Biopharmaceuticals Flashcards
Biologics
medications derived from or produced by living organisms
Types of Biologics
- recombinant proteins
- peptides
- blood factors
- vaccines
- oligonucleotides
- cell based therapy
Importance of Biologics
2018: 73/200 of drug sales were biologics
2003: 5/100 of drug sales were biologics
growing in importance within the pharmacy world
Biologics Used
Monoclonal antibodies (35)
Cytokines (8)
Insulins (9)
Peptides (7)
Vaccines (7)
Properties of Mabs
- glycoproteins with a high content of Beta sheets
- MW: 150,000 daltons (very large)
- quaternary structure with 2 light chains and 2 heavy chains linked by S-S bond
- antigen binding occurs through the variable domain at the complementarity determining region (CDR)
- the constant region helps with biodistribution and 1/2 life
Ex. Humira, Herceptin, Avastin
ADC
- Antibody drug conjugates
3 Parts:
- Antibody
- Cytotoxic agent: designed to kill target cells when internalized
- Linker: attaches cytotoxic agent to antibody
COMBINE TARGET SPECIFICITY OF MAB AND EFFICACY OF SMALL MOLECULE
Cytokines
- interleukins, interferons, erythropoietin’s
- MW: 30.000 daltons
- high content of alpha helix
Ex. Neulasta, Epogen, AVonex, Rebif, Humatrope
Insulins
- MW: 5,800 daltons
- contains an A chain and B chain linked by S-S bond
- high content of alpha helix
- readily associates to form dimers and hexamers
Insulin Analogs
Insulin Lispro (Humalog)
- fast acting insulin
- Lys and Pro on C terminus of B chain are reversed blocking the formation of dimers and hexamers
Insulin Aspart (Novolog)
- fasting acting insulin
- Pro on C terminus of B chain mutated to Asp
Insulin Glargine
- long acting insulin
- Asn at A21 mutated to Gly and two Arg added to C terminus of B chain
- microcrystals are formed to slow release of drug
Peptides
- short proteins less than 50 aa
Ex. Telaprevir (Incevik, Vertex)
Vaccines
Different types:
- inactivated
- attenuated
- toxoid
- conjugate
- subunit
- can be much larger than other biologics
Oligonucleotides
Spinraza (nusinersen) injection is a modified antisense
used to treat spinal muscular atrophy
NUCLEOTIDE NOT PEPTIDE
3 Types of Coronavirus vacines
- Protein Based (spike protein is purified and injected)
- Viral Vector (spike protein purified, adenoviral is injected)
- mRNA (mRNA that codes for spike protein and is purified and injected)
Dosage Forms of BIologics
USUALLY PARENTERAL
Include:
- solution for injection
- pen or autoinjector
- prefilled syringe
- lyophilized powder
Examples of Solution for Injection
Rituxan: lymphoma, leukemia, arthritis (IV)
Synagis: RSV (IM)
Epogen: anemia in renal failure (IV or SubQ)
Xgeva: bone metastases (SubQ)
Lucente: macular degeneration (ocular)
Novolog: diabetes (SubQ)
Avastin: cancer (IV)
Why solution?
- simplest and least expensive to manufacture
- convenient for patients and hospital personnel not requiring reconstitution
- can be inspected visually prior to administration
Clinical concerns of Solution
Efficacy
Sterility
Side Effects
Pain on Injection (volume, pH, tonicity)
Formulation concerns of Solution
Stability
- aggregation
- chemical stability (deamidation, oxidation)
- shelf life
- storage conditions
Manufacturability
- cost
- time
Formulation Variables
Solution
- pH
- ionic strength or tonicity
- drug concentration
- volume
- excipients
Container
- materials
Storage
- refrigeration or room temp or frozen
pH
- rate of degradation can depend on pH
- pH of maximum stability is 3-4 but not acceptable for injection
- additives make the stability worse
- good pH is around 7-7.5
Concentration
- aggregate content increases with increasing protein concentration
- turbidity is also greater when aggregates are present
- with SubQ volumes so small, concentrations of Mab are getting very large increasing the risk of aggregates
How do proteins aggregate?
- when one or more molecules of the protein come together
- Colloidal Interaction
- molecules stick together without change to structure - Unfolding
- partially unfolded proteins expose hydrophobic domains that stick together - Chemical Reaction
- crosslink the protein molecules forming chemical crosslinked aggregates
- Many aggregates like amorphous aggregates and amyloid fibrils are at low energy with high intermolecular contacts
- surfaces are normally more hydrophobic causing the protein to partially unfold and allow the inner hydrophobic domains to stick to the surfaces (especially at the 3-phase boundary) –> leads to aggregates
- shaking the container makes more agitation causing more aggregation
Excipients
- used to help stabilize the protein
- excipients that are preferentially excluded from protein surface promote interactions with water and stabilize the native protein structure
- excipients that are preferentially binding to the protein can lead to denaturation
EXCEPTION: protein binding to ligand can stabilize
What is solution formulation doesn’t work?
- store at refrigerated temperature
- freeze
- freeze dry (lyophilize) or spray dry to create a dried powder
- re engineer the protein molecule
- abandon the drug
Considerations for Solutions
- store at recommended temperature
- protect from light if recommended
- avoid agitation (shaking)
- examine vial for particulates
- be aware of adverse immune responses
Examples of Prefilled Syringes/Pens/Autoinjectors
Humira: for rheumatoid arthritis (pen or prefilled syringe)
Lantus: for diabetes (pen)
Aranesp: for enemia of renal failure (pen or prefilled syringe)
Rebif: for MS (auto injector or prefilled syringe)
Reminders of Syringes/Pens/Autoinjectors
- they are not formulations
- they are medical devices
- the solution inside the pen/syringe/autoinjector is the formulation
TOGETHER THEY ARE CALLED COMBINATION PRODUCTS
Advantages of Syringes/Pen/Autoinjector
- easy to use and convenient
- easy to transport
- discrete
- increased patient compliance
- reduced risk of dosage error
- reduce risk of contamination
Disadvantages of Syringes/Pen/Autoinjector
- higher cost
- cannot mix two drugs
- drug waste due to priming
- aggregation caused by large surface-to-volume ratio and presence of lubricants
Common Features of Syringes/Pen/Autoinjector
- drug solution
- needle
- piston or plunger
- housing
Special Concerns of Syringes/Pen/Autoinjector
- high surface to volume ratio
- lower total volume
- syringe lubricants and oils
Examples of Lyophilized Powder
Remicade: used for rheumatoid arthritis (Mab)
Nulojix: used for renal transplant (Mab infusion)
Orencia: used for rheumatoid arthritis (Mab infusion)
Herceptin: used for breast cancer (Mab)
Benlysta: used for lupus (Mab)
Advantages of Lyophilized Powder
- reduced rates of chemical and physical degradation
- improved drug stability and longer shelf life
- refrigerated storage is not needed
- can be used in medical devices
Disadvantages of Lyophilized Powder
- must be reconstituted prior to injection
- more expensive
- time consuming to manufacture
What is lyophilization?
- removes water by sublimation
- occurs at low temperatures and low pressure
- gentler than other methods of removing water therefore good for fragile drugs
Process of Lyophilization
- Freezing: take product and decrease temperature forming ice
- Vaccum: drop the pressure to allow for sublimation
- Sublimation: going from solid phase to vapor phase without water at low temperatures
- Dry powder: bring product back up to atmospheric pressures when drug is powder
Lyophilization & Instability
- freeze concentration can promote aggregation
- disulfide bond scrambling can be accelerated by freezing and drying
- aggregated or degraded protein can be observed on reconstiution
Excipients to inhibit: lyoprotectants & cryoprotectants
