Drug Solubilisation III Flashcards
Amphiphilic polymers
• Amphiphilic polymers have been widely investigated in
recent times
• Consist of hydrophobic and hydrophilic domains
• In the aqueous environments, the amphiphilic molecules
associate through weak non-covalent hydrophobichydrophobic interactions whereby, the hydrophilic moiety will remain in contact with the aqueous phase whilst the hydrophobic moiety will ‘shield’ themselves, thus forming a polymeric micelle
the critical aggregation concentration (CAC).
The lowest concentration required for a polymeric micelle to form in an aqueous environment
The CAC is affected by a number of factors including
structure and nature of the hydrophobic group and the
addition of electrolytes
Polymeric micelles have several advantages compared to
traditional surfactant micelles.
– They possess lower CAC values (approximately 1000
times lower) than traditional micelles . This makes their
aggregates more stable in aqueous solution and hence
reduce the risk of disruption upon dilution in vivo
– The size of the self-assemblies formed in aqueous
environments are usually between 30 - 100 nm, this size
can increase or decrease on drug loading depending on
the molecular architecture of the polymer and of the drug
four main groups of Amphiphilic polymer
– Block copolymers
– Graft polymers
– Star shaped polymers
– Dendrimers
Block copolymers
• Fabricated from the polymerization of two or more types of monomer units
• Typically one hydrophobic moiety and one hydrophilic moiety is polymerized together giving an amphiphilic diblock copolymer e.g. poly(ethylene oxide)-block-poly(lactic acid) (PEO-b-PLA)
• Triblocks, tetrablocks, pentablocks etc. can also be
synthesised using the same reaction.
• In aqueous solution amphiphilic block copolymers form
polymeric micelles
• As drug delivery vehicles, the hydrophobic moiety of block copolymers is usually composed of biodegradable and biocompatible monomers such as polyesters e.g. poly(caprolactone) (PCL) and poly(lactic aid) (PLA) or poly(amino acids) e.g. poly(aspartic acid)
• The most common hydrophilic segment for block copolymers is poly(ethylene glycol) (PEG), however other hydrophilic monomers have also been reported e.g. poly(ethylene oxide) (PEO), and poly(N-isopropylacrylamide) (PNIPAAm)
Graft polymers
- Amphiphilic graft polymers consists of a homo polymer as the backbone to which hydrophobic pendant groups are ‘grafted’ to form a comb like structure.
- The hydrophobic pendant groups of a comb shaped polymer may consist of homopolymers, copolymers or small molecular weight hydrophobic molecules.
- In the aqueous environment, self-assemblies are formed with a hydrophobic core stabilised by a hydrophilic corona
- Graft polymers can spontaneously aggregate through both INTERmolecular and INTRAmolecular aggregation
Star shaped polymers
- Star shaped amphiphilic polymers are made up of 3 or more linear polymer chains linked to a central polymeric core
- The arms are of comparable lengths and consist of homo-, co- or terpolymers
- The nano aggregates possess a smaller size and solution viscosity compared to linear polymers of the same molecular weight and composition
- Form unimolecular micelles with increased stability compared to block copolymers
- The physical properties of the polymer can be altered by changing the chemical structure and composition of the arm chains
- Star shaped polymers have been reported to enhance the aqueous solubility of hydrophobic drugs such as paclitaxel and prednisolone acetate
Methods of drug loading
- Solvent evaporation
– Both the polymer and drug were dissolved in organic solvents
– The solvents were then removed and the resulting residue was reconstituted with water.
– On the addition of water, self-assembly formation was initiated. - Dialysis
– The polymer and drug were again both dissolved in organic solvents and placed inside a dialysis membrane and exhaustively dialysed against water
– The diffusion of the solvent out of the membrane and water into the membrane drives the formation of self-assemblies.
– The excess free drug was also removed via diffusion gradient out of the dialysis membrane.
– However, the self-assemblies were too large and remained inside the dialysis tubing. - Sonication
– Sonication of the amphiphilic polymers in aqueous phase encourages aggregation formation.
– Upon sonication of the nano-aggregates with the desired hydrophobic drug, easy and efficient drug loading of the self-assemblies occurs.
– The lack of organic solvents in this drug loading method eliminates the safety concerns associated with the previous methods.
What is dendrimer ?
• Highly branched, synthetic and 3D molecules that combine the properties of polymers as well as small discrete molecules.
• They characterized by three dimension shape, high
branching point and nanometric size range
• Dendrimers consist of three main components
- Surface: functional peripheral group
- Interior: affects host-guest properties
- Core: affects 3D shape of dendrimer
Advantages of Dendrimers as Drug Carriers:
Chemotherapeutic drugs have some problems…
- Low solubitlity in water (due to hydrohobicity) and easily
metabolized
Dendrimers as one of the solutions…
- Solubilizing in water (Dendrimers’ solubilities regulatable) and
Less filtered out of bloodstream (unable to exceed the renal threshold)
• They have been one of the most promising polymeric DNA nanocarriers due to their ability to cross cell membranes and reduced clearance from the body.
Synthesis of dendrimers
• Because of branched structure with globular shape, a
large number of active groups can be tailored.
• Several types of dendrimers have been made with
different core materials, surface modification and branching units.
How Dendrimers Carry Drugs ??
- physical encapsulation
- chemical conjugation
• Peptide dendrimers and glycodendrimers are two
dendrimers which have generated great interest for
understanding and controlling biological recognition
events.
• Positively charged dendrimers can enhance intracellular
drug delivery due to the interaction with negatively
charged biological membranes.
• Cationic terminated dendrimers have shown more
toxicity than neutral or anionic group terminated
dendrimers.
• By modification of cationic dendrimers periphery with
negative or neutral group such as carbohydrates, PEG
and acetate the toxicity would be reduced.
Applications
• As antimicrobial: Cationic dendrimers with amphiphilic
properties. However, they are cytotoxic agents due to cationic nature
• As antiviral (Anti-HIV) - Anionic Dendrimers.
• Dendrimers have been tested in preclinical studies as contrast
agents for magnetic resonance.
• There are attempts to use dendrimers in the targeted delivery of drugs and other therapeutic agents.
• Dendrimers can act as carriers, called vectors, in gene
therapy.
