May 1, 2023 1

Vesicular Drug Delivery System Advances and Applications

STES’s SINHGAD INSTITUTE OF PHARMACY NARHE, PUNE-4110 41.

Name of Guide :

Dr. C. R. Kokare

(HOD of Department of

Pharmaceutics)

Name of Student :

Mr. Vijaykumar R. Chavan

M. Pharm (Sem - III)

(Department of Pharmaceutics)

Content May 1, 2023 2

Introduction

Classification of vesicular drug delivery system

1 Lipoidal biocarrier

2 Nonlipoidal biocarrier

Case study

Future aspect

Key Referances

May 1, 2023 3

WHY VASICULAR DDS?Degradation of drug and /or drug loss

Harmful side effects

Bioavailability at the site of disease

Intracellular infection

Conventional therapy is ineffective

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Vesicular Drug Delivery System

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Liposomes Ethosomes Transferosomes

Sphingosomes Pharmacosomes Virosomes

Phytosomes

Classification of Vesicular Drug Delivery System

1. Lipoidal Biocarriers

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Non- lipoidal biocarriers for site-specific

targeting

Niosomes

Bilosomes

Aquasomes

2. Non-lipoidal biocarriers

May 1, 2023 71.Lipoidal Biocarrier

1. Liposomes A minute spherical sac of phospholipid

molecules enclosing a water droplet, especially as formed artificially to carry drugs or other substances into the tissues.

Size ranges from 10-300µm

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Based on Structure Parameter

MLVMultilamillar vesicles (>0.5µm)

OLVOligolamillar

vesicles(0.1 to 10 µm)

ULVUnilamillar

vesicles(All in size)

Multivesicular vesicles(>1.0µm)

MUVMedium

unilamillar vesicles

SUVSmall unilamillar

vesicles(10 to 20nm)

LUVLarge unilamillar

vesicles (>100nm)

Classification of Liposomes

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Passive loading techniques Active loading techniques

Mechanical dispersion Solvent dispersion Detergent removal

Based on Method of preparation

1) Thin film hydration method 2) Ultrasonication3) French Pressure cell4) High pressure extrusion5) Freeze thawed

1) Solvent injection method a) Ether injection b) Ethanol injection2) Reverse phase evaporation technique

1) Detergent removal a) Dialysis b) Coloum chromatography c) Dilution

May 1, 2023 10General Method for Liposome Preparation

Lecithin Charge

Dissolve in organic solvent

Gelation in organic solvent

Drying

Thin film

Hydration

Liposome suspension

Cholesterol

May 1, 2023 111.Thin film hydration method

Advantages and Disadvantages of Liposomes

1. Liposomes increases efficacy and therapeutic index of drug(Actinomycin D).

2. It increases stability via encap--sulation.3. It reduces the toxicity of encapsulating

agent (Amphotericin B,Taxol).4. They helps to reduce the exposure of

sensitive tissue to toxic drugs.5. They have flexibility to couple with site

specific ligands to achieve active targeting.

6. They are non-toxic, flexible, completely biodegradable, biocompatible and non immunogenic for systemic and non systemic administration.

1. Liposomes having low solubility.2. Short half life.3. Sometimes phospholipids

undergoes oxidation and hydrolysis-like reaction.

4. Leakage and fusion of encapsulated drugs/molecules.

5. Production cost is high.6. Fewer stable.

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Advantages Disadvantages

May 1, 2023 132: Ethosomes

Ethosomes are noninvasive delivery carriers that enable drugs to 

reach the deep skin layers and/or the systemic circulation.

10nm – few micron.

The composition of ethosomes:- 1) Water 2) Phospholipid 3) Ethanol

Mechanism of Ethosomes :- Mechanism is divided in two part 1) Ethanol Effect 2) Ethosomes Effect

May 1, 2023 14Mechanism of Ethosomes Penetration

May 1, 2023 15Method of Preparation of Ethosomes

There are two methods:1) Cold method 2) Hot method

Heat at 30 c

Mix non aq.to aq.solution

Rest for 5 min

Drug Ethanol phospholipid

1) Cold method

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2) Hot method preparation for Ethosomes

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Smaller size as compared to conventional vesicles.

Enhanced permeation of drug through skin.

Delivery of large and diverse group of drugs (peptides, protein

molecules).

Low risk profile.

High patient compliance.

Better stability and solubility of many drugs as compared to

conventional vesicles.

The ethosomal system is passive, non-invasive and is available for

immediate commercialization.

Various application in pharmaceutical, veterinary, cosmetic field.

Advantage of Ethosomes

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Limited only to potent molecules

Those requiring a daily dose of 10mg or less.

Its not a means to achieve rapid bolus type drug input, it is usually

designed to offer slow, sustained drug delivery.

Skin irritation or dermatitis due to excipients and enhancers of drug

delivery systems.

Loss of product during transfer from organic to water media.

Disadvantages of Ethosomes

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Pilosebaceous targeting

Transdermal delivery

Topical delivery of DNA

Delivery of anti-arthritis drug

Delivery of antibiotics

Delivery of HIV drugs

Delivery of problematic drug molecules

Transdermal delivery of hormones

Delivery of anti-parkinsonism agent

Delivery of anti-viral drugs

Ethosomes used for cosmetics

Applications of Ethosomes

May 1, 2023 20Transferosomes

It is composed of phospholipid, surfactant, and water for enhanced transdermal delivery.

More stable

High penetration due to high deformability

Biocompatible and biodegradable

Suitable for both low and high molecular weight and also for lipophilic as

well as hydrophilic drugs

Reach up to deeper skin layers

Systemic as well as topical delivery of drug

It is made up of as like liposomes

Protect the encapsulated drug from metabolic degradation

Advantages of Transfersomes

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1. • It is chemically unstable

2. •Purity of natural phospholipids is another effective criteria against adoption of transfersomes as drug delivery vehicles

3. •Transfersomes formulations are expensive

Limitations of Transferosomes

May 1, 2023 22Mechanism of Drug Transportation

May 1, 2023 23

Hydrated using sodium deoxycolatePBF 7.4

For 2 min

Surfactant

Diethyl ether +chloroform

Kept at room temp.(24 hr)

Thin film

Insulin sol 1.40mg/ml in water

Soya lecehitin + cholesterol

Reverse Phase Evaporation Method

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Application of Transfersomes

Delivery of insulin

Delivery of corticosteroids

Delivery of proteins and peptides

Delivery of interferon's

Delivery of anticancer drugs

Delivery of anesthetics

Delivery of NSAIDS

Delivery of herbal drugs

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3.Phytosomes

Phytosome is novel drug delivery system  is a patented technology

(U.S. Patent #4,764,508) that combines hydrophilic bioactive

phytoconstituents of herbs/ herbal extracts and bound by

phospholipids.(soybean phospholipids ,lecithin)

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Advantage of Phytosomes

Phosphatidylcholine used in preparation of phytosomes,

besides acting as a carrier also acts as a hepatoprotective.

Phytosomes show better stability profile due to formation of

chemical bonds between phosphatidylcholine molecule and

botanical extract.

Phytosome are widely used in cosmetics due to there more skin

penetration and have a high lipid profile.

By enhancing the solubility of bile to herbal constituent,

phytosomes facilitates the liver targeting.

May 1, 2023 27Phytosome Vs Liposomes

May 1, 2023 28

PHYTOSOMES LIPOSOMES

In phytosomes active chemical constituents molecules are anchored through chemical bonds to the polar head of the phospholipids.

In liposomes, the active principle is dissolved in the medium of the cavity or in the layers of the membrane. No chemical bonds are formed.

In phytosomes, PC and the individual plant compound form a 1:1or 2:1 complex depending on the substance.

In liposoes, hundred and thousands of phosphatidyl- choline molecules surround the water soluble molecule.

Difference between Phytosome and Liposomes

May 1, 2023 29Method of Preparation

Solvent Evaporation method

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304.Sphingosomes

Sphingosomes can be defined as colloidal, concentric bilayered vesicles

where aqueous compartment is entirely enclosed by a bilayer membrane,

mainly composed of natural or synthetic sphingolipids.

Diameter of about 0.05 μ to 0.45 μ . “In simple way we can say sphingosome is liposome which is composed

of sphingolipid.”

Sphingosomes is more stable than the phospholipid liposome because of

the

(i) Sphingolipid are built up by only amide and ether linkage.

(ii) They also contain a smaller amount of double bonds then lecithin.

(iii) They also absorb a smaller amount oil then lecithin that in

consequence change in geometry and diameter.

May 1, 2023 31Structure of Sphingosomes

May 1, 2023 32General Steps for Preparation of Sphingosomes

May 1, 2023 33Method of Preparation of Sphingosome

1. Lipid Hydration Method

2. Solvent Spherule Method.

3. Sonication Method

4. French Pressure Cell Method

5. Solvent Injection Methods

5a. Ether Infusion Method.

5b. Ethanol Injection Method

6. Detergent Removal Methods

7. Reverse Phase Evaporation Method

8. Calcium-Induced Fusion Method.

9. Microfluidization Method

10. Freeze-Thaw Method

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Sphingosomes have better drug retention characteristics.

They can be administered by subcutaneous, intravenous, intra-arterial,

intramuscular, oral, and transdermal routes of drug administration and so forth.

They provide selective passive targeting to tumor tissue.

Sphingosomes increase efficacy and therapeutic index of the encapsulated

drug.

Stability is increased via encapsulation.

Design of sphingosomes is so flexible to allow coupling with site specific

ligands to achieve active targeting.

(i) sphingolipids are expensive, sphingosomes are not economic.

(ii) Sphingosomes have poor entrapment efficiency.

Advantages of Sphingosomes

Disadvantages of Sphingosomes

May 1, 2023 355.Virosomes

Virosomes are spherical, unilamillar phospholipid bilayer

vesicles incorporating virus derived proteins to allow the

virosomes to fuse with the target cell.

They are lipid based , synthetic vesicles consisting of viral

surface glycoproteins.

They have a typical mean diameter in range 120-180 nm.

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It is an influenza virus.

The envelop made up of influenza

lipids constitute the membrane and

proteins called haemagglutinin (HA)

and neuraminidase (NA) are

intercalated on it.

The nucleocapsid and the genetic

material of the source virus is

present inside the envelop.

Virosomes (conti…)

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Virosomes act both as carrier and as adjuvant with multifunctions

during the induction of an immune response.

The carrier function comprises the positive effects of embedding the

antigen into a higher structure, the virosome particle.

The adjuvant function relates to the immune stimulating properties

of the virosomes and their components on the immune system.

It also suceeds in stimulating specific immunity without causing

non-specific inflammation.

Mechanism of Action

May 1, 2023 38Mechanism of action ( conti…)

May 1, 2023 39

Virosomal technology is approved by the FDA for use in

humans, and has a high safety profile.

No disease-transmission risk.

No autoimmunogenity or anaphylaxis.

Broadly applicable with almost all important drugs (anticancer

drugs, proteins, peptides, nucleic acids, antibiotics, fungicides).

Enables drug delivery into the cytoplasm of target cell.

Advantages of Virosomes

May 1, 2023 402.Non- Lipoidal biocarriers

1.Niosomes

Niosomes are a novel drug delivery system in which

the drug is encapsulated in vesicles composed mainly

of hydrated non-ionic surfactants with or without

cholesterol.

Niosomes are capable of encapsulating both lipophilic

and hydrophilic substances.

The size of a niosome ranges from some 10 nm up to

several micrometers.

Niosomes are unilamellar or multilamellar vesicles.

The vesicle is composed of a bilayer of non-ionic

surface active agents and hence the name niosomes.

May 1, 2023 41Structure of Niosomes

May 1, 2023 42

Liposomes Niosomes

Their ingredients like phospholipids are chemically unstable because of their predisposition to oxidative degradation.

Chemically stable.

They require special storage and handling. They do not require special storage and handling.

Purity of natural phospholipids is variable. Phospholipids are absent.

Liposomes are prepared from double-chain phospholipids.

Niosomes are prepared from uncharged single-chain surfactant and cholesterol .

They are expensive. They are economical.

Comparison of Niosome Vs Liposome

May 1, 2023 43Methods of Preparation

May 1, 2023 44

Solution of the surfactant with cholesterol in a volatile organic solvent

Spray onto the powder of sorbitol kept in a rotary evaporator

The evaporation of the organic solvent yields a thin coat of surfactant

on the sorbitol particles.

This preparation is termed Proniosomes.

Formation of Niosomes from Proniosomes

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Novel technique of Niosome preparation without the use of organic solvent (Green

Method).

In this technique, surfactant, additives, and PBS (pH 7.4) were transferred into a

glass reactor with three necks.

The reactor is positioned in a water bath to control the temperature.

The thermometer is positioned in the first neck, nitrogen supplied through second

neck, and water cooled reflux in the third neck.

Niosome components are dispersed at 70 °C and is mixed for 15sec with high shear

homogenizer and immediately followed by the bubbling of nitrogen gas at 70 °C .

The “Bubble” Method

May 1, 2023 46Advantages of Niosomes

Niosomes are osmotically active, stable, and have long storage time.

Surface modification is very easy because of functional groups on their

hydrophilic heads.

Highly compatible with biological systems and low toxicity because of

their non-ionic nature.

Bio-degradable and non-immunogenic.

Improving therapeutic performance by protecting the drug from

biological environment, and hence better bio-availability.

High patient compliance because of water-based suspension of niosomes.

They can entrap both lipophilic as well as hydrophilic drugs.

They enhance the permeation of drugs through skin.

May 1, 2023 47

Increases the oral bio-availability.

Access to raw materials is convenient.

Targeted drug delivery.

Niosomes enhances the absorption of some drugs across cell membranes to

localize in targeted tissues and elude the reticulo-endothelial system.

Cont…

Disadvantages of Niosomes

During dispersion, both Niosomes and liposomes are at risk of :- Aggregation Fusion Drug leakage Hydrolysis of encapsulated drug.

May 1, 2023 48

Gene delivery:

Vaccine delivery

Leishmaniasis treatment

Anti-cancer drug delivery

Delivery of peptide drugs

Opthalmic drug delivery

Chronic obstructive pulmonary disease(COPD) drug delivery

Brain targeted drug delivery system

Targeting of bioactive agents

To reticulo-endothelial system (RES)

To organs other than RES

Niosomes as carriers for Haemoglobin

Transdermal delivery

Application of Niosomes

May 1, 2023 49Future aspect

Colloidosomes Herbosomes Cubosomes Layerosomes Ufasomes Aquasomes Cryptosmes Discomes Genosomes Photosomes Virosomes Vesosomes Proteosomes

May 1, 2023 50Case study

May 1, 2023 51

Drug : Econazole nitrate

Method : Cold method

Evaluation :

a) Vesicle size and zeta potential

b) Visualization of vesicle by transmission electron microscopy

(TEM)

c) Determination of EN entrapment efficiency (EE)

d) HPLC assay for EN quantification

Evaluation of gels

pH and rheological measurements

Skin permeation of EN from vesicles

Confocal laser scanning microscopy

Stability studies.

May 1, 2023 52Material and method

Materials

Sr no.

Drug SUPPLIERS

1 Econazole Nitrate Gift from FDC (Mumbai India)

2 Soya phosphatidlcholine(30%)

Himedia (Mumbai)

3 Other chemical used in the study on the basis of reagent Grade.

Method

1. Cold method2. Hot method

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Composition and physical characterization of various ethosomal and liposome formulations of econazole nitrate (EN)

Result

Formulation design for the preparation of various econazole nitrate (EN ) ethosomal gels

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Comparative cumulative amount of econazole nitrate permeated from various formulations in a 12-hour study via rat skin.

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Comparative cumulative amount of drug permeated from ethosomal formulations in a 12-hour study via rat skin.

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58Confocal laser scanning microscopyMay 1, 2023

May 1, 2023 59Key Reference

Sunil Kamboj et al,“Vesicular drug delivery systems: A novel approach for drug targeting”,International Journal of Drug Delivery,5 (2013): 121-130

Namdeo G. Shinde et al, “Recent Advances in Vesicular Drug Delivery System” Research Journal of Pharmaceutical Dosage Forms and Technology. 6(2): April-June, 2014, 110-120.

Seema M. Jadhav et al, “Novel vesicular system: an overview”, Journal of Applied Pharmaceutical Science; 02(2012): 193-202.

Nishith Patel, “Liposome Drug delivery system: a Critic Review” ,JPSBR: 2 (2012):169-175.

Abolfazl Akbarzadeh, NANO REVIEW, “Liposome: classification, preparation, and Applications” ,Nanoscale Research Letters ,8(2013):102.

E. Touitou ,et al , “Ethosomes - novel vesicular carriers for enhanced delivery: characterization and skin penetration properties” , Journal of Controlled Release; 65(2000):403–418.

May 1, 2023 60

Marwa h. Abdallah et al, “Transfersomes as a transdermal drug delivery system for enhancement the antifungal activity of nystatin” ,International Journal of Pharmacy and Pharmaceutical Sciences;5(2013): 108-119.

Sahil M. Gavali et al,“clinical transfersome: A new technique for transdermal drug delivery” ,International journal of research in pharmacy and chemistry ; 1(3) (2011):212-230.

Nilesh Jain et al., “Phytosome: A Novel Drug Delivery System for Herbal Medicine”, International Journal of Pharmaceutical Sciences and Drug Research 2(4),(2010); 224-228.

Abhijeet Sunder Kunwarpuriya et al, “Sphingosome: a novel vesicular drug delivery sysytem”, European journal of pharmaceutical And medical research , 2(3),(2015) ;509-525.

Bhamare Gaurav Et Al, Review Article “ Virosome – Drug And Vaccine Delivery System ,” World Journal Of Pharmacy And Pharmaceutical Sciences Volume 3, Issue 10, 437-447.

Key Reference

May 1, 2023 61

S. S. Patel et al, “Review Article Need, Development and Application of Virosomal System in Medicine” International Journal of Pharmaceutical Sciences and Nanotechnology Volume 3 · Issue 3 · October - December 2010

Nilesh Jain et al., “Phytosome: A Novel Drug Delivery System for Herbal Medicine”, International Journal of Pharmaceutical Sciences and Drug Research 2(4),(2010); 224-228.

Abhijeet Sunder Kunwarpuriya et al, “Sphingosome: a novel vesicular drug delivery sysytem”, European journal of pharmaceutical And medical research , 2(3),(2015) ;509-525.

Harshal Ashok Pawar et la, “Phytosome as a Novel Biomedicine: A Microencapsulated Drug Delivery System” Bioanalysis & Biomedicine 7(1): 2015,

Key Reference

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