Dosage Forms Exam 3 Flashcards
1
Q
What are the two types of controlled drug delivery?
A
Temporal (time of release)
Spatial (location of drug)
2
Q
What are the types of drug release control mechanisms?
A
Diffusion-controlled Dissolution-controlled Erosion-controlled Osmotic systems Swelling systems
3
Q
What are the types of diffusion-controlled systems?
A
Reservoir Devices
Matrix Devices
4
Q
What controls release rate in a reservoir system?
A
Membrane surrounding the rug reservoir
5
Q
What controls release rate in a matrix system?
A
The matrix that the drug is mixed in with
6
Q
What type of delivery system is Ocusert?
A
Drug reservoir (has a membrane around reservoir)
7
Q
What is the purpose of the annular ring in Ocusert?
A
It makes it visible (opaque)
8
Q
What type of polymer is Ocusert made of?
A
EVA
9
Q
What type of release mechanism is used in tetracycline periodontal fiber?
A
Drug Reservoir
10
Q
What is the polymer in tetracycline periodontal fibers?
A
Cellulose acetate
11
Q
What is Norplant?
A
Subdermal implant contraceptive (levonorgestrel)
12
Q
What polymer is used for Norplant?
A
Silicone
13
Q
What is the formula for Drug release from a diffusion-reservoir system?
A
M = DSKCst/h
14
Q
What variables are changing in the diffusion system reservoir formula?
A
M = kt
15
Q
What does the graph for a diffusion-reservoir release look like?
A
A diagonal line
16
Q
What does the graph for the rate of release of a diffusion reservoir system look like?
A
Straight line (constant release rate over time)
17
Q
What does M mean?
A
Amount of drug passing through membrane
18
Q
What does D mean?
A
Diffusion coefficient
19
Q
What does S mean?
A
Cross section area
20
Q
What does K mean?
A
Partition coefficient of the membrane
21
Q
What does Cs mean?
A
drug concentration in reservoir (stays constant b/c drug moves closer to fill the space after some drug diffuses out)
22
Q
What does h mean?
A
Thickness of the membrane
23
Q
What does drug release depend on in a diffusion-matrix system?
A
The device geometry
24
Q
What is the simplified equation for drug release from a diffusion matrix?
A
M = kt^(1/2)
25
What is Cd?
Total drug concentration (dispersed + dissolved drug)
26
What is Cs in a diffusion-matrix system?
Solubility of the drug in the polymer
27
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)
28
What is the release rate of the diffusion-matrix?
Releases rate is high at first and then decreases with time
29
What type of controlled release does Nexplanon/Implanon NXT have?
matrix/coating
30
How long can Nexplanon/Implanon be used for?
Up to 3 years
31
What polymer is used in Nexplanon/Implanon NXT?
Ethylene vinyl acetate
32
What are the two types of dissolution system?
Encapsulated (similar to reservoir diffusion system) and Matrix
33
What is the formula for a dissolution-matrix drug release?
M = DS(deltaC)t/h
34
What is Delta C?
Cs-C
35
What variable changes in the Dissolution-Matrix equation (besides t)
S--surface area gets smaller as more of the drug dissolves
36
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
37
What are osmotic delivery systems?
They have a film coating that is permeable to water and not drugs, and resistant to hydrostatic pressure
38
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
39
What is an example of an osmotic delivery drug?
Concerta (Methylphenidate)
40
What is the formula for drug release from osmotic systems?
M = (kS/h)(delta pi) Cst
41
What is delta pi?
The osmotic pressure difference
42
What is k?
Membrane permeability to water
43
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
44
What is the equation of dM/dt for diffusion matrix systems?
dM/dt = (1/2)k(1/t^1/2)
45
What is the shape of a graph for an osmotic system?
Diagonal line
46
What is the shape of the graph of release rate for an osmotic system?
Straight line
47
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
48
What are some erosion-controlled systems?
```
Zoladex
Lupron
Nutropin
Gliadel Wafer
Sustol
```
49
What type of dosage forms to erosion-controlled systems come in?
Gel, injections (particles), wafers
50
What is an indication for gliadel wafer?
Put after a tumor is removed to prevent its further growth
51
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)
52
What polyanhydrides are found in the gliadel wafer?
PCPP-SA or PCPP
53
Which polyanhydride (PCPP or PCPP-SA) degrades faster in water?
PCPP-SA (higher ratios of SA degrade the fastest)
54
Which is more hydrophilic--PSPP or SA?
SA
55
Why is systemic administration of gliadel wafer not good?
It causes bone marrow suppression and pulmonary fibrosis
56
Do gliadal wafers exhibit temporal or spatial control?
Both
57
What is Lupron Depot used to treat?
Prostate cancer
58
What polymer is in Lupron Depot?
Poly(lactic-co-glycolic acid)
59
How long is lupron depot released over?
1-4 months
60
What is PLGA?
Poly(lactic-co-glycolic acids)
61
What are the two parts of PLGA?
Glycolic acid and lactic acid
62
Does a greater ratio of lactic acid or glycolic acid have faster degradation?
Glycolide
63
If two drugs have the same ratio of lactide to glycolide, does a more or less viscuous drug last longer?
More viscuous
64
If two drugs have the same ratio of lactide to glycolide will a higher or lower MW degrade faster?
lower
65
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
66
If a polymer has a low Tg is it going to be solid or liquid at room temperature?
Liquid (and injectable)
67
What is an important property for Sustol Extended Release injection
Low Tg (liquid + injectable at room temperature)
68
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
69
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
70
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
71
What features decrease the side effects of inhaled fluticasone?
- Low bioavailability (first-pass effect)
| - Binds plasma protein (99%_
72
What age can take inhaled fluticasone?
1yo
73
What is the absolute bioavailability of inhaled fluticasone
~10%
74
What is the alveoli surface area?
50-100 m^2
75
Does inhaled insulin powder have a faster or slower onset than subq?
Faster
76
What is the first inhaled insulin powder?
Exubera
77
Is Exubera still being sold?
No
78
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)
79
What is inertial transport?
Driven by momentum
Increases with particle velocity, diameter, and density
Extrathoracic region of lungs
80
What is diffusional transport?
- Ultrafine particles
- Lung periphery (alveoli)
- Tend to be exhaled without depositing
81
What is gravitational transport?
(sedimentation)
Particles >0.1 micrometer
Increase with diameter and density
Bronchial region/alveolar region
82
What are the three particle deposition mechanisms?
Inertial transport
Gravitational transport
Diffusional Transport
83
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)
84
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
85
What is the formula for aerodynaimic diameter (Dae)
(Pp)^0.5D
86
Where will particles 1-5 micrometers deposit?
Lower airways
87
Where will particles >5 micrometers deposit?
Upper airways (from inertial impaction)
88
Where will particles with aerodynamic sizes <1 micrometer deposit?
They may be exhaled
89
What are challenges in pulmonary drug delivery in the upper airways?
Filtering mechanisms from the nasal cavity trap and eliminate particles
90
What reflexes in the upper airways pose challenges to pulmonary drug delivery?
Sneezing and coughing
91
What poses challenges in conducting airways (lung airways) to pulmonary drug delivery?
Mucociliary escalator
| IgA (antibody produced by plasma cells in the submucosa)
92
What challenges are there in drug delivery in alveoli?
```
Alveolar macrophages
Immunologic mechanisms (T&B lymphocytes, IgG)
```
93
What are the two types of aerosols?
```
Liquid droplets (MDI or nebulizer)
Dry particles (DPI)
```
94
pMDI stands for?
Propellant-driven metered-dose inhaler
95
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
96
What is needed for pMDI?
Good inhalation technique (coordination, holding breath, inspiring at correct rate)
97
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
```
98
What is used for children to reduce the error in pMDI use?
SPACER
99
How much of the drug from pMDI is deposited in the oropharynx?
Up to 80%
100
pMDI is only suitable for ____ medications
low-dose
101
___ compatibility issues with pMDI propellant?
Drug/solvent
102
What is a benefit of pMDI?
Less expensive
103
What are the 3 propellants in pMDI?
Chlorofluorocarbon (banned in US)
Hydrofluoroalkane (HFA)
Alkane
104
What is the coselvent used in pMDI?
Ethanol
105
What surfactants are used in pMDI?
Sorbitan trioleate, oleic acid, lecithin
106
Nebulizer: Generate droplets of a drug dispersion using energy from ___ or ____
compressed air, piezolelectric ceramics
107
When is nebulizer delivered to patients' lungs?
On inspiratory flow
108
Who are nebulizers used for?
Young and elderly patients; emergency treatment
109
What are two examples of nebulizer solutions?
```
Tobramycin inhalation
Dornase Alfa (DNase)
```
110
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)
111
Why do jet nebulizers have low drug delivery?
High proportion of drug is stuck in device
112
What are the 3 benefits of new nebulizers?
Smaller
Higher delivery efficiency
Lower residues
113
What are the new types of new nebulizers?
Vibration mesh nebulizer
| Soft mist inhaler (respimat)
114
How is aerosol powder created in DPI?
Airflow--carries the small drug particles to the lungs
115
What determines the amount deposited in the lung?
formulation, device, and airflow
116
When is DPI used?
Asthma, COPD, lung infections, insulin
117
What is passive DPI?
Breath-activated device (aerosol powder generated by inspiratory airflow)
118
What is the issue with passive DPIs?
They have variable performance among patients
119
What are active DPIs?
Power-assisted--mechanical or electrical external energy generates powder aerosols
120
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
121
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)
122
What type of DPI is Handihaler?
Single-unit dose, capsule-based and reloadable
123
What type of DPI is Nexthaler?
Multiple unit-dose
124
What is the purpose of mechanical milling?
Break coarse particles
125
What form of milling is usually used to produce inhalable drug particles
Jet miling
126
What are the properties of jet-milled particles?
Cohesive
High surface energy
High electrostatic charge
127
What are the negatives of jet-milled particles?
Poor flowability
| Poor aerosolization
128
What is spray drying?
Drug is dissolved in a solvent, atomized into small droplets, and dried by hot airflow through solvent evaporation
129
What influences particle deposition?
Geometric diameter, density, morphology, surface energy, electrostatic charge, hygroscopicity
130
What is the purpose of having carrier-based DPI?
Small particles can flow better if they are attached to something bigger--carriers are filler
131
What properties of carriers influence Aerosol performance?
Particle geometric diameter, morphology, surface energy, electrostatic charge, drug to carrier ratio, additives
132
What are the advantages of large porous particles?
Easier flow and aerosolization, less aggregation, less prone to macrophage uptake/removal
133
What is an Anderson Cascade Impactor?
A way to find performance of Aerosol characterization in vitro--measure mass that is left in each stage
134
What are the 3 in vitro parameters in aerosol characterization?
Fine particle dose
Fine particle fraction
Mass median aerodynamic diameter
135
What is Fine particle dose?
The mass of fine drug particles (aerodynamic diameter <5) collected from the in vitro test
136
What is fine particle fraction?
FPD/mass of total drug collected
137
What are the advantages of passive inhalation/exposure chamber for in vivo characterization?
size of aerosols easily controlled, easy operations
138
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
139
What is an exposure chamber?
Animal in a tub with the drug pumped in (nebulizer)--it just inhales from the air
140
What are the two types of active delivery?
Liquid instillation or powder insufflator
141
What are the advantages of active delivery?
Delivered dose can be determined
142
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
143
What are the two main reasons for making a prodrug?
Improving the formulation and administration (more solubility or stable)
Enhancing permeability/absorption
144
What promoiety was attached to phenytoin?
A phosphate
145
What solvent was used for phenytoin?
Alcohol with water
146
What solvent is used for fosphenytoin?
water
147
What enzyme cleaved fosphenytoin to active phenytoin?
Phosphatase (found throughout the body)
148
Why does fosphenytoin have to be stored in the fridge
Prevents degradation to phenytoin
149
How is fosphenytoin dose expressed?
As phenytoin equivalent
150
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
151
What is used to enhance the permeability of latanoprost?
Two methyl groups attached to the OH
152
What cleaves the promoeiety off of latanoprost?
Esterase
153
What drug is latanoprost a prodrug of?
Prostaglandin
154
Why does prostaglandin need a prodrug?
To increase its permeability through the cornea of the eye
155
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
156
What percentage of drugs are considered prodrugs?
10%
157
What are biologics?
Medications derived from living organisms
158
5 examples of biologics
```
Proteins
Peptides
Blood factors
Vaccines
Cell-based therapies
```
159
Molecular weight of MAbs?
150,000 daltons
160
What are antibody drug conjugates?
Antibody is attached to a cytotoxic agent
161
What is the purpose of ADC?
It can deliver cytotoxic agent to a specific target (via antibody)
162
What is the molecular weight of a cytokine?
30,000 daltons
163
What are examples of cytokines (3)?
Interleukins
Interferons
Erythropoetins
164
What is the structure of a cytokine?
Alpha-helices (4-helix bundle)
165
What is the structure of insulin?
A and B chain linked by SS bonds
Alpha helical
Forms dimers, hexamers
166
How big is insulin?
5800 daltons
167
Lispro Insulin
Humalog, Lilly
168
Lispro insulin speed?
Fast acting
169
Insulin aspart
Novolog, Novo Nordisk
170
Insulin aspart speed
Fast acting
171
Insulin glargine speed
Long acting
172
Insulin glargine structure?
A21 mutated to Gly, two Arg added
173
Insulin glargine long-acting mechanism?
Microcrystals form because of the asparagine mutation, which causes slow release
174
How long are peptides?
Less than 50 amino acids
175
What is the structure of peptides?
No secondary structure
176
What is Telaprevir and what is it used for?
Peptidomimetic
| Hep C
177
What is a peptidomimetic?
Peptide like structure, but with side chains that are different from amino acids
178
What dosage form to biologics come in usually?
Parenteral
179
What are the major dosage forms for biologics?
Solutions for injection
Pens/autoinjectors
Pre-filled syringes
Lyophilized solids for reconstitution
180
What are the perks of solution formulations?
Simple
Cheap
Convenient in hospitals (no reconstitution)
Inspected visually before administration (for aggregation)`
181
What are the clinical concerns associated with biologics in solution? (5)
Efficacy
Sterility
Side effects
pain on injection (want to keep it biologic pH)
182
What are the formulation concerns with biologics in solution?
Stability (aggregation, chemical stability, shelf-life, storage conditions)
Manufacturability (cost, manufacturing time)
183
What are formulation variables of biologics in solution?
Solution properties (pH, ionic strength, tonicity, drug concentration, volume, excipients)
Container, closure
Storage conditions
184
What is salmon calcitonin?
A peptide for osteoporosis
185
What determines the rate of degradation of sCT?
pH
186
What pH is sCT most stable at
3-4
187
Do additives increase or decrease the stability of sCT?
Decrease
188
What is beta lactoglobulin?
Milk protein (similar to mabs)
189
How does concentration influence formulation?
Higher concentration have higher aggregate content
190
Why is aggregation risk higher in MAb SC?
The volume has to be small, which makes the concentration high
191
What are the 3 ways that proteins aggregate?
Chemical reaction
Colloidal interaction
Unfolding
192
Does a colloidal interaction involve unfolding?
No
193
What is a chemical reaction for aggregation?
Disulfide bonds
194
How does unfolding cause aggregation?
Unfolding exposes the sticky spots, so proteins stick together in ways that normally wouldn't be accessible
195
Are amyloid fibrils reversible?
No
196
Should you shake a protein solution?
NO
197
Why shouldn't you shake a protein solution?
It causes aggregation!
198
Where is protein aggregation most likely to occur?
At the 3-phase boundary (air, solution, container)
199
Why does aggregation occur?
Proteins unfold to expose hydrophobic parts to container/air, which causes them to form dimers/aggregate
200
What should you do before injecting a protein-containing solution?
Examine it for aggregation
201
How does pH affect solution formulations?
It changes the stability of the components
202
Which is better for stabilization: preferential binding or preferential exclusion?
Preferential exclusion
203
Why is preferentially excluding excipients from the surface better?
They promote interactions with water and stabilize the native protein structure
204
What can happen if an excipient binds to the protein?
Denaturation
205
When can binding to proteins stabilize native structure?
When proteins bind to ligands
206
What is the clinical consequence that can occur with EPO administration?
Body creates anti-EPO antibodies, which causes Pure Red Cell Aplasia (PRCA)
207
What are the symptoms of PRCA?
sudden onset anemia, death
208
What has been associated with increased risk of PRCA?
A change in container closure
209
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
```
210
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
```
211
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
212
Is an insulin pen a dosage form or a medical device?
Medical device
213
What 4 features are usually found in pre-filled syringes, autoinjectors, or pens?
- Drug solution
- Needle
- Piston/plunger
- Housing
214
What are the concerns with pre-fiilled syringes/autoinjectors/pens compared to vials?
Higher surface-to-volume ratio
Lower total volume
Syringe lubricants, oil
215
Proteins are ___ and can unfold when exposed to ____
surfactants; surfaces
216
How do lubricants affect protein dosage forms?
They form oil droplets that create another hydrophobic surface interface for proteins to unfold around
217
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
218
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
219
What are disadvantages of lyophilized powder
Must be reconstituted prior to injection (less convenient)
| More expensive and time-consuming to manufacture
220
How does lyophilization remove water?
Sublimation
221
Lyophilization occurs at __ temperature and ___ pressure
low; low
222
Lyophilization is ____ than other methods of removing water and better for ___ drugs
gentler; fragile
223
What is sublimation?
Changing a solid into a gas
224
What are the steps of lyophilization?
1. Freeze protein solution (to ice phase)
2. Use a vacuum to drop the pressure of the solid
3. Under the vacuum, increase the temperature high enough to cause sublimation (produce water vapor from ice)
4. Cap and seal the dry powder, back to water
225
Are lyophilized particles manufactured as a giant batch or in individual vials?
Individual vials
226
How does lyophilization cause instability?
- Freeze-concentration --> aggregation
- Disulfide bond scrambling accelerated by freezing and drying
- Protein structure perturbed
227
What excipients can prevent protein structure from being perturbed by lyophilization?
Lyoprotectants
| Cryoprotectants
228
What form are biologics marketed in usually?
Lyophilized
229
When do you need to use caution in lyophilized biologics?
- Reconstituting
- Storing and handling
- Administering (inspect for particles)
230
When are lyophilized formulations used?
Biologics that are unstable in solution
