INTRODUCTION:

In last year nanotechnology widely used by many scientists to overcome many challenges associated with drug such as instability, low bioavailability, intestinal absorption and solubility. Nanotechnology has produced a major transformation in the pharmaceutical industry, resulting in the development of advanced drug delivery methods known as nanomedicines for diagnosis and therapy. The fundamental component of nanotechnology is the nanoparticles.¹Nanostructures have the ability to protect drugs from degradation in the gastrointestinal tract, and the technology can allow target delivery of drugs to different areas of the body. Nanoparticles with particle sizes ranging from 1-1000 nm in diameter that exhibit new or enhanced size-dependent properties when compared with larger particles of the same material by passing the liver and delivering medications that aren't particularly water soluble, the method makes it possible to avoid first-pass metabolism. Due to their specific absorption mechanisms, which include absorptive endocytosis and are able to persist in the blood circulation for a long period.²

Many types of nanoparticles include nanosuspension, polymeric nanoparticle, lipid nanoparticle, etc.^3,4these nanoparticles prepare by top-down method that no need to use solvent and bottom-up method need organic solvent that mix with immiscible water and drug precipitate due to low water solubility.^5,6

According to the BCS olmesartan medoxomil is belong to class II that characterized by low water solubility (hydrophobic) with good permeability ,it is angiotensin ll receptor antagonist chemically describe as 2, dihydroxbutenyl4-(1-hydroxy-1-1methylethyl)-2-propyl-1-[p-(o-1H-tetrazol-5ylphenyl)benzyl]imidazole-5-carboxylate,cyclic2,3-carbonate.it is an active orally AT1 receptor antagonist that rapidly desesterified in vivo in intestinal wall to active di acid metabolite olmesartan⁷ the chemical formula is C24H26N6O3 with molecular weight 446.5. it is weak base drug pKa 4.3 and log p 4.4 with the absolute bioavailability of olmesartan medoxomil after oral administration is 26% to 28.6%.⁸

The goal of this research is to prepare olmesartan medoxomil nanoparticle to enhance water solubility and bioavailability of poorly soluble drug.

METERIALS:

Olmesartan medoxomil from li company, china. PVA from Fluka, Germany, HPMC E5 from Baoji, china. poloxamer 188 from Eastman chemical company, USA. soloplus ®BASF SE, Germany. Sodium lauryl sulfate (SLS)BDH Chemical LTD, UK.

METHODS:

Preparation of Olmesartan medoxomil Nanoparticles

Olmesartan nanoparticles prepare by bottom-up techniques by solvent anti-solvent method in which the organic phase prepare by dissolving 10mg of drug in 3 ml methanol and the aqueous phase form by dissolving any type of polymer in water (10mg of polymer + 30mg of distilled water) different type of polymers use include (PVP K30, HPMCE5, soloplus ® and poloxamer 188) then taking the organic phase in syringe with needle 0.6 mm in diameter and put in aqueous phase drop by drop at speed 1ml/min with mechanical stirrer at speed 1000 rpm for 20 min to evaporated the volatile solvent then measure particle size.⁹ the ratio of drug: polymer: co-polymer is shown in table (1).

Table (1) Composition of Olmesartan Loaded Nanoparticles Using Different Parameter and Concentration

Formula code	Drug conc	Polymer type	Polymer conc (mg)	Drug: polymer: co-polymer (tween 80) ratio	Speed rpm	Solvent	Injection speed ml/min
F1	10	Poloxamer 188	5	1:0.5	1000	Methanol	1
F2	10	Poloxamer188	10	1:1	1000	-	1
F3	10	HPMC E5	5	1:0.5	1000	-	1
F4	10	HPMC E5	10	1:1	1000	-	1
F5	10	HPMC E5	20	1:2	1000	-	1
F6	10	Soloplus	5	1:0.5	1000	-	1
F7	10	Soloplus	10	1:1	1000	-	1
F8	10	Soloplus	20	1:2	1000	-	1
F9	10	PVP K30	10	1:1	1000	-	1
F10	10	PVP K30	10	1:1:2	1000	-	1
F11	10	HPMC E5	10	1:1:2	1000	-	1
F12	10	Soloplus	10	1:1:2	1000	-	1
F13	10	Soloplus	10	1:1	1000	Acetone	1
F14	10	soloplus	10	1:1	1000	Ethanol	1
F15	10	Soloplus	10	1:1	500	methanol	1

Characterization of olmesartan medoxomil nanoparticles:

Particle size and poly dispersity index PDI:

Particle size (PS) and polydispersity index (PDI) of nanoparticles were estimated at room temperature using dynamic light scattering technique (DLS) by particle size analyzer nano Laser (Malvern zeta sizer, Spectris Company, United Kingdom).¹⁰

Drug content determination of nanoparticle:

A certain amount of nanosuspension (1mL) was placed into 10 ml volumetric flask contain methanol. After that, the sample was sonicated for 1 hour and filtered through 0.45 filter syringe, and the quantity of drug was quantified spectrophotometrically at its maximum λ max. The calibration curve of methanol was used to determine the amount of olmesartan medoxomil in the nanosuspension.^11,12

Entrapment efficiency measurement:

The proportion of medication encapsulated in the nanoparticles matrix is known as entrapment efficiency (% EE). 2ml of nanosuspension was taken and filled in an eppendorf tube then centrifuged at 16000rpm at 4°C for 20 min. After that, 1 ml of supernatant was removed and the free drug concentration was calculated by measuring the absorbance using a UV spectrophotometer. The percent of EE was calculated using the equation below.¹³

% EE = c initial-c freeintial X 100

Where % EE = percentage of entrapment efficiency. c initial = initial drug concentration and c free = free drug concentration (un entrapped drug).

Morphological Characterization of olmesartan medoxomil nanoparticles by using AFM and TEM:

Atomic Force Microscopy (AFM) strategies have progressed ability to explain colloidal substances and offer three-dimensional imaging of materials with excessive accuracy. AFM presents similarly statistics on the scale and form of nanosized debris and allows the visualization of samples with decision in three dimensions (x-, y-, and z) in an atmospheric or submerged environment. The maximum famous technique for particular qualitative and quantitative characterization of pharmaceutical arrangements in regards to surface capabilities that could effect the very last method traits is atomic force microscopy (AFM).¹⁴

TEM in which microsope that used particle beam of electrons to visualize specimens and generate highly-magnified image. TEM can magnify objects up to 2 million times in order to give better idea of just how small that is.¹⁵

In vitro dissolution study of olmesartan medoxomil nanoparticle:

The USP (type II) dissolution apparatus was used to measured dissolution of olmesartan medoxomil nanoparticles by using dialysis membrane (MWCO12000-14000 Da) the membrane attach to the baddle and then put in dissolution media 900 mL (phosphate buffer pH 6.8 containing 0.5 % SLS) At 37 °C and 50rpm respect to the sink condition. 5mL of sample was taken and replaced with new buffer at each time interval of 5, 10, 15, 20, 25, 30, 45 and 60 min. the amount of olmesartan medoxomil nanoparticle measure spectrophotometery by wave length of the drug in buffer which it is 257nm.¹⁶

Fourier-transform infrared (FTIR) analysis:

The FTIR spectra of olmesartan medoxomil pure drug and nanoparticles solution of the chosen formula were recorded using an FTIR spectrometer (FTIR-8300 Shimadzu, Japan) by grinding the drug with potassium bromide (KBr) and pressing it into a thin film disc using a specific process. At waves number between 4000-400 nm. The FTIR used to determine any sign of interaction or complexation might that happen between olmesartan and other excipients utilizing in the formulation of the nanoparticles. ^{17 ,18}

Statistical analysis:

The outcomes of the research were presented as the mean of three triplicate models SD, and they were compared with (ANOVA) test to see if the variations in the factors that applied are significant at the level of (P < 0.05) and non-significant at the level of (P > 0.05).

RESULTS AND DISCUSSION:

Particle size and PDI analysis:

Particle size measurement for all formula in nm range from (3069-86.38) the Nano Laser Particle Size Analysis (Malvern zeta sizer, Spectris Company, United Kingdom) was designed to quantify the P.S .Polydispersity index is considered as a parameter to realize the particle size distribution of nanoparticles obtained from a particle size analyzer.^19,20 Lower PDI value indicate monodisperse samples, whereas polydisperse sample have higher values of PDI and this indicates a wider particle size distribution.The range of PDI values is 0-0.05 for the monodisperse system,0.05-0.08 for nearly monodisperse, 0.08-0.7 for that of mid-range polydisperse, and >0.7 is a very polydisperse sample.²¹

Table (2) particle size and PDI data of prepeared olmesartan medoxomil nanoparticles

Formula code	Polymer type	Drug:polymer:co-polymer ratio	Solvent	Stirrer speed	Particle size	Pdl
F1	Poloxamer188	1:0.5	Methanol	1000	2311	0.329
F2	Poloxamer188	1:1	-	1000	1331	0.504
F3	HPMC E5	1:0.5	-	1000	137	0.320
F4	HPMC E5	1:1	-	1000	133	0.555
F5	HPMC E5	1:2	-	1000	215	0.411
F6	Soloplus	1:0.5	-	1000	91.5	0.214
F7	Soloplus	1:1	-	1000	86.38	0.082
F8	Soloplus	1:2	-	1000	95	0.254
F9	PVP K30	1:1	-	1000	1242	1.034
F10	PVP K30+ Tween 80 80	1:1:2	-	1000	766.3	0.682
F11	HPMC E5 + Tween 80	1:1:2	-	1000	3069	0.375
F12	Soloplus+ Tween 80	1:1:2	-	1000	93.83	0.141
F13	Soloplus	1:1	Acetone	1000	149.5	0.202
F14	Soloplus	1:1	Ethanol	1000	141.1	0.268
F15	Soloplus	1:1	Methanol	500	104.6	0.203

Effect type of polymer on particle size:

Using different type of polymer for preparation of olmesartan medoxomil NB including (PXX 188, Soloplus ®, HPMC E5, PVP K30) give different particle size range from (86.38-3069). These polymer give different particle size because it effect on lipophilicity,charge, also physicochemical properties, prevent gathering and coalescence at interface. notice that lower particle size obtained in formula F6, F7, F8 contain soloplus in all ratio (1:0.5, 1:1, 1:2 ). Soloplus is amphipathic nature water soluble polymer solubilize poorly water soluble polymer also soothe nanosuspension, soloplus composed from polyvinyl caprolactam and polyvinyl acetate, which represent the hydrophobic moiety, and polyethylene glycol (PEG), which represents the hydrophilic moiety. Soloplus is reflected a surface-active and wetting agent commonly used to provide equilibrium and provide thermodynamic barrier that prevent particle from agglomerate .Also, it has a lower viscosity score than other polymers.^22,23

Figure (1) effect of polymer type and concentration on the particle size

Effect of drug: polymer ratio on olmesartan medoxomil nanoparticle:

Different ratio of drug:polymer use 1:0.5, 1:1, 1:2 of different polymer type (HPMC E5, Soloplus, Poloxamer 188) show different particle size by change in polymer concentration. In the formula (F1, F3, F6) the ratio of drug:polymer concentration 1:0.5 the particle size (2311, 137, 91.5nm) respectively. The result indicated that polymer concentration not enough to wrap the nanoparticle of olmesartan medoxomil. In this case cluster may occur due to low concentration of polymer make it insufficient amount to cover nanopartic. In the formula (F2, F4, F7) the ratio of drug: polymer concentration 1:1 the particle size (1331, 133, 86.38nm) respectively. The result show best nano size better reduction in particle size in compare with other ratio meaning that the polymer concentration enough to envelop nanoparticles formed. In the formula (F5, F8) show the particle size (215, 95) respectively. Show increase in particle size when concentration of polymer increase meaning that aggregation and accumulation occur as a result of increase viscosity of solution. In the formula F9 the polymer PVP K30 give largest particle size 1242nm.²⁴As a result, for all types of stabilizers, the appropriate drug: stabilizer ratio should be determined because suitable stabilizer ratio have an important function in the stabilization of nanoparticles. So, the coverage of the particle surface is insufficient at low stabilizer ratios as well as at higher stabilizer ratio. So, flocculation and aggregation can occur, resulting in decreased sterically and unstable nanosuspensions.²⁴

The effect of solvent on particle size:

In the formula F7 methanol are used in ratio 1:1 drug: polymer conc give particle size 86.38nm but when change solvent for the same formula in the same condition give another particle size such as in F13 using acetone give particle size 149.5nm and in F14 using ethanol give particle size 141.1nm. F7 is best in give lower particle size than F13, F14.²⁵

Figure (2) effect of solvent type on the particle size

Effect of stirring speed on particle size:

By using magnetic stirring nanoparticle measure at speed 500 revolution per minute at formula F7 and the ratio 1:1 of drug to polymer concentration give particle size 104.6nm in compare to same formula at speed 1000 rpm give particle size 86.83nm meaning that at low speed particle will aggregate when increase speed from 500 to 1000rpm increase shear mixing and thus more rapid diffusion of the organic solvent into the water phase. It will induce the fast nucleation of drug particles and produce very small drug particles.²⁶

Figure (3) effect of stirrer speed on particle size

Effect of adding co-stabilizer (co-polymer):

The effect of adding tween 80 as co-stabilizer with the presence of stabilizer (polymer). Tween 80 is a nonionic surfactant used to stabilze the formula play an important role in prevent agglomeration of formula. In the formula F9, F10 by using PVP K30 as a polymer. F9 polymer alone particle size 1242 when added the co stabilizer tween 80 notice the particle size will be 766.3 meaning that tween 80 adsorbed on the external surface of prepared NPs of hydrophobic drug olmesartan medoxomil and provided a mechanical barrier against crystal growth to inhibit agglomeration. In the formula ( F4, F11) by using polymer HPMC E5 in ratio 1:1 notice that particle size in F4 is 133nm but when added tween 80 particle size will increase to 3069 nmalso in the formula (F7, F12 ) containing soloplus as apolymer we notice that F7 particle size is 86.83nm incrase in particle size when using tween 80 in F12 particle size will be 93.83nm , thus polymer and co-stabilizer may prevent transportation from an organic solvent to an aqueous anti-solvent, resulting in poor stabilization and particle accumulation So, this combination is inappropriate for olmesartan medoxomil nanoparticles.²⁷

Figure (4) effect of adding co-stabilizer on particle size

Drug content of olmesartan medoxomil nanoparticle:

Drug content of nanoparticle measure for many formula (F6, F7, F8, F12) contain soloplus in ratio 1:0.5, 1:1, 1:2, and 1:1 contain tween 80 respectively Prepare each formula with sonication for 1hr then measure absorbance in UV ultraviolet, calculate drug content by equation:^28-32

Drug content=practical conc/theoretical conc *100%

So drug content for F6 is 93% , F7 is 98%, F8 is 92% and for formula contain tween 80 drug content is 92%.

Entrapment efficiency of olmesartan medoxomil nanoparticle:

Measure entrapment efficiency of formula that have smallest particle size (F7) that contain drug: soloplus in ratio 1:1 by using ultracentrifuge at 6000rpm for 20 min.^33-39

EE= theoretical conc-practical conc/theoretical conc *100%

The EE for best formula was 98.3% .

Morphological Characterization of olmesartan medoxomil nanoparticles by using AFM and TEM:

AFM is capable of scanning and measures the properties and characteristic of the surfaces. With the high accuracy of the AFM, it is possible to determine the dimensions of nanoparticles with high reliability. AFM allows the visualization of samples with design in three dimensions. This method provides direct information about particle aggregation and therefore, a useful method to support the development and optimization of nanosuspension formulations.^40-43 AFM done for best formula that have smallest particle size 86.83 nm notice that the surface is smooth have no aggregation which indicated particle size distribution and stability of formula.

Figure (5) AFM of (F7) formula with smallest particle size

TEM is atechnique use an electron beam to image a nanoparticle, work at same principle of light microscope but uses electron instead of light, give image better than light microscope because wave length of electron is much smaller than light. Give information about surface features, shape, size and structure.⁴⁴

Figure (6) TEM of (F7) formula with smallest particle size

Fourier-transform infrared (FTIR) of olmesartan medoxomil powder and olmesaran medoxomil nanoparticle:

In compare drug and best formula with the reference notice that there is no interaction in peak occur.^45-49

In vitro drug relase for olmesartan medoxomil nanoparticles:

Dissolution done by using type ll apparatus dissolution instrument in prescence of phosphate buffer PH 6.8 (900ml containing 0.5% sls) at speed 50rpm and temperature 37c. doing dissolution for formula with smallest particle size (F6, F7, F8, F12) all formula of soloplus in the ratio 1:0.5, 1:1, 1:2, and 1:1:2 contain soloplus and tween 80 as co-stabilizer.Make compare between pure drug and other formula, the pure drug give only 17% relase at 30 min and formula of smaller particle size F7 give 100% relase in 30min while F6 give 89% of relase, F8 give 74% relase at 30 min.F12 give relase 83% at 30min. Notice the result of dissolution the best formula F7 give 100% of drug relase at 30 min compare to other formula with larger particle size this according to Noyes whiteny equation that when particle size decrease increase in surface area thus will increase dissolution.We have two factor according to the (FDA) food and drug administered (f1 and f2 ), F1 is difference factor while F2 is the similarity factor, By using similarity factor f2 was done by using model – independent method the range of f2 between (50-100) while for f1(0-15) it was found by compare each formula with pure drug that f2 for F6 is 11.38 , f7 is 5.89 , f8 is 20.52 and f12 is 14.17 .We notice that F6,F7,F12 with the value (11.38 , 5.89 and 14.17) respectively is less than 15 meaning there is no difference in dissolution profile, while for F8 the value (20.52) but all value less than 50 meaning there is no similarity with significance differences of dissolution test of olmesartan medoxomil nanoparticle.⁵⁰

Figure (9) dissolution curve of olmesartan medoxomil (pure drug), F6, F7, F8 and F12

CONCLUSION:

Each patint expected from the treatment best treatment and effective with low concentration and side effect ^51-52, Preperation of nanoparticle by Solvent anti solvent method was efficient method to formulated olmesartan medoxomil nanoparticle it is simple and not require high cost used to increase solubility as well as bioavailabilty of class II drug by decrease particle size sodissolution increase within aminute. Nanoparticle use different polymer type (poloxamer 188, PVP K30, Soloplus®, HPMC E5) in different ratio 1:0.5 ,1:1, 1:2 , found that best solvent for preperation of olmesartan medoxomil nanoparticle is methanol but other solvent like acetone, ethanol increase particle size. Other parameter also affected such as speed and addition of co stabilizer (tween 80) . From the experiment notice that the polymer soloplus give the smallest particle size in all ratio compare with other polymers.

REFERENCE:

1. Ealia SA, Saravanakumar MP. A review on the classification, characterisation, synthesis of nanoparticles and their application. InIOP conference series: materials science and engineering 2017;263(3): 032019.

2. Saadh MJ, Jadullah RK. Nanotechnology in Drug Delivery. Nanotechnology. 2021;3:1129-35. https://doi.org/10.17148/ijarcce.2016.55255

3. Al-Hussaniy HA, Alburghaif AH, Naji MA. Leptin hormone and its effectiveness in re-production, metabolism, immunity, diabetes, hopes and ambitions.J Med Life. 2021;14(5):600-605. doi:10.25122/jml-2021-0153.

4. Scioli Montoto S, Muraca G, Ruiz ME. Solid lipid nanoparticles for drug delivery: pharmacological and biopharmaceutical aspects. Frontiers in molecular biosciences. 2020;7:587997.

5. Al-hussaniy HA, Altalebi RR, Alburagheef A, Abdul-Amir AG. The Use of PCR for Respiratory Virus Detection on the Diagnosis and Treatment Decision of Respiratory Tract Infections in Iraq. J Pure Appl Microbiol. 2022;16(1):201-6.

6. G. A. Reddy and Y. Anilchowdary, “Nanosuspension technology: a review,” IJPI’s Journal of Pharmaceutics and Cosmetology, vol. 2, no. 8, pp. 47–52, 2012.

7. Thakkar, H. P., Patel, B. V., & Thakkar, S. P. (2011). Development and characterization of nanosuspensions of olmesartan medoxomil for bioavailability enhancement. Journal of Pharmacy and Bioallied Sciences, 3(3).

8. Laeis, P., Püchler, K., & Kirch, W. (2001). The pharmacokinetic and metabolic profile of olmesartan medoxomil limits the risk of clinically relevant drug interaction. In Journal of Hypertension, Supplement (Vol. 19, Issue 1). https://doi.org/10.1097/00004872-200106001-00004

9. Kadhim ZJ, Rajab NA. Formulation and Characterization of Glibenclamide Nanoparticles as an Oral Film. International Journal of Drug Delivery Technology. 2022;12(1):387-394.

10. Gadad AP, Tigadi SG, Dandagi PM, Mastiholimath VS, Bolmal UB. Rosuvastatin loaded nanostructured lipid carrier: For enhancement of oral bioavailability. Indian Journal of Pharmaceutical Education and Research. 2016;50(4):605-11. https://doi.org/10.5530/ijper.50.4.13

11. Srinivas NS, Verma R, Kulyadi GP, Kumar L. A quality by design approach on polymeric nanocarrier delivery of gefitinib: formulation, in vitro, and in vivo characterization. International journal of nanomedicine. 2017;12:15. https://doi.org/10.2147/IJN.S122729

12. Mastiholimath VS, Bhagat Ankita R, Mannur VS, Dandagi PM, Gadad AP, Khanal P. Formulation and evaluation of cefixime nanosuspension for the enhancement of oral bioavailability by solvent-antisolvent method and its suitable method development. Indian J Pharm Educ Res. 2020;54(1). https://doi.org/10.5530/ijper.54.1.7

13. Almutairy BK, Alshetaili A, Alali AS, Ahmed MM, Anwer MK, Aboudzadeh MA. Design of olmesartan medoxomil-loaded nanosponges for hypertension and lung cancer treatments. Polymers. 2021;13(14):2272.

14. Abdulbaqi MR, Taghi HS, Abdulelah FM. Synthesis, Application and Evaluation of Bismuth Sulfide (Bi2s3) Metal Nanoparticles as Nanocarriers for Poorly Soluble Class II Drug Clarithromycin. synthesis. 2009;1:2.

15. Kumar CS,. Transmission electron microscopy characterization of nanomaterials. Springer Science & Business Media; 2013.

16. ALZobaidy MA, AlbuRghaif AH, Alhasany HA, Naji MA. Angiotensin-Converting Enzyme Inhibitors May Increase Risk of Severe COVID-19 Infection. Annals of the Romanian Society for Cell Biology. 2021;25(6):17843-9.

17. Al-kuraishy AA, Jalil HJ, Mahdi AS, Al-hussaniy HA. General anesthesia in patient with Brain Injury. Medical and Pharmaceutical Journal. 2022;1(1):24-34.

18. Azeem A, Rizwan M, Ahmad FJ, Iqbal Z, Khar RK, Aqil M, Talegaonkar S. Nanoemulsion components screening and selection: a technical note. Aaps Pharmscitech. 2009;10(1):69-76. https://doi.org/10.1208/s12249-008-9178-x

19. Danaei M, Dehghankhold M, Ataei S, Hasanzadeh Davarani F, Javanmard R, Dokhani A, Khorasani S, Mozafari MR. Impact of particle size and polydispersity index on the clinical applications of lipidic nanocarrier systems. Pharmaceutics. 2018;10(2):57.https://doi.org/10.3390/pharmaceutics10020057

20. Rao S, Song Y, Peddie F, Evans AM. Particle size reduction to the nanometer range: a promising approach to improve buccal absorption of poorly water-soluble drugs. International journal of nanomedicine. 2011;6:1245.https://doi.org/10.2147/ijn.s19151

21. Daebis NA, El-Massik M, Abdelkader H. Formulation and characterization of Itraconazole Oral Nanosuspension: methyl cellulose as promising stabilizer. Ely J Pharm Res. 2015;1(1):102.

22. Yang H, Teng F, Wang P, TianB, Lin X, Hu X, et al. Investigation of a nanosuspension stabilized by Soluplus® to improve bioavailability. Int J Pharm. 2014;477(1–2):88–95.

23. Alhagiesa, A. W., & Ghareeb, M. M. (2021). Formulation and Characterization of Nimodipine Nanoparticles for the Enhancement of solubility and dissolution rate. Iraqi Journal of Pharmaceutical Sciences, 30(2). https://doi.org/10.31351/vol30iss2pp143-152

24. ALobaidy, R. A. R., & Rajab, N. A., Preparation And In-Vitro Evaluation of Darifenacin Hbr as Nanoparticles Prepared as Nanosuspension. Clinical Schizophrenia and Related Psychoses, 2021;15(6).

25. Kim, M. S., Song, H. S., Park, H. J., & Hwang, S. J.. Effect of solvent type on the nanoparticle formation of atorvastatin calcium by the supercritical antisolvent process. Chemical and Pharmaceutical Bulletin, 2012;60(4). https://doi.org/10.1248/cpb.60.543

26. Rashid, A. M., & Abd-Alhammid, S. N.. Formulation and characterization of itraconazole as nanosuspension dosage form for enhancement of solubility. Iraqi Journal of Pharmaceutical Sciences, 2019;28(2). https://doi.org/10.31351/vol28iss2pp124-133

27. Alwan RM, Rajab NA. Nanosuspensions of Selexipag: Formulation, Characterization, and in vitro Evaluation. Iraqi Journal of Pharmaceutical Sciences. 2021;30(1):144-53. https://doi.org/10.31351/vol30iss1pp144-153

28. Patil AS, Hegde R, Gadad AP, Dandagi PM, Masareddy R, Bolmal U. Exploring the Solvent-Anti-solvent Method of Nanosuspension for Enhanced Oral Bioavailability of Lovastatin. Turkish Journal of Pharmaceutical Sciences. 2021;18(5):541.https://doi.org/10.4274/tjps.galenos.2020.65047

29. Shekhawat P, Pokharkar V. Risk assessment and QbD based optimization of an Eprosartan mesylate nanosuspension: In-vitro characterization, PAMPA and in-vivo assessment. International Journal of Pharmaceutics. 2019;567:118415..

30. Shah A, Patel V, Shah S. Formulation Development and Optimization of Nitrendipine Nanosspension with Improved Pharmacokinetic Characteristics. Int J Pharm Sci Nanotech. 2013; 6(2):2053-

31. Aslam S, Jahan N, Rehman KU, Asi MR. Development of sodium lauryl sulphate stabilized nanosuspension of Coriandrum sativum to enhance its oral bioavailability. Journal of Drug Delivery Science and Technology. 2020;60:101957.

32. Gorain B, Choudhury H, Kundu A, Sarkar L, Karmakar S, Jaisankar P, Pal TK. Nanoemulsion strategy for olmesartan medoxomil improves oral absorption and extended antihypertensive activity in hypertensive rats. Colloids and Surfaces B: Biointerfaces. 2014;115:286-94.

33. Akeel Naji H,The psychosocial and economic impact of uveitis in Iraq. Journal of Re-search in Applied and Basic Medical Sciences. 2021;7(4):207–15

34. Jim G, Ngo HV, Cui JH, Wang J, Park C, Lee BJ. Role of Surfactant Micellization for Enhanced Dissolution of Poorly Water-Soluble Cilostazol Using Poloxamer 407-Based Solid Dispersion via the Anti-Solvent Method. Pharmaceutics. 2021;13(5):662.

35. Hassan AA, Nasser EI, Ehab IE. Surfactants solubility, concentration and the other formulations effects on the drug release rate from a controlled-release matrix. African Journal of Pharmacy and Pharmacology. 2014;8(13):364-71.

36. Al-hussaniy HA, Altalebi RR, Tylor FM, Alwash AH, Naji MA, Kadhim ZS, Abu-rghaif AR. Leptin Hormone: In Brief. Medical and Pharmaceutical Journal. 2022;1(1):1-3.

37. Patel Dhaval V, Patel Biraju D, Patel Nilesh K, Sheth Navin R, Dabhi Mahesh R, Dudhrejiya Ashvin V. Quality Improvement Methodologies in Pharmaceutical Manufacturing. Asian J. Management 2010;1(1): 01-03.

38. Rucha A Patel, Meghna P. Patel, Hasumati A. Raj , Nehal Shah. Forced Degradation Studies of Olmesartan Medoxomil and Characterization of Its Major Degradation Products by LC-MS/MS, NMR, IR and TLC. Asian J. Pharm. Ana. 2015;5(3):119-125.

39. Patel Vishakha. D., Raj Hasumati. Ranolazine: A Review on Analytical Method and Its Determination in Synthetic Mixture. Asian J. Pharm. Ana. 2015;5(4): 214-218.

40. Laith Hamza Samein. Preparation and Evaluation of Nystatin-Loaded Solid-Lipid-Nanoparticles for Topical Delivery. Asian J. Pharm. Res. 2014; 4(1):44-51.

41. Rucha A Patel, Meghna P. Patel, Hasumati A. Raj, Nehal Shah. Development and Validation of Stability Indicating high performance liquid chromatographic Method for Olmesartan medoxomil and Indapamide in Tablet. Asian J. Pharm. Res. 2015;5(1):15-23.

42. Sonali P. Mahaparale, Reshma S. Kore. Silver Nanoparticles: Synthesis, Characterization, Application, Future Outlook. Asian J. Pharm. Res. 2019; 9(3):181-189.

43. Rucha A Patel, Meghna P. Patel, Hasumati A. Raj , Nehal Shah. Development and Validation of Stability Indicating High Performance Liquid Chromatographic Method for Olmesartan Medoxomil and Indapamide in Tablet Dosage Form. Asian J. Res. Pharm. Sci. 2015;5(2):91-102.

44. G. Saravanan, SK. Bajidbhee, I. Sri Krishnanjaneyulu. Development and validation of RP-HPLC method for simultaneous estimation of Hydrochlorthiazide and Olmesartan medoxomil in bulk and pharmaceutical dosage form. Asian J. Research Chem 2015;8(2):147-152.

45. G. Venkannaa, G. Madhusudhan, K. Mukkanti, Y. Sampath Kumar. Identification synthesis of process-related impurities (substances) ethyl-4-(1-hydroxy-1-methylethyl)-2-propyl-imidazole-5-carboxylate [key intermediate of Olmesartan medoxomil (Anti hypertensive drug)]. Asian J. Research Chem 2015;8(5):307-317.

46. Awad M, Al-Hussaniy HA, Alburghaif AH, Tawfeeq KT. The role of COVID-19 in myopathy: incidence, causes, treatment, and prevention. Journal of Medicine & Life. 2022;15(12).

47. Salim Mahmood A, Ammoo AM, Ali MH, Hameed TM, Al-Hussaniy HA, Aljumaili AA, Al-Fallooji MH, Kadhim AH. Antiepileptic Effect of Neuroaid® on Strychnine-Induced Convulsions in Mice. Pharmaceuticals. 2022;15(12):1468.

48. Al-Hussaniy HA, Mohammed ZN, Alburghaif AH, Naji MA. Panax ginseng as Antioxidant and Anti-inflammatory to reduce the Cardiotoxicity of Doxorubicin on rat module. Research Journal of Pharmacy and Technology. 2022 Oct 21;15(10):4594-600.

49. Al-Kuraishy HM, Al-Hussaniy HA, Al-Gareeb AI, Negm WA, El-Kadem AH, Batiha GE, Welson NN, Mostafa-Hedeab G, Qasem AH, Conte-Junior CA. Combination of Panax ginseng CA Mey and Febuxostat Boasted Cardioprotective Effects Against Doxorubicin-Induced Acute Cardiotoxicity in Rats. Frontiers in Pharmacology. 2022;13:905828.

50. Al-hussaniy HA, Altalebi RR, Albu-Rghaif AH, Abdul-Amir AG. The Use of PCR for Respiratory Virus Detection on the Diagnosis and Treatment Decision of Respiratory Tract Infections in Iraq. Journal of Pure and Applied Microbiology. 2022 Mar 1;16(1):201-7.

51. Al-hussainy HA, AL-Biati HA, Ali IS. The Effect of Nefopam Hydrochloride on the Liver, Heart, and Brain of Rats: Acute Toxicity and Mechanisms of Nefopam Toxicity. Journal of Pharmaceutical Negative Results¦ Volume. 2022;13(3):393.

52. Al-Hussaniy HA. The Effect of MicroRNA-409-3p for Treatment and Response to Tumor Proliferation of Lung Cancer Cell Lines (In Vitro). Asian Pacific Journal of Cancer Prevention. 2022 Sep 1;23(9):3151-6.

Received on 16.09.2022 Modified on 20.12.2022

Research J. Pharm. and Tech 2023; 16(7):3314-3320.

DOI: 10.52711/0974-360X.2023.00547