INTRODUCTION:

Oral route is the most convenient and easiest route for noninvasive administration. Oral drug delivery system is the most cost-effective and leads the world wide drug delivery market.

Poor water solubility is widely recognized as the main reason for the poor oral absorption of many new chemical entities. Conventional solubilization approaches such as co solvents, salt formation and more recently surfactant-based micellar formation are now widely employed in enhancing the oral absorption of drugs, primarily poorly soluble drugs.

Self Emulsifying Drug Delivery System (SEDDS) is commonly employed to improve the oral exposure of poorly soluble and lipophilic drugs. However, the higher surfactant level is needed in the conventional SEDDS formulations in order to prevent the precipitation of the drug upon dilution with water in the GIT.

The surfactant commonly used in the SEDDS formulations may increase GI side-effects and, therefore, a reduced amount of surfactant in the formulations should be used to minimize the surfactant-induced GI side-effects. ¹ Majority of the new drug candidates have poor aqueous solubility and thereby low bioavailability.

According to an FDA survey conducted between 1995 and 2002, only 9% of the new drug entities belonged to Biopharmaceutical classification system(BCS) class-I category (high solubility-high permeability). By adopting different techniques, such as complexation with cyclodextrins, solid dispersion, Self-emulsifying drug delivery system, solubility and bioavailability of drugs can be improved ².

Definition:

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 agitation³.

Recently, SEDDS have been formulated using medium chain tri-glycerides oils and nonionic surfactants, the latter being less toxic. Upon per oral administration, these systems form fine emulsions (or micro-emulsions) in gastro-intestinal tract (GIT) with mild agitation provided by gastric mobility. Advantage of SEDDS over simple oily solutions is larger interfacial area for partitioning of the drug between oil and water. Thus, for lipophilic drugs with dissolution-limited oral absorption, these systems offer an improved rate and extent of absorption and more reproducible plasma concentration profiles.⁴

Need of SEDDS:

1) SEDDS are promising approach for oral delivery of poorly water-soluble compounds. It can be achieved by pre-dissolving the compound in a suitable solvent and fill the formulation into desired dosage form.

2) The oral drug delivery of hydrophobic drugs can be made possible by SEDDS.

3) The main benefit of this approach is that pre-dissolving the compound overcomes the initial rate limiting step of particulate dissolution in the aqueous environment within the GI tract.

4) However, a potential problem is that the drug may precipitate out of solution when the formulation disperses in the GI tract, particularly if a hydrophilic solvent is used (e.g. polyethylene glycol).

5) If the drug can be dissolved in a lipid vehicle there is less potential for precipitation on dilution in the GI tract, as partitioning kinetics will favors the drug remaining in the lipid droplets.⁵

Advantages of SEDDS:

Potential advantages of these systems include⁶;

1) Enhanced oral bioavailability enabling reduction in dose.

2) More consistent temporal profiles of drug absorption.

3) Selective targeting of drug(s) toward specific absorption window in GIT.

4) Protection of drug(s) from the hostile environment in gut.

5) Control of delivery profiles.

6) Reduced variability including food effects.

7) Protective of sensitive drug substances.

8) High drug payloads.

9) Liquid or solid dosage forms.

Disadvantages of SEDDS⁷:

1) Lack of good predicative in vitro models for assessment of the formulations.

2) Traditional dissolution methods do not work, because formulations dependent on digestion prior to release of the drug.

3) In vitro model needs further development and validation.

4) Different prototype lipid based formulations needs to be developed and tested in vivo.

5) Chemical instabilities of drugs and high surfactant concentrations in formulations (approximately 30-60%) may irritate GIT.

6) Volatile co solvents may migrate into the shells of soft or hard gelatin capsules, resulting in the precipitation of the lipophilic drugs.

The emulsification process or the mechanism of self-emulsification⁸:

Self emulsification is occurs when the entropy is greater than the energy required to increase the surface area of the dispersion. The free energy of the emulsion is a directly proportion to the energy required to create a new surface between the oil and water phases and can be explaining by the equation:

Where,

“ΔG”, =free energy associated with the process,

“N” = number of droplets;

“r”= radius of droplets and

“σ” = 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 who form a monolayer around the emulsion droplets and hence, reduce the interfacial energy as well as providing a barrier to coalescence.⁹

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).

Potential Mechanism for Absorption Enhancement seen in (fig 1)

Drug Profile¹⁰:

Ibuprofen

C₁₃H₁₈O₂Molecular weight: 206.3 grams/mole.

Ibuprofen is (RS)-2-(4-isobutyl phenyl) propionic acid.

Ibuprofen contains not less than 98.5 percent and not more than 101.0 percent of C₁₃H₁₈O₂, calculated on the dried basis. It is a white or almost white, crystalline powder or colorless crystals, odour, slight.

Excipient review:

Pharmaceutical acceptability of excipients and the toxicity issues of the components are critical for the selection of excipients. Self emulsification process is depends upon the nature of the oil/surfactant pair; the surfactant concentration and oil/surfactant ratio; the concentration and nature of co surfactant and surfactant/co-surfactant ratio and the temperature at which self- emulsification occurs^11,12. In self emulsified drug delivery system the specific combinations of pharmaceutical excipients play a major role. The formulated Self Emulsifying Drug Delivery Systems is specific to that particular drug only.

Lipids (0ils and fats):

Oil:

The oil is one of the most important excipients because it can solubilize the required dose of the lipophilic drug or facilitate self emulsification as well as increases the fraction of lipophilic drug transported via the intestinal lymphatic system, thereby increasing absorption from the GI tract depending on the molecular nature of the triglyceride¹³. Unmodified edible oils are not preferred over Modified or hydrolyzed vegetable oils because of their poor ability to dissolve large amounts of hydrophobic drugs and their relative difficulty in efficient self emulsification. Modified or hydrolyzed vegetable oils are widely used to formulate SEDDS owing to their biocompatibility¹⁴. Long and medium chain triglyceride oils are commonly used for the design of self-emulsifying formulations due to different degrees of saturation since these excipients form good emulsification systems with a large number of surfactants to exhibit better drug solubility properties¹⁵. Other suitable oil phases are digestible or non- digestible oils and fats such as linseed oil, walnut oil, soya bean oil, rice bran oil, corn oil, olive oil, canola oil, kalonji oil which are rich in omega-3 and omega-6 fatty acids and animal fats. It has reported that more lipophilic surfactant may play the role of the hydrophilic oil in the formulation. Solvent capacity for less hydrophobic drugs can be improved by blending triglycerides with mono- and di-glycerides^{16, 17, and
18}.

Fat:

Natural fats like goat fat obtained from Capra hircus can be used in the formulation of SEDDS. It has low melting point and low saponification value which makes it an ideal choice of excipients in the formulation. As it is obtained from natural source it can be easily degraded by the body without any side effects^20-32.

Surfactants³:

Surfactants are formed by two parts with different affinities for the solvents. One of them has affinity toward the water (polar solvents) and the other has for oil phase (non-polar solvents). A little amount of surfactant molecules are rest upon the water-air interface and decrease the water surface tension value (the force per unit area needed to make available surface).

The surfactants used in self emulsifying formulations are known to improving the bioavailability by various mechanisms including: increased intestinal epithelial permeability, improved dissolution increased tight junction permeability to GIT.

Surfactants may be classified based on the nature of the hydrophilic group. The four main groups of surfactants are defined as follows,

1) Anionic surfactants

2) Cationic surfactants

3) Ampholytic surfactants

4) Nonionic surfactants

Anionic Surfactants: in these hydrophilic group having a negative charge such as sulphonate (RSO3-) or sulphate (ROSO3-). Carboxyl (RCOO-).

Examples: sodium lauryl sulphate. Potassiumlaurate

Cationic surfactants: in these hydrophilic group having a positive charge.

Examples: quaternary ammonium halide.

Ampholytic surfactants (also called zwitter ionic surfactants) having both a positive and a negative charge.

Examples: sulfobetaine.

Nonionic surfactants: in these hydrophilic group having no charge but derives its water solubility from highly polar groups such as polyoxyethylene (OCH₂CH₂O), or hydroxyl.

Examples: polysorbates (Tweens), Sorbitan esters (Spans).

Number of compounds exhibit surfactant properties may be employed for the formulation of self-emulsifying systems, but the choice is limited because very few surfactants are orally acceptable. The most widely used surfactants are non-ionic surfactants with the relatively high hydrophilic-lipophilic balance (HLB). Various solid or liquid non-ionic surfactants like ethoxylated polyglycolyzed glycerides and polyoxyethylene 20 oleate (Tween 80) are the most widely used.^20-32 Non-ionic surfactants are to be less toxic compared to the ionic surface-active agents, but may cause moderate reversible changes in the intestinal wall permeability. Minimal surfactant content (3%) to avoid the potential toxicological problems associated with high concentration of the surfactant. In self-emulsifying system required to form emulsion and maintain it in the GI tract ranged from 30 to 50% w/w of the formulation. The droplets and/or rapid spreading of the formulation in the aqueous environment, provide a good self emulsifying performance. The Surface active agents are amphophilic in nature, therefore usually able to dissolved and solubilized relatively high amount of the hydrophobic drug. To prevent precipitation within the GI lumen and for the prolonged action of the drug molecules in soluble form, for effective absorption higher surfactant and co-surfactant/oil ratios are used²⁸.

Co-solvents:

Generally high surfactant concentrations (more than 30% w/w) are used in order to produce an effective self emulsifying formulation. Organic solvents are suitable for oral administration (propylene glycol (PG), ethanol, poly ethylene glycol (PEG), etc.) may be help to dissolve large quantity of the hydrophilic surfactant in the drug which is the lipid base and can act as co-surfactant in the self emulsifying drug system. Co-solvent plays the role of the co-surfactant in the self emulsion systems. This systems may exhibit some advantages over the previous formulations that when incorporated in the capsule dosage forms, since alcohol and other volatile co solvents composed in the recently self-emulsifying formulations are to migrate into the shells of soft gelatin, or hard gelatin capsules, resulting in the precipitation of the lipophilic drug. Drug release from the formulation increased with increasing amount of co-surfactant. Co-solvents may help to dissolve large quantity of hydrophilic surfactants or the hydrophobic drug in the lipid base²⁹.

MATERIALS AND METHODS:

IBUPROFEN:

Ibuprofen is a non-steroidal anti-inflammatory drug (NSAID) obtained as gift sample from ESPI Pharmaceuticals Pvt. Ltd, Uppal, Hyderabad.

Properties:

Ibuprofen exhibits anti-inflammatory, analgesic and antipyretic activities. Its analgesic effect is independent of anti-inflammatory activity and has both central and peripheral effects. It potently inhibits the enzyme cyclooxygenase resulting in the blockage of prostaglandin synthesis. It also prevents formation of thromboxane A2 by platelet aggregation. Ibuprofen is a 'core' medicine in the World Health Organization’s "WHO Model List of Essential Medicines”, which is a list of minimum medical needs for a basic healthcare system. It is easily available in the market in the doses of 200mg, 400mg, 600mg and 800mg tablets and capsules. It is a lipophilic drug and hence used in self emulsification process to enhance the bioavailability of the same.

Goat fat³⁰:

Properties:

Goat fat has lower melting point, lower saponification and higher iodine values as compared to those of other fats. Goat fat contains palmitic acid (C_16:0), stearic acid (C_18:0), oleic acid (C_18:1ω₉) and linoleic acid (C_18:2ω₆) as the major components of the fatty acid composition.

Reason: It contains omega 6 fatty acids which help in lowering cholesterol levels. Hence it is preferred over other fats.

Tween-60³¹:

It is a nonionic surfactant, supplied by Hychem chemicals Hyderabad.

Synonyms:-		Polyethylene glycol, Sorbitan monostearate, Polyoxyethylene Sorbitan monostearate.

Molecular Structure:-

Molecular Formula:-	C₂₄H₄₆O₆^.(C₂H₄O)_n

Description:- Emulsifying agent consisting of sorbitol, ethylene oxide and stearic acid (polyoxyethylene-20 Sorbitan monostearate), stearic acid is derived from vegetable oil, purity > 95%, food-grade. Yellow-brownish viscous liquid, no or weak odor. Soluble in water and alcohols, insoluble in oils. HLB value: 14.9 (gives oil-in-water emulsions)¹⁹.

Properties:-

Non-ionic, multi-purpose emulsifier (enables water and oil to mix; affect increased when combined with cetyl alcohol or Sorbitan stearate), dispersing agent, thickener antistat, solubilizer and stabilizer of essential oils. It is an emulsifying agent and acts as a co-surfactant.

METHODS:-

Preparation of standard graph (Ibuprofen):

1) 100mg of drug (ibuprofen) was taken in a 100ml volumetric flask and the volume was made up to mark with 100ml of methanol. This is stock solution A.

2) 10ml of solution A is withdrawn using a pipette and transferred into 100ml volumetric flask and the volume is made up to mark with methanol. This is solution B.

3) From solution B, 1ml, 2ml, 3ml, 4ml, 5ml, 6ml, and 7ml of solution were withdrawn using a pipette and transferred into 10ml volumetric flask each respectively. The solution was made up to mark with methanol. It gives the concentration of 10µg/ml, 20µg/ml, 30µg/ml, 40µg/ml, 50µg/ml, 60µg/ml, and 70µg/ml respectively.

4) The absorbance of the above solutions was measured at 264nm in U.V spectrophotometer using methanol as blank. A plot was constructed by taking absorbance on y-axis and concentration on x-axis.

Figure.2. standard graph of Ibuprofen

Solubility of drug in oils:

1g of drug (ibuprofen) was measured and placed in eight 15ml vials respectively. 10ml of each of linseed oil, walnut oil, soybean oil, rice bran oil, corn oil, olive oil, canola oil, and kalonji oil was pipetted out in each vial respectively. The vials were placed in beakers and kept in rotary shaker for 3 days.

After 3 days the oils were transferred into centrifuge tubes and centrifuged for 10 minutes. The liquid layer was decanted and checked for solubility in different solvents. The solubility of different oils is depicted in Table 2.

Table 2: Solubility of various oils in different solvents:

S.No	Name of oil	n-hexane	Dichloromethane	Chloroform
1.	Linseed oil	-	+	+
2.	Walnut oil	+	+	+
3.	Soy bean oil	+	-	+
4.	Rice bran oil	+	+	+
5.	Corn oil	+	+	+
6.	Olive oil	+	+	+
7.	Canola oil	+	+	+
8.	Kalonji oil (Nigella sativa oil)	+	+	+

“-” indicates insoluble.

“+” indicates soluble.

All the oils were found to dissolve in chloroform. 0.5ml of each of the oils was taken in 50ml volumetric flask and made up to mark with chloroform respectively. 1ml of oil was taken from the above solutions and transferred into 10ml volumetric flask and made up to mark with chloroform and the absorbance of resulting solutions of oils were measured in U.V. spectrophotometer using chloroform as blank at 264nm. A plot was constructed by taking absorbance on y-axis and concentration on x-axis.

Extraction of goat fat³³:

Goat fat was extracted from the adipose tissue of Capra hircus. The extraneous materials were manually separated from the adipose tissue, which was then rendered by the wet process (Attama et al., 2000). The adipose tissue was grated and subjected to moist heat by boiling with about half its weight of water in water bath for 45 min. the molten fat was separated from the aqueous phase after filtering with a muslin cloth. The fat was stored in a refrigerator until used.

Formulation of self-emulsifying tablets:

All the tablets were prepared to contain 200mg of ibuprofen each. Seven batches of tablets containing different proportions of goat fat and Tween 60 were prepared as in Table 3. In each case, the appropriate quantities of goat fat and Tween 60 are heated together in a crucible until completely homogenous. The drug was added and stirred thoroughly. The mix was poured in plastic moulds and allowed to set in refrigerator for one hour. The tablets were removed from the moulds and stored in a cool place until used.

Table 3: Formulations

Batch	Tween 60 (ml)	Goat fat (g)	Ibuprofen (g)
1.	0.3	1.2	1.0
2.	0.3	1.0	1.0
3.	0.3	1.4	1.0
4.	0.4	1.4	1.0
5.	0.6	1.0	1.0
6.	0.8	1.4	1.0
7.	0.7	1.2	1.0

Characterization:

Weight uniformity³³:

For each batch (F₂and F₄), 20 tablets were randomly selected, weighed collectively and then individually using a weighing balance (Sauter, KGD-7470, W. Germany). The result obtained was analysed statistically.

Liquefaction time³³:

Preparation of Simulated Gastric Fluid (SGF)¹⁰:

Place 62.5ml of the 0.2M KCl in 250ml of volumetric flask; add the specified volume of 0.2M

HCl (106 ml for pH 1.2), make up the volume to 250 ml with distilled water.

0.2M KCl: Dissolve 7.45g of KCl in distilled water and dilute to 500ml.

0.2M HCl: Dissolve 3.63 ml of HCl in distilled water and dilute to 500ml.

Absolute drug content:

Preparation of Simulated Intestinal Fluid (SIF)¹⁰:

Saline pH 7.4 Phosphate Buffered: Dissolve 1.19g of disodium hydrogen phosphate, 0.095g of potassium dihydrogen phosphate and 4.0g of NaCl in sufficient water to produce 500ml. adjust the pH if necessary.

Dissolution studies:

Preparation of SGF pH 1.2:

Place 250ml of 0.2M KCl in 1000ml volumetric flask, add the specified volume of 0.2M HCl (425ml for pH 1.2), and make up the volume to 1000ml with distilled water. 0.2M KCl: Dissolve 14.911g of KCl in distilled water and dilute to 1000ml. 0.2M HCl: Dissolve 6.127ml of HCl in distilled water and dilute to 1000ml. The USP apparatus -I method was adopted in this study.The dissolution medium consisted of freshly prepared SGF (900ml) maintained at 37±1ºC. A tablet was placed in the appropriate chamber of the release apparatus containing the dissolution medium, and then agitated at 100rpm. At predetermined time intervals, 5ml portions of the dissolution medium were withdrawn, appropriately diluted and their absorbance determined in the spectrophotometer. The volume of dissolution medium was kept constant by replacing it with 5ml of fresh SGF after each withdrawal. The concentrations were determined with reference to the standard Beer’s plot.

RESULTS AND DISCUSSIONS:

Solubility of drugs in oils:

The absorbance of various oils were found as follows:

Table 4: Measurement of absorbance of various oils at 264nm

S.No	Name of oil	Absorbance
1.	Olive oil	0.134
2.	Rice bran oil	0.381
3.	Soy bean oil	0.464
4.	Walnut oil	0.583
5.	Canola oil	0.754
6.	Kalonji oil	1.246
7.	Linseed oil	1.819

Figure.3 A graph was plotted taking concentration of oils on x-axis and absorbance on y-axis.

The results of weight uniformity tests (Table 5) showed that the F₂and F₄ tablets had low coefficients of variation, and thus passed the weight specifications for compressed uncoated tablets in the compendium (Lund, 1994). Weight variation may be due to sedimentation of active ingredient if insoluble in base. In this case, however, the observed variation may be due to non-uniformity in filling the mould since it was done manually.

Table 5: Results of weight uniformity of F₂ and F₄ formulations

Batch (Formulations)	Mean weight (mean± CV)	Liquefaction time (min±S.D)	Drug content (mg±SD)
F1	380.2±2.3	03.28	189.12±1.34
F2	440.2±1.5	05.28	198.20±2.32
F3	286.1±4.2	18.29	204.31±2.17
F4	552.4±3.2	07.28	200.12±2.24
F5	630.1±3.2	05.43	156.23±1.52
F6	587.2±3.2	06.24	178.12±1.34
F7	164.5±2.3	09.23	145.20±2.32

CV=Coefficient of Variation, SD= standard deviation

Liquefaction time³³:

The liquefaction times (Table 5) were slightly high when compared to disintegration standards for compressed uncoated tablets. This may not pose any problem because agitation was not used in the test. This test was designed to estimate the time it could take the tablets to melt in vivo under no agitation at normal body temperature. At gastrointestinal conditions, however, gastrointestinal motility will likely lower the liquefaction time, resulting in faster emulsification and penetration of the aqueous fluid into tablet interior. This will ensure drug release even before tablet integrity fails. For each batch, 20 tablets were tested (n=20). Statistical treatment of the liquefaction time data indicated low standard deviations (Table 5). However, the average times for the different batches were statistically different. Since the liquefaction times of the tablets were long at 37ºC, the tablets can withstand the effect of temperature increases in the tropics. However, for the tropical areas where temperature increases up to 37ºC or greater are recorded, it is advised that the tablets should be stored in conditions similar to conventional suppository formulation.

Absolute drug content³³:

F₂ and F₄ formulations were selected for absolute drug content calculation. A weight equivalent to average weight of 20 tablets of F₂and F₄ was taken as 440mg and 550mg respectively. The absorbance of the above formulations was determined in U.V spectrophotometer at wavelength of about 264nm.it was done five times for each formulation. The absolute drug content was calculated with reference to standard Beer’s plot.

Dissolution studies:

Table 6 shows the percentage drug release of F₂ and F₄ formulation against marketed drug (Ibuprofen 200mg) during time intervals of 10, 20, 30, 40, 50 and 60 minutes respectively.

Table 6: Results of Dissolution Studies

S.No	Time (in min)	Percentage Drug Release (%)
S.No	Time (in min)	F₂	F₄	standard
1.	10	21.41	26.58	42.81
2.	20	27.79	28.50	48.84
3.	30	31.17	37.18	51.83
4.	40	33.43	64.00	57.84
5.	50	57.84	81.50	58.62
6.	60	84.91	286.96	61.59

Figure.4 A graph was plotted using the above values by taking time on x-axis and percentage drug release on y-axis.

The results as depicted in the graph show that the formulations F₂and F₄show enhanced dissolution when compared to marketed product ibuprofen of dose 200mg. Both F₂ and F₄ formulations show almost similar percentage drug release at 60 minutes of time interval. Hence it is concluded that by increasing the concentration of Tween 60 and decreasing the content of fat enhanced dissolution profiles are obtained. The drug undergoes better self-emulsification by altering the above parameters.

Therefore it can be concluded that the formulations pass the dissolution test.

SUMMARY AND CONCLUSION:

The tablets showed good release profile, as well as acceptable tablet properties. The batches with higher tween60:goat fat content ratios gave better release rates. Under mild agitation as occurs under gastrointestinal conditions, the release rates may be Comparable to those of conventional tablets. This method has advantage of reliance on cheap raw materials such as goat fat. It also employes fewer processing steps. It is best suited for lipophilic drugs where the resulting emulsification gives faster dissolution rates and absorption. It can be used on a small scale in hospitals without need for heavy processing equipment. Invivo evaluation of this novel dosage form is currently in progress. Self-emulsifying drug delivery systems are a promising approach for the formulation of lipophilic drug compounds having poor aqueous solubility. The oral delivery of hydrophobic drugs can be made possible by SEDDSs, which have been shown to substantially improve oral bioavailability. From the formulation point of view it is necessary to consider the emulsification properties of lipid base vehicle and the solubility of drug in the lipid surfactant mixture to form a completely miscible solution so as to solubilize adequate quantities of drug in lipid vehicle. Lipid is having an important role in absorption process. Hence, SEDDS plays an important role in the formulation of poorly water soluble drugs and enhancing their bioavailability. The SEDDS of Ibuprofen was successfully prepared and the tablets prepared passed the various evaluation tests conducted. Therefore, it can be concluded that with further development of this technology SEDDSs will continue to enable novel applications in drug delivery and solve problems associated with the delivery of poorly soluble drugs.

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33. The use of solid self-emulsifying systems in the delivery of diclofenac A.A Attama I.T Nzekwe, P.O Nnamani, M.U Adikwu, C.O Onugu Department of Pharmaceutics, Drug Delivery Research Unit, University of Nigeria, Nsukka, Enugu State, Nigeria Mobil Oil Producing Clinic, Eket Akwa-Ibom State, Nigeria

Received on 21.09.2016 Accepted on 27.10.2016

Asian J. Pharm. Tech. 2016; 6(4): 257-265.

DOI: 10.5958/2231-5713.2016.00037.4