.15