Exam 3 Flashcards
(78 cards)
1
Q
What are the two types of controlled drug delivery?
A
Temporal -
- Sustained release (delayed or extended)
- Pulsatile release
Spatial -
- Systemic, local (ex. transdermal trying to target the skin, and targeted release.
- We want the drug to be fully released at that target organ.
2
Q
What are the 5 advantages of controlled release?
A
- Can maintain optimum drug concentrations
- Improves efficiency of treatment with less amount of the drug
- Minimizes side effects
- Less frequent administration
- Increases patient convenience and compliance with the dosing regimen
3
Q
What are the 5 disadvantages of controlled release?
A
- Relatively high production costs
- Dose dumping (leakage of drug mass)
- Difficult to stop drug release
- Maybe issue of biocompatability of the delivery systems (irritation at site)
- Potential necessity of surgical operation (ex. implant)
4
Q
What are the 5 disadvantages of controlled release?
A
- Relatively high production costs
- Dose dumping (leakage of drug mass)
- Difficult to stop drug release
- Maybe issue of biocompatability of the delivery systems (irritation at site)
- Potential necessity of surgical operation (ex. implant)
5
Q
When is temporal control of drug delivery needed (3) and not needed (3)?
A
Needed:
- Having the best drug conc.-time profiles at the site of action
- Reducing the # of administration frequency
- Simulating multiple dosing
Not needed:
- Drugs with a long half-life
- Drugs that have undesirable long-term effects
- Drugs that require immediate effect
6
Q
What are the mechanisms of the two diffusion-controlled systems (Reservoir and matrix)?
A
Diffusion-controlled: The drug diffusion through the polymer network is the rate-limiting step.
Reservoir - The membrane controls the release rate. The drug reservoir is in the middle and the membrane surrounds it. Ex. Ocusert
Matrix - The drug and matrix are mixed together. The drug slowly diffuses out of the matrix. The drug in the middle takes the longest to diffuse out.
7
Q
What is the mechanism of dissolution-controlled systems?
A
Dissolution systems are either encapsulated with a polymer membrane or are a drug+polymer matrix. The drug is dissolved over time.
You can use the Hixson-Crowell cube-root law to find the cube-root dissolution rate constant
8
Q
What is the mechanism of erosion-controlled systems?
A
The initial release phase is controlled by the diffusion of drug molecules that are on the surface or have access to the surface via pores in the microsphere matrix.
The sustained-release phase is determined by the erosion of the polymer. As the polymer erodes, the entrapped drug molecules are released.
9
Q
What is the mechanism of osmotic systems?
A
Osmotic systems have a film coating that is permeable for water, but not permeable for the drug or excipients. It also is rigid enough that it resists the hydrostatic pressure & pushes out the drug. There are one and two chamber devices.
Ex. Concerta
10
Q
What is the mechanism of swelling systems?
A
As the length of the diffusion pathway is larger, the drug-conc gradient is decreased, which decreases the drug-release rate.
As the mesh size of the polymer network increases, the drug is better able to diffuse out of the polymer network, which increases the drug release rate.
11
Q
What are the differences between membrane-modulated, adhesive dispersion, and matrix dispersion diffusion systems?
A
Membrane-modulated: Reservoir, has 4 clear components (adhesive, rate-controlling membrane, reservoir, and backing membrane)
Adhesive dispersion: Reservoir, 3 clear components (rate-controlling adhesive, reservoir, backing membrane; This one is a little more like a matrix
Matrix dispersion: Matrix, 2 components (drug + adhesive layer, backing membrane)
12
Q
What is the Gliadel wafer?
A
It is a wafer that is placed in the cranium after the tumor gets resected. It displays erosion diffusion. There’s no need to remove it once it’s fully eroded.
13
Q
What is the Lupron depot?
A
It is an IM injection that is used against prostate cancer. The drug is released over a 1-4 month period. This displays erosion diffusion.
14
Q
What is Ocusert?
A
- Reservoir drug release system
- The device sits in the eye and as the drug slowly saturates the membrane, it releases at a very constant rate.
- Poly(ethylene-co-vinyl acetate)
15
Q
What are Tetracycline Periodontal Fibers?
A
It’s a reservoir release system with a cap at either end of the cylinder.
- Cellulose membrane
16
Q
What is Norplant?
A
Non-Erodible subdermal implant that is a reservoir with a constant release rate.
- Silicone capsules containing Levonorgestrel.
17
Q
What are NicoDerm patches?
A
Reservoir release system with a rate controlling membrane, occulsive backing, and adhesive layer
18
Q
What type of dissolution do Habitrol patches have?
A
Matrix release system
19
Q
What type of dissolution is Nexplanon/Implanon NXT?
A
Matrix release system
20
Q
What type of release is the Sustol extended-release injection?
A
Erosion release system
21
Q
What are biologics?
A
Medications derived from or produced by living organisms.
Ex. Recombinant proteins, peptides, blood factors, vaccines, etc.
22
Q
What % of the Top 200 drugs were biologics in 2018?
A
37% of top 200 drugs were biologics.
There are more than 100 biologics on the market. There has been a dramatic increase of importance.
23
Q
What is the most important type of biologics? What are some important features?
A
Monoclonal antibodies (MAb)
- Large molecules (~150,000 daltons)
- Antigen binding site determines how the antibody complementarity determining region (CDR) interacts with the antigen
- Made of largely beta ribbons (not a-helix)
- There is a sugar part that is important for how the antibody will be processed in the body.
Ex. Humira, Herceptin, Avastin
24
Q
What are the 4 main types of MAb derivatives?
A
Chimeric monoclonal antibody - The variable region is mouse, the rest is human. Ex. Remicade
Humanized monoclonal antibody - Mostly human, a little bit mouse.
Human recombinant - Fully human. Ex. Humira, Simponi.
25
What are antibody drug conjugates (ADCs)?
These combine target specificity of the MAb with efficacy of the small molecule drug.
Components: Antibody, linker, and cytotoxic agent.
Ex. The Ab may recognize cancer cells, then the small molecule can kill the cell.
26
What is the structure of a cytokine like and what are some examples of cytokine biologics?
4-helix bundle with molecular weight of ~30,000 daltons.
Ex. Neulasta, Epogen
27
What is the structure of insulin? Why is long-acting insulin "long-acting"?
The A-chain and B-chain of amino acids are linked together by a disulfide bond. Around 5800 daltons (small). Insulin takes on an alpha helical structure and it readily associates to form dimers and hexamers.
Long-acting insulin is long acting because it forms microcrystals upon injection, slowly releasing the drug.
Ex. Insulin Lispro (Humalog), Insulin Aspart (Novolog), Insulin Glargine (Lantus).
28
What are two examples of peptide biologics and what is the peptide structure like? What is a peptide analog?
Victoza & Sandostatin
These are short proteins, usually less than 50 amino acids. These have some secondary structure, but no higher order of structure.
Peptidomimetic is a peptide analog. They look like peptide structure, but the side chains aren't from the 20 amino acids.
29
What are the 5 types of vaccines?
- Inactivated
- Conjugate
- Attenuated
- Toxoid
- Subunit
These can be much wider than other biologics.
30
What is CART-cell therapy?
CART-cell therapy are the first living drugs.
Immune cells (T cells) are removed from the patient's blood then are genetically programmed to fight cancer cells. Then, those cells are multiplied and infused back into the patient. These newly programmed CAR-T cells kill the cancer cells.
Ex. Kymriah
31
What are the 3 types of coronavirus vaccines in development?
Protein based - Spike protein is purified and injected, immune system produces the antibody
Viral vector - Spike protein gene is purified, adenoviral vector is injected, body produces spike protein, immune system produces the antibody
mRNA - mRNA that codes for spike protein is purified and injected, then the body produces that spike protein, and immune system produces the antibody
32
What type of vaccine is the exception for "dosing is usually parenteral"
Oral vaccines
33
What are the 4 common dosage forms for biologics?
Solutions for injection
Pens and Autoinjectors
Pre-filled syringes
Lyophilized solids for reconstitution
34
What are the three reasons that solution formations are popular?
- They are the simplest and least expensive to manufacture
- They are convenient for patients and hospital personnel since they don't require reconstitution
- They can be inspected visually prior to administration (to prevent errors)
35
What are the 4 main clinical concerns for biologics in solution?
- Efficacy
- Sterility
- Side effects (dose-limiting immune response)
- Pain on injection: Can be more or less pain based on volume administered, pH of 7.4, and tonicity, ionic strength
36
What are the 2 big formulation concerns for solutions in biologics?
Stability - Aggregation, chemical stability, shelf-life, and storage conditions
Manufacturability - Cost and manufacturing time
37
What is the issue with pH when formulating solutions in biologics?
The degradation rate depends on pH, and the most stable pH for the biologic is probably not going to be the best pH for injection. Additives make the stability worse, too.
38
Why is concentration an issue when formulating solutions in biologics?
Higher concentration of the drug results in greater aggregation. Especially with subcutaneous injections (require a smaller injection), that solution tends to be pretty concentrated, which increases the aggregation risk.
39
What are the 3 ways that proteins aggregate?
1. Chemical reaction
2. Colloidal interactions
3. Unfolding
It's hard to un-aggregate proteins after they aggregate because the aggregated structure is the most energetically favorable.
40
Why are excipients an issue when formulating solutions in biologics?
Excipients that bind to the protein can lead to denaturation. Excipients can be used to help stabilize the protein, and when they are preferentially excluded from the protein surface, they promote interactions with water and stabilize the native protein structure. However, when they bind to the protein, the structure is destabilized and that leads to denaturation.
41
What does Erythropoetin do? How is that related to PRCA?
- Treats anemia in renal disease
- Formation of anti-EPO antibodies reduces the drug effect and that of any naturally occurring EPO that remains.
- This can cause Pure Red Cell Aplasia (PRCA) which can result in sudden onset anemia and death.
- This increased incidence of PRCA has been associated with a change in the container closure, which shows how important the manufacturing of the biologic is.
42
What can we do if the solution formation doesn't work?
- Store at refrigerated temperature
- Freeze
- Freeze-dry (lyophilize) or spray-dry to create a dried powder for reconstitution
- Re-engineer the protein molecule
- Abandon the drug candidate
43
What are a few practical considerations for solution formulations of biologics?
- Store it at recommended temp
- Protect from light if needed
- Avoid shaking
- Examine the vial for particulates prior to administration
- Be aware of the potential for adverse immune responses
44
What are 6 advantages of pre-filled syringes, pens and autoinjectors?
- Easy to use and convenient for the patient
- Easier to transport than a vial or syringe (more fragile)
- Discrete
- Increased patient compliance/adherence
- Reduced risk of dosage error
- Reduced risk of product contamination
45
What are 4 disadvantages of pre-filled syringes, pens and autoinjectors?
- Higher cost than the vial + syringe
Can't mix two drugs in one pen
- There's drug waste due to priming (have to make sure there's no bubbles in the device)
- The greater the surface-to-volume ratio and presence of lubricants can induce aggregation of protein drugs
46
What are the 4 features of a pre-filled syringe, autoinjector, and pen?
- Drug solution
- Needle
- Piston or plunger
- Housing
47
What are 3 special concerns we need to have with pre-filled syringes, autoinjectors, and pens?
When compared to vials with solution for injection, these pre-filled devices have a higher surface-to-volume ratio, lower total volume, and syringe lubricants (oils).
Proteins (in the syringes) are surfactants that can unfold when they are expose to surfaces or interfaces. So these 3 things are important to keep in mind so that the solution in these pens/syringes don't aggregate.
48
What are some (4) advantages of lyophilized powders?
- Reduced rates of chemical and physical degradation
- Improved drug stability and longer shelf-life
- Refrigerated storage is not usually needed
- Can use lyophilized formulations in pre-filled syringes, pens, and autoinjectors (called "dual-chamber")
49
What are the 2 disadvantages of lyophilized powders?
- Must be reconstituted prior to injection which is less convenient than solutions
- More expensive and time consuming to manufacture
50
What is lyophilization?
- Called "freeze drying"
- This removes water from the solution by sublimation, which is when the solution goes from ice to vapor without ever becoming a liquid.
- It occurs at low temperature and low pressure
- This is gentler than other methods of removing water like boiling, so it's better for fragile drugs
We go from water -> freeze to ice -> vacuum to lower pressure -> sublimation to powder -> reconstitute to water
51
Can lyophilization cause instability?
Yes, it can promote aggregation
- The freezing and drying can promote disulfide bond scrambling
- Lyoprotectants and cryoprotectants are used to keep the protein structure
- The aggregated and/or degraded protein can be seen when it's reconstituted.
52
What's the main clinical consideration we need to have when dealing with lyophilized powders?
These meds were lyophilized because they are unstable as a liquid, so be cautious when reconstituting, storing and handling, and especially when administering. We can visually inspect these when we are administering to look for aggregates.
53
What is the structure and physiology of the skin (from outermost to inner)?
Stratum corneum - Outermost barrier. Very important.
Living epidermis - Living cells w/o capillaries. This is the source of skin color and tanning.
Dermis - Has capillaries. Drugs need to reach these capillaries in order to achieve systemic action. This layer contains pain, thermal, and tactile sensors.
Subcutaneous fatty tissue (+ subq vasculature)
Hair follicles and sweat glands - This is the secondary route of absorption that bypasses the stratum corneum.
54
What's the structure of the stratum corneum and why is it the most important barrier to transdermal drug delivery?
Structure: The dead cells act as "bricks" and the lipid layers act as "mortar."
This is the outermost barrier and it's not very permeable. The dead cells are impermeable, meaning permeation only occurs by partitioning through the lipid material.
55
What are the functions of the skin (6)?
- Containment: The skin contains everything in our body.
- Microbial barrier: pH of the skin is 5, which inhibits the growth of bacteria. Also, sebum (sweat) helps prevent bacteria getting through the skin, too.
- Chemical barrier: This is really important for drug delivery. The lack of permeability of the stratum corneum is much greater than the other barrier membranes in the body.
- Radiation barrier: UV ray exposure stimulates melanin, which absorbs UV rays.
- Electrical barrier: Skin impedes the flow of electrical current. We have to use salt solutions to overcome this when taking EKGs and stuff.
- Thermal barrier & body temp regulation: The skin maintains the 98.6° F tamp by dilating/contracting blood vessels or sweating.
56
Why do we use topical/transdermal route of administration?
Topical - For local effects (ex. on stratum corneum), for effects in deep tissues, also drug may act on the skin's glands
Transdermal - Systemic drug delivery (ex. Xulane patch)
57
What are the common platforms of topical systems? (5 main types)
Ointments
- Hydrocarbon bases (ex. petrolatum, polyethylene dissolved in mineral oil)
- Silicone bases (has polydimethylsiloxane oil)
- Absorption bases: Ointment containing W/O emulsifiers
- Water soluble bases (ex. polyethylene glycol ointment)
Pastes: Ointments into which a high conc. of insoluble particulate solids are added.
Creams: O/W or W/O emulsion
Gels: Hydrogels. Liquid phase trapped in a matrix of polymers.
Rigid Foams: Air or other gas emulsified into a liquid phase.
58
What drugs are suitable for transdermal delivery?
Drugs that have a short systemic half-life and/or undergo extensive first-pass metabolism, requiring frequent dosing.
59
What factors affect drug permeability through the skin?
- Hydration (more hydrated, greater drug permeability)
- Solubility of the drug in stratum corneum
- Excipients (solvents, surfactants)
- pH (affects drug ionization status)
Transdermal delivery is good for drugs with high skin permeability and a low dose requirement.
60
What are the black box warnings for Xulane patches?
150mcg/day norelgestromin and 35mcg/day ethinyl estradiol
- Matrix-type system
Warnings:
- Cardiovascular risk associated with smoking
- Risk of venous thromboembolism
- Transdermal PK profile of ethinyl estradiol is different than oral.
61
What are some potential methods to improve transdermal drug delivery?
- Ionic surfactants: Disorder the lipid layer of stratum corneum to swell and/or leach out some of the structural components, thus reducing the diffusional resistance.
- Ascorbate, dithiothreitol: Reducing agents. These can disrupt the disulfide bonds of proteins in keratinized cells.
- Azone: Nonpolar, oily liquid. These fluidize the intracellular lipid lamella region of stratum corneum.
- Dimethyl sulfoxide (DMSO): Dipolar solvent. This enters the aqueous region of stratum corneum and interacts with the lipid polar heads to expand hydrophilic region between the polar heads.
62
What are potential mistakes patients may make with transdermal patches?
- Preparation (removal of patch, removal of protective foil, alternation of the patch)
- Removal
- Application
- Monitoring (influence of heat, patch displacement)
- Storage and disposal
63
What are the purposes (3) and mechanisms (4) of mucoadhesion?
Mucoadhesion - The state in which a material and the mucus are held together for extended periods of time by interfacial forces. This lengthens the residence time for the dosage form on the mucosal surface.
Purposes
- Controlled release systems
- Enhances absorption of poorly absorbed drug molecules
- It immobilizes the dosage form at the desired site of action
Mechanisms
- Electrostatic interaction
- Hydrogen bonding
- Covalent bonding
- Physical interpenetration
64
What are some properties of mucus that are relevant to mucoadhesion? (secreted by, made of, target for, functions, etc.)
- Mucus is secreted by goblet cells or specialized glands (ex. salivary glands in the oral cavity)
- Most made of water, mucins (glycoproteins), lipids, and inorganic salts
- This is a diffusion barrier for drugs
- Mucus is a target for mucoadhesion
- There are many different layers of mucosa and they all vary in concentration of mucins, and thickness
Functions
- Coats nearly all entry points into the human body that's not covered by skin
- Protects the underlying epithelial tissues (ex. stomach)
- Keeps the mucosal membrane moist, so it acts as lubricant
65
What structures within a mucoadhesive polymer determine the functions/interactions with the mucus glycoproteins? What type of interactions are there? (4)
- If -OH groups, then it does hydrogen bonding
- Only cationic groups can do electrostatic interactions with the mucin (sialic acid is neg)
- Polymers can entangle due to longer structure
- A thiolated polymer can interact with the mucus glycoproteins by forming disulfide bonds
66
What are some drug properties that are desired for mucosal delivery?
Oral mucosa
- Lipophilic
- Small molecular weight drugs
- Maybe hydrophilic macromolecular weight drugs like peptides, oligonucleotides, or polysaccharides, but these would likely require absorption enhancers
67
What's the difference between sublingual and buccal?
Sublingual - Under side of tongue and on the floor of the mouth; Suitable for frequent dosing and short-term delivery; Ex. nitroglycerin sublingual tablet (acute relief)
Buccal - On the cheeks; Gingiva (gum) & Buccal mucosa (lip and cheek lining); Relatively thick & less permeable than sublingual, leading to slower absorption & onset than SL; Less influenced by saliva
68
What's the proper way of applying a buccal drug delivery system?
Oravig tablet:
1. Place the flat side of the tablet onto your dry fingertip
2. Push the round side of the tablet against your upper gum
3. Push the tablet up as high as it will go on the gum. The flat side will be facing the lip
4. Hold the tablet in place by applying slight pressure on the outside of the upper lip for 30 seconds
5. Leave the tablet in place until it dissolves
69
What nasal sections are important for systemic drug absorption and for the potential for drug delivery to the CNS?
Olfactory region - This is were the smell gets to the brain; Small surface area; Provides a direct connection between the CNS and the atmosphere; Has small glands that produce secretions acting as a solvent for odorous substances.
Respiratory region - This is the main site for systemic drug delivery; It's epithelium is covered with mucus that provides humidification and warming of inhaled air and physical/enzymatic protection against foreign compounds.
70
What are the requirements (5) and challenges (3) of ocular drug delivery?
Requirements
- Need to be clear as to not interfere with vision
- Good corneal penetration
- Prolonged contact time with the corneal epithelium
- Simple to use
- Non-irritating and comfortable for the eye
Challenges
- Loss due to dilution in the tear film, fluid spillage, and drainage
- Short residence time due to rapid turnover of tears and aqueous humor
- Not much flexibility in the formulation adjustments due to pH, osmolarity, and solubility
71
How can you reduce drainage in eye drops?
Use viscosity-enhancers like polyvinyl alcohol, methyl cellulose, Timoptix-XE gel, DuraSite, etc.
72
What are some features of cell intraocular implants?
These are loaded with human retinal pigment epithelium cells that are transfected with the CNTF gene to produce CNTF in the eye, which protects the neural cells and retards retinal degeneration. The cells are living inside of the implant.
These implants have to be able to let O2 in, but also let CO2 and the correct amount of drug out.
73
What are some features of the Port Delivery System? What are the 4 components?
- Permanent and refillable
- Surgically inserted through a small incision in the sclera and pars plana
There are 4 components:
- Extrascleral flange (secures device into the eye)
- Self-sealing septum (introduce the drug)
- Body (drug reservoir)
- Porous metal release control element (drug release)
74
What are 3 advantages and 4 disadvantages of mucosal drug delivery?
Advantages
- Avoid the first-pass effect
- It's non-invasive
- There's relative ease and convenience
Disadvantages
- There's a small area of absorption
- You have to be aware of the taste
- The delivery is limited by the molecular weight of the drug
- There can be local tissue irritation
75
What are 3 advantages and 2 disadvantages of oral mucosal delivery?
Advantages
- Avoid first-pass effect
- Rapid absorption & onset of the drug
- It's easy to remove if therapy needs to be discontinued
Disadvantages
- Small surface area (meaning it's not suitable for low potency drugs)
- Limited by taste
76
What is Actiq?
Fentanyl citrate. It's a lozenge on a stick.
- Administered by rotating the stick and dissolving it in the oral mucosal tissue.
Actiq and FENTORA can not be substituted without a dose conversion due to the difference in pharmacokinetic profiles.
77
What are 3 advantages and 4 disadvantages for nasal mucosal delivery?
Advantages
- Avoidance of hepatic first-pass elimination and destruction in the GI tract
- Rapid absorption of drug molecules across the nasal membrane
- Relatively easy and convenient
Disadvantages
- Possible tissue irritation
- Rapid removal of the drug from the site of absorption (mucociliary clearance)
- Pathologic conditions like colds or allergies can alter the nasal bioavailability
- There's a limited area of drug absorption
78
What are 3 advantages and 1 disadvantage to vaginal drug delivery?
Advantages
- Rich blood supply
- High permeability to certain drugs
- Avoids hepatic first-pass
Disadvantage
- Hormone-dependent changes (ex. pH may change)
