Amina Tarek Mneimneh - repository.bau.edu.lb:8080

Design and Development of Biocompatible Lipid-based Nanocarriers

By

Amina Tarek Mneimneh

Thesis

Presented to fulfill the requirements of Master degree in Pharmaceutical

Sciences

(Pharmaceutics and Pharmaceutical Technology)

Department of Pharmaceutical Technology

Faculty of Pharmacy

2019

Design and Development of Biocompatible Lipid-based Nanocarriers.

By

Amina Tarek Mneimneh

Thesis

Presented to fulfill the requirements of Master degree in Pharmaceutical

Sciences

(Pharmaceutics and Pharmaceutical Technology)

Department of Pharmaceutical Technology

Faculty of Pharmacy

Supervised by

Dr. Mohammed M. Mehanna

Assistant Prof. of Pharmaceutical Technology

Faculty of Pharmacy

Beirut Arab University

2019

i

Abstract

Synthesis of new drug alone has been evident to be insufficient to establish

advancement in drug therapy. The conventional drug delivery systems are destined to failure,

due to many factors, mainly low drug solubility, absorption, enzymatic hydrolysis, rapid

metabolism, cellular efflux and variability in plasma concentration. Lipid-based nanocarriers

provide a great prospective of overcoming various technological and stability limitations of

the conventional delivery systems. Lipids can offer wide range of diverse nanocarriers

including, liposomes, niosomes, solid-lipid nanoparticles, lipid-drug conjugate,

nanostructured lipid carriers, microemulsion, nanoemulsion and self-emulsifying delivery

system. Our aim in the current study was to develop and optimize a spontaneous self-

nanoemulsifying drug delivery system (SNEDDS), containing D-limonene as the oily phase,

and Tween®80/propylene glycol mixture as surfactant/co-surfactant. The work was

distributed on three chapters; preparation and optimization of limonene-based self-

nanoemulsifying delivery system, in-vivo evaluation of the tadalafil-loaded SNEDS for its

gastroprotective effect, and in-vitro assessment of levofloxacin-loaded SNEDS for its

antimicrobial activity against Methicillin-resistant Staphylococcus aureus (MRSA)

producing biofilms, and its formulation as an ocular in-situ nanoemulgel.

The optimization of the SNEDS was achieved through the construction of a pseudo-

ternary phase diagram. Limonene-based SNEDS was optimized by evaluating its

physiochemical properties, namely; droplet size, zeta potential, polydispersity index and its

morphology was studied by transmittance electron microscopy. In addition, the stability in

different storage conditions of the formulation for three months was assessed. The optimized

limonene-based SNEDS had the smallest droplet size (113.3 nm), unimodel distribution with

PDI (0.211), the highest percentage transmittance (92.57%) and optimal zeta potential of -

19.13 mV and was stable during the period of study.

Furthermore, the optimized SNEDS was loaded with tadalafil then tested in-vivo for

its protective effect against ethanol-induced injuries in rats, compared to omeprazole. The

results showed significant high gastroprotection percentage (99.59%) in the limonene-based

SNEDS and tadalafil-loaded preparation (99.9%) compared to the omeprazole pre-treated

group (74%). The histological analysis displayed very mild inflammation in the limonene-

ii

based nanoemulsion group with an intact mucosal structure while normal intact epithelial

layer was noticed in tadalafil-loaded SNEDS pretreated group.

Levofloxacin-loaded limonene-based SNEDS was evaluated in-vitro for its

antimicrobial susceptibility on biofilm forming MRSA strain through kinetics of killing and

biofilm assay. The in-situ nanoemulgel ocular irritation was studied by HET-CAM test. The

results revealed that levofloxacin-loaded limonene-based SNEDS showed improved efficacy

to eradicate MRSA biofilm, where the MIC of the loaded SNEDS was 3.12 mg/ml less than

that of drug alone 6.25 mg/ml. HET-CAM test showed no signs of hemorrhage, coagulation

or lysis for the loaded nanoemulgel same as the negative control. The irritation score was

zero. The data and knowledge accumulated from this research suggested that self-

nanoemulsifying delivery system loaded gel is a promising alternative to standard antibiotic

dosage forms against antibiotic-resistant bacteria and those which form impassable biofilms.

iii

Table of Contents List of tables vii

List of figures ix

List of Abbreviation xii

Introduction 1

1. Lipid formulation classification system 2

2. Type of lipid-based drug delivery system 3

2.1. Vesicular systems 3

2.2. Lipid particulate systems 9

2.3. Emulsions 13

Chapter Ⅰ 1

Self-Nanoemulsifying Drug Delivery System Based on D-limonene: Design and Optimization 1

1. Introduction 25

Aim of the chapter 28

2. Materials and methods 29

2.1. Materials 29

2.2. Preliminary screening of surfactants 29

2.3. Preliminary screening of co-surfactants 29

2.4. Construction of pseudoternary phase diagram 29

2.5. Preparation of limonene-based self-nanoemulsifying delivery system 30

2.6. Study of SNEDS characteristics 30

2.6.1. Macroscopic examination 30

2.6.2. Turbidity/transparency measurement 30

2.6.3. Self-emulsification time determination 30

2.6.4. Cloud point determination 31

2.6.5. Transmission electron microscopy (TEM) 31

2.6.6. Globule size and zeta potential measurements 31

2.7. Evaluation of the self-nanoemulsifying delivery system 31

2.7.1 Robustness to dilution 31

2.7.1. Thermodynamic stability studies 32

2.8. Stability upon storage 32

2.9. Statistical analysis 32

iv

3. Results 33

3.1. Selection of surfactants and co-surfactants 33

3.2. Pseudoternary phase diagram of limonene-based SNEDS 34

3.3. Physiochemical characteristics and evaluation of limonene-based SNEDS 37

3.4. Storage stability testing 39

4. Discussion 42

5. Conclusion 46

Chapter II 25

Appraisal of Tadalafil-loaded Limonene-based Self-nanoemulsifying Delivery System Gastroprotective Effect Employing Ethanol-induced Mucosal Injuries Model in Rats 25

1. Introduction 47



2.1. Materials 51

2.2. UV-VIS Spectrophotometric Assay of Tadalafil 51

2.3. Solubility studies 51

2.4. Formulation of tadalafil-loaded limonene-based SNEDS 51

2.5. Evaluation of tadalafil-loaded limonene-based SNEDS 52

2.5.1. Percentage transmittance measurement 52

2.5.2. Self-emulsification time 52

2.5.3. Robustness to dilution 52

2.5.4. Cloud point determination 52

2.5.5. Thermodynamic stability 52

2.6. Physiochemical characteristics of tadalafil-loaded limonene-based SNEDS 53

2.6.1. Determination of droplet size and polydispersity index (PDI) 53

2.6.2. Zeta potential measurement 53

2.6.3. In-vitro drug release and its kinetics 53

2.7. In-vivo assessment 55

2.7.1. Animals 55

2.7.2. Ethanol-induced gastric ulcer 55

2.7.3. Evaluation of gastric lesion 55

2.7.4. Histopathological assessment 56

v

2.8. Stability studies 56


3. Results 58

3.1. UV-VIS spectrophotometric Assay of Tadalafil 58

3.2. Solubility study 59

3.3. Physical stability of tadalafil SNEDS 59

3.4. Physicochemical characteristics of tadalafil-loaded nanoemulsion 60

3.5. In-vitro dissolution studies 60

3.6. Gross evaluation 62

3.7. Histopathological evaluation 66

3.8. Storage stability 66

4. Discussion 70

5. Conclusion 75

Chapter III 47

Levofloxacin-loaded Naturally Occurring Monoterpine-based Nanoemulgel: A Feasible Efficient System to Circumvent MRSA Ocular Infections 47

1. Introduction 76



2.1. Materials and culture 80

2.2. UV-VIS Spectrophotometric Assay of levofloxacin 80


2.4. Preparation of levofloxacin-loaded limonene-based SNEDS 80

2.5. Assessment of levofloxacin-loaded limonene-based SNEDS 81

2.5.1. Thermodynamic stability 81

2.5.2. Self-emulsification time 81

2.5.3. Robustness to dilution 81

2.5.4. Cloud point 81

2.6. Physiochemical characteristics of the levofloxacin-loaded SNEDS 81

2.7. Antibacterial activity of levofloxacin-loaded and unloaded SNEDS 82

2.7.1. Determination of the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) 82

vi

2.7.2. Effect of limonene-based SNEDS on the activity of levofloxacin against biofilm-forming bacteria 82

2.7.3. Regrowth assay 83


2.9. Preparation of levofloxacin-loaded limonene-based in-situ nanoemulgel 83

2.10. Characterization of the levofloxacin-loaded limonene-based in-situ nanoemulgel 84

2.10.1. Determination of visual appearance, clarity and pH 84

2.10.2. Measurement of the gelation temperature 84

2.10.3. Rheological behavior 84

2.10.4. Refractive index 84

2.10.5. Transmission electron microscopy (TEM) 84

2.11. In-vitro release of levofloxacin from limonene-based in-situ nanoemulgel 85

2.12. Ocular irritation test by Hen's Egg Test Chorioallantoic Membrane (HET-CAM) Assay 85


3. Results 87

3.1. UV-VIS spectrophotometric Assay of Levofloxacin 87


3.3. Physiochemical characteristics and physical stability of Levofloxacin- loaded limonene-based SNEDS 88

3.4 . Antibacterial activity of levofloxacin-loaded and unloaded limonene-based SNEDS 91

3.4.1. In-vitro evaluation of the activity of levofloxacin-loaded and free limonene-based SNEDS 91

3.4.2. Effect of levofloxacin loaded and unloaded limonene-based SNEDS on the biofilm-forming ability of MRSA 91

3.4.3. Biofilm regrowth assay 93


3.6. Characterization of the levofloxacin-loaded limonene-based in-situ nanoemulgel 95

3.7. In-vitro release studies 97

3.8. Hen's Egg Test Chorioallantoic Membrane (HET-CAM) irritation test 98

4. Discussion 101

5. Conclusion 106

References 107

vii

List of tables Table 1: Lipid formulation classification system; characteristic features, advantages, and

disadvantages of the basic lipid formulations7 2

Table 2: Differences between nanoemulsions and microemulsions58,59 14

Table 3: Summary of some research articles describing different SNEDDS formulations 22

Table 4: Preliminary screening of different surfactants and co-surfactants based on their %

transmittance 33

Table 5: Analysis of variance of surfactants and co-surfactants screening 34

Table 6: Composition of SNEDS formulations constructing phase diagram 35

Table 7: Physiochemical characteristics of limonene-based SNEDS* 37

Table 8: Abou Zeit-Har ulcer scoring system 56

Table 9: Thermodynamic stability and self-emulsification time tadalafil-loaded and unloaded

limonene-based self-nanoemulsifying delivery system 59

Table 10: T-test values of the physiochemical characteristics of tadalafil-loaded and unloaded

limonene-based nanoemulsion 60

Table 11: T-test values of the mean dissolution rate of tadalafil from limonene-based SNEDS

and aqueous suspension 61

Table 12: Correlation coefficients and kinetics of drug release of tadalafil from limonene-

based self-emulsifying delivery system 62

Table 13: The effect of different treatment modalities on ethanol-induced gastric ulcer in

rats● 65

Table 14: Physical stability of tadalafil-loaded SNEDS at different storage temperatures for

three months* 68

Table 15: Scoring scheme for the Hen's Egg Test-chorioallantoic membrane test for

membrane irritation 86

Table 16: Physiochemical characteristics of Levofloxacin-loaded limonene based SNEDS 89

Table 17: T-test of the physiochemical characteristics of levofloxacin-loaded and unloaded

SNEDS 89

Table 18: MIC and MBC values of levofloxacin aqueous solution, levofloxacin-loaded and

unloaded limonene-based self-nanoemulsifying delivery system against 49 MRSA strain* 92

Table 19: T-test value for biofilm inhibition of free and loaded levofloxacin SNEDS 93

1

In the recent years, it has been evident that synthesizing new drug alone is not

sufficient to establish advancement in drug therapy. The conventional drug delivery

systems are destined to failure, due to many factors, mainly low drug solubility, poor

absorption, enzymatic degradation, rapid metabolism, cellular efflux and variability in

plasma concentration1. Poorly soluble drugs are a considerable challenge for researchers,

regarding their low aqueous solubility, bioavailability and high lipophilicity. So, a new

pharmaceutical delivery system or a drug carrier that acts as a reservoir is needed for the

optimal delivery of drug to the targeted site within appropriate time frame and effective

concentration. In-vivo fate of the drug isn’t influenced only by the properties of the drug

itself, but also by its carrier system characteristics, which could provide controlled or

localized release of the drug according to the desired therapy2. Lipids are the major

constituents of biological membranes. Incorporation of lipids in drug delivery has been a

trend in the past decades. Lipid based carriers are composed of phospholipids, cholesterol,

cholesterolesters and triglycerides among others3. The physiochemical diversity of lipids,

their biocompatibility and their resemblance to body tissue constituents offer a promising

system for poorly water soluble and lipophilic drugs4. Lipid carriers (LCs) provide several

advantages that enable it to be an ideal vehicle for drug delivery. Namely; it can be

manipulated according to product requirements whether its disease conditions, rout of

administration, stability, toxicity or efficacy. In addition, Lipid based formulations (LBFs)

can provide a controlled release delivery based on their biocompatibility with body tissue

after administration, it’s not susceptible to erosion phenomena, feasibility of scaling up5,

moreover, it provide enhanced drug loading, ability to carry both lipophilic and

hydrophilic drugs and stability. However, LCs face certain limitations such as, lipid

crystallization that leads to polymorphism with different drug loading capacity, different

shapes and various kinetic distributions. High pressure homogenization technique is most

commonly used and it might cause drug degradation in high molecular weight

compounds3. Lipid-based carriers are recognized as safe and efficient hence they have

been used as alluring candidates for pharmaceutical, as well as vaccines, diagnostics, and

nutraceutical formulations. Therefore, lipid-based drug delivery (LBDD) systems have

gained much importance in the recent years due to their ability to improve the solubility

and bioavailability of drugs with poor water solubility.

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