1. INTRODUCTION:

Plasmodium falciparum causes Cerebral Malaria, a life-threateningneurological conditionwhich primarily affects children in Asia and Africa. Symptoms consisted of clouding ofconsciousness, cerebral convulsions, and coma,which can lead to death in the infected person¹. Artemether is highly efficacious antimalarial drug and works by inhibiting nucleic acid and protein synthesis in erythrocytic stage of micro-organism. It is rapidly metabolized and highly bound to plasma protein leads to low bioavailability. It is always used in combination with other antimalarial agents to provide quick onset of action and improve the bioavailability².

The drug delivery through the nasal mucosa is a potential way for faster drug absorption as it bypass the gastrointestinal route and found to be more permeable than the gastrointestinal system^3,4. It provides a good way to administer drugs like proteins and peptides that are active at low dosage and have no/minimal oral bioavailability⁵.

Nanoemulsionshave attracted the interest of scientific communities since they provide more potential benefits than conventional emulsions. It isa colloidal particulate system with a submicron size (20 to 200 nm)and provides a large surface area for drug absorption. It is a kinetically and thermodynamically stable isotropic dispersion of two immiscible liquids, i.e.oil and water, converted to single phase with the help of a suitable surfactant and co-surfactant. It is optically translucent and has flexible rheological behaviour with high encapsulation capacityand bioavailability^6,7.

Muco-adhesion is the attachment of two surfaces such as the adherence of polymer film and mucous membrane. Mucin, a glycoprotein, is the main component of the mucous membrane, which plays adsorptive, secretory, and protective functions. Also, have the ability to provide controlled release of drug from polymer film⁸.

Theprimary objective of this research is to design anartemether nano emulsion for nasal drug delivery to enhance the bioavailability and brain uptake of the drug. The formulations were optimized and investigated for globule size, polydispersity index, viscosity, zeta potential, entrapment efficiency, and pH determination. The optimized batch with optimum formulation variables was further prepared and analysed using DSC, and PXRD techniques. Morphologic evaluation and internal drug loading of optimized formulation was carried out via photomicrographs of TEM. Drug release kinetic modelling and stability studies were also conducted to obtain drug release behaviour and stability of the formulations respectively.

2. MATERIALS AND METHOD:

2.1 Materials:

Artemether was procured from Yarrow Researching Relationships, Mumbai, India. Tween 20, Oleic acid and Polyethylene glycol 400 were obtained from Sisco Research Laboratory, India. Chitosan and Dialysis Membrane were obtained from Himedia Laboratories Pvt. Ltd., Mumbai.

2.2 Method of preparation of mucoadhesive nanoemulsion:

The spontaneous nano-emulsification method was used for the preparation of mucoadhesivenanoemulsion⁶. Oil phase was taken in a beaker and heated to 45–50^°C for 5 min. The drug artemether (1mg/ml) was added toit and stirred on a magnetic stirrer at 500rpm. Mix the surfactant and co-surfactant (S_mix) separately and added to the above mixture. In another beaker, chitosan (medium molecular weight) solution (1%w/v) was prepared in 0.1% glacial acetic acid.The oil solution was then injected dropwise with a 10cc syringe (24gauge) into the chitosan solution with stirring. After 1 hour of homogenization, the coarse emulsion was sonicated on a probe sonicator to form a nanoemulsion.

2.3 Preformulation Studies:

2.3.1 Organoleptic properties:

The obtained drug was characterized for organoleptic properties like colour, odour and other physical properties like melting point, solubility for the identification purposes.

2.3.2 UV-Visible Spectrophotometric Analysis:

Weigh accurately 100mg of artemether and dissolved in 100ml of ethanol to make mg/ml solution.Various concentrations were made (10 to 40μg/ml) using this stock solution and then scanned for UV-Visible absorption using UV-Visible spectrophotometer in the range of 200-400nm and λ_max was determined⁹.

2.3.3 Fourier Transform Infrared Spectrophotometry (FTIR) Analysis:

The KBr pellet method was used to examine the FTIR spectrum of the drug. The sampleswere triturated with dry potassium bromide (KBr)in a motor & pestle and applied a pressure of 1000psig using a hydrostatic press for 3 minutesto make a pellet. Thispellet was placed in the FTIR sample holder, and analysed in absorption band from400 to 4000 cm^-1, and the results were compared to the reference IR spectra of drug¹⁰.

2.3.4 Differential Scanning Calorimetry:

DSC evaluates the change in enthalpy of a sample thatcould be exothermic, endothermic or may involve a change in heat capacity (glass transition). For this, a 5 mg sample was put in thealuminiumpan and kept in the DSC unit along with a similar pan as a reference. Heating was carried out at a heating rate of 10˚C/min in a range of 40-200˚Cwitha nitrogen environment¹¹.

2.3.5 Screening and selection of oil:

Drug solubility in various oils namely, castor oil, olive oil, oleic acid, linoleic acid, sunflower oil, and isopropyl myristate was evaluated by mixing an excess quantity of drug in 1 ml of the individual oil on a vortex mixer at 37°C for 72 hours.After mixing, the centrifugation of the samples was carried out at 3000 rpm. The supernatant was separated, diluted appropriately and analysed for drug concentration using a UV-visible spectrophotometer¹².

2.3.6 Screening and selection of surfactants andco-surfactants:

The surfactant and co-surfactant were selectedbased onmiscibility test. Various surfactants namely, tween 80, tween 60, tween 20, and span 80and co-surfactants namely, polyethene glycol 400, polyethene glycol 200, polyethene glycol and ethanol were used for this study. The ingredients were mixed in a 1:1ratio for surfactants and co-surfactants respectively.The samples were vortexed for about 5 minutes, then let rest at room temperature for 24 hours¹³.

2.4. Design of Experiments:

The Central Composite design (CCD) was usedto evaluate the consequences of oil, S_mix and stirring time on four response variables; globule size (Y1), zeta potential (Y2), polydispersity index (Y3) and drug content (Y4)of mucoadhesive nanoemulsion. The software Design Expert (version 13.0, Stat ease Inc, Minneapolis, USA)was used and it provided 17 runs of experiments aspresented in Table 1.

Table 1: Description of RSM-CCRD for independent and dependent variables

Independent Variables (Formulation variables)	Levels
Independent Variables (Formulation variables)	-1	0	+1
(A) Oil(ml)	1.3	1.4	1.5
(B) S_mix (ml)	2.6	2.8	3
(C) Stirring time (min)	10	15	20
Dependent variables (Response variables)	Constraints
Globule size (nm)	Minimum
Polydispersity Index	Minimum
Zeta Potential (mV)	Maximum
Drug Content (%)	Maximum

2.5. Selection of finaloptimized formulation:

The desirability value was used as a marker in finalizing the optimized formulation. The desirability valueabove 0.5 indicating the good (acceptable) response value and the below 0.5 desirability value represents the unacceptable value.

2.6 Characterization of the optimized formulation:

2.6.1 Globule size and PDI:

A zeta sizer (Nano-ZS90,Malvern Instruments, Worcestershire, UK) was used to determine the globule size and polydispersity index of NE. Additionally, a stable monodispersed system with PDI values 0.0 to 0.3provide a stable system.The formulations were measured at 25^°C and 90^° angle after appropriate dilution with deionized water. The samples were sonicated for 2-3 min to reduce the multiple scattering effect¹⁴.

2.6.2 Zeta Potential:

Zeta potential was measured by using Zetasizer (ZS-1000 HAS, Malvern Instruments, UK)¹⁵. The samples were filled in a sample cell up to the mark and analyzed for net charge on the formulation.

2.6.3 Determination of Viscosity:

The stability of the nanoemulsion formulation is very much depended upon the viscosity of the formulation. The viscosity of the formulation was measured using the Brookfield viscometer with spindle No. III at a rotation of 100rpm¹⁶.

2.6.4 pH determination:

pH plays a versatile role inthe stability and compatibility of the formulation.Unbalanced pH irritates the site of administration.The pH of the formulation was evaluated using digital pH meter¹⁷.

2.6.5 Drug content determination:

The dose of any formulation is largelydepended upon itsdrug content. For this, NE formulation corresponding to 20mg of the drug was added to a volumetric flask and diluted with PBS pH 6.4 up to 10ml. The obtained solution was then filtered through a 0.45 membrane filter after being sonicated for 10minutes. The percentage drug content was analysed spectrophotometrically at wavelength 251nm¹⁸.

Amount of drug in nanoemulsion

% Drug content = -------------------------------------- × 100

Equivalent concentration of all ingredients taken

2.6.6 Drug entrapment efficiency:

The extent of entrapment of the drug in the formulation was evaluated by drug entrapment efficiency. Each 10 ml sample was centrifuged at 3500rpm for 30min. After centrifugation, the supernatant transparent layer was taken and diluted suitably. The samples were measured as 251nm using UV-VIS spectrophotometer¹⁹.

Amount of drug in nanoemulsion

% Entrapment Efficiency = --------------------------- × 100

Amount of initial drug added

2.6.7 In-vitro drug release studies:

A Franz diffusion cell was employed for in-vitro drug release study. It consisted of a receptor compartment and a donor compartmentwith a sampling port and enclosed in a water jacket to keep the temperature at 37°C±2°C. A pre-treated dialysis membrane (molecular weight. cut off 12,000–14,000, a pore size of 2.4nm, Sigma Aldrich, Bangalore, India) was used and placed between the two chambers. The phosphate buffer (PB) pH 6.4 was used as diffusion media as this is the physiological pH of nasal cavity. The media wasstirred at 200rpm using a magnetic bead to maintain uniform distribution of drug within the media. Samples from the receptor compartment were taken at various intervals of time for 24h and the amount of the drug was analysed spectrophotometrically²⁰.

2.6.8 Drug Release Kinetics:

The drug release data was subjected to release kinetic models including zero order, first order, Higuchi, Korsmeyer-Peppas etc to find out the mechanism of drug releasefrom the formulation²¹.

2.6.9 Stability study:

The artemether nanoemulsion was subjected to stability studies for 3 months at different conditions of temperature and humidity (4 ± 3°C, 25 ± 2°C/60 ± 5RH, and 40 ± 2°C/75 ± 5RH) and evaluated for physical stability (creaming, phase separation or flocculation). For this purpose, centrifugation of samples (each 10 ml)was carried out at 3500 rpm for 30 min.The stability of nanoemulsion in terms of change in globule size and polydispersity index was also evaluated²².

3. RESULTS AND DISCUSSIONS:

3.1 Preformulation Studies:

3.1.1 Organoleptic properties:

The drug was characterized for organoleptic properties and was found to be a white fine crystalline powder with no odour. Itis very soluble in acetone, freely soluble in ethyl acetate, soluble in DMSO, sparingly soluble in aqueous buffer and practically insoluble in distilled water.

3.1.2 UV Spectrophotometric Analysis:

UV spectral scan of the artemether was analysed in ethanol and phosphate buffer pH 6.4. It showed the maximum absorbance at 251nm in both the solvent andwas found as per the reported values (245-252nm) representing the authenticity of the drug and used for further analysis. The absorbance curve was found to be linear in a concentration range of 5 to 30µg/ml with R² value of 0.999.

3.1.3 FTIR spectrum analysis:

The FTIR spectrum of the pure drug is studied for identification purposesand is shown in Figure 1. The different characteristic peaks of artemether are given in Table 2.All the peaks in the spectrum were found at their place confirming that the drug sample was authentic²³.

Figure 1: FT-IR spectrum of Artemether

Table 2: FTIR spectral peaks of Artemether

Functional group	Type of vibration	Artemether (cm^-1)	Reference region (cm^-1)
C-H	Stretching	2954.14	3000-2850
CH³	Bending	1451.82, 1375.30	1450-1375
R-O-CH³	Stretching	1252.10, 1034.77	1250-1040
C-O-O-C	Bending	1189.90	1195.95
-O-O-C	Stretching	875.03	857
-O-O-	Stretching	751.33	746

3.1.4. Differential Scanning Calorimetry:

The DSC thermogram of artemether is shown in Figure 2. It exhibited broad endothermic peaks at 76.92^˚C, 180.45^˚C, 248.00^˚C and exothermic peak at 261.72^˚C as given in Table 3. A change in enthalpy was recorded at each melting point represented the amount of heat absorbed/evolved.This gives an idea about the extent of crystalline/amorphous natureof the drug. These peaks of the drug were found in range with the reported ones which confirmed the purity and authenticity of the drug²⁴.

Figure 2: DSC Thermogram of Artemether

Table 3: DSC Thermogram of Artemether

Peak	Melting point of the drug (⁰C)	Enthalpy change (J/g)
Endothermic	76.92	101.37
Endothermic	180.45	11.268
Endothermic	248.00	26.793
Exothermic	261.72	21.041

3.1.5 Screening and Selection of Oils:

The selection of oil played an important role in the formulation as increased solubility of the drug into the oil maximizes the drug loading²⁵. The calculated solubility of the drug in castor oil, olive oil, oleic acid, linoleic acid, sunflower oil, and isopropyl myristate was found to be 137.4±5, 278.7±13, 336.1±9, 217.3±11, 14.1 ±3 and 37.4±6µg/ml. The solubility of artemether was found to be highest in the oleic acid and was finalized for the NE formulation.

3.1.6 Screening and Selection of Surfactant:

Selection of surfactants and co-surfactant is a crucial factor in the NE formulationowing to good stability¹⁴. A mixture of a high HLB value surfactant and a low HLB co-surfactant always gives a stable emulsionwhich cannot be achieved by using single emulsifier.Oleic acidfound highest miscibility in tween 80 and PEG 400 and hence wereselected as surfactant and co-surfactant respectively for the development of nanoemulsion.

3.2 Formulation, Optimization and Evaluation of Nanoemulsion:

3.2.1 Optimization of formulation and model statistics:

Artemether nanoemulsions were optimized by using the CCD model of design expert software^®v13.Various formulations were formulated and evaluated for dependent variables given in Table 4. 3D response surface plots were developed in order to depict how independent variables affect responses. The predicted R²and adjusted R²values for globule size, zeta potential, PDI and drug content were found to be in close agreementwith each other representing that the model was accurate, reliable and can be used for this experiment. The F-value was found to be 137.74, 236.17, 367.84 and 79.94 for globule size, zeta potential, PDI and drug content indicating that pure errors were at their minimum level in this experiment. The optimized formulation consisted of 1.5ml of oil, 2.6ml of S_mixand 20 minutes of stirring time.

Table 4: Independent variables and response values of Globule size (Y1), Zeta potential (Y2), PDI (Y3) and Drug content (Y4)

Run	Oil (ml)	S_mix(ml)	Stirring time (min)	Globule size (nm)	Zeta potential (mV)	PDI	Drug content (%)
1	1.3	2.6	10	51.3	-18.9	0.479	52.1
2	1.4	2.8	23.409	59.1	-19.2	0.304	54.23
3	1.4	3.13636	15	69.1	-18.7	0.321	62.11
4	1.5	3	20	23.4	-12.2	0.623	60.91
5	1.4	2.8	15	57.8	-18.8	0.415	60.98
6	1.3	2.6	20	14.49	-23.1	0.283	59.25
7	1.56818	2.8	15	58.9	-19.4	0.321	46.16
8	1.4	2.8	25	99.2	-25.6	0.489	53.29
9	1.5	2.6	10	66.2	-20.2	0.313	54.21
10	1.3	3	10	44.2	-21.2	0.312	62.11
11	1.4	2.46364	15	16.6	-13.1	0.522	56.29
12	1.4	2.8	15	58.2	-19.1	0.492	59.98
13	1.4	2.8	6.59104	27.2	-13.1	0.308	59.24
14	1.3	2.6	20	73.8	-20.2	0.551	58.19
15	1.23	2.8	15	118.9	-26.6	0.723	59.99
16	1.3	3	20	90.8	-24.7	0.603	57.68
17	1.5	3	10	104.8	-25.7	0.316	61.09

3.3 Optimization of Mucoadhesive Nanoemulsion:

3.3.1 Effect on globule size:

The effect of independent variables on the globule size (nm) is shown in Figure 3(A). The particle sizes were measured in a range of 14.49nm to 118.9nm and found to be decreasedwith decrease in oil concentration in the NE formulation. Similarly, globule size decreased with decrease in surfactant concentration. This is due to the fact that surfactant reduced the surface tension leading to the formation of small sized globules¹⁴. For the preparation of SNEDDS, it is desired to have a globule size in the range of 20-200nm.

3.3.2 Effect on zeta Potential:

Zeta potential is an indicator of stability of the nano emulsion formulation. The zeta potential was observed to be in the range of -13.7 to -26.6 mVas shown in Figure 3(B). Higher concentration of the oil led to the more negative values of zeta potential owing to the presence of free fatty acids present in the oil. The non-ionic nature of both the surfactant and co-surfactant provided steric stabilization to the formulation .The optimized formulation had zeta potential of -23.1 mVindicating good stability of dispersion owing to electrostatic repulsive forces between the particles.

3.3.3 Effect on PDI:

The effect of independent variables on the PDI of nanoemulsion formulation is shown in Figure 3 (C). According to studies, the PDI of NE decreased with increased S_mix concentration up to a certain point, and then increased at further increase in S_mix values.The optimized formulation had a PDI value of 0.283 indicating the uniformly dispersed globules with good stability.

3.3.3 Effect on drug content:

The drug content was measured in a range of 46.16 to 62.11% as shown in Figure 3(D). The drug content was decreasedwith decrease in oil concentration and surfactant concentration too. The drug content is found to be in good range to provide the desired therapeutic effect.

3.4 Selection of finaloptimized formulation:

The desirability value was used as a marker to find out the optimized formulation. The final optimized formulation consisted of 1.3ml of oil, 2.6ml of S_mix, and 20 minutes of stirring time with a desirability value of 0.724 indicated that the desired responses were easy to achieve. The difference between the predicted values and observed experimental values was at their minimum level indicated the validation and accuracy of the model. The optimized formulation was further prepared and subjected to evaluation.

3.5 Evaluation of Mucoadhesive Nanoemulsion:

Viscosity is directly related to the residence time in the nasal mucosa and is depends on the amount of surfactant and co-surfactant used. The pH and viscosity of the optimized formulation was found to be 6.4 and 53.6 cPas represented its non-irritant nature with longer residence time in nasal mucosa. The entrapment efficiency of the final optimized formulation was observed as 83.5%.

3.6 In-vitro drug release studies and release kinetics:

The optimized mucoadhesive NE formulation was subjected to in vitrodrug release analysis in PBS pH 6.4. The amount of drug released from the prepared mucoadhesive nanoemulsion was found to be 93.17% in 24 hours showing the sustained release formulation.The initial high drug release was due to the small sized globules in the mucoadhesive NE which gives a huge surface area for drug release^19-21. The later controlled release effect of drug was found owing to the matrix diffusion which effectively limits the rate of drug release from mucoadhesive NE formulations⁷. This drug release data was fitted into various release kinetic models and were found to be 0.962, 0.640, 0.829 and 0.998 for zero order, first order, Higuchi model, and Korsmeyer-Peppas model respectively. The maximum R²value was found for the Korsmeyer-Peppas model suggested that the drug was released from the formulation via a non-Fickian drug transport mechanism³².

4. CONCLUSION:

The mucoadhesive nanoemulsion formulation was successfully optimized and formulated to enhance the bioavailability of artemether bypassing the hepatic first-pass metabolism and promoting the brain uptake of the drug. The values of adjusted R²were found to be very close topredicted values indicatingthe success of the optimization technique. In-vitro release experiment showed theinitial faster release followed by slow release of drug from mucoadhesive nano emulsion formulation. There lease kinetic study indicating the non-Fickian controlled release effect of NE formulation as it follows a Korsmeyer-Peppas (R²= 0.998) model. Based on these research findings, it was concluded that intranasal delivery of artemether-loaded mucoadhesive nanoemulsion formulation is a better approach and a smart way for effective and targeted delivery of drug in the brain.

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Received on 30.04.2023 Modified on 19.07.2023

Research J. Pharm. and Tech 2024; 17(5):2139-2145.

DOI: 10.52711/0974-360X.2024.00338