TD: Delivery of Biopharmaceutics Flashcards
Why are proteins/peptides good drug molecules?
Proteins and peptides show high efficacy due to low toxicity and high specificity
Problems associated with proteins/peptides as drugs regarding delivery
- Solubility & Permeability
- Molecular Weight
- Complex structure: changes in activity/degradation and stability
- Susceptibility to degradation
A.Chemical
B.Enzymatic
Describe the solubility of biopharmaceutics (proteins/pepides)
- Almost all BCS class III
- Solubility depends on structute, which is made of AA. Amino acids range from very hydrophobic to very hydrophilic. Majority are very hyrophillic therefore fast dissolution.
- The overall protein hydrophobicity is dependant on:
- the type of amino acids in the sequence.
- the arrangement of the hydrophobic and hydrophilic amino acids.
Describe the effect ionisatiion has on the solubility of proteins/ peptides
- Proteins/peptides usually have complex solubility versus pH profiles.
- Aqueous solubility is minimal at the isoelectric point (pI) where the drug is neutral or has no charge.
- Ionisation (and therefore solubility) of peptides/proteins varies so much due to the fact that they are composed of amino acids.
- Ionisation and therefore solubility of proteins/peptides affected by amino acids in their structure. Different amino acids will have different pKa values.
- Makes formulation more complicated as their solubility varies with pH more than most small molecules particularly in GI tract.
Describe permeability/ absorption of proteins/peptides
Mucosa permeability
- Generally peptides are hydrophilic with a very low log P value
- Plus high molecular weight
- => Leads to low permeability across biological membranes
- Two possible absorption pathways : paracellular or transcellular
- Both very unlikely if protein administered by itself
- Paracellular - hydrophillic molecules most likely to undergo so this route most likley however proteins/peptides big so unlikely to fit though cell gaps (unlikely)
- Transcellularly:
- Passive - most common for small molcules but large molecules and poor lipid sol (unlikely)
- Carrier mediated - if comes into contact with receptor which recpgonises it (possible)
- Transcytosis - drug taken up by pinocytosis and carried across membrane (possible)
Describe the complex structure of proteins/peptides and how this releates to stability
- Unlike most small molecules which are fairly flat, planar molecules with relatively straight chains, peptides/proteins have far more complex structures.
- They have primary, secondary, tertiary structures (some even have quaternary structures!).
- This is very complex and is affected by the environment (pH, solvents, ions present) the protein/peptide is in and so again makes it difficult to formulate.
- Different conformations will not have the same potency/activity as binding sites may be hidden in one conformation and exposed in another.
- Conformation may also affect their susceptibility to enzymatic breakdown.
- NEEDS TO BE IN NATIVE CONFORMATION TO HAVE ITS EFFECT!!!
- Rarely encountered by small organic molecules but common with
- peptides/proteins due to loss of their native three dimensional structure in unfavourable conditions.
- If they move away from their native structure it can have several consequenes (see picture). These can be reversible. It is important for the protein/peptide to be in its native conformation on release
Describe the types of chemical degradation that can occur
Depends upon amino acids in structure and environment protein in.
- Oxidation by radicals: potential oxidation sites of proteins include the side chains of cysteine (Cys), tryptophan (Trp) and tyrosine (Tyr) as they are more electron rich than other amino acids and radicals are electron deficient (electrophilic).
-
Proteolysis: cleavage of peptide bonds.
- Chemical or enzymatic
- Chemical: Hydrolysis of peptide bonds in acidic pH
Describe enzymatic degradation that can occur
1) Extracellular metabolism
- Degradation by peptidases present at both the site of administration and in the mucosal barrier.
- The presence of pepsin, trypsin and chymotrypsin in gastric and intestinal secretions.
- The presence of proteolytic enzymes (aminopeptidases, endopeptidases, carboxypeptidases, deamidases) in various mucosal epitheliums.
2) Intracellular metabolism
- Peptide metabolism can occur intracellularly by aminopeptidases.
- The paracellular pathway can avoid this type of metabolism.
what are protein/peptide delivery systems?
- Enzyme inhibitors/chelators and absorption enhancers
- Liposomes
- Microparticles
- Polyelectrolyte delivery systems:
- Chitosan
- Amphiphilic polymers
How do enzyme inhibitors and absorption enhancers work?
Example of each?
Enzyme inhibitors (e.g. puromycin) are used to deactivate GI tract enzymes.
Absorption enhancers (e.g. traditional surfactants) open tight junctions between epithelial cells, i.e. in mucosa.
What are the problems with absorption enhancers and enzyme inhibitors?
- Co-administration of these with proteins/peptides has proven to be fairly ineffective.
- Absorption enhancers tend to cause permanent damage to mucosa by irreparably changing cell morphology
- Enzyme inhibitors can interfere with normal digestion and can permanently denature proteases
- Neither are very effective as the protein/peptide is not co-localised with the enhancer/inhibitor. The peptide/protein may also pass through GI tract before inhibitors/enhancers can have effect.
Why are liposomes good?
Why are they bad?
How do proteins interact?
Advantages of microparticles?
Limitations?
Advantages:
- Protect from GI
- MUDF
- Promote absorption
- More stable in GI (to liposome)
- higher drug loadinf (than lipsomes)
Limitation: inconsitant release (triphasic)
¡Need to use w/o/w or o/o emulsions to encapsulate peptides/proteins due to their hydrophilic nature (See Microencapsulation lecture for advantages/limitations of this).
¡Microparticle production involves the use of organic solvents which can denature proteins/peptides.
¡Hydrophobic polymers on degradation produce an acidic microenvironment which can denature proteins/peptides. This can be overcome to some extent by co-encapsulating antacids (e.g. calcium carbonate).
¡Their hydrophobic nature can also cause rapid release and denaturation. Therefore there have been moves towards the use of amphiphilic or hydrophilic polymers.
Describe the use of polyelectrolyte polymers
What are these?
Adv?
Polyelectrolyte polymers are those which have ionisable groups on their structure: they can have either a positive or negative charge
Hydrophilic polymers, e.g. Chitosan
Amphiphilic polymers - See Drug Targeting lectures for more info
Postive polymer cation ion + negative protein/peptidr form PEC (polyelectolyte complex)
Adv: Produced in aqueous enviromenr thereofre not same negative effect of degradation of peptides from solvents
Where does chitosan come from?
Use
Adv
Neg
Chitosan is a naturally occurring polysaccharide derived from chitin which is extracted from the shells of crustaceans. It has good biodegradability, biocompatibility and bioadhesive properties which are ideal for pharmaceutical delivery systems. Also doesn’t produce acidic enviroment which may degrade protein like hydrophobic polyers
Chitosan has come to prominence in the field of peptide/protein delivery as it has been shown to promote penetration of proteins/peptides across nasal (Pharmaceutical Research 19, 2002, pages 998-1008) and intestinal mucosa (Journal of Controlled Release 45, 1997, pages 14-23) when in the form of a solution or a particulate delivery system.
However it is only soluble in acidic conditions and precipitates in blood, small intestine fluid unless administered in a strongly acidic buffer.
Derivatives, including thiolated and trimethylated chitosan, have been developed which overcome this problem as well as allowing it to chelate GI enzymes (Biomaterials 30, 2009, pages 5691-5700).
