Chapter 12-13

Question 1

Phytosomes

Answer 1

Phytosome is a complex of a natural active ingredient and a phospholipid.

This complex results from the reaction of stoichiometric amounts of phospholipid with the selected polyphenol (like simple flavonoids ) in a nonpolar solvent.

Question 2

Differences between Lyposomes and phytosomes

Answer 2

1. In liposomes no chemical bond is formed and the phosphatidylcholine molecules surround the water soluble substance.
2. In a liposome, the material is simply emulsified.
3. In phytosomes the phosphatidylcholine and the plant components actually form a 1:1 or a 2:1 molecular complex depending on the substance(s) complexes, involving chemical bonds.
4. This difference results in better absorption of phytosomes than liposomes showing better bioavailability.

Question 3

Lyposomes VS. phytosomes

Answer 3

1. Liposomes are much bigger than phytosomes
2. There is the formation of new bonds in phytosomes, whereas no chemical bond is formed in liposomes.
3. In liposomes, there are hundreds or thousands of PC ( phosphatidylcholine ) molecules surrounding the water-soluble compounds. Conversely, the molar ratio of PC ( phosphatidylcholine ) and natural ingredients is 1:1 or 2:1 for phytosomes depends on the chemical bond forming material
4. In liposomes the natural active ingredients are dissolved in the medium or wrapped by the membrane. In phytosomes the active ingredients are anchored through chemical bonds to the polar head of phospholipids.
5. In liposomes, the ingredients are dissolved in the central part of the cavity, with limited possibility of molecular interaction between the surrounding lipid and a hydrophilic substance.
6. In a Phytosome® the ingredient is dispersed into lecithin, a dietary surfactant and can be compared to an integral part of the lipid membrane.

Question 4

Cubosomes

Answer 4

Cubosomes are nanoparticles but instead of the solid particles, cubosomes are self- assembled liquid crystalline particles of certain surfactant with proper ratio of water with a microstructure that provides unique properties of practical interest.

Cubosomes consist of honeycombed (cavernous) structures separating two internal aqueous channels and a large interfacial area.

Question 5

Liposome vs Nanoemulsion vs Lipid nanoparticle

Answer 5

1. Liposome: lipid bilayer enclosing an aqueous core
2. Nanoemulsion: lipid monolayer enclosing a liquid-lipid core
3. Lipid nanoparticle: lipid monolayer enclosing a solid-lipid core

Question 6

Polymersomes

Answer 6

1. Polymersomes are nanostructures composed of amphiphilic block copolymers that have a size range from 50 nm to 5 μm and encapsulate drugs inside the vesicle membrane.
2. They are capable of encapsulating hydrophobic and hydrophilic drugs and they can be surface functionalized.
3. Polymersomes share many similarities with liposomes, but are **more stable and less permeable to small water-soluble molecules than liposomes. **

Question 7

Reverse micelles

Answer 7

Phase inversion of particle-stabilized emulsions from oil in water to water in oil can be achieved either by
variation of the particle hydrophobicity (transitional) or by variation of the oil/water ratio (catastrophic).

Question 8

Application of a liposome

Answer 8

LN (liposomal nanomedicines can be used to deliver cancer cell-killing drugs into tumours

Question 9

Emulsion

Answer 9

Emulsion – is a mixture of two or more liquids that are normally immiscible.

In an emulsion, one liquid (the dispersed phase) is dispersed in the other (the continuous phase)

Question 10

Emulsifying Agents

Answer 10

Emulsifying Agents are the substances added to an emulsion to prevent the coalescence of the globules of the dispersed phase.

These agents have both a hydrophilic and a lipophilic part in their chemical structure. (i.e. amphiphiles)

All emulsifying agents concentrate at and are adsorbed onto the oil:water interface to provide a protective barrier around the dispersed droplets.

In addition to this protective barrier, emulsifiers **stabilize the emulsion by reducing the interfacial tension of the system. **

Question 11

Classification of emulsions

Answer 11

1. Based on dispersed phase:
   
   • Oil in Water (O/W): Oil droplets dispersed in water
   • Water in Oil (W/O): Water droplets dispersed in oil
2. Based on size of liquid droplets:
   
   • 0.2 – 50 mm Macroemulsions (Kinetically Stable)
   • 5-200 nm Microemulsions (Thermodynamically Stable)

Question 12

Common Emulsifying Agents

Answer 12

1. Surfactants:
   
   • ​Anionic: sodium stearate, potassium laurate
   • Nonionic: polyglycol, fatty acid esters, lecithin.
   • Cationic: Quaternary ammonium salts
2. Solids: Finely divided solids with amphiphilic properties such as soot, ** silica, and clay. **
3. For microemulsion only surfactantas are know to be active as emulsifier.
4. For macroemulsion, a greater variety of components such as surfactants, polymers, and colloidal particles (or nanoparticle) can be active as emulsifiers.

Question 13

Bancroft’s rule for emulstions states:

Answer 13

​ “The phase in which an emulsifier is more soluble constitutes the continuous phase.”

1. In Oil in Water emulsions – use emulsifying agents that are more soluble in water than in oil (High HLB surfactants).
2. In Water in Oil emulsions – use emulsifying agents that are more soluble in oil than in water (Low HLB surfactants).

Question 14

What affects the type of emulsion?

Answer 14

1. the ratio of the oil to water(non-polar to polar)phase;
2. •the chemical properties and the concentration of the emulsification agent;
3. the temperature; the presence of **additives; **
4. for solid particles as the stabilizing agents (Pickeringemulsions) the wetting conditions (contact angles of the oil and water phases on the solid)

Question 15

Many synthetic and herbal drugs possess the problem of poor oral bioavailability, and the reason are: $$

Answer 15

• their very low water solubility
• poor permeation through the biological membrane.
• Poorly soluble drugs have suffered from low bioavailability and inefficacy in therapy due to their low dissolution profile in biological fluid.
• Without a proper level of drug concentration in the gastrointestinal (GI) fluid, the drugs cannot be effectively transported by the epithelia of the GI tract, resulting in **low systemic absorption. **
• Several plant actives in spite having potent in vitro pharmacological activities have failed to demonstrate similar in vivo response.

Question 16

although most bioactive molecules of plants are biologically polar or water-soluble, they are difficult to pass through the lipid-rich biological membrane and be absorbed by human, the reasons of which include: $$

Answer 16

1) large molecular weight,

**2) low lipid solubility **

The interaction had been atributed to formation of hydrogen bond and/or hydrophobic interaction between the two molecules.

Question 17

Shapes of aggregates ($$often)

Basic shapes:

Micelles’ shapes:

Superstructures:

Answer 17

Basic shapes:

• spheres
• cylinders
• bilayers
• vesicles

micelles’ shapes:** spheres and cylinders**

Superstructures:

• micellar crystals
• lamellar phases
• bicontinuous networks

Question 18

Benefits of phyto-phospholipid complexation

Answer 18

1. Enhanced bioavailability: (+) facilitaing membrane permeation, (+) Improving solubility
2. Reduce Dose –> Enhancing systemic absorption
3. Value addition (+)lipid profile improvement (+)Hepato protection
4. Hepatic/Tumor Targeting –> passive targeting
5. Sustained action –> modified release profile
6. Safe –> Non toxic and non mutagenic (FDA approved)

Question 19

1. Are most bioactive molecules of plants polar or water-soluble?
2. Why these bioactive molecules of plants are difficult to pass through the lipid-rich biological membrane and be absrobed?
3. Why phytosomes are more bioavailable than conventional herbal extracts?

Answer 19

1. Yes,
2. (1) large molecular weight, (2) low lipid solubility (3) formation of H(+) bond and/or hydrophobic interactions between drug and lipid (phyto-phospholipid complex). Van der Waals forces.
3. Phytosomes have enhanced capacity to cross the lipoidal biomembrane and reach the systemic circulation

Question 20

Cochleates:

Answer 20

phospholipid-calcium precipitates derived from the interaction of anionic lipid vesicles with divalent cations such as calcium.

Cochleates have a defined multilayered structure consisting of a solid, lipid bilayer sheet rolled up in a spiral.

Cochleates were first described by Papahadjopoulos in 1975 as an intermediate in the preparation of large unilamellar liposomes,

They have the ability to deliver a variety of drugs, such as antifungal agents, polypeptides, proteins, vaccines, oligonucleotides and genes.

Question 21

What kind of drugs can be encapsulated in cochleates?

Answer 21

Cochleates contain both hydrophobic and hydrophilic surfaces, they are suitable to encapsulate both hydrophobic drugs like amphotericin B and clofazimine and hydrophillic drugs like doxorubicin.

1. Hydrophilic molecules can be accommodated between the lipid bilayers
2. Hydrophobic molecules can be accommodated in the inner hydrophobic space

Question 22

Cochleates formation.

Answer 22

1. Cochleates are formed as a result of the condensation of small unilamellar negatively charged liposomes.
2. In the presence of calcium, the small phosphatidylserine (PS) liposomes fuse and form large sheets. These sheets have hydrophobic surfaces and, in order to minimize their interactions with water, tend to roll-up into the cigar-like cochleate.

Question 23

1. For cochleates, the molar ratio of divalent cations and phospholipids is:
2. Ca2+ function in the cochleate
3. Amphotericin B is an an;fungal drug often used intravenously for systemic fungal infections. (Fungilin, Fungizone, Abelcet, AmBisome, Fungisome, Amphocil, Amphotec).

Describe synthesis

Answer 23

1. For cochleates, the molar ratio of divalent cations and phospholipids is 1:2.
2. Ca2+ maintains the cochleate in its rolled form, and bridges each successive layer through ionic interaction.

Question 24

1. The loading efficacy of the cochleates depends upon the (2): $$$
2. the particle size of the drug-cochleate complex depends on (1): $$$
3. The main components of cochleates are (2) $$

Answer 24

1. The loading efficacy of the cochleates depends upon the physical chemistry of the drug to encapsulate
2. the particle size of the drug-cochleate complex depends on the process used to encapsulate.
3. The main components of cochleates are phosphatidylserine (PS) and calcium, two natural compounds.

Question 25

1. Explain how the cochlea survives the GI track and process of release.
2. DEscribe the drug release of a cochleate inside a macrophage

Answer 25

1. The unique structure of the cochleate protects the drug as it travels through the GI tract and into the blood stream.
   
   • Once the cochleate is absorbed through the GI tract, it is engulfed by the target cell in the bloodstream, called macrophages , and **taken to the site of infection. **
2. Once then gulfed by the macrophage, the lower calcium levels inside the macrophage compared to the high level of calcium outside the macrophage triggers the cochleate to open, thus releasing the drug.

Question 26

Cochleates ADVANTAGES:

Answer 26

1. They are more stable than liposomes because the lipids* in nanocochleates are *less susceptible to oxidation. They maintain structure even after lyophilization, whereas liposome structures are destroyed by lyophilization.
2. They have the potential or slow or timed release of the biologic molecule in vivo as nanocochleates slowly unwind or otherwise dissociate.
3. They have a lipid bilayer matrix which serves as a carrier and is composed of simple lipids which are found in animal and plant cell membranes, so that the lipids are non-toxic, nonimmunogenic and non-inflammatory.
4. the use of nanocochleates allows iv drugs to be administered orally (e.g. Amphotericin B, a potent antifungal).
5. They improve oral bioavailability of a broad spectrum of compounds, such as those with poor water solubility, and protein and peptide biopharmaceuticals, which have been difficult to administer.
6. They reduce toxicity stomach irritation and other side effects of the encapsulated drug.
7. They encapsulate or entrap the subject drug within a crystal matrix rather than chemically bonding with the drug.

Question 27

Cochleates DISADVANTAGES

Answer 27

1. They require specific storage condition.
2. Sometimes aggregation may occur during storage; this can be avoided by the use of aggregation inhibitor.
3. The cost of manufacturing is high C

Question 28

1. Bilayer structures:
2. Lamellar liquid crystals:
3. Bicontinuous cubic liquid crystals:

Answer 28

1. Bilayers are the basic repeating or building unit for a variety of macroscopic self-assembly structure: Examples:

• vesicles
• biological membrane ​​

2. Lamellar liquid crystals are a stacked form of extended bilayer self-assembled unit with one-dimensional symmetry.
3. Bicontinuous cubic liquid crystals: consist of a regularly curved bilayer unit (the secondary building unit) with clearly defined 3-D geometry

Question 29

1. What are liquid Crystals
2. Liquid crystal structure depends on (2): $$$
3. Liquid crystals ordering and molecular mobility.

Answer 29

1. liquid crystals are groups of organic compounds that show both crystalline solid and isotropic liquid characteristics **at ambient temperature and pressure. **
2. Temperatue and concentration
3. Liquid crystals - show some degree of geometrical ordering but with **some degree of molecular mobility. **

Question 30

1. Liquid crystals are _______________ ________ and their phases are also called ________
2. Type of intermolecular forces
3. Appearance of liquid crystals

Answer 30

1. Liquid crystals are thermodynamically stable and their phases are also called mesophase.
2. Weak intermolecular forces are the only interaction to retain this state.
3. Their macroscopic appearance ofen looks like a gellish solid but with some degree of fluidity, and they often show crystalline solid - like properties such as optical anisotropy.

Question 31

Based on the origin of intermolecular interactions that induce the ordering, liquid crystals are classified as

1. ________ _______ crystals
2. ________ ________ crystals.

Answer 31

1. thermotropic liquid crystals: are induced by temperature
2. lyotropic liquid crystals: are formed by the change of concentrations. Thus, lyotropic liquid crystals are always present with solvent.

Question 32

1. Thermotropic liquid crystals can be formed from:
2. Name-lable the 4 appearance of liquid crystal phases in a temperature profile (TEST $$$)

Answer 32

1. Thermotropic liquid crystals can be formed from single - or multicomponent systems. But no solvent is involved in their formation process.
2. Phases:
   
   1. Smetic liquid crystal phases, on average, the molecules are parallel to one another and are arranged in layers
   2. Nematic liquid crystal phase is characterized by molecules that have no positional order but tend to point in the same direction
   3. Cholesteric liquid crystals are also known as chiral nematic liquid crystals. They organize in layers with no positional ordering within layers, but a director axis which varies with layers.

Question 33

1. Liquid crystals always retain some degree of structural order, so they can always show characteristic _____________ ___________.
2. But the structural order also can be manipulated by external forces including: $$$

Answer 33

1. Liquid crystals always retain a certain degree of structural order, so they can always show characteristic optical properties.
2. The structural order also can be manipulated by external forces including:
   
   1. Electric field,
   2. magnetic field,
   3. temperature

Question 34

1. The most popular building blocks of Lyotropic Liquid Crystals are those found in:
2. Unlike in cases of thermotropic liquid crystals, the formation of lyotropic liquid crystals is, for the most part, the result of:

Answer 34

1. surfactant solutions. Similar states are also found in solutions of amphiphilic polymers.
2. Unlike in cases of thermotropic liquid crystals, the formation of lyotropic liquid crystals is, for the most part, the result of multistep self-assembly of primary building units.

Question 35

Which one has more variety of structural diversity Surfactant liquid crystals or thermotropic liquid crystals?

Answer 35

Surfactant liquid crystals have more variety of structural diversity than thermotropic liquid crystals and usually exist in equilibrium with monomers.

They are often in equilibrium with other self - assembled aggregates, including normal micelles, reverse micelles, vesicles, and microemulsions.

Question 36

1. Krafft boundary –
2. Three typical liquid crystal structures are

Answer 36

1. the crystal solubility boundary of surfactants.

Below this boundary, surfactant solution is in the form of hydrated crystal equilibrated with its monomer or in crystal hydrated form at high concentration.

Above this boundary, surfactant solutions are clear and homogeneous.

The micelle region includes spherical- , rod- , and wormlike micelles.

liquid crystal regions appear at their high concentrations after the semidilute regime.

2. Three typical liquid crystal structures are hexagonal, cubic, and lamellar. They are also called middle phase, viscous isotropic phase , and neat phase , respec;vely