Dosage Forms Exam 3 Flashcards
What are the two types of controlled drug delivery?
Temporal (time of release)
Spatial (location of drug)
What are the types of drug release control mechanisms?
Diffusion-controlled Dissolution-controlled Erosion-controlled Osmotic systems Swelling systems
What are the types of diffusion-controlled systems?
Reservoir Devices
Matrix Devices
What controls release rate in a reservoir system?
Membrane surrounding the rug reservoir
What controls release rate in a matrix system?
The matrix that the drug is mixed in with
What type of delivery system is Ocusert?
Drug reservoir (has a membrane around reservoir)
What is the purpose of the annular ring in Ocusert?
It makes it visible (opaque)
What type of polymer is Ocusert made of?
EVA
What type of release mechanism is used in tetracycline periodontal fiber?
Drug Reservoir
What is the polymer in tetracycline periodontal fibers?
Cellulose acetate
What is Norplant?
Subdermal implant contraceptive (levonorgestrel)
What polymer is used for Norplant?
Silicone
What is the formula for Drug release from a diffusion-reservoir system?
M = DSKCst/h
What variables are changing in the diffusion system reservoir formula?
M = kt
What does the graph for a diffusion-reservoir release look like?
A diagonal line
What does the graph for the rate of release of a diffusion reservoir system look like?
Straight line (constant release rate over time)
What does M mean?
Amount of drug passing through membrane
What does D mean?
Diffusion coefficient
What does S mean?
Cross section area
What does K mean?
Partition coefficient of the membrane
What does Cs mean?
drug concentration in reservoir (stays constant b/c drug moves closer to fill the space after some drug diffuses out)
What does h mean?
Thickness of the membrane
What does drug release depend on in a diffusion-matrix system?
The device geometry
What is the simplified equation for drug release from a diffusion matrix?
M = kt^(1/2)
What is Cd?
Total drug concentration (dispersed + dissolved drug)
What is Cs in a diffusion-matrix system?
Solubility of the drug in the polymer
What is the shape of the M curve in a diffusion-matrix?
It is a hyperbole (releases a lot at first, and then fairly small amount)
What is the release rate of the diffusion-matrix?
Releases rate is high at first and then decreases with time
What type of controlled release does Nexplanon/Implanon NXT have?
matrix/coating
How long can Nexplanon/Implanon be used for?
Up to 3 years
What polymer is used in Nexplanon/Implanon NXT?
Ethylene vinyl acetate
What are the two types of dissolution system?
Encapsulated (similar to reservoir diffusion system) and Matrix
What is the formula for a dissolution-matrix drug release?
M = DS(deltaC)t/h
What is Delta C?
Cs-C
What variable changes in the Dissolution-Matrix equation (besides t)
S–surface area gets smaller as more of the drug dissolves
What is the shape of the dissolution-Matrix drug curve?
It starts out as a straight line (constant release) and then tapers down to a steady concentration
What are osmotic delivery systems?
They have a film coating that is permeable to water and not drugs, and resistant to hydrostatic pressure
How do osmotic delivery systems work?
Water fills the membrane and increases hydrostatic pressure, which pushes the drug out of orifices that it is permeable through
What is an example of an osmotic delivery drug?
Concerta (Methylphenidate)
What is the formula for drug release from osmotic systems?
M = (kS/h)(delta pi) Cst
What is delta pi?
The osmotic pressure difference
What is k?
Membrane permeability to water
What is added to the equation if the drug also has a membrane that releases drug through simple diffusion?
DSKCst/h
like a Reservoir diffusion system
What is the equation of dM/dt for diffusion matrix systems?
dM/dt = (1/2)k(1/t^1/2)
What is the shape of a graph for an osmotic system?
Diagonal line
What is the shape of the graph of release rate for an osmotic system?
Straight line
How do erosion-controlled systems work?
The initial release is very slow, from the surface of the drug/pores in the matrix–like diffusion controlled system. The sustained-release depends on the erosion of the polymer–as it degrades, it begins to behave like a dissolution controlled system
What are some erosion-controlled systems?
Zoladex Lupron Nutropin Gliadel Wafer Sustol
What type of dosage forms to erosion-controlled systems come in?
Gel, injections (particles), wafers
What is an indication for gliadel wafer?
Put after a tumor is removed to prevent its further growth
What is BCNU?
Active ingriedient in Gliadel wafer–it has a short half life, but is slowly released to overcome though (manages residual tumor growth)
What polyanhydrides are found in the gliadel wafer?
PCPP-SA or PCPP
Which polyanhydride (PCPP or PCPP-SA) degrades faster in water?
PCPP-SA (higher ratios of SA degrade the fastest)
Which is more hydrophilic–PSPP or SA?
SA
Why is systemic administration of gliadel wafer not good?
It causes bone marrow suppression and pulmonary fibrosis
Do gliadal wafers exhibit temporal or spatial control?
Both
What is Lupron Depot used to treat?
Prostate cancer
What polymer is in Lupron Depot?
Poly(lactic-co-glycolic acid)
How long is lupron depot released over?
1-4 months
What is PLGA?
Poly(lactic-co-glycolic acids)
What are the two parts of PLGA?
Glycolic acid and lactic acid
Does a greater ratio of lactic acid or glycolic acid have faster degradation?
Glycolide
If two drugs have the same ratio of lactide to glycolide, does a more or less viscuous drug last longer?
More viscuous
If two drugs have the same ratio of lactide to glycolide will a higher or lower MW degrade faster?
lower
What are the properties of the longest acting poly(lactic-co-glycolic acid)s?
They have a high lactide to glycolide ratio and a high molecular weight/viscosity
If a polymer has a low Tg is it going to be solid or liquid at room temperature?
Liquid (and injectable)
What is an important property for Sustol Extended Release injection
Low Tg (liquid + injectable at room temperature)
How does a swelling-controlled system work?
The polymer swells, increasing the length of diffusion pathways which decreases drug concentration gradients and decreases the drug release rate
How could sewlling-controlled systems increase drug release rate?
Mesh size of polymer network increases, which increases drug diffusivities in the polymer network, which increases drug release rate
How can hydrolysis be used in controlled drug delivery systems?
A drug is covalently bound to a matrix former via hydrolyzable bondings–the rate of hydrolysis determines the rate of drug release through the polymer
What features decrease the side effects of inhaled fluticasone?
- Low bioavailability (first-pass effect)
- Binds plasma protein (99%_
What age can take inhaled fluticasone?
1yo
What is the absolute bioavailability of inhaled fluticasone
~10%
What is the alveoli surface area?
50-100 m^2
Does inhaled insulin powder have a faster or slower onset than subq?
Faster
What is the first inhaled insulin powder?
Exubera
Is Exubera still being sold?
No
What are the 4 regions of the respiratory tract?
Extrathoracic region (head and neck)
Upper bronchial region (Trachea and bronchi)
Lower bronchial region (bronchioles)
Alveolar region (nonciliated thoracic airways and airspaces)
What is inertial transport?
Driven by momentum
Increases with particle velocity, diameter, and density
Extrathoracic region of lungs
What is diffusional transport?
- Ultrafine particles
- Lung periphery (alveoli)
- Tend to be exhaled without depositing
What is gravitational transport?
(sedimentation)
Particles >0.1 micrometer
Increase with diameter and density
Bronchial region/alveolar region
What are the three particle deposition mechanisms?
Inertial transport
Gravitational transport
Diffusional Transport
What factors determine particle sedimentation velocity?
- Density of particles
- Acceleration from gravity
- Volume diameters
- Slip correction factors
- Shape factors (fibers, elongated particles, needles, spheres)
- Viscosity of fluid (air)
What is aerodynamic diameter?
Geometric diameter of a particle with a unit mass density (1g/cm3) that would settle at the same velocity as the particle of interest
What is the formula for aerodynaimic diameter (Dae)
(Pp)^0.5D
Where will particles 1-5 micrometers deposit?
Lower airways
Where will particles >5 micrometers deposit?
Upper airways (from inertial impaction)
Where will particles with aerodynamic sizes <1 micrometer deposit?
They may be exhaled
What are challenges in pulmonary drug delivery in the upper airways?
Filtering mechanisms from the nasal cavity trap and eliminate particles
What reflexes in the upper airways pose challenges to pulmonary drug delivery?
Sneezing and coughing
What poses challenges in conducting airways (lung airways) to pulmonary drug delivery?
Mucociliary escalator
IgA (antibody produced by plasma cells in the submucosa)
What challenges are there in drug delivery in alveoli?
Alveolar macrophages Immunologic mechanisms (T&B lymphocytes, IgG)
What are the two types of aerosols?
Liquid droplets (MDI or nebulizer) Dry particles (DPI)
pMDI stands for?
Propellant-driven metered-dose inhaler
pmDI: A ___ volume of ____ drug dispersion is isolated in a metering chamber and released through a ____. As the released drug dispersion begins to _____ with the atmospheric pressure, it is _____
small volume; pressurized drug dispersion; spray orifice
equilibriate; propeled from container, forming spray of droplets
What is needed for pMDI?
Good inhalation technique (coordination, holding breath, inspiring at correct rate)
What are the 5 biggest errors in MDI use?
Hand-breath discoordination Breath hold too short Inspiratory flow too rapid Inadequate shaking of inhaler Abrupt stop of inhalation
What is used for children to reduce the error in pMDI use?
SPACER
How much of the drug from pMDI is deposited in the oropharynx?
Up to 80%
pMDI is only suitable for ____ medications
low-dose
___ compatibility issues with pMDI propellant?
Drug/solvent
What is a benefit of pMDI?
Less expensive
What are the 3 propellants in pMDI?
Chlorofluorocarbon (banned in US)
Hydrofluoroalkane (HFA)
Alkane
What is the coselvent used in pMDI?
Ethanol
What surfactants are used in pMDI?
Sorbitan trioleate, oleic acid, lecithin
Nebulizer: Generate droplets of a drug dispersion using energy from ___ or ____
compressed air, piezolelectric ceramics
When is nebulizer delivered to patients’ lungs?
On inspiratory flow
Who are nebulizers used for?
Young and elderly patients; emergency treatment
What are two examples of nebulizer solutions?
Tobramycin inhalation Dornase Alfa (DNase)
What are the 4 drawbacks of jet nebulizers?
- more time consuming
- Require hygienic maintenance of equipment
- Bulky
- Low drug delivery efficiency (5-20% to lungs)
Why do jet nebulizers have low drug delivery?
High proportion of drug is stuck in device
What are the 3 benefits of new nebulizers?
Smaller
Higher delivery efficiency
Lower residues
What are the new types of new nebulizers?
Vibration mesh nebulizer
Soft mist inhaler (respimat)
How is aerosol powder created in DPI?
Airflow–carries the small drug particles to the lungs
What determines the amount deposited in the lung?
formulation, device, and airflow
When is DPI used?
Asthma, COPD, lung infections, insulin
What is passive DPI?
Breath-activated device (aerosol powder generated by inspiratory airflow)
What is the issue with passive DPIs?
They have variable performance among patients
What are active DPIs?
Power-assisted–mechanical or electrical external energy generates powder aerosols
What are the differences b/w single unit-dose and multiple unit-dose DPIs?
Single Unit: Smaller inhaler, simpler design
Multiple unit: Convenient for frequent use, larger inhaler, more complex design
What are the two types of multi-unit dose inhalers?
Multi-unit dose (where each dose is divided)
Multi-dose reservoir (where doses are all combined, but only one is inspired at a time)
What type of DPI is Handihaler?
Single-unit dose, capsule-based and reloadable
What type of DPI is Nexthaler?
Multiple unit-dose
What is the purpose of mechanical milling?
Break coarse particles
What form of milling is usually used to produce inhalable drug particles
Jet miling
What are the properties of jet-milled particles?
Cohesive
High surface energy
High electrostatic charge
What are the negatives of jet-milled particles?
Poor flowability
Poor aerosolization
What is spray drying?
Drug is dissolved in a solvent, atomized into small droplets, and dried by hot airflow through solvent evaporation
What influences particle deposition?
Geometric diameter, density, morphology, surface energy, electrostatic charge, hygroscopicity
What is the purpose of having carrier-based DPI?
Small particles can flow better if they are attached to something bigger–carriers are filler
What properties of carriers influence Aerosol performance?
Particle geometric diameter, morphology, surface energy, electrostatic charge, drug to carrier ratio, additives
What are the advantages of large porous particles?
Easier flow and aerosolization, less aggregation, less prone to macrophage uptake/removal
What is an Anderson Cascade Impactor?
A way to find performance of Aerosol characterization in vitro–measure mass that is left in each stage
What are the 3 in vitro parameters in aerosol characterization?
Fine particle dose
Fine particle fraction
Mass median aerodynamic diameter
What is Fine particle dose?
The mass of fine drug particles (aerodynamic diameter <5) collected from the in vitro test
What is fine particle fraction?
FPD/mass of total drug collected
What are the advantages of passive inhalation/exposure chamber for in vivo characterization?
size of aerosols easily controlled, easy operations
What are the disadvantages of passive inhalation/exposure chamber for in vivo characterization?
Actual delievered dose is difficult to determine
Very small proportion of dose delivered to lung
What is an exposure chamber?
Animal in a tub with the drug pumped in (nebulizer)–it just inhales from the air
What are the two types of active delivery?
Liquid instillation or powder insufflator
What are the advantages of active delivery?
Delivered dose can be determined
What are the disadvantages of active delivery?
- Need complex surgery
- Distribution of drug in the lung is poor for liquid instillation
- Aerosol particle sizes from insufflation could vary depending on formulation
What are the two main reasons for making a prodrug?
Improving the formulation and administration (more solubility or stable)
Enhancing permeability/absorption
What promoiety was attached to phenytoin?
A phosphate
What solvent was used for phenytoin?
Alcohol with water
What solvent is used for fosphenytoin?
water
What enzyme cleaved fosphenytoin to active phenytoin?
Phosphatase (found throughout the body)
Why does fosphenytoin have to be stored in the fridge
Prevents degradation to phenytoin
How is fosphenytoin dose expressed?
As phenytoin equivalent
What are the pros of fosphenytoin?
It is in water–so it can be injected more quickly, doesn’t precipitate, and is closer to the ideal pH
What is used to enhance the permeability of latanoprost?
Two methyl groups attached to the OH
What cleaves the promoeiety off of latanoprost?
Esterase
What drug is latanoprost a prodrug of?
Prostaglandin
Why does prostaglandin need a prodrug?
To increase its permeability through the cornea of the eye
What is a soft drug?
An active drug that is administered with a promoiety that will inactivate it–for rapid metabolism of the active drug
What percentage of drugs are considered prodrugs?
10%
What are biologics?
Medications derived from living organisms
5 examples of biologics
Proteins Peptides Blood factors Vaccines Cell-based therapies
Molecular weight of MAbs?
150,000 daltons
What are antibody drug conjugates?
Antibody is attached to a cytotoxic agent
What is the purpose of ADC?
It can deliver cytotoxic agent to a specific target (via antibody)
What is the molecular weight of a cytokine?
30,000 daltons
What are examples of cytokines (3)?
Interleukins
Interferons
Erythropoetins
What is the structure of a cytokine?
Alpha-helices (4-helix bundle)
What is the structure of insulin?
A and B chain linked by SS bonds
Alpha helical
Forms dimers, hexamers
How big is insulin?
5800 daltons
Lispro Insulin
Humalog, Lilly
Lispro insulin speed?
Fast acting
Insulin aspart
Novolog, Novo Nordisk
Insulin aspart speed
Fast acting
Insulin glargine speed
Long acting
Insulin glargine structure?
A21 mutated to Gly, two Arg added
Insulin glargine long-acting mechanism?
Microcrystals form because of the asparagine mutation, which causes slow release
How long are peptides?
Less than 50 amino acids
What is the structure of peptides?
No secondary structure
What is Telaprevir and what is it used for?
Peptidomimetic
Hep C
What is a peptidomimetic?
Peptide like structure, but with side chains that are different from amino acids
What dosage form to biologics come in usually?
Parenteral
What are the major dosage forms for biologics?
Solutions for injection
Pens/autoinjectors
Pre-filled syringes
Lyophilized solids for reconstitution
What are the perks of solution formulations?
Simple
Cheap
Convenient in hospitals (no reconstitution)
Inspected visually before administration (for aggregation)`
What are the clinical concerns associated with biologics in solution? (5)
Efficacy
Sterility
Side effects
pain on injection (want to keep it biologic pH)
What are the formulation concerns with biologics in solution?
Stability (aggregation, chemical stability, shelf-life, storage conditions)
Manufacturability (cost, manufacturing time)
What are formulation variables of biologics in solution?
Solution properties (pH, ionic strength, tonicity, drug concentration, volume, excipients)
Container, closure
Storage conditions
What is salmon calcitonin?
A peptide for osteoporosis
What determines the rate of degradation of sCT?
pH
What pH is sCT most stable at
3-4
Do additives increase or decrease the stability of sCT?
Decrease
What is beta lactoglobulin?
Milk protein (similar to mabs)
How does concentration influence formulation?
Higher concentration have higher aggregate content
Why is aggregation risk higher in MAb SC?
The volume has to be small, which makes the concentration high
What are the 3 ways that proteins aggregate?
Chemical reaction
Colloidal interaction
Unfolding
Does a colloidal interaction involve unfolding?
No
What is a chemical reaction for aggregation?
Disulfide bonds
How does unfolding cause aggregation?
Unfolding exposes the sticky spots, so proteins stick together in ways that normally wouldn’t be accessible
Are amyloid fibrils reversible?
No
Should you shake a protein solution?
NO
Why shouldn’t you shake a protein solution?
It causes aggregation!
Where is protein aggregation most likely to occur?
At the 3-phase boundary (air, solution, container)
Why does aggregation occur?
Proteins unfold to expose hydrophobic parts to container/air, which causes them to form dimers/aggregate
What should you do before injecting a protein-containing solution?
Examine it for aggregation
How does pH affect solution formulations?
It changes the stability of the components
Which is better for stabilization: preferential binding or preferential exclusion?
Preferential exclusion
Why is preferentially excluding excipients from the surface better?
They promote interactions with water and stabilize the native protein structure
What can happen if an excipient binds to the protein?
Denaturation
When can binding to proteins stabilize native structure?
When proteins bind to ligands
What is the clinical consequence that can occur with EPO administration?
Body creates anti-EPO antibodies, which causes Pure Red Cell Aplasia (PRCA)
What are the symptoms of PRCA?
sudden onset anemia, death
What has been associated with increased risk of PRCA?
A change in container closure
What are some options if a solution formulation doesn’t work?
Store it at refrigerated temp Freeze Freeze-dry or spray-dry for dried powder Re-engineer protein molecule Abandon drug candidate
What are advantages of pre-filled syringes, pens, and autoinjectors
Easy to use/convenient Easier to transport Discrete Increase patient compliance Reduce risk of dosage error Reduce risk of product contamination
What are some disadvantages of pre-filled syringes, pens, and autoinjectors?
Cost (higher than vial + syringe)
Can’t mix drugs
Drug waste due to priming
Greater surface-to-volume ratio, can induce aggregation of protein drugs
Is an insulin pen a dosage form or a medical device?
Medical device
What 4 features are usually found in pre-filled syringes, autoinjectors, or pens?
- Drug solution
- Needle
- Piston/plunger
- Housing
What are the concerns with pre-fiilled syringes/autoinjectors/pens compared to vials?
Higher surface-to-volume ratio
Lower total volume
Syringe lubricants, oil
Proteins are ___ and can unfold when exposed to ____
surfactants; surfaces
How do lubricants affect protein dosage forms?
They form oil droplets that create another hydrophobic surface interface for proteins to unfold around
Do formulation concerns for biologics in solution apply to pre-filled syringes, autoinjectors, and pens?
Yes! They still have a solution dosage form, just delivered in a different medical device
What are advantages of lyophilized powders?
Reduced rate of degradation
Improved stability/longer shelf-life
Not refrigerated
Used in pre-filled syringes, pens, and auto-injectors
What are disadvantages of lyophilized powder
Must be reconstituted prior to injection (less convenient)
More expensive and time-consuming to manufacture
How does lyophilization remove water?
Sublimation
Lyophilization occurs at __ temperature and ___ pressure
low; low
Lyophilization is ____ than other methods of removing water and better for ___ drugs
gentler; fragile
What is sublimation?
Changing a solid into a gas
What are the steps of lyophilization?
- Freeze protein solution (to ice phase)
- Use a vacuum to drop the pressure of the solid
- Under the vacuum, increase the temperature high enough to cause sublimation (produce water vapor from ice)
- Cap and seal the dry powder, back to water
Are lyophilized particles manufactured as a giant batch or in individual vials?
Individual vials
How does lyophilization cause instability?
- Freeze-concentration –> aggregation
- Disulfide bond scrambling accelerated by freezing and drying
- Protein structure perturbed
What excipients can prevent protein structure from being perturbed by lyophilization?
Lyoprotectants
Cryoprotectants
What form are biologics marketed in usually?
Lyophilized
When do you need to use caution in lyophilized biologics?
- Reconstituting
- Storing and handling
- Administering (inspect for particles)
When are lyophilized formulations used?
Biologics that are unstable in solution
