Niosomes and Liposomes Flashcards
what is the manufacturing process for liposomes and niosomes?
1-Phospholipid or non-ionic surfactant (and the second amphiphilic compound and a membrane fluidity modulator, cholesterol) are dissolved in an organic solvent.
2 Evaporation of the solvent under heat.
3 Dry lipid film formation on the surface of the vessel.
4 Aqueous buffer solution containing the drug is added and the vessel is subjected to sonication or shaking at temperatures above the phase transition temperature (Tc).
5 Multi-lamellar vesicles will form and a suspension containing the vesicles in aqueous liquid are formed.
how do you form uni-lamellar vesicles from MLVs?
ultrasound
pressure filtration
dialysis
what do we do to remove entrapped drug from aq medium in ULVs?
hence size exclusion chromatography, gel chromatography, or dialysis can be
applied to remove the unentrapped drug
how do you entrap the drugs in liposomes/niosomes?
Lipophilic drug is mixed together with the lipids and dissolved in the organic solvent
➢After rehydration of the film, the lipid drug molecules are formed inside lipid bilayer
➢If the drug substance has some hydrophilic groups, some drug molecules will also be found in the aqueous inner cavity of the vesicles. The amount depends on the partition coefficient of the drug between water and lipid
➢Direct encapsulation of hydrophilic drugs can be achieved by dissolving them in the buffer used for rehydration of the dried lipid film. However, the method shows poor entrapment efficiency(20–30%) and larger amounts of drug will remain in the buffer
how can you indirectly encapsulate hydrophilic drugs?
Therefore:
- permeability of bilayer membranes of empty liposomes is increased and the drug diffuses via the bilayer into the inner cavity.
- Use of dehydration (lyophilisation)/rehydration
cycles to increase permeability leads to fairly MLVs.
how can entrapment of doxorubicin via indirect encapsulation be achieved?
two ways
method 1: liposome with same ph of buffer and drug sub + OH and +H
method 2: LIPOSOME pushing out NH3 and doxorubicin-NH2 coming in
why is storage stability an issue with liposomes?
If liposomes are suspended in an aqueous
solution, the stability of liposomal products with hydrophilic drugs is low, because the drug will gradually diffuse from the inner cavity through the bilayer into the outer phase.
what precautions are taken to reduce instability in liposomes?
Due to use of lipids: liposomal preparations are subjected to oxidation antioxidant (e.g. 0.1% a–tocopherol) is used.
Hydrolysis of the ester bonds of lipids can take place minimised at pH=6.5
what happens on storage of liposomes?
On storage, small liposomes will fuse to form larger, thermodynamically more stable vesicles. Hence, products containing SUVs and LUVs are freeze-dried to be reconstituted before the administration (this is possible for parenteral formulations but not for topical applications)
when is the reconstitution process not suitable?
is not suitable to products containing hydrophilic drugs, because the liposomal bilayers are temporarily porous during the process permitting the drug to diffuse out of the vesicle into the reconstitution medium.
what are some interrelated factors influencing the physio-chemical properties of niosomes?
hydration temperature
➢nature of the drug
➢choice of the main surfactant
➢nature of the membrane additives (co-surfactant
and fluidity modulating agent)
what happens at temperatures above the phase transition?
niosomes do not form spontaneously
what are some areas of potential use for niosomes?
Parental
➢pulmonary
➢oral for the delivery of peptides
➢in ophthalmic preparations
what are the benefits of using liposomes/niosomes to encapsulate drugs?
Solubilisation of drugs
(If the drug is lipid soluble it can be incorporated into the lipid part of the vesicle, e.g. minoxidil and amphoteracin B)
➢Drug release can be modified
(e.g. delay of drug release and alteration of drug permeability via biological membranes)
➢Site avoidance (The uptake of vesicles such as liposomes and niosomes into heart, kidneys, brain and the gut wall is minimal and thus dose-limited side effects and toxicity are usually reduced compared with free drug)
➢Site-directed targeting
(If charged molecules are incorporated, leading to anionic or cationic liposomes, or if, groups such as antibodies are attached site-targeted drug delivery can be achieved)
➢Clearance by RES
(useful for treatment of RES diseases)
give an example of pharmaceutical application of liposomes
retinoids- in the treatment of acne
what does effectivity of minoxidil depend on?
depends on the size of vesicles
smaller vesicles= more drug substance molecules
how does it passivel target liver and spleen to improve efficacy and to reduce toxicity?
treatment of systemic fungal infections with Amphotericin B (polyene antibiotic) is associated with renal toxicity
➢liposomal Amphotericin B (Ambisome®) targetsliver and spleen passively whereby reducing renaland general toxicity at normal doses
➢was first liposomal preparation licensed for clinical use
how does it actively target lungs?
➢Coating of vesicles with polyethylene oxide
➢Encapsulation of anti-tuberculosis drugs such as rifampicin or isoniazid reduces their toxicity and improves their efficacy
define pro-liposomes
are dry free flowing solid drug
products with a dispersed system that can form a liposomal suspension in contact with an aqueous phase.
what do pro-liposomes need?
usually they need carrier systems such as sodium chloride or sugar such as trehalose, sorbitol, mannitol.
what are the advantages of pro-liposomes?
Pro-liposomes are effective formulations to solve problems associated with liposomes:
Aggregation
Sedimentation
Fusion
Hydrolysis and oxidation
Drug leakage
Also, pro-liposomes could improve the oral
delivery of the drugs due to their abilities to
retain their integrity at the absorption site
why is advantageous for pro-liposomes to be dry free flowing powders?
stable phospholipid formulations
scale-up production
prolonged shelf-lives
what is the importance of pro-liposomes as drug delivery systems?
Drug targeting
➢Drug solubilisation
➢Drug protection
➢Controlled release properties
➢Cationic - DNA complex for gene delivery into
cells
how do you manufacture pro-liposomes?
1 Particulate based pro-liposome
Sugar particles (300-500mm), phospholipid, cholesterol the drug All in chloroform>
Evaporation of solvent, rotary evaporator>
Dry powder
2 Alcohol based pro-liposomes
Phospholipid, cholesterol, the drug dissolve in 95% ethanol > ethanolic lipid solution containing the drug >
Sugar such as sucrose or mannitol is then suspended in the solution >
Evaporation of ethanol: spray drying can be used >
Dry pro-liposome powder
what are the characterisation methods for pro-liposomes?
Morphological properties
Particle size and particle charge characteristics
before and after reconstitution
flow properties
Drug content uniformity
Encapsulation efficiency
Thermal analysis
Cytotoxicity to specific cells
In-vitro drug release
what are the possible routes of drug admin for pro-liposomes?
parenteral
pulmonary
oral
transdermal
what are some advanced liposomal formulations?
Non conventional liposomal formulations
PEGylated (long circulating) liposomes
Immunoliposmes based cancer
therapeutics
PEGylated Immunoliposmes with cytotoxic
drugs
what are the properties of ph sensitive liposomes?
phase transition in
alkaline media lead to increasing membrane fluidity
and release of encapsulated materials
what are the properties of heat sensitive and ion sensitive liposomes?
They leak more readily at
temperatures above the phase transition temperature. They are formulated to be stable at normal body temperature, 37°C, and they release the drug upon hyperthermia (inside the tumour). They can enhance the delivery of cytotoxic drugs to the inside of tumours. Example: Prolieve®
what are PEGylated liposomes?
“PEGylated liposomes”: the surface of vesicles is modified with hydrophilic polymers, which will reduce the agglomeration tendency of the vesicles
and will avoid recognition and removal of the vesicles by the RES. The polymer (PEG) is conjugated to the terminal amine groups
(phosphatidylethanolamine).
what is PEGylated liposomes associated with?
PEG is strongly associated with water
molecules (hydration), it provides a hydrated surface layer around the liposomes, no detection of the vesicles by macrophages and the RES.
what size PEGylayed liposomes can target solid tumours passively?
100nm
how do PEGylayed liposomes maintain stability?
In vivo stability of liposomes is important
for targeted liposomes: they should maintain stability in the plasma till release of contents at the target site.
what are immunoliposomes?
Immunoliposomes are antibody conjugated liposomes.
Liposomes can carry drugs or therapeutic nucleotides and when they conjugated with monoclonal antibodies (mAb): the entrapped drug(s) will release into targeted cells.
why are immuniliposomes beneficial?
Beneficial than liposomes due to retention of immunoliposomes (via the mAb)to tumour through stable linkages
how do immunoliposomes work?
Liposome acts as a drug carrier
The antibody allows bringing the drug system specifically to its target.
Tumour cells have molecules for recognition but also they have common characteristics with normal cells.
Accordingly, it is essential to find a suitable target for effective immunoliposomalformulations.
Tumor-overexpressed proteins …TARGET
what about negatively charged liposomes?
more rapidly removed from circulation than neutral or positively charged liposomes: lipid composition (phosphatidylserine, phosphatidic acid, and phosphatidylglycerol versus sterically shielded phosphatidylinositol).
what can liposomal uptake be reduced by?
stericallystabilised additives “Steric stabilisation” means the colloidal stability resulting from addition of hydrophilic polymers or glycolipids into liposomes.
what do sterically stabilised liposome show?
prolonged stay in the circulation as compared with non-stabilised liposomes and also they are less reactive toward serum proteins and less susceptible to RES uptake
