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ABSTRACT Approximately 40% of new drug candidates have poor water solubility and oral delivery of such drugs is frequently associated with implications of low bioavailability,high intra and inter subject variability and lack of dose proportionality.Bioavailability problems of lipophilic drugs can be solved by formation of Self-Micro Emulsifying Drug Delivery System(SMEDDS).SMEDDS appears to be unique and industrially feasible approach to overcome the problem of low oral bioavailability associated with lipophilic drugs.Self-micro emulsifying formulations are mixtures of oils and surfactants,ideally isotropic, and sometimes containing cosolvents,which emulsify spontaneously to produce fine oil-in-water emulsion when introduced into aqueous phase under conditions of gentle agitations.The digestive motility of the stomach and intestine provide the agitation necessary for self emulsification in vivo.This describes SMEDDS as one of the most important approaches to overcome the formulation difficulties of potent lipophilic drugs. 2


SELF MICROEMULSIFYING DRUG DELIVERY SYSTEM INTRODUCTION : These are the isotropic mixtures of oil and surfactants or one or more hydrophilic solvents and co-solvents. SMEDDS can be formulated to give sustained release dosage form by adding polymeric matrix which is non ionizable at physiological pH . After ingestion in contact with GI fluids forms a gelled polymer making it possible to release the micro emulsified agent in a continuous & sustained matter by diffusion. According to the Biopharmaceutical Classification System (BCS) poorly soluble compounds are categorized as Class II and IV drugs, compounds which feature poor solubility and high permeability, and poor solubility and poor permeability, respectively. 3

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If a class II drug can be maintained in a solubilized state in the lumen of the gut one can achieve an absorption profile more like that of a class I drug. 4


DIFFERENCE BETWEEN SMEDDS AND SEEDS SMEDDS SEDDS They produce transparent emulsions with a droplet size of less than 50 nm. The concentration of oil is less than 20%. Ex:Simvastatin,Halofantrine,Atorvastatin,Silymarin. They produce opaque emulsions with a droplet size between 100 -300 nm. The concentration of oil is 40-80%. Eg:Tocotrienol,Progesterone,Indomethacin..etc. 5

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The following should be considered in the formulation of SMEDDS : 

The following should be considered in the formulation of SMEDDS 1 : The solubility of the drug in different oils , surfactants , co solvents. 2 : The selection of oil, surfactant and co solvent based on the solubility of the drug. 3 : Preparation of the phase diagram. 4 : The preparation of SMEDDS formulation by dissolving the drug in a mixture of oil, surfactant & co solvent. 7


FORMULATION OF SMEDDS 1. Drugs with low aq solubility present a major challenge during formulation as their high hydrophobicity prevents them from being dissolved in most approved solvents. 2. The novel synthetic hydrophilic oils & surfactants usually dissolve hydrophobic drugs to a greater extent than conventional vegetable oils. 3. The addition of solvents such as ethanol,PG, & PEG may also contribute to the improvement of drug solubility in the lipid vehicle. 8


COMPOSITION : Oils Surfactants Co solvents/Co surfactants OILS Long chain trigyceride and medium chain triglyceride oils with different degrees of saturation have been used in in the design of SMEDDS. 9 COSOLVENTS 1. Organic solvents such as ethanol,propylene glycol(PG) and polyethylene glycol(PEG) are suitable for oral delivery and they enable the dissolution of large quantities of either the hydrophilic surfactant or the drug in the lipid base. 2.Labrasol was used as cosurfactant as it has the ability to solubilise many drugs. 3.Tween 80 and Cremophor EL were used as surfactants for improving the drug loading capability.


SURFACTANTS Surfactant molecules can be classified based on the nature of hydrophilic group within the moleecule. The four main group of surfactants are defined as follows, 1.Anionic surfactants 2.Cationic surfactants 3.Ampholytic surfactants 4.Nonionic surfactants 10

1 . Anionic surfactants, where the hydrophilic group carries a negative charge such as carboxyl(RCOO-),sulphonate(RSO3-) or sulphate(ROSO3-). E.g: Potassium laurate, sodium lauryl sulphate. 2. Cationic surfactants where the hydrophlic group carries a positive charge. E.g: Quarternary ammonium halide. 3. Ampholytic ( zwitterionic) surfactants contain both positive & negative charge. E.g: Sulfobetaines. 11 4. Nonionic surfactants, where the hydrophilic group carries no charge but derives its water solubility from highly polar groups such as hydroxyl OCH2CH2O). E.g.: Sorbitan polyoxyethylene(esters(spans),polysorbates (Tweens). The usual surfactant strength ranges between 30-60% w/w of the formulation in order to form a stable SMEDDS.

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DRUG PROFILE Candesartan Cilexetil a prodrug, is hydrolyzed to candesartan during absorption from the gastrointestinal tract., practically insoluble in water. Category: Antihypertensive Agents Subcategory: Angiotensin II Receptor Antagonists 14

Drug Profile Of Candesartan Cilexetil : 

Drug Profile Of Candesartan Cilexetil Chemical name: (±)-1-Hydroxyethyl 2-ethoxy-1-[p-(o- 1 H-tetrazol-5-ylphenyl)benzyl]-7-benzimidazolecarboxylate, cyclohexyl carbonate (ester). Formula: C33H34N6O6 Molecular weight: 610.67 g/mol BCS Class: class II Dose: 2- 32 mg Route: Oral Protein binding: >99% Half Life: 9 hours LogP of Candesartan: 5.282 15

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OBJECTIVE OF THE STUDY 1.The low bioavailability of hydrophobic drugs with extremely low water solubility can be a serious problem. 2.Different approaches like micronised powders, molecular inclusion complexes, co-precipitates with water-soluble polymers, micellar solutions in surfactant systems have been taken to achieve a desired level of drug solubility and dissolution rate. 3.To develop a SMEDDS of Candesartan Cilexetil to increase its saturation solubility and dissolution velocity thereby bioavailability. 4.To construct Pseudo-ternary phase diagrams to identify the micro emulsion region and the selected formulations were assessed for their efficiency of self emulsification. 16


SOLUBILITY STUDIES 1. Solubility of Candesartan Cilexetil in individual vehicles,various oils, surfactants and cosurfactants was determined by taking excess of drug and added to 10 gm of each of the selected vehicle in a 20 ml cap vial respectively. 2.After sealing, the mixture was heated at 40 ◦C to facilitate the solubilization using a vortex mixer. 3.Mixtures were shaken with shaker at 25 ◦C for 60 h. After reaching equilibrium, each vial was centrifuged at 3500 rpm for 12 min, and the supernatant solution was used to determine the concentration of Candesartan Cilexetil using HPLC and the results were shown in the following table. 17


CONSTRUCTION OF PSEUDO-TERNARY PHASE DIAGRAMS To obtain an optimum formula of the Candesartan Cilexetil SMEDDS, which can form a microemulsion upon dilution with water, pseudo-ternary phase diagrams of oil, surfactant, cosurfactant and water were constructed using the water titration method at ambient temperature. The Candesartan Cilexetil concentration was fixed to 3.1%. Based on preliminary solubility experiments, Miglyol 812 was used as the oil phase, Tween 80 and Cremophor EL as surfactants and Labrasol was used as the cosurfactant. For each phase diagrams at a specific ratio of surfactant/cosurfactant 1:1, 1:2 and 2:1 were used. 18


CONSTRUCTION OF PSEUDO-TERNARY PHASE DIAGRAMS 10 – 40% of oil was used as SMEDDS could not be formed at an oil content ≥ 50%. After the drug was dissolved in surfactant and cosurfactant mixture by heating to 40 0C to facilitate solubilisation using vortex mixer, oil was added and mixed to form transparent and homogenous mixture. Then, each mixture was titrated with water while gentle agitation in order to reach equilibrium quickly. The phase boundary was determined by observing the sample appearance, phase clarity and flow ability. After the identification of microemulsion region in the phase diagrams, the microemulsion formulations were selected at desired component ratios. All the ratios in this study are reported as weight-to-weight ratios (W/W). Trial version of the software was used to plot the ternary phase diagrams. 19


CONSTRUCTION OF PSEUDO-TERNARY PHASE DIAGRAMS 20 Pseudo-ternary phase diagrams indicating the efficient self-emulsification region of Cremophor EL/Labrasol = 2:1 (w/w) (a), 1:2 (w/w) (b), 1:1 (w/w) (c). (the gray area represents O/W microemulsion existence region).


CONSTRUCTION OF PSEUDO-TERNARY PHASE DIAGRAMS 21 Pseudo-ternary phase diagrams indicating the efficient self-emulsification region of Cremophor EL/Labrasol = 2:1 (w/w) (a), 1:2 (w/w) (b), 1:1 (w/w) (c). (the gray area represents O/W microemulsion existence region).

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22 The effect of oil content and S/CoS (Cremophor EL/ Labrasol) on existence range of O/W microemulsion.

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23 The effect of oil content and S/CoS (Tween 80/ Labrasol) on existence range of O/W microemulsion.


FACTORS AFFECTING SMEDDS 1.CONCENTRATION OF THE DRUG: Drugs which are administered at high dose are not suitable for SMEDDS unless they exhibit extremely good solubility in atleast one of the components of SMEDDS preferably lipophilic base. 2.SOLUBILITY OF THE DRUG: SMEDDS maintain the drug in solubilised form.If the surfactant & co surfactant contribute to a great extent for solubilisation then there is risk for precipitation. 24 3.POLARITY OF THE LIPID PHASE: The polarity of lipid phase is one of the factors that govern the release of the drug from the microemulsion. HLB, chain length,degree of unsaturation of the fatty acid, molecular weight of the hydrophilic portion & concentration of the emulsifier govern the polarity of droplets.


ADVANTAGES OF SMEDDS: Protection of sensitive drug substances. The emulsion droplets will deliver the drug to gastrointestinal mucosa in the dissolved state readily accessible for absorption. When a polymer is incorporated in terms of SMEDDS it gives prolonged release of medicament. Low viscosity. They are comprised of aqueous and oily components and therefore can accommodate both hydrophilic as well as lipophilic drugs. 25


ADVANTAGES OF SMEDDS: Liquid or solid dosage forms. Most consistent temporal profiles of drug absorption. SMEDDS has potential to deliver peptides that are processed to enzymatic hydrolysis in GIT. Enhanced oral bioavailability enabling reduction in dose. SMEDDS present drug in a small droplet size & well proportioned distribution and increase the dissolution and permeability. Since drugs can be loaded in inner phase and delivered to lymphatic system can bypass first pass metabolism. Thus SMEDDS protect drugs against hydrolysis by enzymes in the GI tract & reduce the presystemic clearance in the GI mucosa & first pass metabolism 26


CONCLUSION Candesartan Cilexetil was formulated as a SMEDDS in an attempt to increase its release rate and bioavailability & for direct filling into hard gelatin capsules for oral administration. The formula composition for SMEDDS was obtained based on solubility evaluation,pseudoternary phase diagrams & droplet size analysis. The optimised formulation showed rapid self microemulsification in an aqueous media. The results from this study demonstrated the utility of SMEDDS to enhance solubility and dissolution of sparingly soluble compounds like candesartan which may result in improved therauptic performance. 27


REFERENCES Lipinski, 2000 C.A. Lipinski, Drug-like properties and the causes of poor solubility and poor permeability, J. Pharmacol. Toxicol. Methods 44 (2000), pp. 235–249. SummaryPlus | Full Text + Links | PDF (530 K) | View Record in Scopus | Cited By in Scopus Lipinski et al., 1997 C.A. Lipinski, F. Lombardo, B.W. Dominy and P.J. Feeney, Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings, Adv. Drug Deliv. Rev. 23 (1997), pp. 3–25. SummaryPlus | Full Text + Links | PDF (2455 K) | View Record in Scopus | Cited By in Scopus Lipinski, C. (2002) poor aqueous solubility–an industry wide problem in drug discovery. American pharmaceutical review 5, pp. 82-85. Merisko-Liversidge E, Liversidge GG, Cooper ER: Nanosizing: a formulation approach for poorly-water-soluble compounds. Eur J Pharm Sci 18: 113-120, 2003 W.N. Charman, M.C. Rogge, A.W. Boddy, B.M. Berger, Effect of food and a monoglyceride emulsion formulation on danazol bioavailability, J. Clin.Pharmacol. 33 (1993) 381–386. 28


REFERENCES Merisko-Liversidge et al., 1996 E. Merisko-Liversidge, P. Sarpotdar, J. Bruno, S. Hajj, L. Wei, N. Peltier, J. Rake, J.M. Shaw, S. Pugh, L. Polin, J. Jones, T. Corbett, E. Cooper and G.G. Liversidge, Formulation and antitumor activity evaluation of nanocrystalline suspensions of poorly soluble anticancer drugs, Pharm. Res. 13 (1996), pp. 272–278. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (51) P. Ghirardi, G. Catenazzo, O. Mantero, G.C. Merotti and A. Marzo. “Bioavailability of Digoxin in a New Soluble Pharmaceutical Formulation in Capsules.” J. Pharm. Sci. 66 (2): 267-269 (1977). R.N. Gursoy, S. Benita, Self-emulsifying drug delivery systems (SEDDS) for improved oral delivery of lipophilic drugs, Biomed. Pharmacother. 58 (3) (2004) 173–182. A.J. Humberstone, W.N. Charman, Lipid-based vehicles for the oral delivery of poorly water soluble drugs, Adv. Drug Deliv. Rev. 25 (1997) 103–128. E.A. Mueller, J.M. Kovarik, J.B. van Bree, J. Grevel, P.W. Lucker, K. Kutz, Influence of a fat-rich meal on the pharmacokinetics of a new oral formulation of cyclosporine in a crossover comparison with the market formulation, Pharm. Res. 11 (1994) 151–155. 29