INTRODUCTION:

Among currently marketed formulations around 40% and more than 70% of molecules under development stage today are facing bioavailability problems because of their poor solubility¹. We can’t avoid these poorly soluble drugs owing to their superior therapeutic effects and led us to develop formulation strategies to enhance bioavailability². If formulated with lipids oral bioavailability of poorly water-soluble drugs may be enhanced. One of the accepted approaches is lipid and surfactant-based drug delivery systems such as Self- nano emulsifying drug delivery systems^3,4.

Self-Nano emulsifying drug-delivery systems (SNEDDS) have evolved as an effective delivery system due to their proven ability to augment bioavailability of poorly soluble drugs⁵.

SNEDDS is a thermodynamically stable isotropic mixture of drug dissolved in oil, surfactant and co-surfactant when introduced into an aqueous medium under gentle agitation that form a spontaneous oil-in-water nanoemulsion with a droplet size less than 200 nm⁶. The free energy required for self-nano emulsification process is low, consequently the process will occur spontaneously³.

Several potential advantages of SNEDDS were drug was presented in a solubilized form inside the gastrointestinal (GI) lumen in a Nano sized globule thus providing greater interfacial area for drug dissolution there by enhancing absorption⁷, improving lymphatic transport, evading hepatic first-pass effect, providing greater chemical and enzymatic stability, and also by inhibiting P-glycoprotein (P-gp) mediated drug efflux,. Components of SNEDDS and their concentrations have profound effect upon droplet size of the formed nanoemulsion which may affect its in-vitro and in-vivo performance^6,8.

The excipients used in SNEDDS include oils (synthetic origin/natural origin), surfactants (hydrophobic/ hydrophilic), Co-surfactants (hydrophilic/hydrophobic). Once prepared, the SNEDDS can be administered as solutions in the form of liquid-encapsulated soft gelatin capsules or liquid-filled HPMC capsules for convenient oral administration as unit dosage form. since 1997 pharmaceutical market was Experienced with a few nSNEDDS-based products cyclosporin (Sandimmun Neoral, Novartis Pharmaceutical Ltd.), and subsequently for ritonavir (Norvir1, Abbott Laboratories), and saquinavir (Fortovase1, Roche Pharmaceuticals, but the best utilization of this pharmaceutical formulation strategy is still on its way⁹.

Oral antihyperglycemic agent Repaglinide widely used for the treatment of non-insulin-dependent diabetes mellitus, which was invented in 1983. Repaglinide stimulating the release of insulin from the pancreas there by lowers blood glucose. Repaglinide is a poorly water-Soluble compound, with water solubility of approximately 20μg/mL, possessing high lipophilicity (logP = 3.97) and relatively low oral bioavailability (around 56%) which is attributed to poor dissolution (BCS class II) and it also undergoes hepatic first pass metabolism^10,11,12. Compounds having aqueous solubility lower than 100µg/mL commonly suffer dissolution-limited absorption¹³. The current investigation was carried out to increase dissolution characteristics of Repaglinide by preparing as SNEDDS.

MATERIALS AND METHODS:

Materials:

Repaglinide was a generous gift of Aurabindo Pharma Pvt Ltd., Vizag, India. Deve Herbs, Delhi supplied corn oil, Castor oil, Sun flower oil, Coconut oil, Almond oil were obtained from Aromatique. Brij35, Triacetin, Span 20, Span 80, Tween 20, Tween 80 were purchased from Loba chem. Pvt. Ltd, Mumbai, India. Cremophor RH40 was a gift sample provided by B.A.S.F Corporation. Transcutol P was generous gift sample by Avra Synthesis Pvt Ltd, Hyderabad, India.

Methods:

Solubility studies:

Solubility is an important parameter in determining the excipients for the formulation of SNEDDS. The solubility in various vehicles like oil, surfactant and co-surfactant was determined by shake flask method, studies were conducted by dissolving an excess amount of drug in 2ml of the vehicle. Then the mixture was vortexed and kept for 72hrs in a rotary shaker to facilitate the solubilisation. The samples were subjected to centrifugation at 3000rpm for 30min, the supernatant liquid was filtered and diluted with suitable organic solvent. drug concentration in each vehicle was quantified by UV-Spectrophotometer¹⁴.

Construction of Ternary Phase Diagram:

Ternary phase diagrams were constructed to identify the regions of self-emulsification and to optimize the percentage of oil, surfactant, and co-surfactant in the liquid SNEDDS formulations. The various mixture of s-mix was prepared by using surfactant and co-surfactant from 1:1 to 1:9; 2:1 to 9:1. All s-mix ratios were examined manually for clear nanoemulsion formation upon dilution with water. The ratios which formed nanoemulsion are subjected to the ternary diagram for analyzing the nano region followed by % transmittance.

Formulation of liquid SNEDDS:

SNEDDS formulations were prepared by using components like oil, surfactant, and co-surfactant mixing in different ratios¹⁵. A unit dose of repaglinide (2mg) was loaded into the oil. The SNEDDS were prepared by dissolving the drug in oil and by adding surfactant and co-surfactant. The resultant mixture was mixed continuously by using a vertex mixture to get a homogenous isotropic mixture to add drop by drop water to form an emulsion¹⁶. This is also known as the self-emulsification method (also known as Phase inversion composition method; standard admixture method).

Characterization:

1. Percent Transmittance:

The formulation was diluted with 500ml of distilled water and the resultant solution was examined for any turbidity. Thereafter, it’s percent transmittance was measured by using UV Visible spectrophotometer at 638.2nm against distill water as blank¹⁷.

2. Self-emulsification time:

This test was carried out in USP dissolution apparatus type-II. The undiluted 1mLformulations were added to 250mL of water and maintain the temperature at 37°C with 50rpm to provide gentle agitations. The time taken by the formulation to form emulsion was noted and visually observed for any turbidity¹⁸.

3. Cloud Point measurement:

The formulations were subjected to cloud point value. Each formulation was diluted with water in the ratio of 1:100 and heated. The temperature was gradually increased up to the cloudiness was observed in the beaker by visually¹⁹.

4. Measurement of Globule size and PDI:

The globule size and PDI of the reconstituted SNEDDS can be obtained by using Malvern Zeta Seizer. The mean globule size and PDI were recorded²⁰.

5. Centrifugation study:

The Screened formulations were subjected to centrifugation at 5000RPM for 30 minutes. The formulation was subjected to visual observation for any precipitation, phase separation and cracking. Stable formulations are selected for further works^21,22.

6. Dispersibility Test:

All the undiluted formulations were diluted with water at ratio of 1:200 in a beaker at room temperature and provide agitations by manually. Observe visually for clarity and turbidity according to grading scale from grade A to grade E²³.

7. In vitro Drug release study:

In vitro drug release study was carried out for all formulations, Marketed product and pure drug by conventional method. HPMC capsule size “00” filled with SNEDDS (equivalent to 2mg repaglinide) separately were put in 900mL of 7.4 phosphate buffer at 50rpm and 37±0.5ºC using USP apparatus type II. At predetermined time intervals (5, 10, 15, 30, 45, and 60) aliquots of samples (5mL) were collected and filtered through membrane filter, suitably diluted and analyzed spectrophotometrically at 243nm. The in vitro dissolution data were analyzed and interpreted by plotting a graph for cumulative percentage drug release was against time (h).

RESULTS AND DISCUSSION:

Solubility:

Solubility is the utmost parameter in developing a formulation. The solubility of drug molecule in the formulation excipients is necessary to avoid precipitation before undergoing formation of emulsion in situ manner ^24,25. The main perspective in oil consideration is drug loading capacity for formulation which means high solubility of drug that lowers the usage of other excipients in formulation thereby decreasing their toxicity²⁶.

The solubility of the repaglinide was conducted in different LCT’s (Castor oil, Sun flower oil, Coconut oil, almond oil) and MCT’s (Corn oil, Papaya seed oil, Triacetin, caprylic acid), which favors lymphatic transportation. Among various oils, corn oil (14mg/mL) has shown a high solubilizing capacity for repaglinide compared with other oils due to presence of medium chain triglycerides which favors high solubilizing capacity²⁷.

By selecting good combination of high HLB value and low HLB value surfactants which increases solubility and formation of nano emulsion²⁸. The solubility of repaglinide was more in surfactant than in oils. This would be attributed to intermediate partition coefficient of repaglinide²⁹ (Log P=5). The solubility results were presented in the following Table no: 1. From the saturation solubility results of the repaglinide shown that maximum solubility was found in Cremophor RH40 (21mg/mL) and Transcutol (48mg/mL) were selected as surfactant and co surfactant.

Table No. 1: Solubility of Repaglinide in various vehicles

S. No	Vehicle	Solubility (mg/mL)
1	Corn oil	14
2	Papaya Seed oil	6
3	Triacetin	4
4	Caprylic acid	2
5	Castor oil	2
6	Sun flower oil	1
7	Coconut oil	5
8	Almond oil	3.5
9	Cremophor RH 40	21
10	Brij 35	10
11	Transcutol	48
12	Span 20	2
13	Span 80	8
14	Tween 20	11
15	Tween 80	3

Construction of Ternary Phase Diagrams:

The self-emulsification process depends upon selection of individual excipients in the formulation³⁰. From the ternary phase diagrams we can observe the self nano emulsifying region which helps in selection of appropriate ratios of compounds³¹. It also helps in selection of suitable excipients ratios for preparing formulation which forms spontaneous emulsion within GI condition upon mild agitation.

The ternary diagram were drawn in absence of Repaglinide by using distill water for formation of emulsion. The region which was shaded indicates the desired nano emulsion droplet size. From the trails (Table No: 2) different combinations of S mix (Surfactant : Co Surfactant) combinations were done from 1:1 to 1:9 and 2:1 to 9:1 by using different oils, only the corn oil has ability to form nano emulsion with small emulsifying region only and the ratios which shown nano emulsion are subjected to ternary phase diagrams. From the diagram we selected 10 ratios (Table No: 3) and carried out further work which has high oil concentration which helps in increasing solubility of drug³².

Table No. 2: – Ternary Trail Ratio’s

S. No	Ternary Trails Ratio Combinations
1	S-mix Ratio (Cremophor RH 40 – Transcutol) from 1:1 to 1:9 and 2:1 to 9:1 with Corn oil
2	S-mix Ratio (Cremophor RH 40 – Transcutol) from 1:1 to 1:9 and 2:1 to 9:1 with Papaya Seed oil
3	S-mix Ratio (Cremophor RH 40 – Transcutol) from 1:1 to 1:9 and 2:1 to 9:1 with Triacetin oil
4	S-mix Ratio (Cremophor RH 40 – Transcutol) from 1:1 to 1:9 and 2:1 to 9:1 with Caprylic acid oil
5	S-mix Ratio (Cremophor RH 40 – Transcutol) from 1:1 to 1:9 and 2:1 to 9:1 with Castor oil
6	S-mix Ratio (Cremophor RH 40 – Transcutol) from 1:1 to 1:9 and 2:1 to 9:1 with Coconut oil
7	S-mix Ratio (Cremophor RH 40 – Transcutol) from 1:1 to 1:9 and 2:1 to 9:1 with Almond oil
8	S-mix Ratio (Cremophor RH 40 – Transcutol) from 1:1 to 1:9 and 2:1 to 9:1 with Sun flower oil

Fig 1: Ternary phase diagram of corn oil: cremophor RH 40: transcutol P (Smix ratio 8:1)

Table No 3: -Composition of Repaglinide loaded SNEDDS

Composition (%w/w)
S. No	Formulation code	Corn oil	Cremophor RH40	Transcutol
1	F1	15	70	15
2	F2	12	73	15
3	F3	10	75	15
4	F4	8	77	15
5	F5	5	80	15
6	F6	15	75	10
7	F7	12	75	13
8	F8	10	75	15
9	F9	8	75	17
10	F10	5	75	20

Percent Transmittance:

The selected ratios were carried out percent transmittance to check the presence of nano size emulsion droplet. Each undiluted formulation was diluted with 5mL of distill water and subjected to percent transmittance by using UV Spectrophotometer. The values of percent transmittance were presented in Table No: 4. From the results we observed that formulation prepared by corn oil with cremophor RH 40 and Transcutol has shown that high percent transmittance (>95%) for only 2 formulations, it indicates the formed emulsion was in nano size ³³. The formulations (F5, F10) which shown nanosize is carried out for further evaluation tests.

Table No. 4: Percent Transmittance

S. No	Formulation Code	Percent Transmittance	Absorbance
1	F1	1.2	0.312
2	F2	0.3	0.622
3	F3	3.1	0.593
4	F4	88.4	0.076
5	F5	98.9	0.028
6	F6	7.1	0.503
7	F7	0.3	0.828
8	F8	84.8	0.087
9	F9	87.6	0.081
10	F10	99.9	0.030

Self-Emulsification Time:

After administration of SNEDDS, where they are exposed to GI fluids to form emulsion, they should disperse quickly upon GI movements²³. The Self emulsification time (SET) is a major parameter for assessing efficiency of formulation. The values of self-emulsification time were presented in Table No: 5. The formulations which having high concentration of cremophor RH 40 requires more time to get disperse in to medium. Due to the surfactant will form gel upon contact with water therefore more amount of shear force to disperse intermediate structures into medium to form emulsion^19,34.

Table No 5:- Self Emulsification Time

S. No	Formulation Code	Self Emulsification Time (Sec)	Dispersibility and Precipitation	Phase Separation
1	F4	103	A	XX
2	F5	105	A	XX
3	F8	103	A	XX
4	F9	107	A	XX
5	F10	110	A	XX

Grade A – good dispersibility and no precipitation xx- not observed

Dispersibility test, Phase separation and Precipitation:

Visual observations for phase separation and precipitation of SNEDDS formulations were reported in Table No: 5. All formulations were found to grading A dispersibility with no precipitation and no phase separation.

Particle Size:

The undiluted formulation was diluted with 5ml of water then subjected to zeta seizer to determine the particle size of the emulsion. The droplet size will have significant effect in drug absorption and distribution if the particle droplet size is small then it has large interfacial area which promotes drug diffusion ³².From the values we observed that there is no significant difference in mean droplet size with small PDI values suggesting that good uniformity of droplet size distribution after dilution. The following Table No: 6 shows the particle size values.

Table No. 6: Particle Size

S. No	Formulation Code	Particle Size (nm)	PDI
1	F4	160	0.318
2	F5	153	0.325
3	F8	165	0.315
4	F9	169	0.321
5	F10	158	0.338

Fig 2: particle size analysis by zeta sizer

Cloud Point and Optical clarity:

The cloud point describes at which temperature the formulation is going to unstable due to dehydration of polyethylene chains present in surfactants^19,35and while the optical clarity explains about the transparency of the formulation which depends upon the matter present in the formulation. From the results (Table No: 7) prepared formulations shown cloud point above 80°C that means formulation is stable and avoiding phase separation in the GIT¹⁶. The optical clarity of the diluted formulation after 24hrs was determined by using UV Spectrophotometer was found to be above 98%, by correlating with % transmittance values that formulation contains nano size particles.

Table No. 7: Optical clarity and Cloud Point

S. No	Formulation Code	Cloud Point	Optical Clarity
1	F4	79±1.45	88.4±0.25
2	F5	84 ± 1.34	98.07±0.52
3	F8	78±0.90	87.6±0.54
4	F9	83±1.24	84.8±0.63
5	F10	80 ± 1.78	97.9±0.73

In-vitro Dissolution:

The in vitro drug release states that the entrapped drug release pattern from the formulation into the medium/ gi fluids³⁶. The invitro drug release profile was carried out for pure drug, prepared formulations and marketed formulations. The release pattern states that drug release has significantly increased in the prepared formulation than pure drug. Repaglinide is a BCS class-II drug which has low solubility at in situ which results to low solubility. From the release pattern has shown that high drug release from the formulation which represents the solubility of the drug has been increase due to formation of nano sized particle size which has high interfacial area for diffusion. Maximum release was observed from the F5, F10(97.8% and 98% of drug release) for 60 min with non-significant manner (Table No: 8). This may be due to their small mean droplet size (153nm and 158 nm) and proper composition of excipients in formulation. Repaglinide marketed tablet was seen to release 62 percent of drug at the end of 60 minutes, and pure drug has shown only 32 percent. The SNEDDS formulations of repaglinide F5, F10 had good release in less time as discussed. The in-vitro drug release studies results in phosphate buffer are clear evidence of enhanced dissolution of the Repaglinide by increasing solubility and by decreasing particle size there by increasing the surface area leaving the drug into fine dispersions into dissolution media which increases dissolution rate.

Fig 3: Comparative In-vitro Drug Release Studies

ACKNOWLEDGEMENT:

The authors are grateful to the authorities of University College of Pharmaceutical Sciences, Acharya Nagarjuna University for the facilities.

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

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Received on 25.02.2020 Modified on 11.04.2020

Research J. Pharm. and Tech. 2020; 13(11):5283-5288.

DOI: 10.5958/0974-360X.2020.00924.5

S. No	Formulation	5 (Min)	10 (Min)	15 (Min)	30 (Min)	45 (Min)	60 (Min)
1	Pure Drug	3.41	11.27	18.49	23.75	29.16	32.28
2	F4	11.56	38.94	49.47	60.75	74.89	88.70
3	F5	12.56	41.08	50.46	63.54	76.90	97.42
4	F8	12.78	42.86	51.25	62.47	77.89	89.74
5	F9	13.34	39.33	48.47	68.75	79.52	92.47
6	F10	13.07	35.1	51.45	71.29	83.26	98.69
7	Marketed Product	9.72	19.35	30.67	49.58	54.52	62.98