B33 CAN Pharmaceutics Flashcards
Formulation of cancer drugs depends upon
The Physiochemical & Biopharmaceutical properties of the patient
Intended dose & route of administration
Disease Factors (types of cancer & location)
The patient (ADME)
How does therapeutic window guide formulation
Cancer drug formulations by simplest pharmaceutics profile route
Narrow therapeutic window
Variation in patients
Dosing close to MTD
Routes of Administration for cancer drugs
Oral
Parentarel formulations
- I.V. , I.M. , S.c.
Oral route of administration cancer drugs
Drugs has to be absored via gut Stays in Stomach Proteases break down protein drugs (E.g Mabs) Subject to first pass metabolism Fed & fasted effects
Parenteral formulations in cancer drugs
Avoids N&V and first pass
- Accurate dosing
- Flexibility of dose & schedule
- Rapid onset of action
- Rapid withdrawal of drug
- No fed/fasted effect
- Avoids first pass metabolism
Requirments for IV formulation
- Sterile production
-Formulation stability
Particle size
Solubility
Clearance time
No preservatives
Sub-cutaneous (e.g I.M.) affects
Local or systemic affect needed
Rapid absorption for drugs with good solubility
High collagen content in muscle (can bind charged drugs)
Muscles highly vascularised
Topical effects
Formulations needed to retain drug at/in skin
Shouldnt penetrate into deep tissue and enter circulationq
How do the constrains placed on the use of I.V. route affect the form of drug used?
1) Sterility and size play a factor
2) No precipitation can occur in blood stream
How can chemistry solve formulation problems (Etoposide & doxorubicin)
Eptoposide is in solution containign sodium salicylate
Parabens used in lyophilised formulation
Etoposide (Topoisomerase II inhibotor) & sodium salicylate
Before
- Low solubility in water
- Tendecy to precipitate or crystallise
- Binds strong to plasma proteins
After Sodium salicylate
- Improved aq. solubility
- Reduced precipitaton
- Reduced protein binding
- Enhanced F
Doxorubicin and Parabens
Before
- Dox forms stacked dimers and self aggregates
- Pi-Pi interactions strong between aromatic rings
After additon Parabens
- Disrupts the self assembly and dimerisation of drug
- Enabiling rapid dissolution from lyophilised formulation
- Enhanced F
- More predictable dosing
Reduced protein binding (Etopside)
- Congregation of lots of charges prevents protein binding
Albumin
Albumin binds hydrophobic drugs
Epimerization
Chemical process when an epimer is made to transform into its chiral counterpart
Doxorubicin Amino group allows for…?
The Amino group in Dox allows for doxorubicin to be formulated as a salt (powder for reconsitiation)
Formulation problems for proteins
Proteins are amphiphilic
- Contain charged amino acids & hydrophoic regions
- If the protein is denatured or assembled at an interface associaton & aggregation can occur
Protein aggregation at intersurface interfaces
- Protein hydrophobic region comes into contact with vial
- Hydrophobic region adsorbs to vial surface
- Other part of protein ‘wobbels about’
- Another protein can bind to the hydrophillic region and form OLIGOMERS (Aggregates and coalescense)
Hydrophobic & hydrophillic parts of protein forming Particles in bulk solution
Hydrophobic region of protein adsorbs to interface
Hydrophillic region is exposed in solution
Shedding of protein due to binding leads to;
Visible & sub-visible particles detected in bulk
When formulating for proteins what should you be wary of
Not possible to deliver by oral route (proteins degraded by proteases in stomach)
Charge
Solubility
Stability
Size
What is Enhanced Permeabiility and Retention
EPR is Enhanced permeation and retention effect
- In arease around solid tumours or inflammation, the integrity of blood vessels changes -> materials transported also effected
Allowing for increased permeation and reteniton of materials
How do we avoid systemic toxicity (doxorubicin is a potent small cytotoxic agent)
- Enhanced Permeation and Retention effect
- Encapsulate doxorubicin into virus-sized carrier
Factors affecting the EPR effect
Vehicle related
- Particle size
- Carrier vehicle
Tumour related
- Tumour Type
- Microenvironment
External mediators
- Radiation
- COX inhibitor
Other factors defining passive targeting
- Prolonged blood circulation of drug carries important
- Extravasation is slow
- Reticuloendothelial system (RES) in liver,spleen and lung removes small molecules
Size matters
Liposomal Doxorubicin - Parts and what they do
PEG outer finders (Shield)
(Highly hydrated so for protein to adsorb to it must displace H20)
Liposomal phospholipid bilayer - (encapsulates drug)
(
Doxorubicin HCL - Loaded inside by pH gradient
(precipitates and aggregates inside increasing drug load)
Liposomal delivery and EPR effect
Small molecules diffuse IN *& OUT easily
Individual cancer cells within tumour pump out small molecules via Efflux transporters
Release of Doxorubicin intracellulary avoids efflux pumps
No efflux pumps for large liposomes so retention
Palmar-plantat syndrome is due to?
Palmar-plantar syndrome is damage to peripheral sites due to unwated accumulation of Liposomal doxorubicin at sites with POOR CIRCULATION
Albumin in blood transports HYDROPHOBIC molecules this allows it too act as…
Albumin binds to hydrophobic molecules in circulation, can be used as a drug carrier e.g Paclitaxel
Exploits albumin receptor (gp-60) mediated transport across EC
Mode of action : Potent & water insoluble drug
1) Administration followed by rapid dissolution
2) Binding to albumin
3) binding to albumin-specific receptors on EC leads to activation of TRANSCYTOSIS
(albumin & drug carried in via vesicles)
4) Release drug into tumour interstitum
5) Tumour uptake -> tumour cell death
What can happen to a poorly soluble drug when injected
Reduced uptake into target cell Protein binding will occur Stays in body for a long time (long clearance time( Dosing can be unpredictable F is low
What are the adv. to a patient using liposomal formulation of anti-cancer drug
Can have drug precipitate within liposome -> high drug loading
Less protein binding so drug is cleared from circulation quicker
PEG -> longer circulation of free drug
Can exploit natural mechanisms (Albumin gp60 transport across ECs)
What are the disadv. to a drug manufactoror in development liposmal formulation
Limiting factor for drug loading
Liposomes highly diluted on injection
- Drug leakage
- Balance of stability liposome and drug release
Methotrexate use
Management of acute lymphoblastic leukamie
Methotrexate MOA:
antimetabolite
Antagonist of folic acid
Immunosuppresant properties
Inhibits DHFR -> preventing formation of THF from DHF which is necessary for DNA, RNA and protein synthesis
Cell cycle-specific
PK (Pharmacokinetics of MTX)
MTX needed for parentaral for cancer due to Long circulation and residence time needed (Only kills actively rapidly divinding cells)
Low dose rapidly absored from GI tract , High doses less well absorbed (Only a finite number of influx carriers of RFC)
I.M. MTX rapidly and COMPLETELY absorbed
Explains why oral MTX dosing isn’t suitable for Cancer
MTX toxicity is due to..
The penetration of Ascitic fluids
- Acts as depot and enhances toxicity even after serum concentrations fall
MTX PK - Active transport mechanism -> TRAPPING
MTX enters cell by active trasnport
-> converted into cojugate drug that is NOT ACTIVELY exported
MTX can remainin body several months
Consequence of MTX conjugate drug trapping
Can lead to development of resistance
- > Decrease influx and increased efflux
- > Impaired polyglutamylation (needed for active conjugate drug)
Practical issues with MTX treatment
MTX pharmacokinetics highly variable
- Affected by AGE, RENAL & HEPATIC function
- Does not diffuse across lipi membranes
Main route of Elim
- Glomerular filtration
- Active tubular secretion
- Toxicity dependent on duration
Practical issues with MTX treatment
MTX can bind to plasma proteins
Negative effects of aspirin and other NSAIDs
- Displace MTX from protein - increased serum levels of free MTX
Inhibit MTX secretion in proximal tubule reducing RENAL clearance
- Increase duration of MTX exposure hence INCREASE toxicity
High dose MTX can result in…?
High dose MTX can result in SUPERSATURATION of the urin with MTX and metabolites
Crystals cause intrarenal obstruction (acute renal failure)
Crystal formation;
Acid urine
Crossing the blood-brain barrier
MTX development of resistance
Intervention in DNA and RNA sythesis can form resistant phenotypes
MTX overdose
Antidote folinic acid is given I.V.
- Maintains high hydration avoiding acidic urine
Single acute oral ingestions rarely cause ADE: (Absorption of MTX is active, easily saturated, F decrease high doses)
What problems arise due to protein binding in MTX (comapre with ABRAXANE)
The volume of distribution of MTX is 0.6L/KG. It is poorly lipid soluble.
Protein binding also leads to MTX being excreted slower. and a variation that leads to toxicity threapetuic windows
What are the adv. and disadv. of drugs which exploit active transport processes
Adv
- Allow MTX to be taken up by active process by receptors
Disadv.
- Development of resistant at cell membrane level
- Can decrease influx with changes in RFC and with increased efflux of MTX
Treatment of prostate cancer requires….?
Treatment of prostate cancer requires sustained release of PEPTIDE THERAPEUTIC
Goserelin is a…?
Goserilin is a DECAPEPTIDE AGONIST of Lutenising hormone releasing hormone LHRH
SHORT HALF LIFE - CONSTANT INJ
How to get slow sustained release for LHRH?
Polymer material that dissolves slowly and reveals new drug reservers continually
Achieving Slow Dissolution: Option 1
HMW water-soluble polyemer that disentagles over time
Achieving slow Dissolution:
Option 2
Polymer that chemically breaks down
Achieving slow dissolution O1: Problems
Unreliable as dependent on entalngment
Most polymers dissolve to quick
How is polymer excreted after?
Designing polymers that slowly break down in the body needs…?
A chemical group that hydrolyses
General rule on rate of hydrolysis & Polymer
Anhydrides > Orthoesters > Esters > Amides(peptides)
Polymer must be water-insoluble but LMW degradation products must be water soluble
Degradation is…?
Erosion is…?
Degradation is the chemical breakage of bonds
Erosion only starts when the polyer chains have decreased in MW enough to drive WATER solubilty
Poly(lactid acid) polyermised from….
Polylactic acid polyermised from DIMER called LACTIDE
The effect of stereochemistry on PLA degradation…?
& explained?
DL-Lactic acid takes 1 year
L-Lactic acid takes 2 years to degrade fully
Explained by CRYSTALLINITY, L-Lactic acid is semi-crystalline and DL-Lactic acid is amorphous
(DENSER, LESS WATER PEN, SLOW HYDROLYSIS)
PLA undergoes BULK EROSION
Water penetration and chain scission is FASTER than erosion (SOME drug escapes with these)
PLA + Glycolic acid
Adding Glycolic acid, GA is more susceptible to hydroylsis (DUE to lack hydrophoic Methyl group)
Increasing GA in PLGA …..?
Incrreasing GA in PLGA should INCREASE degradation rate in patient
The effect of AUTOCATALYSIS
Autocatalyic degradation is in rod systems
(dosing more rapid than predicted)
Hydration and fragmentation of the rod allows drug release by diffsuion
LMW chains increase early erosion
+ Increase LOCAL acidity as PLGA cannot escape rod
What parameters can be varied in polymer formations to control the release of drug
Amount of LMW and HMW polyermers added
The ratio between the sterochemistry ( DL vs L-lactic avid)
Ratio between polymer and GA added
Adeno virions drug delivery
1) Adenovirus virions bind to CAR and intergrins on plasma membrane
2) Virions enter cell by receptor-medidated endocytosis
3) Endosome acidifies and capsid breaks down releaseing viral contents
siRNA MOA:
After internilization into cell, siRNA duplex Recongnizd and unfolded by RNA inducing silecning complex (RISC)
RISC catalyses cleavge of mRNA of specific sequence and PREVENTS it from being transcribed into protein
Endonuclease occurs
Biological barriers & Delivery challengs of siRNA
Rapidly degrades by nucleases
Size allows glomerular filtration (ELIMINATED With URINE)
Hydrophlic
Toxicity or Off target effects
Cancer cells have efflux transporters for small molecule drugs but not for liposomes
TRUE
