Journal of Pharmaceutical Research And Opinion 1:3 (2011) 80 – 84.
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RESEARCH
SELF EMULSIFYING DRUG DELIVERY SYSTEM Vishesh Kumar Pal* Sir Madanlal Institute of Pharmacy Etawah, U.P. ARTICLE INFO
ABSTRACT
Received 30 June 2011 Accepted 17 August 2011
Oral route has always been preferred route for formulators and has dominated over other routes of administrations. The major problem in oral drug formulations is low and erratic bioavailability, which mainly results from poor aqueous solubility. Approximately 40% of new chemical entities exhibit poor aqueous solubility and present a major challenge to modern drug delivery system, because of their low bioavailability. The aim of this study was to formulate a SEDDS containing a lipophilic drug, loratadine, and to explore the potential of carriers for such system. Formulation development and screening was done based on results obtained from phase diagrams and characteristics of resultant microemulsions. The optimized formulation for in vitro dissolution and pharmacodynamic studies was composed of Labrafac CM10 (31.5%), Tween 80 (47.3%), and polyethylene glycol 400 (12.7%).Self micro emulsifying drug delivery systems are isotropic mixtures of oil, surfactant, cosurfactant and drug with a unique ability to form fine oil in Water microemulsion upon mild agitation following dilution with aqueous phase. Among various approach selfemulsifying drug delivery system has gained more attention due to enhanced oral bio-availability enabling reduction in dose, more consistent temporal profiles of drug absorption, 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. ©2011, JPRO, All Right Reserved.
Corresponding Author: Vishesh Kumar Pal.
[email protected] Sir Madanlal Institute of Pharmacy Etawah. U.P.
KeyWords: Self emulsifying drug delivery system, oral bioavailability, lipid based formulations, poorly water soluble drugs.
INTRODUCTION One of the most popular and commercially viable formulation approaches for solving these problems is selfemulsifying drug delivery systems (SEDDS). The basic difference between self emulsifying drug delivery systems (SEDDS) also called as self emulsifying oil formulation (SEOF) and SMEDDS is SEDDS typically produce opaque 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 also the concentration of oil in SMEDDS is less than 20 % as compared to 40-80% in SEDDS. Efficacy of lipophilic drug is often hindered due to their poor aqueous solubility leading to low absorption after in vivo administration. Self-emulsifying drug delivery systems (SEDDS) are mixtures of oils and surfactants, ideally isotropic, and sometimes containing co-solvents, which emulsify spontaneously to produce fine oil-in-water emulsions when introduced into aqueous phase under gentle agitation6, 7,39,40,41. Recently, SEDDS have been formulated using medium chain tri-glycoside oils and nonionic surfactants, the latter being less toxic. The poorly water-soluble drugs such as HIV protease inhibitors, glycoprotein inhibitors and anticancer drugs have problems to create and maintain a good solubility in gastrointestinal tract. The process of self-emulsification proceeds through formation of liquid crystals (LC) and gel phases. SMEDDS formulations are isotropic mixtures of an oil, a surfactant, a co surfactant (or solubilizer), and a drug. The basic principle of this system is its ability to form fine
oil-in-water (o/w) microemulsions under gentle agitation following dilution by aqueous phases (i.e., the digestive motility of the stomach and intestine provide the agitation required for self-emulsifi cation in vivo in the lumen of the gut) SEDDS are isotropic mixtures of drug, oil/lipid, surfactant, and/ or cosurfactant, which form fine emulsion/lipid droplets, ranging in size from approximately 100 nm (SEDDS) to less than 50 nm for selfmicro emulsifying drug delivery systems (SMEDDS), on dilution with physiological fluid. ADVANTAGES OF SMEDDS Improvement in oral bioavailability Dissolution rate dependant absorption is a major factor that limits the Bioavailability of numerous poorly water soluble drugs. The ability of SMEDDS to present the drug to GIT in solubilised and micro emulsified form (globule size between 1- 100 nm) and subsequent increase in specific surface area enable more efficient drug transport through the intestinal aqueous boundary layer and through the absorptive brush border membrane leading to improved bioavailability. E.g. In case of halofantrine approximately 6-8 fold increase in bioavailability of drug was reported in comparison to tablet formulation. [1] Dosage form development of SEDDS Dry emulsions Dry emulsions are powders from which emulsion spontaneously occurs in vivo or when exposed to an 80
Pal et. al/Self Emulsifying Drug Delivery System aqueous solution. Dry emulsions can be useful for further preparation of tablets and capsules. Dry emulsion formulations are typically prepared from oil/ water (O/W) emulsions containing a solid carrier (lactose, maltodextrin, and so on) in the aqueous phase by rotary evaporation [2], freeze-drying [3] or spray drying [4–6]. Myers and Shively obtained solid state glass emulsions in the form of dry ‘foam’ by rotary evaporation, with heavy mineral oil and sucrose. Such emulsifiable glasses have the advantage of not requiring surfactant [2]. In freeze-drying, a slow cooling rate and the addition of amorphous cryoprotectants have the best stabilizing effects, while heat treatment before thawing decreases the stabilizing effects [3]. The technique of spray drying is more frequently used in preparation of dry emulsions. The O/W emulsion was formulated and then spray-dried to remove the aqueous phase. The most exciting finding in this field ought to be the newly developed enteric-coated dry emulsion formulation, which is potentially applicable for the oral delivery of peptide and protein drugs. This formulation consisted of a surfactant, a vegetable oil, and a pH-responsive polymer, with lyophilization used [7].Recently, Cui et al. prepared dry emulsions by spreading liquid O/W emulsions on a flat glass, then dried and triturated to powders
appropriate dilution, a spherical droplet will be formed again (figure 1 ). Fig. 1
Representation of the of commonly encountered phases upon addition of water to an oilsurfactant Combination (from Jonson et al., Surfactants and Polymers in aqueous solution.Wiley, 1998.) MATERIALS AND METHODS: Materials Animals Male Holtzman rats (weighing approximately 250 ± 30 g) were used for the comparative lipid-lowering studies. The animals were maintained at a constant light (14L: 10D), temperature (24°C-25°C), and humidity (60%) and were supplied with food and water ad libitum. The animal requirement was approved by the Institute Animal Ethics Committee IAEC), and all experiments were conducted as per the norms of the Committee for the Purpose of Supervision of Experiments on Animals, India. Fenofi brate was obtained as a gift sample from Cipla Ltd (Mumbai, India). Loratadine was purchased from Hakim Pharmaceutical Co. (Tehran, Iran). Labrafil, Capryol PG, Transcutol and Labrasol were gift from Gattefosse (Gattefosse Corp., Saint-Priest, France) and Span 20 from Merck (Germany). Dialysis bag was purchased from Toba Azema Co, Tehran (Iran). Minitab14 software was used for experimental design and the evaluation of the effect of variables on responses. Cremophor RH 40 (polyoxyl 40 hydrogenated castor oil), Cremophor EL (polyethoxylated castor oil), and Solutol HS 15 (polyoxyethylene esters of 12 hydroxystearic acid) were obtained from BASF (Mumbai). Gelucire 44/14 (PEG-32 glyceryl laurate) and 50/13 (PEG32 glyceryl palmistearate) were received from Colorcon Asia (Mumbai). Span 20 (sorbitan monolaurate), Tween 80 (polyoxyethylene sorbitan monooleate), and PEG 400 were bought from Merck (Mumbai, India). Deionized water was prepared by a Milli-Q purifi cation system from Millipore (Molsheim, France). Acetonitrile and methanol used in the present study were of high performance liquid chromatography (HPLC) grade. All other chemicals were reagent grade. Empty hard gelatin capsule shells were generously donated by ACG Capsules (Mumbai)
MECHANISM OF SELF-EMULSIFICATION It is apparent from equation that the spontaneous formation of the interface Between the oil and water phases is energetically not favored. However, according to Reiss 48, self-emulsification occurs when the entropy change that favors dispersion is greater than the energy required to increase the surface area of the dispersion. In addition, the free energy of a conventional emulsion formation is a direct function of the energy required to create a new surface between the two phases and can be described by equation48 Where, G is the free energy associated with the process (ignoring the free energy of mixing), N is the number of droplets of radius, r, and s represents the interfacial energy. With time, the two phases of the emulsion will tend to separate, in order to reduce the interfacial area, and subsequently, the free energy of the systems. Therefore, the emulsions resulting from aqueous dilution are stabilized by conventional emulsifying agents, which Form a monolayer around the emulsion droplets, and hence, reduce the interfacial energy, as well as providing a barrier to coalescence. In the case of selfemulsifying systems, the free energy required to form the emulsion is either very low and positive, or negative (then, the emulsification process occurs spontaneously). Emulsification requiring very little input energy involves destabilization through contraction of local interfacial regions.
In emulsification process the free energy (ΔG) associated is given by the equation In which ‘N’ is Number of droplets with radius ‘r’ and ‘σ’ is interfacial energy.
METHODS Formulation of Self emulsifying drug delivery system (SEDDS) Various amount of comprising materials either of surfactant, co-surfactant, oil and transcutol P (liquid) as solubilizer, were formulated by admixing the components (Table 1). Then loratadine with defined amount added to the mixture, shake well and then kept at 40 ° C for a time period necessary to solve the drug. We used two-phase include liquid paraffin oil and Labrafil (liquid). Thus, two
Dilution phases Upon dilution of a SMEDDS formulation, the spontaneous curvature of the Surfactant layer changes via a number of possible liquid crystalline phases. The droplet structure can pass from a reversed spherical droplet to a reversed rod-shaped droplet, hexagonal phase, lamellar phase, cubic phase and various other structures until, after 81
Pal et. al/Self Emulsifying Drug Delivery System series of formula was obtained, which in both surfactant Span 20 and co-surfactant Capriol (liquid) were used.
formation of self-micro emulsifying formulations (SMEDDS)40,64,65,66. Formulations consisting only of the surfactant mixture may form emulsions or microemulsions (when surfactants exhibit different low and high HLB) 43, micelle solution or, in some particular cases, niosomes, which are non-ionic, surfactant-based bilayer vehicles67.
EXCIPIENTS USED IN SEDDS Oils: Both long- and medium-chain triglyceride (MCT) oils with different degrees of saturation have been used for the design of self-dispersing formulations. Unmodified edibleoils provide the most `natural' basis for lipid vehicles, but their poor ability to dissolve large amounts of hydrophobic drugs and their relative difficulty in efficient self-emulsification markedly reduce their use in SEDDS.In contrast, modified or hydrolyzed vegetable oils have contributed widely to the success of the above systems40, 57, 58. Since they exhibit formulative and physiological advantages. These excipients form good emulsification systems, with a large number of non-ionic surfactants approved for oral administration, while their degradation products resemble the end products of intestinal digestion. MCTs were preferred in the earlier self-emulsifying formulations39,59. Because of higher Fluidity, better solubility properties and self-emulsification ability, but evidently, they are considered less attractive compared to the novel semi-synthetic medium chain derivatives40 which can be defined rather as amphiphilic compounds Exhibiting surfactant properties. In such cases, the more lipophilic surfactant may play the role of the hydrophilic oil in the formulation40,43. Solvent capacity for less Hydrophobic drugs can be improved by blending triglycerides with mono- and di glycerides.45
Co-solvents Relatively high surfactant concentrations (usually more than 30% w/w) are needed in order to produce an effective self-emulsifying system. Organic solvents, suitable for oral administration (ethanol, propylene glycol (PG), polyethylene glycol (PEG), etc.) may help to dissolve large amounts of either the hydrophilic surfactant or the drug in the lipid base. These solvents Characterization of particle size Thus, 1 mL of formulated solution was added to 100 mL of 0.1N hydrochloric acid, and then the particle size was measured using particle size analyzer. The mean particle diameter and polydispersity index (PDI) of dispersions were calculated by laser light diffractometry, using Malvern Master Sizer SM 2000K (High Performance Particle Sizer; Malvern Instruments Ltd., Malvern, United Kingdom). EVALUATION Thermodynamic stability studies: The physical stability of a lipid –based formulation is also crucial to its performance, which can be adversely affected by precipitation of the drug in the excipient matrix. In addition, poor formulation physical stability can lead to phase separation of the excipient, affecting not only formulation performance, but visual appearance as well. In addition, incompatibilities between the formulation and the gelatin capsules shell can lead to brittleness or deformation, delayed disintegration, or incomplete release of drug. 1. Heating cooling cycle: Six cycles between refrigerator temperature (40C) and 450C with storage at each temperature of not less than 48 h is studied. Those formulations, which are stable at these temperatures, are subjected to centrifugation test.
Surfactants Non-ionic surfactants with a relatively high hydrophilic± lipophilic balance (HLB) were advocated for the design of self-dispersing systems, where the various liquid or solid ethoxylated polyglycolyzed glycerides and polyoxyethylene 20 oleate (Tween 80) are the most frequently used excipients. Emulsifiers derived from natural sources are expected to be safer than synthetic ones and are recommended for SDLF (self dispersed lipid formulation) use40,58,60,61, despite their limited ability to self-emulsify. Non-ionic surfactants are known to be less toxic compared to ionic surface-active agents, but they may cause moderate reversible changes in intestinal wall permeability6, 62. Amemiya et al. proposed a new vehicle based on a fine emulsion using minimal surfactant content (3%) to avoid the potential toxicological problems associated with high surfactant concentration 63. The usual surfactant concentration in self-emulsifying formulations required to form and maintain an emulsion state in the GI tract ranged from 30 to 60% w/w of the formulation. A large quantity of surfactant may irritate the GI tract. Thus, the safety aspect of the surfactant vehicle should be carefully considered in each case. The high HLB and subsequent hydrophilicity of surfactants is necessary for the immediate formation of o/w droplets and/or rapid spreading of the formulation in the aqueous environment, providing a good dispersing/selfemulsifying performance. The surfaceactive agents are amphiphilic by nature, and they are therefore usually able to dissolve and even solubilize relatively high quantities of the hydrophobic drug. The latter is of prime importance for preventing precipitation within the GI lumen and for the prolonged existence of the drug molecules in soluble form, which is vital for effective absorption 59. The lipid mixtures with higher surfactant and co-surfactant/oil ratios lead to the
Centrifugation: Passed formulations are centrifuged thaw cycles between 21 0C and +25 0C with storage at each temperature for not less than 48 h is done at 3500 rpm for 30 min. Those formulations that does not show any phase separation are taken for the freeze thaw stress test. Freeze thaw cycle: Three freeze for the formulations. Those formulations passed this test showed good stability with no phase separation, creaming, or cracking. 68 Dispersibility test The efficiency of self-emulsification of oral nano or micro emulsion is assessed using a standard USP XXII dissolution apparatus 2. One milliliter of each formulation was added to 500 mL of water at 37 ± 0.5 0C. A standard stainless steel dissolution paddle rotating at 50 rpm provided gentle agitation. The in vitro performance of the formulations is visually assessed using the following grading system: Grade A: Rapidly forming (within 1 min) nanoemulsion, having a clear or bluish appearance. Grade B: Rapidly forming, slightly less clear emulsion,having a bluish white appearance. Grade C: Fine milky emulsion that formed within 2 min. Grade D: Dull, grayish white emulsion having slightly oily appearance that is slow to emulsify (longer than 2 min). 82
Pal et. al/Self Emulsifying Drug Delivery System Grade E: Formulation, exhibiting either poor or minimal emulsification with large oil globules present on the surface. Grade A and Grade B formulation will remain as nanoemulsion when dispersed in GIT. While formulation falling in Grade C could be recommend for SEDDS formulation. (18)
sought to achieve sustained release, increase the bioavailability, and decrease the gastric irritation of ketoprofen include preparation of matrix pellets of nanocrystalline ketoprofen,(8) sustained release ketoprofen microparticles(9) and formulations(9), floating oral ketoprofen systems(10), and transdermal systems of ketoprofen(11)
Turbidimetric Evaluation Nepheloturbidimetric evaluation is done to monitor the growth of emulsification. Fixed quantity of Selfemulsifying system is added to fixed quantity of suitable medium (0.1N hydrochloric acid) under continuous stirring (50 rpm) on magnetic plate at ambient temperature, and the increase in turbidity is measured using a turbidimeter. However, since the time required for complete emulsification is too short, it is not possible to monitor the rate of change of turbidity (rate of emulsification (13) (19)
Protection against Biodegradation:The ability of self emulsifying drug delivery system to reduce degradation as well as improve absorption may be especially useful for drugs, for which both low solubility and degradation in the GI tract contribute to a low oral bioavailability. Many drugs are degraded in physiological system, may be because of acidic PH in stomach, enzymatic degradation or hydrolytic degradation etc REFERENCE 1. Khoo SM, Humberstone AJ, Porter CJ, Edwards GA and Charman WN. Formulation design and bioavailability assessment of lipidic self-emulsifyingFormulations of Halofantrine. Int J of Pharm 1998; 167: 155-164 2 Myers, S.L. and Shively, M.L. (1992) Preparation and characterization of emulsifiable glasses: oil-in-water and water-in-oil-in-water emulsion. J. Colloid Interface Sci. 149, 271–278 3 Bamba, J. et al. (1995) Cryoprotection of emulsions in freeze-drying: freezing process analysis. Drug. Dev. Ind. Pharm. 21, 1749–1760 4 Christensen, K.L. et al. (2001) Technical optimization of redispersible dry emulsions. Int. J. Pharm. 212, 195–202 5 Hansen, T. et al. (2004) Process characteristics and compaction of spray-dried emulsions containing a drug dissolved in lipid. Int. J. Pharm. 287, 55–66 6 Jang, D.J. et al. (2006) Improvement of bioavailability and photostability of amlodipine using redispersible dry emulsion. Eur. J. Pharm. Sci. 28, 405–411 7 Toorisaka, E. et al. (2005) an enteric-coated dry emulsion formulation for oral insulin delivery. J. Control Release 107, 91–96 8. Vergote GJ, et al. An oral controlled release matrix pelletformulation containing nanocrystalline ketoprofen. Int J Pharm. 2001; 219:81-87. 9. Yamada T, Onishi H, Machida Y. Sustained release ketoprofen microparticles with ethylcellulose and carboxymethylethylcellulose. J Control Release. 2001;75:271-282. 10. Roda A, et al. Bioavailability of a new ketoprofen formulation for once-daily oral administration. Int J Pharm. 2002;241:165-172. 11. El-Kamel AH, et al. Preparation and evaluation of ketoprofen floating oral delivery system. Int J Pharm. 2001; 220:13-21 12. Rhee Y-S, et al. Transdermal delivery of ketoprofen using microemulsions. Int J Pharm. 2001; 228:161-170 .13. Patil P, Joshij, paradkar. Effect of formulatiuon variables on preparation and evaluation of gelled selfemulsifying drug delivery system (SEDDS) of ketoprofen.AAPS Pharm Sci Tech.2004; 5(3):34-42 14. Pouton CW, Charman WN. The potential of oily formulations for drug delivery to the gastro-intestinal tract. Adv Drug Deliv Rev. 1997; 25:1-2. 15. A.T.M. Serajuddin, et al. Effect of vehicle amphiphilicity on the dissolution and bioavailability of a poorly watersoluble drug from solid dispersion, J. Pharm. Sci. 1988; 77: 414-417.
Viscosity Determination The SEDDS system is generally administered in soft gelatin or hard gelatin capsules. So, it can be easily pourable into capsules and such system should not too thick to create a problem. The rheological properties of the micro emulsion are evaluated by Brookfield viscometer. This viscosities determination conform whether the system is w/o or o/w. If system has low viscosity then it is o/w type of the system and if a high viscosity then it is w/o type of the system. (13, 14) Droplet Size Analysis Particle Size Measurements The droplet size of the emulsions is determined by photon correlation spectroscopy (which analyses the fluctuations in light scattering due to Brownian motion of the particles) using a Zetasizer able to measure sizes between 10 and 5000 nm. Light scattering is monitored at 25°C at a 90° angle, after external standardization with spherical polystyrene beads. The nanometric size range of the particle is retained even after 100 times dilution with water which proves the system’s compatibility with Excess water.(13,14 ) Refractive Index and Percent Transmittance Refractive index and percent tranmittance proved the transparency of formulation. The refractive index of the system is measured by refractometer by placing drop of solution on slide and it compare with water (1.333). The percent transmittance of the system is measured at particular wavelength using UV-spectrophotometer keeping distilled water as blank.If refractive index of system is similar to the refractive index of water(1.333) and formulation have percent transmittance > 99 percent, then APPLICATION Improvement in Solubility and bioavailability: If drug is incorporated in SEDDS, it increases the solubility because it circumvents the dissolution step in case of ClassП drug (Low solubility/high permeability). Ketoprofen, a moderately hydrophobic (log P 0.979) nonsteroidal antiinflammatory drug (NSAID), is a drug of choice for sustained release formulation has high potential for gastric irritation during chronic therapy. Also because of its low solubility, ketoprofen shows incomplete release from sustained release formulations. Vergote et al. (2001) reported complete drug release from sustained release formulations containing ketoprofen in nanocrystalline form(8) Different formulation approaches that have been 83
Pal et. al/Self Emulsifying Drug Delivery System 16. Amidon, G.., et.al. A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability, Pharm.Res. 1995; 12: 413-420. 17. S. Shafiq, et al. Development and bioavailability assessment of ramipril nanoemulsion formulation Eur. J. Pharm. Biopharm 2007; 66: 227–243 18. Patil p, Vandana p, paradkar p formulation of selfemulsifying drug delivery system for oraldelivery of .
simvastatin: In vitro and in vivo evaluation. Acta pharma. 2007; 57: 111-122 19. Vergote GJ, et al. An oral controlled release matrix pellet formulation containing nanocrystalline ketoprofen. Int J Pharm. 2001; 219:81-87. 20. Yamada T, Onishi H, Machida Y. Sustained release ketoprofen microparticles with ethylcellulose and carboxymethylethylcellulose. J Control Release. 2001; 75:271-282.
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