Impact Factor: 5.6     h-index: 26

Document Type : Original Article

Authors

Research Laboratory of Green Organic Synthesis & Polymers, Department of Chemistry, Iran University of Science and Technology

Abstract

Irritable bowel syndrome (IBS) is a disorder of intestinal function characterized by chronic pain in the abdominal region, discomfort, bloating, and changes in bowel habits with no other organic causes. Diarrhea and constipation are the dominant signs of this disease that may alternately appear. One of the most commonly used treatments for this disease is the use of antispasmodic drugs such as Mebeverine hydrochloride (MBH), which can directly affect the smooth muscle of the gastrointestinal tract and relieve spasms caused by that without affecting the intestinal motility. Accordingly, the mechanism of action for this specific drug has a direct relaxing effect on smooth muscle. Some studies have shown that the anti-contractile effect of Mebeverine is not only limited to a specific system, which can consequently result in multiple side effects. By using nanotechnology and nano-carriers, biodegradation of drugs or biologically active substances can be prevented, and target cells can also be reached. The rate of drug release is slow but nonstop. In this study, Mebeverine hydrochloride drug was encapsulated using niosomic carriers. Correspondingly, niosomes were prepared using thin-layer dipping techniques, including specific cholesterol ratios, tween 80, and polyethylene glycol. After that, the size of the particle diameter and the amount of encapsulation and drug release were measured. Finally, it was indicated that the drug release from the formulation was at a slow rate.

Graphical Abstract

Preparation and Characterization of Mebeverine Hydrochloride Niosomes as Controlled Release Drug Delivery System

Keywords

Main Subjects

Introduction

Irritable bowel syndrome (IBS) is a disorder or disease that can be conventionally determined by symptoms such as cramping, abdominal pain, bloating, constipation, and diarrhea, occurring more usual in women than men. In addition, it usually commences before the age of 35 years old in about half of the people, Chauhan [1].  IBS leads to considerable amounts of discomfort and pain; however, it does not constantly make serious troubles for the intestines, so fortunately, no severe disease like cancer would appear [2-4].

As an antispasmodic agent, Mebeverine hydrochloride is utilized in physical treatments of irritable bowel syndrome and mucous colitis under several conditions [5]. Moreover, it is a highly water-soluble drug with the poorest oral bioavailability among the other drugs [6].

Mebeverine HCl at the cellular level directly acts on the gut muscles to make them relatively more relaxed and recovered. Besides, it possesses a short-lasting half-life of 2.5 h, and 75% of its overall amount is bonded with plasma protein, which is rapidly absorbed after its oral administration, the peak plasma concentration taking place during 1-3 h. Nevertheless, the drawback of the Mebeverine HCl drug is the vast first-pass metabolism that is considerable in the gut wall and liver organs. A high plasma concentration of Veratric acid, as one of the key inactive metabolites of Mebeverine HCl rather than negligible amounts of the parent drugs, was seen in plasma 20-30 minutes posterior to its oral consumption. [7]. A dose of 135 mg of  Mebeverine appears to be effective in relieving the symptoms of irritable bowel syndrome, but the higher frequency of the drug usage can consequently yield a high plasma concentration, which finally results in some systemic side effects such as the decreased heartbeat rate and blood pressure [8].

Hence, Mebeverine HCl was chosen as a model drug because it satisfies the required pharmacokinetic and physicochemical characteristics throughout a controlled delivery process [9, 10]. The purpose of designing the sustained or controlled delivery systems is to decline the dosing frequency or enhance the drug’s effectiveness by imposing some localizations on the action regions leading to a decrease of essential dose or introduction of uniform drug delivery to the body. The “sustained release dosage form” can be defined as a form of dosage that uninterruptedly releases one or more drugs in a pre-arranged pattern for a definite time duration, either in a systematical target organ or in a selected one [11].

Sustained release dosage forms provide the enhanced and improved involvement of plasma drug levels, less dosage frequency, more negligible side effect, increased efficiency, and constant delivery. The drug’s release happens at a pre-identified rate for a specific period to govern a specified drug concentration with minor side effects [12].

For many years, the key advantage of administering a single dose of a drug released over an extended period instead of multiple doses has been quite clear to the pharmaceutical industry experts. The desire to maintain a near-constant or uniform blood level of a drug can usually be interpreted as better patient compliance and the improved drug’s clinical efficacy for its intended usage. Various drug delivery approaches have been tested to keep the release of drugs, such as triple-layered tablets (Geomatrix®technology) and osmotic pumps with laser-drilled holes (OROS® technology). The ways mentioned above are complex and relatively costly to be manufactured. Therefore, there would be a development tendency to invent some new formulations’ blends leading a sustained release of drugs to be readily available, as well as leading inexpensive excipients into account [2].

In recent decades, drug delivery systems (DDS) using vesicular carriers have attracted great interest in the pharmaceutical field due to their potential to provide a high encapsulation efficiency and controlled release, which can carry hydrophilic and hydrophobic drugs [13]. Some of the other related significant points of the proposed drug delivery system are as follows: Biocompatibility, biodegradation, prolonged circulation in the blood, and the ability to target a specific area [14, 15].

Nanotechnology is one of the most high-tech, advanced, and applied science in the pharmaceutics field. Many different categories of nanoparticles such as polymeric and metal nanoparticles, liposomes, niosomes, solid lipid particles, micelles, quantum dots, dendrimers, microcapsules, cells, cell ghosts, lipoproteins, and different nano-assemblies are currently in hand [16, 17].

Drug delivery systems that use particulate carriers such as liposomes or niosomes have been proved to possess unique advantages over conventional dosage forms due to the action of particles as drug reservoirs, which can carry both hydrophilic drugs and hydrophobic drugs that adjust drug’s release rate. Liposomes significantly encompass phospholipids prepared from double chain phospholipids (neutral or charged). Niosomes can also be offered as a substitute for phospholipid vesicles. Moreover, the hydrated blend of cholesterol and non-ionic surfactants yields these lipid vesicles, which are usually developed to increase the stability of liposomes [18, 19].

Niosomes are vesicles composed of non-ionic surfactants, which are biodegradable, relatively nontoxic, more stable, and more cost-effective compared to liposomes as an alternative for liposomes [20, 21]. Furthermore, niosomal vesicles can be small unilamellar, multilamellar or large unilamellar. Accordingly, niosomes can encapsulate large quantities of material in a relatively low volume of vesicles. Recently, niosomes have been investigated as a drug delivery paradigm to provide better oral bioavailability, bearing in mind stability and high penetration assets using the biological membrane [16].

To prevent vesicle aggregation and to improve stability, niosome formation needs the existence of a particular class of charge-inducing agents. Furthermore, due to their potential to focus on specific cells, the charged vesicles may gain a higher therapeutic efficiency than neutral vesicles [16]. In this regard, this systemic research was designed to deal with preparation methods, characterizations, factors affecting release kinetic, advantages, and applications of niosome [22, 23].

As a product, spherical stable uniform vesicles encompassing lansoprazole were prepared using Reverse Phase Evaporation (REV) technique. Guinedi et al. have also used the same method to develop niosomes with some acetazolamides and then claimed that the produced spherical vesicles were yielded with a relatively less drug entrapment than the multilamellar vesicles. In some similar research works, Gyanendra et al. developed in their study the isoniazid niosomes by the reversed-phase evaporation way [24].

Materials and Methods

In the present study, Mebeverine hydrochloride was obtained from Pursina pharmaceutical company, Iran. The non-ionic surfactants used in this research as vesicle forming materials were Tween 80, Brij 35, and Span 60, which were prepared from Sigma Chemical Co. (St. Louis, MO, U.S.A.), and Cholesterol (Chol) was gained from Fluka (Switzerland). It should be noted that the rest of the starting materials, including reagents and solvents, all had an analytical grade.

Niosome formation

In this research, the reverse phase evaporation technique was used for preparing niosomes [25]. In this regard, before encapsulating MBH in niosomes, pre-formulation feasibility research was performed with no active agent to get the vesicle formation and also to select the most fitted optimal factors to be used in the formulation preparation. Chemical names and HLB values of nonionic surfactants in the niosome formulations are listed in Table 1. Afterward, into an aqueous phase that can be used for drug addition, surfactants were all dissolved in a mixture containing both ether and chloroform ingredients. The resultant multi-component system was then become homogenized, and hence, the present organic phase was evaporated under the condition that had the reduced pressure to form niosomes dispersed in the aqueous phase. After preserving the obtained formulations, the shape and morphology of the vesicles were perceived using an optical microscope (Sigma VP-500, Zeiss, Germany). Subsequently, the superior surfactant (Tween 80) was selected for the fabrication of niosome as carriers of medicine after finalizing the case of choosing the optimum formulation.

Table 1: Chemical names and HLB values of non-ionic surfactants in the niosome formulations

Code

Type of Surfactant

Chemical Designation

HLB Value

molecular weight (g/mol)

The presence of cholesterol crystals

Aggregation

F1

Span 20

Sorbitan monolaurate

8.60

346

-

+

F2

Span 40

Sorbitan monopalmitate

6.70

402

-

+

F3

Span 60

Sorbitan monostearate

4.70

430

+

+

F4

Tween 20

polyoxyethylene [20] sorbitan monolaurate

16.7

1226

+

-

F5

Tween 60

polyoxyethylene [20] sorbitan monostearate

14.9

1310

+

-

F6

Tween 80

polyoxyethylene [20] sorbitan monooleate

15.0

1309

-

-

F7

Brij 35

Polyoxyethylene [23] lauryl ether

16.9

1198

-

+

Preparation of mebeverine hydrochloride-loaded niosomes

The Reverse Phase Evaporation (REV) technique with slight modifications was used in this study to prepare mebeverine hydrochloride-loaded niosomes. In addition, PEG with the similar molar ratios and drug loading of mebeverine hydrochloride were then prepared to enhance the stabilization and uniform distribution of particles and the inhibition of unwanted compaction that amplifies the zeta potential on PEG. For a moment, assortments of surfactant Tween 80 and cholesterol with or without PEG were precisely dignified into a long-necked quick fit round-bottom flask in different molar ratios and consequently dissolved in 5 ml of a chloroform/methanol mixture (2:1, v/v). After that, the organic solvents were gradually vaporized under the reduced pressure circumstances in a rotary evaporator (Rotavapor type R 110, Heidolph, Germany) at 50 °C. Accordingly, this process was continued to the situation until a thin, dry film of components was shaped on the internal wall of the revolving flask. The film was then re-dissolved in 10 mL diethyl ether and a solution by dissolving the drug in acetone along with 5 mL distilled water was introduced to the system. Afterward, the obtained mixture was sonicated for 2 min, swirled by hand, and re-sonicated for another 2 min in a sonicator bath (P30H, Elma, Germany). To guarantee the removal of residual diethyl ether, the subsequent opalescent scattering was rotary evaporated between 5 and 10 minutes. The niosomal suspension was left to mature overnight at 4 °C.

Characterization of mebeverine hydrochloride niosomes

Scanning electron microscopy (SEM)

The niosomes were perceived using scanning electron microscopy (SEM) (sigma VP-500, Zeiss, Germany). Before performing the microscopic study, the obtained samples were directly mounted on an SEM sample holder using double‑sided sticking tape, which was previously coated with a gold film of thickness 200 nm under the reduced pressure of 0.001 mmHg.

Infrared absorption spectroscopy (IR)

Infrared absorption spectroscopic (IR) analyses were performed using a spectrophotometer (Hitachi 295, Tokyo, Japan) by applying the KBr disc technique. Subsequently, the samples, including the selected freeze-dried niosomes, MBH powder, and the physical mixture containing MBH and cholesterol, were comprehensively scanned over 4000 to 400 cm-1.

Separation of the un-entrapped drug

The dialysis method was utilized to eliminate the free un-entrapped drug [26]. In addition, the un-entrapped free MBH was also detached by the addition of 1ml of niosomes into the glass tube. In this regard, a cellulose membrane was attached to one end, which was exhaustively dialyzed against 100 ml of phosphate-buffered saline (pH 7.4) for 1 h at 4 °C each time. The dialysis of free MBH was accomplished with a buffer solution in which no further MBH was observable. The drug concentrations were spectrophotometrically identified at 263 nm (S700 UV/Visible, Shimadzu, Japan) against phosphate-buffered saline (pH 7.4) as a blank. Moreover, the concentration of the entrapped drug was gained by deducting the quantity of un-entrapped drug from the overall drug that was hypothetically calculated earlier using the equation 1 as follows:

Particle size and zeta potential

Niosomes size distribution and zeta potential were also determined using photon correlation spectroscopy (Zetasizer Nano ZS, Zetaplus; Brookhaven, USA). The size distribution analysis was performed at a scattering angle of 90 at 25 °C, whereas the zeta potential was measured using a disposable zeta cuvette. The mean diameter/zeta potential standard deviation of six determinations was planned for each sample by applying multi-modal analysis.

In vitro drug release studies

In-vitro drug release studies were done on the prepared niosomal formulations at constant pH of 7.4 using a dialysis bag (with a molecular weight cutoff of 12000–14000 Da). An amount of niosomes equivalent to 100 mg of MH was then weighed, put in a bag, and placed into a beaker containing 100 mL of PBS. This beaker was placed over a magnetic stirrer (50 rpm). Accordingly, the temperature was preserved at 37 °C. Aliquots (4 mL) were periodically withdrawn, and equal volumes of fresh medium equilibrated at 37 oC were then replaced [27]. This test was continued for 24 h. The withdrawn samples were spectrophotometrically analyzed for drug content at 263 nm [28]. A different experiment was performed with a free MH solution in the same PBS to check the ultimate constraining and the effect of dialysis membrane on drug release.

Kinetic modeling

The in vitro release of the drug was considerably recorded by fitting the cumulative drug release into the kinetic models. Correspondingly, this could also be simply calculated from the slope of the linear steady section of the % cumulative amount released vs. time (h) plot. The attained release data were fitted using different approaches such as zero order, first order, and Higuchi kinetic models to regulate the mechanism of drug release from the numerous consignments. The correlation coefficients (R2) were determined for different drug release kinetic models, which were then compared with each other for weighting their accuracies.

Results and Discussion

Preparation and characterization of niosomes

Different methods exist to prepare niosomes, such as reverse phase evaporation, bubble method, ether injection, and proniosome. However, the best applied one was selected and then optimized in this research. It is noteworthy that large single-wall niosomes possess several advantages compared with multi-layer niosomes, such as a high encapsulating ratio in water solute drugs and a low consumption of surfactant encapsulated drug release with a repeatable rate [29].

MBH niosomes with an identical molar ratio of cholesterol to surfactant were prepared using the reverse evaporation method. Moreover, the morphology, size, and release rate of the prepared niosomes were evaluated for drug content using zeta potential, IR, and scanning electron microscopy (SEM), in vitro drug release. Figure 1 illustrates the SEM micrographs of nano-niosomes, in which Tween-80 was used as the surfactant during synthesis. As shown, using this surfactant, the product would have higher degrees of uniformity with a higher quantitative amount compared to the case of applying other surfactants such as Span and Brij. In addition, the measured size of the average diameter for niosome for Tween-80 had a good agreement with data extracted from zeta potential’s characterization.

Scheme 1: Preparation and Characterization of Mebeverine Hydrochloride Niosomes

Figure 1: SEM microphotograph of (a) span, (b) brij, and (c) tween niosome preparation

 

The comparative IR spectra of cholesterol/Tween-80 and niosome, as a product, are shown in Figure 2. Accordingly, the characteristic formation peak of niosomes is the carbonyl peak shift from 1735 to 1650. Correspondingly, this can be attributed to the hydrogen bond formation between Tween carbonyl and cholesterol hydroxyl [14]. IR spectra can also be used to evaluate the drug interaction with niosome multi-layer structure as well as comparing drug, niosome, and drug-containing niosome (Figure 3).

Notably, the drug bands are assumed to be appeared at 2945 cm−1 due to the presence of OH groups (3381 cm−1), which are attributed to C-H Aliphatic, C=O of the ester group (1717 cm−1), ether-based C-O (1265 and 1221 cm−1), N-H (2461 cm−1), and a broad band. The disappearance of such peak was also shown to be caused by the low ratio of drug to niosomes or, in other word, interaction of drug H atom with C=O bond of niosomes that leads to the elimination of 2461 peak.

Figure 2: FTIR spectra of (a) cholesterol, (b) tween 80, and (c) niosomes

Figure 3: FTIR spectra of (a) drug, (b) unloaded niosomes, and (c) niosomes carrying the drug

Figures 4 and 5 show the Zeta potential and particle size analyses for the produced samples. The decrease in the average size and potential of the drug-containing nano-niosomes surface produced by sonication were measured using zeta potential at 25 °C. Furthermore, the size, drug loading, entrapment efficiency, and potential of zeta niosomes carrying PEGed drug with no PEG, are listed in Table 2.

Figure 4: Zeta potential of vesicles carrying pegylated MBH

Figure 5: Particle size distribution of vesicles carrying pegylated MBH

Table 2: Properties of MBH-loaded niosomes

Zeta potential (mV)

Mean size (nm) (Z average)

Entrapment efficiency %

Drug loading %

Formulations

-4.59

333

85%

8.5%

Unloaded niosomes

-38.38

310

95%

10%

PEGed niosomes

 

It should be noted that zeta potential is a criterion for identifying particle stability, as particles with a zeta potential of more than +30 mV or less than -30 mV are considered stable particles [30]. When zeta potential increases, a higher repulsive interaction takes place that consequently leads to the formation of more stable- and uniform-distributed particles. Accordingly, it can be seen that -5 and -38 mV values of zeta potential for drug-containing Nano-niosomes and PEGed one can be assigned to the low and high stabilities of nanoparticles.

 Drug encapsulating efficiency

UV observation for the above-mentioned formulation with and without PEG were measured using a spectrophotometer, and the related niosome drug percentage can also be calculated by equation 1.

As can be inferred, using PEG during the fabrication of niosomes, the encapsulated drug value has increased up to 95%, and the loaded drug has also reached 10%. The finding of this investigation is in good accordance with the related data previously reported in related studies [31].

Characterization of physicochemical properties of MBH

The melting point of the Mebeverine drug was estimated to be 135 °C. For constructing a calibration graph for MBH as well as identifying its corresponding maximum absorption wavelength, UV absorption of all the standard gradually diluted MBH was measured using a spectrophotometer. Afterward, the standard graph was yielded, and governing equation of the line was then determined, as indicated in Figure 6.

Evaluation of MBH release from nano niosomes

The standard graph of MBH was utilized to record the release rate of nano-niosome-based MBHs in different time durations. The drug delivery pattern in environmental circumstances was performed according to Figure 7. Drug delivery profiles of simple Nano-niosomes and PEGed one in different time durations up to 24 hours in two different pH values of 1.5 (like acidic gastric condition) and 7.4 (like colon acidic condition) were calculated using a UV-Visible spectrophotometer. In the case of using PEGed Nano-niosomes, more than 85% of the drug amount was delivered in 24 hours at pH = 7.4 in a controlled and ordered manner. It should be noted that only 7% of the loaded MBH was delivered from Nano-niosomes in 2 hours at pH = 1.5 due to a complex formation between the drug and the components of the produced chemicals.

The drug is usually got protonated in acidic media within the container, so the emissivity of the drug decreases through the bi-layered vesicol membrane, which also inhibits encapsulated drug diffuse in vesicol. In this regard, it can be anticipated that this nano-niosomes can be transferred through the gastric and deliver their contained drug in the small intestine.

Figure 6: UV-calibration curve of mebeverine hydrochloride

Figure 7: Release of mebeverine HCl from loaded and unloaded niosomes in 0.1N HCl (2 h) and pH 7.4 (22 h)

Drug delivery kinetics

At this stage, in vitro release data of niosomal formulations from both dissolution mediums were fitted to different equations, and optimal kinetic models were then obtained to explain the release kinetics of MBH from niosomes. According to the obtained results and by comparing statistical accuracy’s criteria of drug release rates with the zero-order model, it was proven that the model with the highest R2 value also has the enhanced flexibility of niosomes and transformation with respect to the others. The in vitro release of Mebeverine HCl from pegylated niosomes fitted by zero-order, fist order, and Higuchi model are presented in Figures 8, 9, and 10, respectively. In addition, Table 3 lists the R2 values calculated after being fitted as the comparative criterion of the three proposed models.

Figure 8: In vitro release of Mebeverine HCl from niosomes pegylated fitted in zero-order release

Figure 9: In vitro release of Mebeverine HCl from niosomes pegylated fitted in the first-order release

Figure 10: In vitro release of Mebeverine HCl from niosomes pegylated fitted by Higuchi plot

Table 3: Value of coefficient of regression (R2) for three proposed models

Formulation Code

Zero-order model

First-order model

Higuchi order model

R2

R2

R2

F1)  pegylated

0.985

0.943

0.879

F2) nonpegylated

0.916

0.940

0.945

Conclusion

In this research, MBH niosome was prepared in two different forms, namely simple and PEGed and their drug loading and release properties were investigated. The results of this research showed a higher encapsulation efficiency in PEGed form, in comparison to the simple form reported in a research performed by Cosco et al. However, the size analysis of the nano-particles indicated that the diameter of the PEGed particles was less than the one with no PEG that might be due to the enhancement of hydrophilic property and diffusivity behaviors of PEG. Correspondingly, this effect causes significant compressibility and a consequent decrease in the diameter size of the synthesized vesicol. Furthermore, the higher encapsulation efficiency of PEGed niosomes with respect to the simple one can be reported due to a vesicol compressing and drug delivery decline from its wall leading to the encapsulation efficiency enhancement. This trend can also be traced to the drug delivery pattern of this phenomenon. In this case, a lower drug delivery rate in PEGed niosomes than in the other formulation proved this assumption that the corresponding released drug under PEGed condition is less than that in other situations with similar durations.

Acknowledgments

We thank the Iran University of Science and Technology for partial support of this work. The kind donation of Mebeverine hydrochloride by Pursina pharmaceutical company is also gratefully acknowledged.

 

Funding

This research did not receive any specific grant from fundig agencies in the public, commercial, or not-for-profit sectors.

 

Authors' contributions

All authors contributed toward data analysis, drafting and revising the paper and agreed to responsible for all the aspects of this work.

 

Conflict of Interest

We have no conflicts of interest to disclose.

 

ORCID

Mohammad Reza Naimi-Jamal

https://www.orcid.org/0000-0002-8305-7234

HOW TO CITE THIS ARTICLE

Seyed Mohammad Hossein Hosseini, Mohammad Reza Naimi-Jamal, Maryam Hassani. Preparation and Characterization of Mebeverine Hydrochloride Niosomes as Controlled Release Drug Delivery System. Chem. Methodol., 2022, 6(8) 591-603

https://doi.org/10.22034/CHEMM.2022.337717.1482

URL: http://www.chemmethod.com/article_150853.html

[1]. Chauhan D., Patel A., Shah S., Influence of selected natural polymers on in vitro release of colon targeted mebeverine HCl matrix tablet, International Journal of Drug Development & Research, 2012, 4:315 [Google Scholar]
[2]. Reddy B.V., Swetha K.N., Navaneetha K., Formulation and evaluation of mebeverine hydrochloride sustained release tablets, Asian Journal of Pharmaceutical Research, 2015, 5:58 [Crossref], [Google Scholar], [Publisher]  
[3]. Dandagi P.M., Mastiholimath V.S., Gadad A.P., Kulkarni A.R., Konnur B.K., pH-sensitive mebeverine microspheres for colon delivery, Indian Journal of Pharmaceutical Sciences, 2009, 71:464 [Google Scholar], [Publisher]  
[4]. Camilleri M., Diagnosis and treatment of irritable bowel syndrome: a review, Jama, 2021, 325:865 [Crossref], [Google Scholar], [Publisher]
[5]. Illangakoon U.E., Nazir T., Williams G.R., Chatterton N.P., Mebeverine‐loaded electrospun nanofibers: Physicochemical characterization and dissolution studies, Journal of pharmaceutical sciences, 2014, 103:283 [Crossref], [Google Scholar], [Publisher]  
[6]. Swathi P., Velrajan G., Formulation and evaluation of targeted and controlled release mebeverine hydrochloride microspheres, International Journal of Pharma and Bio Sciences, 2013, 4:11 [Google Scholar]
[7]. El-Nabarawi M.A., Teaima M.H., El-Monem R.A., El-Nabarawy N.A., Gaber D.A., Formulation, release characteristics, and bioavailability study of gastroretentive floating matrix tablet and floating raft system of Mebeverine HCl, Drug design, development and therapy, 2017, 11:1081 [Crossref], [Google Scholar], [Publisher]  
[8]. Sanjeevani D., Madhavi P., Ajinath S., Satish S., Development of sustained release tablet of Mebeverine hydrochloride. Journal of Pharmaceutical Education and Research, 2013, 4:64 [Google Scholar], [Publisher]  
[9]. Abdel-Hamid S.M., Abdel-Hady S.E., El-Shamy A.A., El-Dessouky H.F., Formulation of an antispasmodic drug as a topical local anesthetic, International journal of pharmaceutics, 2006, 326:107 [Crossref], [Google Scholar], [Publisher]
[10]. Daniluk J., Malecka-Wojciesko E., Skrzydlo-Radomanska B., Rydzewska G., The Efficacy of Mebeverine in the Treatment of Irritable Bowel Syndrome—A Systematic Review. Journal of Clinical Medicine, 2022,  11:1044 [Crossref], [Google Scholar], [Publisher]
[11]. Mamidala R.K., Ramana V., G Sandeep., Lingam M., Gannu R., Yamsani M.R., Factors influencing the design and performance of oral sustained/controlled release dosage forms, International Journal of Pharmaceutical Sciences and Nanotechnology, 2009, 2:583 [Google Scholar]
[12]. Ratilal D.A., Gaikwad Priti D., Bankar Vidyadhar H., Pawar Sunil P., A review on: sustained released technology, Int J Res Appl Pharm, 2011, 2:1701 [Google Scholar]
[13]. Bansal S., Aggarwal G., Chandel P., Harikumar S.L., Design and development of cefdinir niosomes for oral delivery, Journal of Pharmacy & Bioallied Sciences, 2013, 5:318 [Crossref], [Google Scholar], [Publisher]
[14]. Sharma V., Anandhakumar S., Sasidharan M., Self-degrading niosomes for encapsulation of hydrophilic and hydrophobic drugs: an efficient carrier for cancer multi-drug delivery, Materials Science and Engineering: C, 2015, 56:393 [Crossref], [Google Scholar], [Publisher]
[15]. Sims Jr K.R., Advancing Anti-Biofilm Nanoparticle Drug Delivery Systems. University of Rochester, 2019 [Google Scholar], [Publisher]  
[16]. Hasan A.A., Madkor H., Wageh S., Formulation and evaluation of metformin hydrochloride-loaded niosomes as controlled release drug delivery system, Drug delivery, 2013, 20:120 [Crossref], [Google Scholar], [Publisher]
[17]. Ramburrun P., Khan R.A., Choonara Y.E., Design, preparation, and functionalization of nanobiomaterials for enhanced efficacy in current and future biomedical applications. Nanotechnology Reviews, 2022, 11:1802 [Crossref], [Google Scholar], [Publisher]
[18]. Bendas E.R., Abdullah H., El-Komy M.H.M., Kassem M.A., Hydroxychloroquine niosomes: a new trend in topical management of oral lichen planus, International journal of pharmaceutics, 2013, 458:287 [Crossref], [Google Scholar], [Publisher]
[19]. Mokale V., Niosomes As an Ideal Drug Delivery System. Journal of Nanosciences Research & Reports, 2021, 3:2 [Crossref], [Google Scholar]
[20]. Imran M., Shah M.R., Ullah F., Ullah S., Elhissi A.M., Nawaz W., Ahmad F., Sadiq A., Ali I., Glycoside-based niosomal nanocarrier for enhanced in-vivo performance of Cefixime, International journal of pharmaceutics, 2016, 505:122 [Crossref], [Google Scholar], [Publisher]  
[21]. Vahid N.F., Marvi M.R., Naimi-Jamal M.R., Naghib S.M., Ghaffarinejad A., Effect of surfactant type on buckypaper electrochemical performance, Micro & Nano Letters, 2018, 13:927 [Crossref], [Google Scholar], [Publisher]
[22]. Bini K.B., Akhilesh D., Prabhakara P., Kamath J.V., Development and characterization of non-ionic surfactant vesicles (niosomes) for oral delivery of lornoxicam, International Journal of Drug Development and Research, 2012, 4:147 [Google Scholar], [Publisher]  
[23]. Masjedi M., Montahaei T., An illustrated review on nonionic surfactant vesicles (niosomes) as an approach in modern drug delivery: Fabrication, characterization, pharmaceutical, and cosmetic applications, Journal of Drug Delivery Science and Technology, 2021, 61:102234 [Crossref], [Google Scholar], [Publisher]  
[24]. Kumar G.P., Rajeshwarrao P., Nonionic surfactant vesicular systems for effective drug delivery—an overview, Acta pharmaceutica sinica B, 2011, 1:208 [Crossref], [Google Scholar], [Publisher]  
[25]. Usama A., Fetih G., El-Faham T., Performance of meloxicam niosomal gel formulations for transdermal drug delivery, British Journal of Pharmaceutical Research, 2016, 12:1 [Google Scholar], [Publisher]  
[26]. Ibrahim.M.M., Shehata T.M., Tramadol HCl encapsulated niosomes for extended analgesic effect following oral administration, Journal of Drug Delivery Science and Technology, 2018, 46:14 [Crossref], [Google Scholar], [Publisher]
[27]. Arzani G., Haeri A., Daeihamed M., Bakhtiari-Kaboutaraki H., Dadashzadeh S., Niosomal carriers enhance oral bioavailability of carvedilol: effects of bile salt-enriched vesicles and carrier surface charge, International journal of nanomedicine, 2015, 10:4797 [Crossref], [Google Scholar], [Publisher]
[28]. Shehata T.M., Abdallah M.H., Ibrahim M.M., Proniosomal oral tablets for controlled delivery and enhanced pharmacokinetic properties of acemetacin, AAPS PharmSciTech, 2015, 16:375 [Crossref], [Google Scholar], [Publisher]  
[29]. Moghassemi S., Hadjizadeh A., Nano-niosomes as nanoscale drug delivery systems: an illustrated review, Journal of controlled release, 2014, 185:22 [Crossref], [Google Scholar], [Publisher]  
[30]. Kirby B.J., Hasselbrink Jr E.F., Zeta potential of microfluidic substrates: 1. Theory, experimental techniques, and effects on separations, Electrophoresis, 2004, 25:187 [Crossref], [Google Scholar], [Publisher]  
[31]. Yang H., Deng A., Zhang J., Wang J., Lu B., Preparation, characterization and anticancer therapeutic efficacy of cisplatin-loaded niosomes, Journal of microencapsulation, 2013, 30:237 [Crossref], [Google Scholar], [Publisher]