Final Flashcards
(27 cards)
Explain the two kinds of in-vitro stability of proteins.
Covalent interactions (chemical): bonds forming or breaking - deamidation, oxidation, disulfide exchange, proteolysis
Noncovalent interactions (physical): proteins physically changing - denaturation, aggregation, precipitation, adsorption
Explain the ways in which you can modify proteins to use them as drugs/tx.
Protein sequence modification (site-directed mutagenesis): changing sequence of AAs
PEGylation: adding PEG to protein to make it work better in body and resist breakdown
Fusion protein: combining 2+ proteins/parts of proteins to make bigger, better one with unique properties
Formulating with permeabilizers
Antibody-Drug Conjugates
Microsphere/Nanosphere/Liposome encapsulation
Explain the mechanism behind: diffusion-controlled drug delivery (reservoir & matrix)
Reservoir: drug contained in reservoir by polymer membrane. released over time through pores.
Matrix: drug floating in polymer matrix. dissolved/dispersed over time.
Explain the mechanism behind: chemically-controlled drug delivery (erosion & chemical rxn)
Erosion (geometry): drug floating in matrix. matrix eroded over time, allowing drug to be free.
Chemical rxn: Drug located on polymer backbone. Reacts with water/enzyme and is released from backbone.
Explain the mechanism behind: solvent-controlled drug delivery (osmosis & swelling)
Osmosis: osmotic pump with two compartments (filled with osmotic agent or drug) separated by semi-permable membrane.
Swelling: Drug stored inside membrane. Water enters membrane, causing it to swell and expel drug.
What is the purpose behind drug delivery systems based on molecular buffers?
- Prevent drug degradation
- Control pharmacokinetics
- Better biodistribution
How are drug delivery systems based on molecular buffers beneficial over other controlled drug delivery systems?
- Control pH of soln. to minimize drug degradation
- Improve pt comfort and compliance
- Improve efficacy of delivery
Why were the buffer systems modified?
- Change logP (inc. buffer hydrophobicity)
- Stability
What are the routes of transdermal drug delivery (TDD)?
Transappendegeal: through hair follicle, sweat gland, or sebaceous gland
Para/intercellular: btwn cell spaces
Trans/intracellular: through hydrophobic molecules, carried by receptors, or absorption
What are some of the barriers specific to TDD?
Diffusion of drug through skin and into systemic circulation
What are some critical design elements of TDD?
- Therapeutic indication
- Desired drug delivery profile (i.e. dose level, duration)
—- - Skin adhesion profile
- Application site
- Ease of application
- Patch size, shape, appearance, comfort
- Wear period
- Patch cost
—- - Components: chemically + physically compatible
- Backing: provide protection from external factors during application period
- Membrane: moderate rate of drug release
- Adhesive: maintain contact with pt skin, incorporate drug and excipients in drug-in-adhesive TDD systems
What are some advantages of TDD?
- Provides smooth plasma concentrations of drug
- Administration through skin avoids pH variations seen with GI transit
- Avoids first-pass metabolism
- Self-administration possible
- Drug intake can be stopped at any point by removing patch
- Simplified medication regimen (improved pt compliance and reduced side effects)
- Non-invasive
- Equivalent therapeutic effect can be elicited with less amount of dose if given as transdermal patch compared to orally
- Comparable characteristics with IV infusion
- Can be route of choice in nauseous or unconscious pts
What are some disadvantages of TDD?
- Drug, adhesive, or excipients may cause rashes, local irritation, erythema, or contact dermatitis
- Barrier fxn of skin changes from one site to another in same person, person-to-person, and with age
- Patch may be uncomfortable to wear and can fall off unnoticed
—- - Only drugs with lipophilic character can effectively cross stratum corneum (drugs must have some desirable physiochemical properties for penetration)
- Drugs with hydrophilic structure will not be able to reach systemic circulation unless modified to some suitable form
- Ionic drugs cannot be delivered
—- - Only potent drugs are suitable candidates bc of natural limits of drug entry imposed by skin’s impermeability
- Doses of 5 mg or less only can be administed per day
- Cannot achieve high drug levels in blood/plasma
How do permeation enhancers work to enhance TDDs?
- Through actions on subcutaneous lipids, SC proteins, desmosomes (cell-to-cell adherence molecules), tight junctions btwn cells
- Nature of drug’s SC solvent
- Drug formulation itself
What are the basic principles behind physical enhancements to TDD?
Eletroporation: since ionized drugs don’t cross skin easily, provides access for large or hydrophobic substances that are otherwise unable to cross skin effectively. electrical pulse disturbs phospholipid bilayer of cell membrane, causing pores to be formed.
Sonophoresis: utilizes ultrasound to enhance delivery of topical medications
Iontophoresis: uses voltage gradient on skin. molecules are transported across stratum corneum by eletrophoresis and electroosmosis. electric field also increases permeability of skin. these phenomena, directly and indirectly, constitute active transport of matter due to an applied electric current
Microneedles: usually applied through even single needle or small arrays. arrays used are collection of microneedles, ranging from a few to several hundred, attached to applicator, patch, or other solid stamping advice. arrays are attached to skin and given time to allow for effective drug administration. some microneedles are made of a drug to be delivered to body but shaped into needle so they will penetrate skin.
Why is TDD ideal for vaccines?
- Painless (no needle sticks)
- Single dosing ability
- Better immune response through delayed release through skin
- Self-administered
- No need to keep cold
What is a trasnfersome?
Highly efficient edge activator-based ultra-flexible vesicles capable of non-invasively trespassing skin by virtue of their high, self-optimizing deformability
What is one advantage of each of the following nanoparticle platforms: polymeric, inorganic, and lipid-based?
Polymeric: tend to form hydrogels, so suitable nanocarriers for hydrophilic drugs, peptides, proteins, and oligonucleotides
Inorganic: unique physical, electrical, magnetic, and optical properties
Lipid-based: can entrap various cytotoxic drugs
How do size, shape, charge, and coating change the effectiveness of nanoparticle formulation?
- Size: smaller nanoparticles can penetrate tissues more effectively
- Shape: certain shapes may have better cellular uptake, influencing their therapeutic efficacy (extravasion)
- Charge: surface charge affects interactions with cells and proteins, influencing stability and targeting
- Coating: improve biocompatibility, prevent aggregation, and enable targeted delivery
How are viral vectors used for gene delivery?
Adeno-associated virus (AAV) is versatile viral vector technology that can be engineered for very specific functionality in gene therapy applications
- Inserting gene
- Infection
- Expression
- Therapeutic purpose
What are the pros and cons of viral vectors?
Pros:
- Receptor-mediated cell binding
- Effective integration
Cons:
- Immune recognition
What are the pros and cons of non-viral vectors?
Pros:
- Quality control
- Avoid immune system
- Highly modifiable
Cons:
- Inefficient gene expression
How are viral vectors for gene therapy produced?
- Wild-type AAVs carry ssDNA with Rep and CAP (capsid, virion structure, outer shell) between two IRT/LTR (inverted terminal repeats)
- In lab, cut pathogenic part and ITR. Leave only Rep and CAP to free up space for therapeutic gene to be packaged into virus as well (Rep CAP plasmid).
- Transgene cassette is gene of interest or gene of sequence
What are some modifications to enhance AAV targeting and decrease toxicity?
To prevent off-target hits and toxicity, combination of ubiquitous (promotor), cell-specific enhancers, and gene of interest is engineered into viral DNA to make sure it goes into target tissue and does what it’s supposed to do
