Drug Solubilisation II

Question 1

Cyclodextrins

Answer 1

• Cyclodextrins are cyclic oligosaccharides that possess a rigid conical structure
• They consist of a hydrophilic exterior and a hydrophobic inner core
• The hydroxyl groups on the exterior of the cyclodextrin structure form hydrogen bonds with water resulting in the formation of inclusion complexes

Question 2

Mechanism of drug encapsulation

Answer 2

• An inclusion complex is formed when a water molecule located in the lipophilic central cavity of the cyclodextrin is removed and is replaced by a lipophilic guest (i.e. a hydrophobic drug)
• The central cavity plays host to hydrophobic moieties of suitable size through non covalent hydrophobic interactions
• This forms an alternative to micellar solubilisation
• The solubility of hydrophobic drug is enhanced by physical entrapment inside the central cavity of the cyclodextrin.
• Cyclodextrins have been reported to increase solubility, enhance bioavailability and protect drugs throughout their journey in vivo
• Worldwide 35 drugs are commercially marketed as solid dosage or liquid based cyclodextrin formulations

• However, cyclodextrins are not a generic solubilising agent to hydrophobic drugs
– Their solubilising capacity is drug dependant on size and steric structure
– In order for the hydrophobic drug to reside within the central core, it must physically fit into the well structured environment of the cyclodextrin.

Question 3

Calixarenes

Answer 3

• Calixarenes are a family of cyclic oligomers which possess three-dimensional structures
• They are commonly used as starting materials or building blocks in the design of supramolecular systems
• Calixarenes form 3D cup-like structures with well defined upper and lower rims containing a central cavity in both the solid state and in solution
• Calixarenes possess a metal binding site and a hydrophobic pocket for host guest interaction with organic molecules
• They enhance the solubility of hydrophobic drugs via hydrophobic interaction
• Calixarenes are not completely rigid molecules as their shape can be varied with different solvents, functional groups and temperature
• They possess a number of advantages over cyclodextrins, they can be chemically modified easily using low toxicity chemical reactions.
• Functional groups can easily incorporated via the
upper or lower rim of the structure to enable targeted
delivery or to further enhance aqueous solubility
• They have relatively low production costs and are less
toxic than the cyclodextrins
• However like cyclodextrins, calixarenes exhibit drug
specificity, whereby the drugs need to be physically small enough and sterically able to reside within the central cavity
• Therefore calixarenes do not form generic drug
solubilisers

Question 4

Solubilisation of propofol

Answer 4

• Calix[4]resorcinarenes possess a hydrophobic pocket for host-guest interaction with organic molecules. These hydrophobic-hydrophobic interactions can be exploited in the solubilisation of hydrophobic drugs.
• Propofol is a commonly used short acting anaesthetic agent with favourable pharmacokinetic abilities. However, its poor physiochemical properties result in low aqueous solubIlity (0.1 mg/mL) which hinders its use.

Question 5

Nanonization

Answer 5

• The decreased size of nanodrug crystals results in increased surface area to volume ratio.
• Here enhanced solubility is experienced and thus the drug may be delivered intravenously.
• Additionally, lower dosages can be administered exhibiting similar therapeutic effects to large doses of the drug crystals.
• This results in reduced side effects, a more efficient and cost effective system.
• In oral drug delivery, the greater surface area results in faster dissolution and greater absorption across the gastroinstestinal tract resulting in increased drug bioavailability.
• In pulmonary drug delivery, smaller particles are able to be delivered more effectively deep into the tissues of the lungs, once at the target site their increased solubility aids in their absorption across mucal membranes.

Question 6

Disadvantages nanoization

Answer 6

• Cannot be applied to all drug molecules
• Stability issues
• Does not rival use of excipients

Question 7

Polymer-drug conjugates

Answer 7

• Concepts of using polymers in design of therapeutic agents widely investigated for number of decades.
• Polymers – long chain molecules formed of repeating units (high molecular weight)
• Polymers easily tailored for functionality using different chemistries / modifications

Question 8

Polymer-drug conjugates consist of

Answer 8

• Biocompatible polymer
• Solubiliser
• Drug
– Linker
• Targeting moiety

Question 9

Advantages of Polymer-drug conjugates

Answer 9

• Can offer protection to drug
• Can increase circulation times
• Can increase drug penetration
• All benefits of other nanotechnologies

Question 10

disadvantages of Polymer-drug conjugates

Answer 10

• May need to use complex chemistry for linkers

* Drugs may be permanently conjugated

Question 11

Summary

Answer 11

• Cyclodextrins form cup-like structures where drugs can encapsulate into hydrophobic ‘cave’
• Calixarenes form similar structures but possess greater degree of flexibility
• Nanonization is the process of milling larger crystals into smaller entities with increased solubility
• Polymer-drug conjugates can be formed to enable drug solubilisation and increased circulation