Design, Development and Evaluation of Solid Form of Liquid

Self-Nanoemulsifying Formulation for improving the Oral Bioavailability of Itraconazole

 

Vinod Kumar Yadav, Balamuralidhara V*, Hemanth Kumar S

Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Mysuru - 570015, Karnataka, India.

 

ABSTRACT:

The aim of the present study is to improve the dissolution rate and developed Itraconazole solid powder. Cotton seed oil, tween 80 and transcutol were selected as key ingredients to formulated self-nanoemulsifying drug delivery system. Ternary phase diagrams were constructed, several formulations were designed. These formulations were characterized and evaluated for parameters such as thermodynamic stability, emulsifying rate, robustness to dilution and pH effects, globules size, zeta potential, in vitro study etc. The optimized formulation has globules size of 141.20±0.69 nm, pdi 0.29±0.04, zeta potential 11.2±0.69 mV and fast dissolution as within 30 min with more than 90 % drug released. Further cytotoxicity studies of optimized formulation revealed safe formulation. Using neusilin US2 as solid adsorbent method to transformed the optimized formulation into powder form. It was further characterized and evaluated and the obtained results are acceptable. In vitro drug released of solid self-nanoemulsifying formulation and liquid self-nanoemulsifying formulation has almost similar. Thus, can conclude that implementation of solid approach of this strategy could be considered as alternative approach.

 

 

1. INTRODUCTION:

Oral drug delivery system is safe, comfortable and widely accepted by patient. Due to lack appropriate dissolution and absorption efficacy, only a small fraction of the drug reaches into the systemic circulation resulting in poor bioavailability thus resulting in inadequate therapeutic efficacy^1,2. Itraconazole belongs to BCS class II and was selected as model drug. Itraconazole is a poor aqueous soluble drug thereby dissolution rate is limiting step for it absorption³. Several formulations have been developed with the objective to enhance the therapeutic efficacy of drug by improving dissolution profile^4,5.

 

However, among various formulations, self-nanoemulsifying drug delivery system (SNEDDS) is a strategic and promising approach due to present of pre-dissolve drug and high durability. Self-nanoemulsifying drug delivery system improves the bioavailability via several mechanisms such as improved solubilization efficacy, promote drug absorption via lymphatic system thereby avoiding hepatic first pass metabolism, protect drug from efflux and food effects etc. It is already a well-established drug delivery system and is available for several marketed drug products representing its effectiveness and efficacy. Self-nanoemulsifying drug delivery system is an isotropic mixture of oil either natural or synthetic, surfactant and co-surfactant (cosolvent) which forms small globules called nanoemulsion when comes in contact with the gastrointestinal tract or other fluids on mild agitation. The nanosize range of globules has larger surface areas which easily solubilize in the gastrointestinal fluids thus improving the dissolution rate and drug absorption and permeation across the cell membrane^6,7. Recently, several research investigations have claimed some drawbacks of liquid self-nanoemulsifying formulation such as lack of stability, leaching of volatile substance into the gelatine shell, handling, stability etc. Thus, aim of this research work was to developed solid form of liquid self-nanoemulsifying formulation. Solid adsorbent technique is simple, easy and suitable approach to transform liquid self-nanoemulsifying drug delivery system into solid self-nanoemulsifying drug delivery system⁸. The most important and remarkable advantage of this technique is that there is no special device required for solidification.

 

2. MATERIAL AND METHODS:

2.1 Material:

Itraconazole was obtained gift sample from Hetro Labs Ltd., India, Labrafill M 1994 CS, Plurol oleique CC 497, Transcutol P, Labrasol, Labrasol PG, Labrasol ALF, were procured as gift samples from Gattefosse, Mumbai, India. Hariol IPM was procured as gift sample from Subhash chemical Pune, India. Cotton seed oil, peanut oil was procured as gift samples from Genuine Chemicals Co., Mumbai. Capmul MCM EP and Captex 200 were gift sample from Abitec Group, USA, Tween 80 from Loba Chemie Pvt Ltd., Mumbai, Triethyamine, Polyethylene glycol 200, Polyethylene glycol 400 was procured from Merck, Mumbai. Neusilin US2 and Fujicalin SG obtained gift samples from Gangwal Chemical, Thane, India. All other chemicals were used analytic grade.

 

2.2 Method:

2.2.1 Selection of lipid components:

Solubility study method was used to assess the suitable lipid components. An excess amount of drug was introduced into 1mL of selected different vehicles in 2 ml capacity of eppendraff tube, and mixed in vortex mixer for 10 min. These tubes were placed in an isothermal shaker at 25±1℃ for 72 h to reach equilibrium solubility. The equilibrated samples were removed and centrifuged at 3000rpm for 15 min to remove undissolved drug. The supernatants were filtered using 0.45µm filter paper and diluted with methanol. The samples were analyzed using UV spectroscopy method to estimate the amount of drug dissolve in various components. All experiments were performed in triplicate⁹.

 

2.2.2 Construction of ternary phase diagrams:

Ternary phase diagram plays a massive role to identify nanoemulsion area and also widely used to design the formulation. Pseudo ternary phase diagrams were constructed by using aqueous titration method. The selected lipid components were used to make the ternary phase diagram with using 4 components such estimated oil, surfactant, co surfactant, and aqueous phase (distilled water). Surfactant and co surfactant mixture (Smix)S/CoS) in each group were mixed in different ratios (1:0, 1:1, 1:2, 1:3, 1:4, 2:1, 3:1, 4:1). The several composition of mixture was taken and titrated using double distilled water and visually observed for phase clarity and followability¹⁰.

 

3. Characterization of self-nanoemulsifying prepared formulations:

3.1 Thermodynamic stability studies:

Thermodynamic stability study was performed on selected formulations from phase diagrams to identify and avoid the metastable issues¹¹. Following were the tests;

 

A. Centrifugation:

The liquid self-nanoemulsifying formulation was subjected to centrifugation studies. The selected formulations were centrifuged at 3500rpm for 30 mins to analyse the formulation stability in the term of phase separation or precipitation.

 

B. Heating and cooling cycle:

This is an approach used to estimate the formulation stability at different established temperatures. This study was carried out at two different temperatures i.e., 4°C and 45°C with six cycles and storage above 48 hours at each temperature.

 

C. Freeze Thaw Cycle:

Free thaw cycle study was carried out at different temperatures such as -21ºC and +25ºC. The formulations were stored for over 48 hrs at each temperature, and visually observed.

 

3.2 Dispersibility Test or Self-emulsification test:

Dispersibility test is conducted to assess self-emulsification efficacy (rate of emulsification) of formulation. This test was performed by using a standard USP XXII dissolution apparatus II as per as previous described method. 1ml or 0.5ml sample was taken from each formulations and dispersed in dissolution media contain 500ml of milli-Q with constant stirring for 50rpm at 37±1°C temperature in water¹². Visually examined the formulations for phase separation or precipitation using grade system to selected suitable formulation as follow;

Grade A: Nanoemulsion rapidly formed either within 1 min or 30 sec. as clear or bluish appearance.

Grade B: Nanoemulsion rapidly formed either within 1 min but slightly less clear or bluish white appearance.

Grade C: Nanoemulsion formed milky within 2 min.

Grade D: Dull, greyish white emulsion having slightly oily appearance greater than 2 min.

Grade E: Either poor or minimum emulsification with large oil globules.

3.3 Robustness to Dilution and pH Effect:

The selected SNEDDS formulations were studies for robustness to dilution and pH effect by diluting 50, 100 and 1000 and 3000 times in various diluted media i.e. water and phosphate buffer1.2, phosphate buffer 6.8, and phosphate buffer 7.4. The diluted samples were stored for 24 hrs and visually observe for any indication of phase separation or drug precipitation. The formulations which have no sign of precipitation or cloudy and produce clear or slightly bluish clear nanoemulsions in various diluted medias with numerous dilution ranges is indication to pass the test¹³.

 

3.4 Refractive index and percent transmittance:

Refractive index and percent transmittance is used to analysis the transparency of formulation. Abbe type refractometer was used to determine the refractive index. However, percent transmittance was measured at particular wavelength using UV spectrophotometer by using distilled water as blank.

 

3.5 Viscosity:

Viscosity is also one of the important parameter for determination of release and stability efficacy.

 

3.6 Measurement (Assessment) of globule size, polydispersity index and zeta potential:

In this study, globules size, polydispersive index and zeta potential of selected formulations were collectively determined by Microtrac (Nanotrac Wave, USA). The size of the globules is vital and impact key role in solubility, permeability, degradation,  stability etc.[14]

 

3.7 In vitro drug released studies:

This study was performed using dissolution apparatus II in triplicate as previously described. The in vitro drug release studies of the selected liquid self-nanoemulsifying formulations, pure drug and solid self-nanoemulsifying drug delivery system were performed using USP dissolution test apparatus II (TDT-08L; Electrolab Lab) containing 900ml of dissolution media (phosphate buffer pH 1.2 at 37±0.5°C temperature with 50rpm. 5ml sample aliquots from each formulation at pre-determined time intervals such as 0, 5, 10, 15, 20, 30, 45, and 60 minutes was collected. An equal amount of fresh media was added to each withdraw sample with stable temperature. The withdrawn samples were analysed through UV-visible spectrophotometer (UV-1700) at 255nm⁹.

 

3.8 Cytotoxicity study:

The cytotoxicity study of optimized liquid self-nanoemulsifying formulation was carried out on Caco-2 cells by MTT method as previous described methods. Caco-2 cells were seeded in 96-well plates at a density of 8 × 103 cells/well (1x10⁴ cells, 2x10⁵ cells) and incubated for 72 hrs at 37⁰C in CO₂ incubator. Then the solutions were removed at the predetermined times such as 24, 48 and 72 hrs. The formed formazan crystals were dissolved in 100 - 150µL of dimethyl sulfoxide. After solubilization, the absorbance of the solubilized solution was estimated at the wavelength of 570nm using microplate reader¹⁵.

 

3.9 Solid self-nanoemulsifying drug delivery system (S-SNEDDS):

Generally, self-nanoemulsifying drug delivery system is formulated in liquid or semisolid form and encapsulated within the soft gelatin capsule. Recently, several research investigations have revealed some drawbacks of liquid self-nanoemulsifying drug delivery system such as drug precipitation; handling etc. Solid adsorbent method has preferred due to easy and flexibility¹⁶.

 

4. Solid state characterizations:

4.1 Fourier-transform infrared spectroscopy (FTIR):

An FTIR study was used to determine the possible interaction of drug, lipid components, solid adsorbent and solid self-nanoemulsifying formulation. Each sample was mixed with potassium bromide (KBr) in 1:4 ratio and ground to a fine powder using mortar and pestle and made into transparent KBr pellet using a hydraulic pressure (Beckman Instruments Inc., Fullerton, USA) set at 4-5 tons pressure. FTIR spectrophotometer was used to scan the prepared pellets of different samples from the range of 4000-400 cm-1 (FTIR 8400 S, Shimadzu.)¹⁷

 

4.2 DSC Studies:

Thermal analysis of pure drug, solid adsorbent and solid self-nanoemulsifying formulation were determine by using DSC -60 Shimadzu, Japan). Briefly, about 2-3mg of pure drug, solid adsorbent and solid self-nanoemulsifying formulation were separately weighed and taken in non-hermetically aluminium pans and crimped respectively. An empty pan, sealed in the same way as that of the sample, was used as a reference. The DSC thermogram covered the range of 20-300°C with 10^oC/min heating rate under constant 50mL/min flow rate purging of nitrogen. DSC thermograms were analyzed using TA universal analysis software¹⁸.

 

4.3 X-RD studies:

X-RD studies of pure drug, solid adsorbent and solid self-nanoemulsifying formulation were measured using an X’Pert PRO diffractometer from a range of 2° to 60°C at a rate of 2°C per minute at scanned over 2θ¹⁹.

 

4.4 Scanning electron microscopy:

The topography of drug, solid adsorbent and solid self-nanoemulsifying formulation were examined using scanning electron microscopy (S-4100, Hitachi, Japan). For this, samples were mounted through metal stub with a double sided carbon adhesive tape and gold coated in vacuum, individually. The SEM images were captured at magnitudes of 100, 500 at 15 kV of an accelerating voltage. [20]

 

5. RESULT AND DISCUSSION:

5.1 Selection of lipid components:

Selection of lipid components was done based on higher drug solubility. Among of various oils, cotton seed oil was selected, tween 80 was selected as surfactant, transcutol P as co-surfactants due to higher solubility. Thus, cotton seed oil, tween 80 and transcutol P are key ingredients of the formulation. While, appropriate drug solubility is crucially important else not easy to maintain the drug in solubilized form in gastrointestinal fluids and may cause precipitation which may lead to lack of efficacious therapeutic activity. Cotton seed oil is natural oil and widely used solubilizing agent in lipid drug delivery system. Natural oils are more biocompatible with the biological membrane and high durability. However, most of drug molecules have reveals low solubility with natural oils because of less fatty constituents and few drug reveals appropriate solubility. Thus, physiochemical properties of drug molecules and oil are consider as important as play the most significant role in drug delivery system. Surfactant is one of basic components and especially non-ionic surfactant has preferred due to less toxicity and robustness. Tween 80 is non-ionic surfactant, biocompatible, non-toxic in nature, and also less affected by pH and ionic strength. While, an access amount of surfactant in formulation may lead to allergic or gastrointestinal irritation therefore should be avoided²¹. While, co-surfactant or cosolvent has used to accelerate the formulation solubilization efficacy and also reduces surfactant concentration thereby considered as co-surfactant. Although, the selected oil, surfactant and co-surfactant were used to formulate the self-nanoemulsifying drug delivery system.

 

5.2 Construction of ternary phase diagrams:

Ternary phase diagrams were constructed using optimized surfactant and cosurfactant (Smix) with oil in several ratios against double distilled water. The shadow area present in ternary phase diagram is representing nanoemulsion area and it used for formulation designed. Whereas, several formulations were designed with varies composition of selected oil, surfactant and co-surfactant. Although, in this research has preferred to select the suitable formulation with minimum level of surfactant. Although, the ternary phase diagram of optimized formulation is showing in Figure 1.

 

Figure 1. Ternary phase diagram of optimized formulation (D8)

 

5.3 Thermodynamic stability test:

This study has performed in order to avoid the metastable formulation and enable the appropriate formulation composition. Nanoemulsion has thermodynamically stable which formed using a certain range of basic components without precipitation or phase separation. Whereas, thermodynamic stability of nanoemulsion can ensure the kinetic stability and avoid of precipitation or phase separation as oppose macroemulsion.

 

5.4 Dispersibility tests:

Dispersibility test has performed to ensure the emulsification rate of nanoemulsion from the SNEDDS formulation after oral administration. However, formulation (Smix 1:0) without using co-surfactant has only contained surfactant takes longer time for emulsification process. Therefore, it realised that use of co-surfactant play important role in reduction of surface tension thereby improve the emulsification rate as well as solubilization efficacy. The rate of emulsification was found of the selective formulations such as for D7 was 44 ±5 s, D8 was 39±3 s, F11 was 56 ±6 s, F14 was 52 ±7 s. and F15 was 58±4 s. Whereas, the rate of emulsification selected formulations have under the specified grade A therefore, can be ensure uniform dispersion in gastrointestinal fluids and remain as self-nanoemulsifying form.

 

5.5 Formulation:

The fundamental selection criteria of this drug delivery system had followed. Among several formulations, D7, D8, F11, F14 and F15 formulations have passed preliminary tests as showed in Table 1. These formulations appropriate emulsification rate without precipitation or phase separation. These preliminary studies make it more reliable and an appreciate drug delivery system and also avoid unnecessary wastage of drug, chemicals and time. However, these selective formulations have used to formulate with drug and further characterized, evaluated and optimize the formulation among of these formulations based of the fast dissolution rate, globules size and appropriate emulsifying rate.

 

Table 1. Showing formulations those passed thermodynamic stability and dispersibility tests.

 

5.6 Viscosity:

Viscosity of nanoemulsion may influence the drug release rate and stability. Viscosity of formulation was in the range of 21.56±05 to 28.46±0.4 cps. It has reported that lower viscosity of nanoemulsion have tendency to form oil in water type of nanoemulsion and follow Newtonian type of flow property. However, selected formulations have found lower viscosity thus reveals good impact on stability.

 

5.7 Refractive index and Percentage transmittance:

The results of these parameters are indicating transparent formulations and date mentioned in table 2. However, due to facts of maximum size of droplets of the formulation is no longer than 1/4^th of visible wavelength light. Therefore, nanoemulsion scatters little light thus appears transparent or translucent. Refractive index of the selected SNEDDS formulation were showed similar to the water refractive index (1.33). Percentage transmittance of selected formations was showing above of 95%. However, these studies reveal appropriate transparency of formulations.

 

5.8 Assessment of Globules size, polydispersive index and zeta potential:

These are the most and important and reliable parameters of nano drug delivery system which influences various properties of such as dissolution rate, absorption, stability and potency. However, an appropriate range of globules size, polydispersive index (pdi) and zeta potential of nanoemulsions are the necessity for efficacious drug delivery system and therapeutic efficacy. Formulation D8 has found smaller globules size as 141.20±0.69 nm as showed in Figure 2. Nano size globule has good transparency with effective surface area which partitioning drug in between oil and water. Polydispersive index is an important property to indicate the particle size distribution. Zeta potential is another important property of nanoemulsion for stability. However, the zeta potential of selected formulation has within the range thus to ensure to protect from precipitation and maintain stability during storage as mentioned in Table xxx. However, these parameters of selected formulations were showed in table 2

 

Table 2. Represent numerous parameters of selected formulations:

Mean ±SD (n=3)

 

5.9 In Vitro drug release studies:

In vitro dissolution studies of selected SNEDD formulations (D7, D8, E11, F14 and F15) and pure drug were carried out in Phosphate buffer 1.2 as mention in Figure 3. Although, in case of pure drug at the end of 30 min only 11.40 % drug released due to lack of aqueous solubility. Whereas, SNEDDS formulations have reveals more than 91% drug released at the end of 30 min. It is clear indicating that reduction of globules size increase surface area with improved wetting efficacy thereby appropriate dissolution efficacy occurred. Thus, on the basis of the results, it can be concluded that dissolution rate does not affect oral bioavailability of drug through this strategy.

 

Figure 2. In vitro drug released of self-nanoemulsifying formulations and pure drug

 

5.10 In vitro cytotoxic studies:

Cytotoxic study of optimized formulation (D8) was estimated by Caco-cell. F1 (empty formulation) and F2 (drug loaded formulation) are showing survival % of Caco-2 cell at different times intervals 24, 48 and 72 hours. The result was prone significant cytotoxicity effects for both samples (F1 and F2) and statistically, p value was > 0.05 as demonstrating insignificant result. Thus, the developed self-nanoemulsifying formulation considered safe and biocompatible.

 

5.11 Solid self-nanoemulsifying Drug delivery system (S-SNEDDS):

The SENDDS formulation basically formulated in the liquid dosage form. Therefore, solidification approach has used to transform the liquid SNEDDS into solid SNEDDS. However, selection of suitable solid adsorbent has done based on performance of high loading efficiency and free flowing property as mention in Table 3¹⁰.

 

Table 3. Loading efficiency and free flowing property of selected solid adsorbents

Mean ±SD (n=3)

 

5.12 Development of Solid Self nanoemulsifying Drug Delivery System (S-SNEDDS):

Finally, neusilin US2 has selected as a suitable adsorbent. The optimized liquid SNEDDS formulation (D8) and solid adsorbent neusilin US2 were taken separately and liquid SNEDDS formulation (D8) was continuously added into adsorbent in china disc with continue mix with help of glass rod (to ensure uniform distribution of liquid SNEDDS into solid adsorbent) until the free-flowing powder obtained. Then the acquired powder has further carryout micromeritics studies to assess the flow properties as mentioned in Table 4 and evaluated other necessary parameters. Then, the resultant dry powder passed through the sieve number 60 and stored at ambient temperature until further use.

Table 4. Micromeritics parameters of solid self-nanoemulsifying drug delivery system (D8)

 

Solid state characterizations:

5.13 Fourier transforms infrared spectroscopy studies:

Fourier transforms infrared spectroscopy was used to analyse the possible interactions between drug and solid self-nanoemulsifying formulation. The infrared spectra of pure drug, liquid self-nanoemulsifying formulation, neusilin US2 and solid self-nanoemulsifying formulation were analyzed. The solid self-nanoemulsifying spectra showed no overlapping absorption peaks as indicating that the developed formulation compactible with each excipient.

 

5.14 Differential scanning colorimetry studies:

The thermal behaviours of pure drug, neusilin US2 and solid self-nanoemulsifying formulation were determined and showing in Figure 5. In Figure 5 (a) showed sharp endothermic peak of pure drug was detected at 172.5℃. While, in Figure 5 (b) no any peaks were detected in solid carrier neusilin US2 231.02℃ and in Figure 5 (c) solid self-nanoemulsifying formulation 99.08℃. The result has indicates the solid self-nanoemulsifying formulation is in the amorphous form.

 

5.16 Reconstituted globules size and poly dispersive index of solid self-nanoemulsifying drug delivery system:

The transformed solid self-nanoemulsifying was further evaluated globule size and polydispersive index showing in Table 5. The measurements of these parameters have slightly changed in globule size such as 142.68±1.38 nm. While, polydispersive index value indicates same as compared with the liquid self-nanoemulsifying formulation. Therefore considers as a suitable approach of solid dosage form.

 

Figure 3. Schematic of DSC analysis of a) pure drug, b)neusilin US2 and c) solid self-nanoemulsifying formulation.

 

 

Table 5. Globule sixe and Poly dispersive index of solid nanoemulsifying drug delivery system.

Mean ±SD (n=3

 

5.17 Comparative in vitro drug release studies of S-SNEDDS:

The comparative in vitro drug released studies of solid self-nanoemulsifying formulation and pure drug were performed in phosphate buffer 1.2 using dissolution apparatus II. The drug released from solid self-nanoemulsifying dosage form exhibit faster compared with pure drug as mentioned Figure 6. Although, the in vitro drug has indicated that there is insignificant dissolution profile variations in between liquid SNEDDS and S-SNEDDS. Whereas, desirable dissolution profile of drug is the most important aspects of suitable solid adsorbent as the developed solid formulation has reveals appropriate dissolution profile. Thus, solid approach could be considered as alternative and acceptable tactic in this drug delivery system. However, both the formulations were kept in the dissolution medium for four hours; no any sign of drug precipitation or separation was observed as indicated stable drug delivery system. Thus, from this result can conclude that implementation of solid approach to form solid dosage form has an alternative and suitable approach.

 

Figure 4. In vitro drug released of solid self-nanoemulsifying formulation and pure drug

 

5.18 X-RD studies:

X-rd analysis of pure drug, neusilin US2 and S-SNEDDS formulation were performed and showed in Figure 7. The X-rd spectra of pure drug has shown in Figure 7 (a) which reveals high characteristic peaks due to longer range order as indicates crystalline nature of drug. Whereas, x-rd spectra of neusilin US2 has indicates in Figure 7 (b) which reveals no sharp peak. Whereas, X-rd spectra of S-SNEDDS formulation shown in Figure 7 (c) as indicates do not have sharp peak or bragg peaks because of short range order of molecules. However, it is clear indicates that solid SNEDDS formulation have being in amorphous form thus, improved the drug solubility and dissolution rate.

 

Figure 5. X-RD spectra of (a) pure drug, (b) XRD spectra of Neusilin US2, and (c) solid self-nanoemulsifying formulation

 

5.19 Scanning Electron Microscopy (SEM):

SEM analysis of solid self-nanoemulsifying formulation which reveals spherical shape. Therefore, it can be concluded that solid dosage form not affects the formulation properties and reveals amorphous in nature. Therefore, implementation of solid approach of in this strategy can be considered as alternative and suitable approach.

 

Figure 6. Schematic represent SEM analysis of (a) pure drug, b) Solid formulation.

 

6. CONCLUSION:

Self-nanoemulsifying drug delivery system has successfully developed using lipid components and improved the dissolution efficacy of selected drug and successfully transformed into solid powder form. The developed formulation showed suitable dissolution rate thus, it not limiting steps for absorption. However, suitable formulation composition of a drug delivery system is crucially important to succeed the desired therapeutic efficacy. However, implementation of solidification approach has overcome the limitations as improve potency and durability of this strategy. Although, this approach not only enhanced the dissolution rate but also transformed into solid form which improve the stability and patient compliance. Thus, self-nanoemulsifying drug delivery system is considered as a robust drug delivery system and also useful for other drugs those have lack of appropriate dissolution efficacy.

 

7. ACKNOWLEDGEMENTS:

The authors acknowledge to Hetro, Gattefosse (Mumbai), Subhash chemical (Pune), India, Gangwal Chemical (Thane), India, Abitec Group, USA for providing generous gift simples.

 

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Accepted on 16.12.2019           © RJPT All right reserved

Research J. Pharm. and Tech 2020; 13(6):2639-2646.