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Formulation and Evaluation of Self-emulsifying Drug Delivery System of Aceclofenac
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Formulation and Evaluation of Self-emulsifying Drug Delivery System of Aceclofenac


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Formulation and Evaluation of Self-emulsifying Drug Delivery System of Aceclofenac …

Formulation and Evaluation of Self-emulsifying Drug Delivery System of Aceclofenac
use:Improve Aceclofenac delivery to body

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  • 1. WELCOME TO MY PRESENTATION Department of Pharmacy Noakhali Science and Technology University Sonapur,Noakhali 3814,Bangladesh 1
  • 2. Formulation and Evaluation of Self- emulsifying drug delivey system of Aceclofenac Department of Pharmacy Noakhali Science and Technology University Sonapur,Noakhali 3814,Bangladesh Presented by ASIFUL ALAM Roll-ASH0903017M Session: 2008-2009 2
  • 4. AIM AND OBJECTIVE Most of the new drug candidates in development today are sparingly soluble and associated with poor bioavailability The main purpose is to prepare SMEDDS for oral bioavailability enhancement of a poorly water soluble drug 4
  • 5. Research design 5
  • 6. Bio-pharmaceutical classification system 6
  • 7. INTRODUCTION SEDDS or self-emulsifying oil formulations (SEOF) are defined as Isotropic mixtures of natural or synthetic oils, solid or liquid surfactants or, alternatively, one or more hydrophilic solvents and co-solvents/ surfactants. SEDDS typically produce emulsions with a droplet size between 100 and 300 nm while SMEDDS form transparent micro-emulsions with a droplet size of less than 50 nm. The concept of SEDDS for pharmaceutical purpose was initially developed by the Group of Groves (Dunkan QM et al., 2000, Fernando- Warnkulasuriya GLP et al., 1981). 7
  • 8. Protection of sensitive drug substances More consistent drug absorption, Selective targeting of drugs toward specific absorption window in GIT Protection of drug(s) from the gut environment. Control of delivery profile Reduced variability including food effects Enhanced oral bioavailability enabling reduction in dose High drug loading efficiency. ADVANTAGES OF SEDDS 8
  • 9. For both liquid and solid dosage forms. These dosage forms reduce the gastric irritation produced by drugs. Emulsion are sensitive and metastable dispersed forms while S(M)EDDS are physically stable formulation that are easy to manufacture. As compared with oily solutions, they provide a large interfacial area for partitioning of the drug between oil and water. DRAWBACK OF SEDDS: Lack of good in vitro models for assessment of the formulations for SEDDS. The traditional dissolution methods does not work, because these formulations potentially are dependent on digestion prior to release of the drug. 9
  • 11. OILS: Oils are the most important excipient because oils can solubilize the lipophilic drug in a specific amount. Both long-chain triglyceride and medium-chain triglyceride oils with different degrees of saturation have been used for the formulation of SEDDSs. Unmodified edible oils have poor ability to dissolve large amount of hydrophilic drugs. Modified or hydrolyzed vegetable or edible oils have contributed widely to the success of SEDDSs owing to their formulation and physiological advantages. Corn oil, Olive oil, Oleic acid, Peppermint oil, Hydrogenated soya bean oil, Hydrogenated vegetable oils,Soyabean oil, Peanut oil, Beeswax 11
  • 12. Surfactant • 1: Anionic Surfactants, where the hydrophilic group carries a negative charge such as carboxyl (RCOO-), sulphonate (RSO3 -) or sulphate (ROSO3 -). Examples: Potassium laurate, SLS • 2: Cationic surfactants, where the hydrophilic group carries a positive charge. Example: quaternary ammonium halide. • 3: Ampholytic surfactants (also called zwitterionic surfactants) Example: sulfobetaines. • 4: Nonionic surfactants, where the hydrophilic group carries no charge but derives its water solubility from highly polar groups such as hydroxyl or polyoxyethylene (OCH2CH2O). Examples: Sorbitan esters (Spans), Polysorbate (Tween). o Nonionic surfactants with high Hydrophilic Lipophilic Balance (HLB) values are used in formulation of SEDDS (e.g., Tween, Labrasol, Labrafac CM 10, Cremophore, etc.). o The usual surfactant strength ranges between 30–60% w/w of the formulation in order to form a stable SEDDS. 12
  • 13. COSOLVENTS/COSURFACTANTS Cosolvents may help to dissolve large amounts of hydrophilic surfactants or the hydrophobic drug in the lipid base. These solvents sometimes play the role as co-surfactant in the microemulsion systems Drug release is increased with increasing concentration of cosurfactant in formulation. Examples of cosolvents: Ethanol Propylene glycol Polyethylene glycol Cremphore EL 13
  • 14. Mechanism • The process by which self-emulsification takes place is not yet well understood. • But ,According to ‘Reiss’ self emulsification occurs when the entropy change that favors dispersion is greater than the energy required to increase the surface area of the dispersion. • The free energy of the conventional emulsion is a direct function of the energy required to create a new surface between the oil and water phases and can be described by the equation: ΔG = Σ N π r2 σ • Where, • ΔG is the free energy associated with the process (ignoring the free energy of mixing), N is the number of droplets of radius r and σ represents the interfacial energy. • In the case of self-emulsifying systems, the free energy required to form the emulsion is either very low and positive or negative (then, the emulsification process occurs spontaneously). • Lesser interfacial tension→lesser free energy →stable emulsion 14
  • 15. METERIALS Aceclofenac Peppermint oil Capmul PG8 Tween 80 Cremphore EL Microcrystalline Cellulose (MCC PH101) Capsule shell 15
  • 16. FORMULATION OF SEDDS Ingredient Amount(mg) Amount (mg) Amount (mg) Amount (mg) F1 F2 F3 F4 Aceclofenac 100 100 100 100 Peppermint oil 50 50 50 Capmul PG8 50 Tween 80 150 50 50 100 Cremphore EL 100 100 50 Microcrystalline Cellulose 300 300 300 300 Total 600 600 600 600 16
  • 17. PREPARATION OF SEDDS Accurately weighed amount of drug was placed in a glass vial, and oil, surfactant and cosurfactant were added. Then the components were mixed by gentle stirring and vortex mixing for 30 min. This mixture were heated at 40ºC on a magnetic stirrer, until drug was perfectly dissolved. The mixture was stored at room temperature until further use. Finally filled using a Hand operated capsule machine having A bed with 200- 300 holes, a capsule loading tray, a powder tray .. 17
  • 18. IN VITRO EVALUATION OF SEDDS Appearence Weight Uniformity Drug Content Micromeritic Properties Thermodynamic stability Studies Dispersibility test Ph Determination In-vitro Release studies(zero order, first order, higuichi model, hixson-crowel plot, Krosmeyer-peppas kinetics ) 18
  • 19. 1. Apperance: The filled capsules showed no signs of leakage, discoloration, pinholes and shell distortion. Aceclofenac loaded SEDDS appeared as clear homogenous at room temperature. No traces of particulate matter nor drug precipitation were observed. 2. Weight Unifomity: None of the capsules were found to deviate from the average capsule by more than 7.5 % and were found to comply with I.P’96 standards for uniformity of weight for capsules 3. Drug Content: The drug content of various self-microemulsifying formulations was found to be within the range of 99-101% which was in agreement with pharmacopoeial specifications. 19 Capsule Weight Variation (%) F-1 1.50±0.02 F-2 2.26±0.01 F-3 2.18±0.03 F-4 1.68±0.04 Capsul e Drug Content (%) F-1 99.28±0.07 F-2 99.34±0.09 F-3 98.17±0.06 F-4 97.19±0.07
  • 20. 4.Micromeritic Properties • The self emulsifying powders were evaluated for bulk density (BD), tapped density (TD), compressibility (Carr’s) index and angle of repose. The bulk density of different formulations Batch 1, 2, 3 and 4 were found to be in the range of 0.21 to 0.57 and tapped density from 0.37 to 0.71 respectively. The compressibility index (29.99%) indicated poor flowability of aceclofenac. Angle of repose was determined for the measurement of flowability. The formulations 1, 2 and 4 showed improved flowability in the form of powder. This was further supported by the value of Hausner’s ratio (<1.25).The improved flowability of self emulsifying powders may be due to good sphericity and small size of granules. 20
  • 21. 5.Thermodynamic stability studies:  The poor physical stability of the formulation can lead to phase separation of the excipient, which affects not only formulation performance, as well as visual appearance of formulation.  Incompatibilities between the formulation and the gelatin capsules shell can lead to brittleness or deformation, delayed disintegration, or incomplete release of drug.  For thermodynamic stability studies we have performed three main steps, they are- Heating cooling cycle Centrifugation Freez thaw cycle 21
  • 22. • All the formulations were found to remain stable after centrifugation and freeze-thaw cycle process and no phase separation or drug precipitation was observed. Particle size and polydispersity remained unaffected after freeze- thaw process, thus confirming the stability of developed microemulsions.. self-microemulsification efficiency: Formulations were found to release the contents immediately upon rupturing and self-emulsify within a minute. 22
  • 23. 6.Dispersibility test : The efficiency of self-emulsification of oral nano or micro emulsion is assessed by using a standard USP XXII dissolution apparatus 2 for dispersibility test. One millilitre of each formulation was added in 500 mL of water at 37 ± 1 0 C at 50 rpm. It passes the test  If it is rapidly forming (within 1 min) nanoemulsion, having a clear or bluish appearance. Or  If it is rapidly forming, slightly less clear emulsion, having a bluish white appearance. Or  If it is fine milky emulsion that formed within 2 min. 7.Ph DETERMINATION 23 ACF incorporation into SEDDS lowered the pH of the systems towards acidic side; this change may be attributed to the acidic nature of the drug. After the dilutions of the preconcentrates with distilled water, the pH values were found to increase. This may be probably due to encapsulation of major quantity of drug into microemulsion and so decrease in acidic nature of the systems
  • 24. In-Vitro Drug Release Studies Dissolution Study Procedure a) The in vitro dissolution studies were performed using USP type-IΙ dissolution apparatus (Rotating Peddle method) at 100 rpm. b) The dissolution medium consisted of potassium di-hydrogen phosphatebuffer of pH 7.4 up to 900 mL, maintained at 37°C ± 0.5°C. c) An aliquot (5 mL) was withdrawn at specific time intervals which replaced by equivalent amount of buffer solution. d) The drug content was determined by UV-visible spectrophotometer (SHIMADZU UV- 1800 spectrophotometer) at 276 nm. 24
  • 25. In-Vitro Drug Release Studies 25 To know the mechanism of drug release from these formulations, the data were treated according to: 1. Zero order (cumulative amount of drug released vs time), 2. First-order (log cumulative percentage of drug remaining vs time), 3. Higuchi’s (cumulative percentage of drug released vs square root of time), 4. Korsmeyer et al.’s (log cumulative percentage of drug released vs log time) and 5. Hixson-Crowell (cubic root of percent drug release vs time) pattern for kinetics of drug release during dissolution process.
  • 26. 26
  • 27. Code Zero order regression coefficient (r2 ) First order regression coefficient (r2 ) Higuchi equation regression coefficient (r2 ) Korsmeyer’ s regression coefficient (r2 ) Hixon-Crowell regression coefficient (r2 ) F-1 0.919 0.922 0.919 0.861 0.884 F-2 0.902 0.905 0.902 0.882 0.889 F-3 0.902 0.967 0.902 0.825 0.861 F-4 0.917 0.930 0.917 0.922 0.910 Release kinetics parameters of designed Self-emulsifying Aceclofenac Capsule: 27
  • 28. The dissolution data (from the values of 0 to 2 hours to know which drug release) of all formulations were fitted into various mathematical models (zero- order, first-order, Higuchi, , Hixon-Crowell plot, Korysmeyer-Pappas model) to know which mathematical model will best fit for the drug release profile. From release kinetics parameters we can say that the highest regression coefficient value (r2 ) the best-fit model for all formulations was Higuchi model. It is clearly indicated that, the formulations did not follow a zero-order release pattern because the regression value for all formulations did not show high linearity. When the data were plotted according to the first-order equation, the tablets showed a first order release, with regression value of (F1 to F4) 0.912, 0.905, 0.967, 0.930. The formulations showed to be best expressed by Higuchi’s equation, as the plots showed high linearity with regression value of (F1 to F4) 0.919, 0.902, 0.902, 0.917 , indicating that the release of drug follows the Higuchi release kinetics and diffusion is the dominating mechanism for drug release. 28
  • 30. 30 Drug Name Compound Dosage form Company Indication Neoral® Cyclosporine A/I Soft gelatin capsule Novartis Immune suppressant Norvir® Ritonavir Sof tgelatin capsule Abbott Laboratories HIV antiviral Fortovase® Saquinavir Soft gelatin capsule Hoffmann-La Roche inc. HIV antiviral Agenerase® Amprenavir Soft gelatin capsule Glaxo Smithkline HIV antiviral Convulex® Valproic acid Soft gelatin capsule Pharmacia Antiepileptic Lipirex® Fenofibrate Hard gelatin capsule Genus Antihyper- lipoproteinemic Sandimmune® Cyclosporine A/II Soft gelatin capsule Novartis Immuno suppressant Targretin® Bexarotene Soft gelatin capsule Ligand Antineoplastic Rocaltrol® Calcitriol Soft gelatin capsule Roche Calcium regulator Gengraf® Cyclosporine A/III Hard gelatin capsule Abbott Laboratories Immuno suppr MARKETED PRODUCTS OF SEEDS
  • 31. CONCLUSIONCONCLUSION • SEDDSs are a promising approach for the formulation of liphophilic drugs and to improve the oral bioavailability of drugs with poor aqueous solubility. • The current study demonstrated a successful and simple method to prepare self emulsifying aceclofenac Capsule, where Capsule produced emulsion with uniform drug content to enhance its aqueous solubility and dissolution rate. The prepared SE Capsule showed a significant improvement in in-vitro and in comparison with pure drug. The developed SEDDS were found to exhibit good release activity . This potential technique has ability to develop stable dosage forms which can be scaled up • It appears that more drug products will be formulated as SEDDS in the very near future and these aspects are the major areas for future research into S-SEDDS.
  • 32. Thanking you Have a good day………………. 32