Therapeutic Peptide: formulation and delivery Flashcards
What is the difference between peptides and proteins?
peptides have less than 50 amino acids
proteins have more than 50 amino acids
insulin has 51 amino acids but it classified as a peptide
What are the classes of biopharmaceuticals?
recombinant therapeutic proteins
- human growth hormone, traztuzumab (Herceptin)
peptides
- insulin, calcitonin, gosrelin, oxytocin
blood products
- factor VIII, gamma globulin, serum albumin
vaccines
- peptides
nucleic acids
- anti-sense oligonucleotides
polysaccharides
- LMW heparin
What are the challenges associated with peptides/proteins in vitro?
very large and unstable molecules
structure is held together by weak non-covalent forces
easily destroyed by relatively mild storage conditions
hard to obtain in large quantities
What are the challenges associated with peptides/proteins in vivo?
elimination by B and T cells
proteolysis by end/exo peptidases
small proteins are filtered out by the kidneys rapidly
unwanted allergic reactions may develop
loss due to insolubility/adsorption
What are the formulation strategies for peptides?
protein sequence modification (site directed mutagenesis)
PEGylation
micro/nanoparticle encapsulation
formulating with permeation enhancers
- surfactants, bile salts, fatty acids
use of enzyme inhibitors
- trypsin, elastase
How does site directed mutagenesis (protein sequence modification) take place?
amino acid substitutions at specific sites takes place in a protein
- e.g. Met to a Lau substitution reduces the likelihood of oxidation
- strategic placement of cysteines to produce disulphides to increase melting temperature
How does PEGylation take place? What is its purpose?
PEG (polyethylene glycol) is a non-toxic, hydrophilic, neutral polymer
- affects the surface characteristics of the particulate system
functions
- increases in vivo circulation half-life
- increases protease resistance
- increases solubility and stability
- decreases immunogenicity
- decreases depot loss at injection sites
What is encapsulation? What is its purpose? How can it be done?
process involves encapsulating protein or peptide drugs in small polymer or lipid based particles
- for protection from proteolytic enzymes
- to achieve sustained drug release
two types of materials can be used
- non-biodegradable = ethylene co-vinyl acetate, polymethacrylic
- biodegradable = gelatin, polylactic co-glycolic acid (PLGA)
What is complexation?
process of shrinking and swelling of pH sensitive microparticles
microparticle system with polymethacrylic acid + PEG
- in the stomach (pH 2) pores in the polymer shrink and prevent protein release
- in the small intestine (neutral pH) the pores swell and release protein
How does polymer types affect drug release profile?
hydrophilic
- best for burst release
= gelatin
hydrophobic
- best for sustained release
- tends to denature proteins
= polylactic co-glycolic acid (PLGA)
hybrid (amphiphilic)
- best for sustained release
- retains proteins structure
How can excipients be used to stabilise peptides/proteins?
- permeation enhancers
addition of stabilising salts or ions
- zinc for insulin = reduces solubility which increases storage stability
addition of polyols to solubilise
- glycerol or polyethylene glycol
addition of sugars or dextran to displace water or reduce microbial growth
use of surfactants to reduce adsorption and aggregation
- CHAPS
What are peptide micelles?
peptides and proteins can be loaded into micelles for release via pH or redox triggers
peptide micelles can be decorated for cell targeting
peptide core composite allows for peptide/protein solubilisation
What are the advantages and disadvantages associated with parenteral delivery?
advantages
- allows for rapid and complete absorption
- allows for smaller dose size (less waste)
- avoids first pass metabolism
disadvantages
- problems with overdosing, necrosis
- local tissue reactions/hypersensitivity
- patient compliance issues
How does unigene technology work to allow peptide delivery?
tablet formulation has
- enteric coating = prevents dissolution in the stomach and enables the tablet to dissolve in the small intestine
- protease inhibitors = block break down of peptides/proteins before exerting its effects
- absorption enhancers = enables peptide absorption across the intestinal wall
How do transdermal patches work?
proteins are embedded in a simple matrix with additives
- patch is coated with small needles that penetrate the dermal layer
- proteins diffuse directly into the blood stream via capillaries
