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PHRM 829 Exam 3 > Biopharmaceuticals > Flashcards

Biopharmaceuticals Flashcards

1
Q

Biologics

A

medications derived from or produced by living organisms

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2
Q

Types of Biologics

A
  • recombinant proteins
  • peptides
  • blood factors
  • vaccines
  • oligonucleotides
  • cell based therapy
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3
Q

Importance of Biologics

A

2018: 73/200 of drug sales were biologics

2003: 5/100 of drug sales were biologics

growing in importance within the pharmacy world

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4
Q

Biologics Used

A

Monoclonal antibodies (35)
Cytokines (8)
Insulins (9)
Peptides (7)
Vaccines (7)

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5
Q

Properties of Mabs

A
  • 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

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6
Q

ADC

A
  • 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

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7
Q

Cytokines

A
  • interleukins, interferons, erythropoietin’s
  • MW: 30.000 daltons
  • high content of alpha helix

Ex. Neulasta, Epogen, AVonex, Rebif, Humatrope

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8
Q

Insulins

A
  • 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
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9
Q

Insulin Analogs

A

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

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10
Q

Peptides

A
  • short proteins less than 50 aa

Ex. Telaprevir (Incevik, Vertex)

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11
Q

Vaccines

A

Different types:
- inactivated
- attenuated
- toxoid
- conjugate
- subunit

  • can be much larger than other biologics
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12
Q

Oligonucleotides

A

Spinraza (nusinersen) injection is a modified antisense

used to treat spinal muscular atrophy

NUCLEOTIDE NOT PEPTIDE

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13
Q

3 Types of Coronavirus vacines

A
  1. Protein Based (spike protein is purified and injected)
  2. Viral Vector (spike protein purified, adenoviral is injected)
  3. mRNA (mRNA that codes for spike protein and is purified and injected)
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14
Q

Dosage Forms of BIologics

A

USUALLY PARENTERAL

Include:
- solution for injection
- pen or autoinjector
- prefilled syringe
- lyophilized powder

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15
Q

Examples of Solution for Injection

A

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)

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16
Q

Why solution?

A
  • simplest and least expensive to manufacture
  • convenient for patients and hospital personnel not requiring reconstitution
  • can be inspected visually prior to administration
17
Q

Clinical concerns of Solution

A

Efficacy
Sterility
Side Effects
Pain on Injection (volume, pH, tonicity)

18
Q

Formulation concerns of Solution

A

Stability
- aggregation
- chemical stability (deamidation, oxidation)
- shelf life
- storage conditions

Manufacturability
- cost
- time

19
Q

Formulation Variables

A

Solution
- pH
- ionic strength or tonicity
- drug concentration
- volume
- excipients

Container
- materials

Storage
- refrigeration or room temp or frozen

20
Q

pH

A
  • 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
21
Q

Concentration

A
  • 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
22
Q

How do proteins aggregate?

A
  • when one or more molecules of the protein come together
  1. Colloidal Interaction
    - molecules stick together without change to structure
  2. Unfolding
    - partially unfolded proteins expose hydrophobic domains that stick together
  3. 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
23
Q

Excipients

A
  • 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

24
Q

What is solution formulation doesn’t work?

A
  • store at refrigerated temperature
  • freeze
  • freeze dry (lyophilize) or spray dry to create a dried powder
  • re engineer the protein molecule
  • abandon the drug
25
Q

Considerations for Solutions

A
  • store at recommended temperature
  • protect from light if recommended
  • avoid agitation (shaking)
  • examine vial for particulates
  • be aware of adverse immune responses
26
Q

Examples of Prefilled Syringes/Pens/Autoinjectors

A

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)

27
Q

Reminders of Syringes/Pens/Autoinjectors

A
  • they are not formulations
  • they are medical devices
  • the solution inside the pen/syringe/autoinjector is the formulation

TOGETHER THEY ARE CALLED COMBINATION PRODUCTS

28
Q

Advantages of Syringes/Pen/Autoinjector

A
  • easy to use and convenient
  • easy to transport
  • discrete
  • increased patient compliance
  • reduced risk of dosage error
  • reduce risk of contamination
29
Q

Disadvantages of Syringes/Pen/Autoinjector

A
  • higher cost
  • cannot mix two drugs
  • drug waste due to priming
  • aggregation caused by large surface-to-volume ratio and presence of lubricants
30
Q

Common Features of Syringes/Pen/Autoinjector

A
  • drug solution
  • needle
  • piston or plunger
  • housing
31
Q

Special Concerns of Syringes/Pen/Autoinjector

A
  • high surface to volume ratio
  • lower total volume
  • syringe lubricants and oils
32
Q

Examples of Lyophilized Powder

A

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)

33
Q

Advantages of Lyophilized Powder

A
  • 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
34
Q

Disadvantages of Lyophilized Powder

A
  • must be reconstituted prior to injection
  • more expensive
  • time consuming to manufacture
35
Q

What is lyophilization?

A
  • removes water by sublimation
  • occurs at low temperatures and low pressure
  • gentler than other methods of removing water therefore good for fragile drugs
36
Q

Process of Lyophilization

A
  1. Freezing: take product and decrease temperature forming ice
  2. Vaccum: drop the pressure to allow for sublimation
  3. Sublimation: going from solid phase to vapor phase without water at low temperatures
  4. Dry powder: bring product back up to atmospheric pressures when drug is powder
37
Q

Lyophilization & Instability

A
  • 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

PHRM 829 Exam 3 (4 decks)

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