1
Q
Some drugs do not need comparative bioavailability testing. Which types of drugs are these?
A
Drugs injected directly into the blood stream
Comparative bioavailability studies measure the level fo a medicinal ingredient in the blood of a healthy human volunteer
2
Q
Do the quality standards for brand name drugs and generic drugs differ?
A
No, the quality standards are the same
3
Q
The ingredients, manufacturing processes and facilities for all drugs must meet:
A
The federal guidelines of Good Manufacturing Practices
4
Q
Drug manufacturers must perform a series of tests both during and after production to show that:
A
Every drug batch made meets the requirements for that product
5
Q
Défine pharmaceutical equivalence
A
Two drug products that have the same active ingredient, dosage form, strength, route of administartion and condtions of use
6
Q
Define bioequivalence
A
The term used to describe substantially similar rate and extent of absorption of the active ingredient
7
Q
Bioequialence verifies that the active ingredient in a generic drug will be absorbed into the body to the same____ and ____ as its corresponding reference product
A
- Extent
- Rate
8
Q
When 2 drugs are deemed bioequivalent, they are expected to have the same profile for ____ and ____ When administered under the conditions listed in the product labeling
A
- Safety
- Efficacy
9
Q
Define therapeutic equivalence
A
A generic drug product that contains the same active ingredient in the same dose in the same dosage form, and demonstrates bioequivalence
It may be substituted for the innovator product as permitted by provincial and territorial formularies
10
Q
Bioequivalent data provides an estimte of:
A
- The fraction of the drug absorbed
- The rate of absorption
- Drug’s distribution and elimination
11
Q
Why may bioavailability studies be required for new formulations?
A
If there is a change in inactive ingredient of a drug product already approve, to ensure that the change in ingredient will not significantly affect the performance of the drug in patients
12
Q
Define absolute bioavailability
A
The fraction of the administered dose that reaches the systemic circulation relative to an IV dose
13
Q
Define relative bioavailability
A
The fraction of the dose of a test product that reaches the systemic circulation relative to a non-i.v reference product
14
Q
How do we determine absolute bioavailability?
A
By measuring the concentration of the therapeutic ingredient and/or its therapeutic metabolite(s), in blood, as a function of time
15
Q
What is the therapeutic index?
A
- The relationship between desired and undesired effects of a drug
- The ratio between a drug’s median toxic dose and its median effective dose
16
Q
Define the median toxic dose
A
Toxic effect in 50% of the people tested
17
Q
Define the median effective dose
A
Desired effective efect in 50% of the people tested
18
Q
Bioavailability data are used to determine:
A
- The amount of drugs absorbed
- The rate at which the drug was absorbed
- The duration of the drug,s presence in the bioloic fluid or tissue correlated to the patient’s response
- The relationship between drug blood levels and clinical efficacy and toxicity
- To compare different dosage forms of a drug
19
Q
What is the deciding factor for whether or not a drug candidate is selected for further development?
A
Bioavailability
It should be investigated early in drug development and used throughout development
20
Q
The bioavailability of a drug depends on:
A
- Physicochemical properties of the drug substance
- Route of administration
- Non-medicinal ingredients
- Manufacturing process
21
Q
Bioavailability helps to elucidate:
A
- Process by which a drug is released from its dosage forma nd reaches the sites of action
- Impact of pre-systemic metabolism and/or transpprters
- Drug’s pharmacokinetic properties
- Effect of food on absorption
- Relative bioavailability
- Information on labeling or formulation optimization
22
Q
Bioavailability studies compare the performance of two drugs with the same:
A
- Drug
- Dosage form
23
Q
Bioequivalence studies will be applied to any systematically available drug product that:
A
Wille be used to provide therapeutic effects at an active site different from the site of absorption:
* Oral tablets
* Capsules and suspensions
* Transdermal products
* Nasal or rectal dosage forms
Oral solutions are excluded since their behaviours are expected to not be different between products
24
Q
Bioequivalence studies are carried out in how many phases?
A
2
25
Describe the first phase of bioequivalence studies
Healthy, fasted volunteers are randomized into two groups: one recieves the reference (innovator) dosage form, the other the test (generic) dosage form in the first period of the study
26
Describe the second phase of bioequivalence studies
After the first dose has been eliminated, the subjects recieve the other dosage form
27
When are blood samples taken during a bioequialency test?
At established intervals
28
What is analyzed in the blood samples from bioequivalence studies
Drug and/or metabolites
29
What parameters are determined from the blood samples during a bioequivalence test? What can this prove
* Cmax
* Tmax
* AUC
To be therapeutically equivalent to a reference product, there must be no statistically significant different in the above parameters
30
What is the acceptable average differences in the test paramaters between reference and generic products during a bioequivalency test?
3-4%
31
What is a key consideration when selecting a dosage form?
Whether it is intented for local of systemic effects
32
Different dosage forms generally result in different:
* Absorption rates
* Times of onset
33
The difference in absorption between dosage forms is a function of the:
* Formulation
* Route of administration
34
What percentage of marketed medicine is delivered orally?
90%
35
Which dosage form contributes to patient compliance the most?
Oral dosage forms
36
Oral dosage forms can be which types of formulation?
* Solid dosage forms: tablets and capsules
* Liquid dosage forms
37
What are some of the major challenged of immediate release oral delivery?
* Variability of the amount of drugs absorbing into the circulatory system
* Difficulty swallowing
* Certain drugs (such as nonsteirodal anti-inlfammatory drugs) can become lodged into the esophagus and damage the esophagal mucosa
38
How is the gastric emptying affect liquid and solid dosage forms?
* Liquid: faster gastric emptying
* Oral: slower gastric emptying
39
What is the general disintegration time of capsules in the GI track?
Within 6 minutes
40
What is the general disintegration time of tablets in the GI track?
Within 15 minutes
41
What are some challenged when considering the small intestine?
* Influx transporters are found in the duodenum and jejunum
* Many drugs are metabolized by CYP 450 (CYP 3A4)
* Several drugs are effluxed back onto the intestine's lumen
42
What are the main challenges of the stomach?
* Acidity
* Enzymes
43
What are the main challenges of the small intestine?
* Food products
* Enzymes
* Dissolution
44
What are the main challenges of the liver?
* Entero-hepatic loop
* First-pass effect
45
What are the main challenges of the blood?
* Protein binding
46
What are the main challenges of the site of therapeutic action?
* Small fraction of dose taken
47
Most ingredients in pharmaceutical dosage forms occur in solid states as:
* Amorphous powders
* Crystals
48
Define powder
Intimate mixture of dry, finely divided drugs and/or chemicals that may be intended for internal or external use
49
What physical and chemical characteristics are acertained before the use of a solid material in a drug?
* Morphology
* Purity
* Solubility
* Flowability
* Stability
* Particle size
* Uniformity
* Compatibility with other components
50
Solid materials are subjected to various treatments to enable:
* Efficient production of the finished dosage form
* Optimum therapeutic efficacy
51
Medicinal & non medicinal ingrediant powders are:
* Blended to produce solid dosage forms
* Suspended in liquid vehicles
* Inforporated in semi-solid bases to prepare creams or ointments
* Agglomerated into granules
52
What is the general size range of particles of pharmaceutical powders?
1mirco-meter-10mm
53
What are the United States Pharmacopeia's classification of particle size?
* Very coarse
* Coarse
* Moderately coarse
* Fine
* Very fine
54
Particle sizes influence important factors, such as:
* Dissolution rate
* Suspendability
* Uniform distribution
* Penetrability
* Lack of gritiness
55
How does particle size affect dissolution rate?
* Dissolution rate is extended for larger particles because microionization improves dissolution rate
* Reduced for smaller particle sizes
56
How does particle size affect suspendability?
* Finer dispersions require paryocle size of 0.5-10 micrometers
* Larger particle sizes may prevent suspendability
57
How does particle size affect uniform distribution?
* For the drug substance in the powder mixture or solid dosage form
* To ensure dose-to-dose content uniformity
58
How does particle size affect penetrability?
* For particles to be inhaled
* Required particle size of 1-5 micrometers
59
How does particle size affect lack of gritiness?
* In creams, ointments etc.
* Required particle size of 50-100 micrometers
60
What is a granule?
Agglomerates of smaller particles of powder
61
By what two methods can granules be prepared?
* Wet methods
* Dry methods
62
Describe the wet method of granule preperation
* Moisten the powder
* Pass through a screen of desired mesh size
* Dry by air or heat
63
Describe the dry method of granule preperation
* Powders passed through a roll compactor
* Passed through granulating machine for desired particle size
64
What are the advantages of granules over powders?
* Better flowing properties
* Reduced surface area = more stable to humidity, less likely to cake or harde
* More easily wetted by liquids = perferred for products to be constituted into solutions/suspensions (certain antibiotic drugs)
65
Why are effervescent granulated salts made?
To mask undesirable taste of medicinal agents
66
What are effervescent granulated salts made of?
Granules generally containing a dry mixture of:
* Medicinal ingredients
* Sodium bicarbnate
* Citric acid
* Tartaric acid
67
What happens when an effervescent tablet is added to water?
* The acids and bases react
* Liberation of CO2
68
What is a key consideration when developping tablets?
Exposure of the drug substance to the dissolution process may involve a few steps: dosage form --> granules --> fine particles
69
Name the process that happens from a dosage form to granules
Disintergration
70
Name the process that happens from granules to fine particles
Deaggregation
71
Name different types of tablets
* Compresed tablets
* Film-coated tablets
* Enteric-coated tablets
* Buccal and sublingual tablets
* Chewable tablets
72
What are some qualities that tablets must have?
* Accurate and uniform weight
* Homogeneity
* Absence of incompatilibilites
* Stability and hardness
* Ease of disintergration
* Reasonable size and shape
* Pleasing appearance
* Easy of manufacturing
* Economy of production
73
What is the desirble tablet hardness
5-6kg
74
What is the desired tablet thickness?
2.0mm
75
What is the desired tablet weight for a tablet?
200mg +/-5%
76
What is the desired Content uniformity of a tablet?
90%-110%
77
What is the desired disintegration time of a tablet?
less than 5 minutes
78
What is a film coated tablet?
Compresed tablets with a thin polymer coating layered onto the tablet as a thin film
79
What are the caracteristics of an enteric-coated tablet?
* Delayed release
* Coating generally dissolves in a higher pH range (ex. after moving into the samll intestine)
* Protects the drug at acidic pH range
80
What are the caracteristics of buccal and sublingual tablets?
* Designed to be dissolved in the buccal pouch or under the tongue
* Drug absorption may occur through oral mucosa
* Protects from gastric juices
81
What are the caracteristics of chewable tablets?
* For children or adults who have difficulty swallowing
* Flavoring is important
* Generally, must be chewed and should not be swallowed whole
82
What are the quality standards and compedial requirements for tablet weight and USP weight variation test?
Ten tablets weighed individually and average calculated
83
What are the quality standards and compedial requirements for content uniformity?
* Ten tablets are assayed
* Content of medicinal ingredient in each tablet calculated: must be between 90-110% and stds. under 6%
* Homogeneous distribution expected
84
What are the quality standards and compedial requirements for tablet thickness?
* Measured by hand gauge
85
What are the quality standards and compedial requirements for tablet hardness and friability?
* Tablets should be: hard enough to resist breaking during normal handling, soft enough to disintergrate properly
* No more than 1% weight loss during friability test
86
What are the quality standards and compedial requirements for tablet disintergration?
* Six tablets are assayed
* Tubes lowered and raised in immersion fluid at 29-30 cycles per minutes at 37 degrees celsius
* Disintergration must be achieved according to the compendium requirement
87
What are the quality standards and compedial requirements for tablet dissolution?
* An indication of bioavailability
* Allows for in vitro selection of formulation
* In dissolution fluid at 37 degrees celsius
* Batch-to-batch consistency is vital
88
What are the advantages of tablets?
* Accurate dosage/minimum variability
* Absence of alcohol
* Concentration variability
* Elegance
* Patient acceptance
* Convinence (light and compact)
* Tamper
* Low cost
* Easiest/cheapest to package and ship
* Ease of administration
* Special release profiles possible
* Suited for large-scale production
* Best overall properties of all oral dosage forms
89
What are some tablet disadvantages?
* Swallowing
* Difficult to extemporaneously prepare
* Some drugs resist compression
* Poorly wetting drugs, slow dissolving drugs, immediate to large dosages
* Bitter taste/bad odor
* Oxygen/moisture-sensitive require coating
90
What does parenteral mean according to its definition?
Para = outside enetron = entestine
Denotes other than the oral route
91
Parenteral injections are:
Sterile, pyrogen-free preparations intended to be administered parenterally
92
What are pyrogens?
Fever-producing organic substances arising from microbial contamination
93
What does parenteral formulation mean in practice
* Drugs that are injected, a delivery system that bypasses the body's protective chemistry in the gastrointestinal tract and the low permeability barrier of the skin
94
What are the different types of parenteral routes?
* Intravenous route
* Intramuscular route
* Subcutaneous route
* Intradermal route
95
When is parenteral administration used?
* Rapid drug action is desired
* Patient is uncooperative
* Patient is unconscious
* Patient is unable to accept or tolerate oral medication
* The drug is innefective by other routes
96
What are some advantages of IV injection?
* Rapid drug action vs other routes
* Absorption is not a factor
* Optimum drug level reached with accuracy and immediacy
* May be lifesaving in emergencies
* Rapid drug action vs. other routes
* Absorption is not a factor
* Optimum drug levels reached with accuracy and immediacy
* May be lifesaving in emergencies
97
What are some disadvantages of IV injection?
* Risk of thrombus & embolus caused by needles
* Healyj issues due to the presence of particulate matters
* Once the drug is administered it cannot be retrieved
98
What are some important cosiderations for IV formulations?
* Ensure accuracy in dosing
* Strict aseptic precautions must be taken at all times
* Syringes and needles must be sterilized as well
* Point of entrance must be disinfected
* Should generally be an aqueous solution
* Must mix with circulating blood
99
The intramuscular parenteral route provides effects that are:
* Less rapid than IV
* Longer lasting than IV
100
Administration by the intramuscular parenteral route should be:
* Point of injection should be far from nerves and blood vessels
* Volume of administration limited to 2-5mL
101
What drugs can be administered through the subcutaneous route?
* For small amounts
* For drugs such as insulin
102
What drugs can be administered through the intradermal route?
* Immunization
* For very small amounts, about 0.1mL
103
What are the official types of injections?
* Injection
* For injection
* Injectable e ulsion
* Injectable suspension
* For injectable suspension
104
What defines an injection formuation?
Liquid preperation containing the drug substance
105
What defines a for injection formulation
Dry solids that combine with a vehicle to produce a solution for injection
106
What defines an injectable emulsion formulation?
Liquid preperation containing th drug substance dissolved or dispersed in an emulsion medium
107
What defines an emulsion formulation?
A heterogenous system consisting of at least one immiscible liquid intimately dispersed in another in the form of droplets, whose diameters generally exceed 0.1micro meter
108
What are the reasons for making an emulsion?
* Emulsion dosage forms are appropriate when the drug is not miscible in the desired solvent or a co-solvent system
* Poorly miscible/soluble drugs can be placed in a suitable vehicle for administration
* Stability
* Taste/odor
109
What defines an injectible suspension formulation?
Liquid preparation of solid suspended in a liquid medium
110
What defines a suspension formulation?
* A suspension is a 2 phase system consisting of a finely divided solid dispersed in a solid, liquid or gas
* Preperations contain finely divided drug particles (the suspensoid) distributed somewhat uniformely throughout a vehicle in which the drug exhibits a minimum degree of solubility
111
What are reasons to make a suspension formulation?
* Emulsion dosage forms are appropriate when the drug is not miscible in the desired solvent or a cosolvent system
* Poorly miscible/soluble drugs can be placed in a suitable vehicle for administration
* Stability
* Taste/odor
112
What defines a for injectable suspension formulation?
Dry solids that combine with a vehicle to produce a preperation for injectable suspension
113
The design of a parenteral dosage form must offer:
* One dose in a manageable size unit
* Comfort
* Microbial stability
* Sterility
* Chemical stability
* Microbial stability
* Convenience and ease of use
* Release of drug
114
What criteria is there for a dose in manageable size for parenteral injection?
Good water solubility is essential
115
What criteria is there for comfort in parenteral injection?
* Use of tonicity agents
* Rapid dilution of drugs enhance comfort
116
What criteria is there for microbial stability for parenteral injection?
Must be sterile
complete absence of viable microorganisms
117
What criteria is there for chemical stability for parenteral injection?
* Use of buffers for appropriate pH
* Unstable drugs are prepared as powders for reconstitution
* Human serum albumin may be used to prevent adsorption
118
What criteria is there for convenience and ease of use for parenteral injection?
Use of devices enhances convenience of delivery
119
What criteria is there for release of drug for parenteral injection?
* Use of suspensions and oily solutions to prolong the release of the drug
* Oily solutions are formulated in sterile vegetable oils which are not miscible with body fluids. This requires the drug to partition into the body water and slows absorption
120
What are some important caracteristics for non-aqueous vehicles for parenteral injection?
* For medicinal ingredients with limited water solubility, or susceptibility to hydrolysis
* Non-toxic and non-irritating, the product label must inicate the type of oil used
* Not exert pharmacological activity of its own
* Not affect the activity of other ingreidents
* Stable at various pH
* Viscosity and fluididty that allow for ease of injection
* Sufficiently high boiling point
* Miscibility with body fluids
121
What are some general ingredients in parenteral injections?
* Antibacterial preservatives
* Buffers
* Solubilizers
* Antioxidants
122
What is the issue with having a high concentration of antibacterial preservatives?
They are generally toxic in large amounts and are irritating
123
What are the key formulation issues with parenteral products?
* Physcial issues
* Chemical issues
* Packaging issues
124
What are some of the physical issues of parenteral drug formulation?
Changes in the solubility of one of the components:
* Related to diferent pH requirements for drug solubility
* Related to the dilution of drugs solubilized by cosolvents
Precipitates related to dilution of drugs solubilized by surfactants
125
What are some chemical issues when formulating parenteral injections?
Admixture of drugs or drug and diluent that causes drug degredation
* Hydrolysis (acidic pH)
* Oxidation (colour change
Difficult to detect
126
What are some packaging issues when formulating parenteral injections?
* Leaching
* Sorption
* Adsoption
127
What is leaching in a parenteral drug formulation?
* Drug solutions formulated with surfactants, co-solvents and oily solvents leach DEHP, a lipid soluble compound used as a plasticizer, out of the packaging and into the drug solution
* Solutions containing surfactants, cosolvents and oily solvents should be stored in glass or polyethylene containers, and administered with non-DEHP plasticized administration sets
128
What is sorption in a parenteral drug formulation?
* Sticking on the surface of the container, administration set or inline filter
* Involves large protein drugs or very lipid soluble drugs that have affinity for plastic or glass surfaces
* Plastics, particularly polyvinyl chloride, bind lipid soluble drugs
129
What is adsorption in a parenteral drug formulation?
* Adsorption to the inner lining of IV containers and tubing
* Primarily involves peptides & proteins (ex. insulin, monoclonal antibodies)
130
What is a startergy to prevent adsorption?
Additio of human albumin
131
What is absorption in a parenteral drug formulation?
* Plastic materials facilitate drug absorption
* Most common with PVC
132
Define drug delivery system
The way a dosage form releases the drug and delivers it to the site of action
133
Drug delivery systems control the pharmacological effect of the drug as it can influence the:
* Pharmacokinteic profile of the drug
* Rate of drug release
* Site and duration of drug action
* Side-effect profile
134
An optimal drug delivery system ensures that the active drug is available at the site of action for the correct:
* Time
* Duration
135
The drug concentration at the appropriate site should be:
* Above the minimum effective concentration (MEC)
* Below the minimum toxic concentration
136
The desired concentration of a drug is dependent on the:
* Frequency of dosing
* Drug clearance rate
* Route of administration
* Drug delivery system used
137
Define a modified release dosage form
Any dosage form that releases drug according to a release profile other than immediately
138
What is an immediate release dosage form?
* Release the drug immediately of at least as quicly as possible after administration
* Useful if fast onset of action is required
* If the drug has a short half-life, this may require frequent dosing and potentially lead to low patient compliance
139
Modified release drugs are designed to:
* Modify the release of the drug over a given time or after the dosage form reaches the required location
* To remain intact in the stomach
139
What is the gastric emptying time-line for a modified release drug form?
* The drug moves into the small intestine approx. 2 hours after the last small particles of food have left the stomach
* They reach the colon approximately 4-12 hours after they have emptied from the stomach
140
Is food a concern when considering the relase of a modified release drug form?
No, the extent and rate of drug release are not affected by administration with food
141
What are the three types of modified release drug forms?
* Delayed
* Targeted
* Extended
142
Describe delayed release formulations
* Formulated to release the medicinal ingredient at a time other than immediately after administration, generally in the small intestine or the colon
* Delayed release from oral dosage forms can control where the drug is released e.g at the small intestine
* Most popular approach has been the use of enteric coats, which are composed of acidic polymers that dissolve as the pH of the intestine increases
* Another approach is to build a lag time into the dosage form with coatings that slowly erode to release the drug at the time typical gastrointestinal transit would carry it to the target location
* Third approach, the preperation of prodrugs that are cleaved to the active agent by colonic bacteria, ensures that drug release is confined to the colon
143
What happens once a delayed release formulation releases its drug?
The delivery is immediate and its plasma concentration versus time curve is similar to the one for immediate dosage forms
144
Define an extended release drug formulation
Allows for the drug to be released over prolonged time periods
145
What are benefits of extended release drugs?
* The frequency of dosing can be reduced
* Benificial for patients with chronic diseases, especially when they need to take medicine for prolonged periods of time, often for the rest of their lives
146
What are the three mecanisms invloved in extended release dosage forms?
* Dissolution controlled
* Dissolution-diffusion controlled
* Diffusion controlled
147
What is oxycontin?
* Microporous matric tablet containing oxycodone for twice daily use
* The drug is mixed with an insoluble polymer ans soluble channeling agents
* These agents are dissolved by gastrointestinal fluids creating channels
* Drug molecules are released through these channels
* The tablet is designed to release some drug immediately and the remainder over 12 hours
148
What are the two types of extended release formulations?
* Sustained release
* Controlled release dosage forms
149
Describe sustained release, extended release dosage forms
* Maintains the rate of drug release over a sustained period
* This may reduce the frequency of dosing from three times a day to once a day. Sustained release dosage forms achieve this mostly by the use of suitable polymers, which are used to either coat granules or tablets or to form a matric in which the drug is dissolved or dispersed
* Oral dosing: if the release of the drug from the dosage form is sustained such that the release takes place throughout the entire gastrointestinal tract, one could reduce Cmax and prolong the time interval of drug concentration in the tehrapeutic range
150
Describe controlled release dosage forms
* Delivery of drugs in the ody at pre-determined rates
* It attempts to control drug levels in the target tissues or cells
* Implies low toxicity and improved therapeutic index
151
Controlled-release formulation offer what type of release profile?
* Sustained release profile
* Lead to rpeidctable constant plamsa concentrations, independently of the biological environment of the application site
* They control the drug concentration un the body, not just the release of the drug from the dosage form
152
Controled release drugs are administered using which dosage forms?
* Transdermal
* Oral
* Vaginal
153
What is an example of a controlled release drug delievery?
Osmotic pump
Drug compounds are delivered in
* a controled pattern oer a long period of time by the proces of osmosis
* At predetermined zero order rate for a prolonged period of time
154
How can the release caracteristics be predicted for an osmatic pump?
By analysing the known properties of the drug and the dosage form
* The delivery profile in indepenent of physiological actors of the gastrointestinal tract
155
Osmotic pumps can be used for which type of delivery?
Systemic or targeted delivery
156
For osmotic pumps, the dilvery of the drug is drier by:
osmotic presure difference on both sides of the semi-permeable membrane
157
Define osmotic pressure
* The pressure that would be required to stop water from diffusing thorugh a barrier by osmosis
* It refers to how hard the water would "push" to get through the barrier in order to diffuse to the other side
* Osmotic pressure is proportional to temperature and concentration
158
The rate of drug release from an osmotic pump depends on the:
* Drug solubility
* Osmotic pressure of the core
159
The drug compound of an osmotic pump would be preferably?
* Short to moderate half-life
* Disease requiring prolonged treatment
* Sufficient solubility (the release rate depends on the solubility of the solute inside the drug delivery system) or meaningful solubility
160
What are the global components of osmotic pumps?
* Drug compound
* Semi-permeable membrane
* Osmotic agent
* Wicking agents
* Solubilizing agents
* Delivery orifice
161
What are the desired caracteristics of the semi-permeable membrane of an osmotic pump?
* Polymer coated film
* Permeable to the passage of water
* Inpermeable to the passage of the medicinal and non-medicinal ingredients
* Inert
* Able to maintain its dimensional intergity to provide a constant osmotic driving force during drug delivery
162
What are the desired caracteristics of the osmotic agent (osmogen) of an osmotic pump?
* When in contact with water, osmogens dissolve, which created osmotic pressure buildup inside the pump and pushes the drug compound outside the pump through the delivery orifice
* A combination of osmogens are used for optimum results
163
What are the desired caracteristics of the wicking agents of an osmotic pump?
* Have the ability to draw water into the porous network of a delivery device
* They help to increase the contact surface area of the drug with the incoming aqueuous fluid
* They help enhance the rate of drug released from the orifice of the drug
163
What are the desired caracteristics of the solubilizing agents of an osmotic pump?
* Increase the solubility of the drug molecules
* Highly water-soluble drugs would demonstrate a high release rate that would be zero order
* They act: via complexation and inhibit crystal formation, as surfactants
164
What are the desired caracteristics of the delivery orifice of an osmotic pump?
Must be oprimized in order to control drug release
* Should not be too large: may prevent build up of pressure, would allow exit of solute without pressure
* Should not be too small: development of hydrostatic pressure
* May prevent zero-order release
* May deform the membrane and prevent zero-order release
165
The delivery orifice can be created by:
* Mechanical drill
* Laser beam
* Incorporation of pore-forming agents
166
An elementary osmotic pump is composed of?
* Core tablet: the medicinal ingredient must have a suitable osmotic pressure
* Smi-permeable membrane: usually cellulsoe acetate
* Drilled orifice: drilled through the membrane coating
167
What is the operation of an EOP once swallowed?
* Tablet exposed to an aqueuous environment
* Osmotic pressure of the soluble drug inside the tablet draws water through the semi-permeable coating
* A saturated aqueuous solution of drug is formed inside the device
* Increase in volume due to imbibition of water raises the hyrostatic pressure inside the tablet
* Flow of saturated solution of active agent out of the device through a small orifice
168
What are some advantages of osmotic pumps?
Easy to design and achieve a zero-order release rate, which would be:
* High
* Delayed or pulsed
* Programmed and predictable
For oral delivery
* Release rate is not affected by the GI tract content, conditions and pH
High degree of in vitro - in vivo correlation
169
What are some disadvantages of osmotic pumps?
* Special equipment required
* Variable residence time in the GI tract
* May cause irritation or ulcer due to release of saturated solution of drug
170
What is a nanocarrier?
* System that loads drugs incorporated into organic or inogranic matrixes with a size of 10-1000nm
* Considerably smaller in size that biological macromolcules
* 100 to 1000 times smaller than a cancer cell
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What are the advantages of nanocarriers?
* Display superior intracellular uptake
* Increased ability to overcome biological barriers e.g smaller capillaries, which have an average size of 3 micrometers
* Controlled release
* Specific targeting
* Reduced drug resistance
* Reduced toxicity
* Overall improved bioavailability
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What are the different types of nanocarriers?
* Lipid-based nanocarriers
* Polymeric nanocarriers
* Inorganic nanoparticles
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What is the general shape of lipi based nanocarriers?
Generally spheric in shape and include:
* Liposomes
* Lipid nanoparticles
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What is the general shape of polymeric nanocarriers?
* Dendrimers
* Polymer micelles
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What is the general shape of inorganic nanoparticles?
* Invlove metals
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What purposes can nanoparticles have?
* Therapeutic use
* Diagnostic use
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Define nanoparticle
A microscopic polyer, protein or lipid-based structure betwen 1 and 200nm in size (ex. liposomes, polymeric miscelles)
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What is a liposome?
Closed bilayer structure spontaneously formed by hydrated phospholipids that are used as efficient delivery systems for drugs due to their capability to encapsulated molecules that are:
* Hydrohilic
* Amphipathic
* Lipophillic
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Why does the liposome shape form?
It is the most thermodynamically stable structure in water
* Hydrophilic head toweards the outside
* Hydrophobic chain towards the inside
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What are the two shape classifications of liposomes?
* Unilamellar vesicles (ULV)
* Multilamellar vesicles
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What are the two types of lipids that are commonly used to construct the basic structure of the vesicle?
* Phospholipis
* Cholesterol
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What is the source of commonly used phospholipids?
* Egg phosphatidylcholine
* Soya phosphatidylcholine
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Why is cholesterol added to the lipid mixture of a liposome?
* Minimizes instability
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How does cholesterol insert itself into the phospholipid layer?
* Nonpolar rings are embedded in the hydrophobic core
* Hydroxyl functional group interacts with the phospholipid head groups
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What roles does cholesteral insertion play?
* Modulating membrane rigidity and therefore stability (bulky steroid rings restrict mobility of the phospholipids at higher temperatures
* Increasing fluidity (prevents packing at lower temperatures
* Enhances the permeability of the bilayer, which enhances the encapsulation efficency of drugs
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What are the general steps of liposome preperation?
* Preperatio of the lipids for hydrating
* Hydration
* Sizing to a homogeneous distribution of vesicles
* Encapsulation
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How are lipids prepared for hydration?
* Solubilization of dried lipids in an organic solvent such as chloroform or cyclohexane
* The solvent must be acceptable for humans in trace amount
* The following factors are considered: optimum size, size distribution, shlef-life of the vesicles the medium in which the lipi vesicles are dispersed, the physicochemical characteristics of the material to be entrapped, batch-to-batch reproductibility
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Liposomes can be catergorized as:
Simple
Stealth
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What is a stealth liposome
Liposome that carries a hydrophilic coating, and offers a longer circulating time
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Define targeted delivery
A process intended to overcome limitations associated with routine drug administrations by delivering drugs specifically to diseased cells and tissues while not exposing healthy tissues
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An ideal targeted delivery must, where applicable:
* Ensure minimal loss in transit
* Protect the drug from metabolism and premature clearance
* Retain the drug at the target site for a desired period
* Facilitate the drug transport into the cell
* Deliver the drug to the appropriate intracellular target
* Be biodegradable, biocompatible and nin-antigenic
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Targeted release helps to:
Enhance the activity and specificity of the drug and reduce its toxicity and side effetcs
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What is passive targeting?
Exploits the natural condition of the target organ or tissue
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What is active targeting?
Ues targeting groups such as antibodies to bind to specific receptors on cells
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How is active targeting achieved?
* Cell surface antigens
* Receptirs
* Membrane transporters
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What is a vaccine according to health canada?
Complex biologic products designed to induce a protective immune response effectively and safely. Vaccine are expected to offer protectin against the disease for which they were created
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What are the ideal characteristics of a vaccine according to health canada?
* Causing minimal adverse effects
* Effective in providing lifelong protection against disease after a signle dose that can be administered at birth
* Inexpensive
* Stable during shipment and storage
* Easy to administer
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An ideal vaccine should:
Induce a complete, humoral and cellular immune response
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What was the original approach to vaccines?
1. Isolation of a pathogen
2. Attenuation or inactivation
3. Injection
200
What are the ingredients used in vaccines?
* Preservatives
* Adjuvants
* Stabilizers
* Residual cell culture materials
* Residual inactivating ingredients
* Redisual antibiotics
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What are the 4 different types of vaccines
* Whole pathogen vaccines (live attenuated/inactivated)
* Subunit vaccines (ex. Protein)
* Nucleic acid vaccine (ex. mRNA, DNA)
* Viral vectored vaccines
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Describe the virus life cycle of SARS-Cov-2
1. SARS-Cov-2 virus enters the host cell via interaction between viral spike and host angiotensin-converting enzyme 2 (ACE2) proteins
2. Virus replication and release from the host cells
3. A subset of viruses will be engulfed and digested by antigen presenting cells (APCs) like macrophages or dendritic cells
4. Fragmented SARS-Cov-2 antigens will be presented to T helper cells, which will in turn interact and activate B cells
5. ANtibody-mediated neutralization occurs where sarscov2 antibodies bind to viral antigens and prevent virus interaction and entry into host cells
6. B cells multiplu and transform themselves into plasma cells
7. These plamsa cells quickly produce veru large amounts of antibodies and release them into the blood
8. Some of the activated B cells transform into memory cells and become part of the memory of the adaptive immune system
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What are some advantages of mRNA vaccines?
* The development process of mRNA vaccines is faster than the conventional protein vaccine
* In vitro transcription reaction is easy to carry out, has a high yeild and can be scaled up
* The mRNA vaccine enables the synthesis of antigen proteins in situ, eliminating challenges associated with protein purification and long-term stabilization
* Transportation and storage of mRNA may be easier than protein-based vaccine (less prone to degradation when protected properly)
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What are some disadvantages of mRNA vaccines?
* Instability or mRNA in vivo mostly due to enzymatic degredation by Rnases
* Delivery and encapsulation efficiency is not optimum (negative charge prevents most mRNA translocation across the negatively charged cell membrane, large size makes effcient encapsulation and delivery more challenging)
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What are the types of mRNA used in vaccines?
1. Conventional RNA
2. Self-amplifying mRNAs
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Describe conventional mRNA
* 1000 to 5000 nucleotides
* translated in the cytosol until its degradation without additional replication
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Describe self-amplifying mRNAs
* Posess a self-adjuvant nature
* Derived from the genomes of single stranded RNA viruses
* Encodes the proteins of interest in larg amount and the replication machinery to replicate themselves
* Larger than conventional mRNA vaccines (8000-12000 nts.)
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What are some current strategies to improve the mRNA vaccine process?
Overcome the stability and translation challenges:
* 5' cap modification
* Nucleosie modification in antigen expression
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The 7 méthylguanosine at the 5' cap:
* Enhances mRNA stability
* Allows the ribosome to recognize the beginning of mRNA
* Improves translation efficiency
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What is the commonly performed 5' cap modification for mRNA?
Adding a regular cap analog, m7GpppG structure to the mRNA transcription system
211
What is the nucloside modification in antigen expression for mRNA?
A particular nucleoside undergoes modification after the trancription process. Once selected base is substituted with an analogous modified NTP at each location
Most common invloves pseudo-uridine (reduces the activation of the immune system by inhibiting toll-lik e receptor-mediated recognition and decreasing cytokine concentrations and biomarker efficacy in dendritic cells
Reduces the trabslational inhibition triggered by the unmodified nucleotide
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What are some other formulation strategies for mRNA drugs?
* Purification:Using high-performance lipi chromatography purifiaction (removes the by-products from in vitro transcription such as dsRNA that could prevent mRNA translation)
* Nanoparticle encapsulation: increasing the delivery efficiency of mRNA in vivo (improving the reproductibility of nanoparticles at various scales with contrllable sizes using continuous-flow micro-fluidic devices
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What are the most common routes of administration for mRNA vaccines?
* Interadermal
* Subcutaneous
* Intramuscular
* Intravenous
* Intranodal
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Injection an mRNA vaccine via the intradermal route:
* Delivers mRNA directly into the dermis region
* The region has dense CY
* The following antigen-presenting cells (APCs) in the dermis tissue would internalize the mRNA vaccine: macrophages, dermal dendritic cells
* The vascular and lymphatic vessels in the dermis would help transport mRNA vaccines and APCs to the draining lymph nodes to activate B and T cells
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What are the major limitations of the intradermal route?
* Small injection volumes
* High risk of local adverse effect, including swelling, pain, erythema and pruritus
To overcome: multiple injection sites
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Injection an mRNA vaccine via the subcutaneous route:
* Delivers mRNA vaccines directly into the subcutis region under the dermis
* Region is mainly composed of a loose network of apidose tissues and few immune cells compared to the dermis
* Allows for larger injection volume than ID
* Causes less pain and lower pressure than ID
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What is the major limitation of the subcutanous route for an mRNA injection?
Absorption rate in this region is slow, may cause vaccine degredation
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What does the intramuscular route provide for mRNA vaccine administration?
* Delivers mRNA vaccine directly into the muscles
* Muscles contain a large network of blood vessels that can help recruit and recirculate immune cells such as APCs to the injection site
* Larger injection volume compared to ID injection
* Milder local side effetcs compared to iD and SC
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What does the intravenous route provide for mRNA vaccine administration?
* Delivers mRNA vaccines directly into the systemic circulation
* Provides the largest administration volume of all delivery routes discussed
* Yields the largents amound of encoded proteins
* Preferred when a high functional concentration of antibodies is required in circulation
* Generally delivers mRNA to the liver
* Allows direct access of mRNA vaccines to immune cells and lymphoid organs in the circulatroy system (increased vaccination efficacy)
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What is the major limitation of the IV route?
Vaccine delivery problems due to
* Presnce of plasma proteins, enzymes and mechanical forces in the circulatory system
* Introduction of the mRNA and delivery carriers into the same circulation may cause systemic side effetcs (spleen injury, lymphocyte depletion)
221
What does the intranodal route provide for mRNA vaccine administration?
* Delivers mRNA vaccines directly into the peripheral lympoid ograns where APCs and T or B cells interact
* Efficient way of vaccination since the APCs in lymphoid organs can eadily internalize the injected mRNA vaccine
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What are the major limitations of IN mRNA injection?
* Requires ultrasound guidance for humain injection
223
Which route of administration is considered the ideal site for immunogen delivery? Why?
The skin
* Presence of a variety of antigen-presenting cells
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What are some major considerations for the effectivness of a directly injected mRNA vaccine?
Level of antigen expression in antigen presenting cells, which is influenced by
* Efficiency of the carrier
* Presence of dsRNA or unmodified nucleotides
* Level of optimization of the RNA sequence
Mutation and migration to the lymphoid tissue
Ability of the vaccine to activate robust T cell and B cell responses
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What are the basic ingredients of mRNA vaccines?
* Medicinal ingredient: mRNA
* Non Medicinal ingredients: lipids (ionisable), lipids (helper), salts, sugar
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What is the function of nucleosie modified mRNA in mRNA vaccines?
Encodinh the viral spike glycoprotein of SARS Cov 2
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What is the function of ionizable lipids in mRNA vaccines?
* Functional lipid component of the drug product
* Positive charge binds the negatively charged mRNA hereby encasing the mRNA
* Facilitate the entrance of the drug product into the cell
* Allows the escape of the mRNA from the endosome via fusion with the endosome
228
What is the function of lipid helper polyethylene glycol lipid in mRNA vaccines?
Forms a protective layer which:
* Stabilises the LNP
* Contributes to storage stability
* Reduces non-specific binding to proteins
* Increases the half-life of the drug in vivo admin: providing so-called stealth properties to prevent their rapid elimination from blood circulation by macrophages
* An excessive quantity of PEG reduces the entrance into the cell and interaction with the endosmal membrane
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What is the function of lipid helper phospholipids in mRNA vaccines?
* Forms a stable bilayer structre under PEG surface
230
What is the function of lipid helper cholesterol in mRNA vaccines?
* Provides structural intergrity and stability to the delivery system
* Prevents nanoparticles from clumping
231
What is the function of salts in mRNA vaccines?
* Considered as phosphate-buffered saline (PBS)
* Maintains and stabilizes the pH
232
What is the function of sugar in mRNA vaccines?
* Cryoprotectant to prevent damage of nanoparticles during freezing
* Provides enhanced speicificty towars certain receptors
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What is the lipid nanoparticle preperation for microfluidic mixing of lipids with mRNA?
1. Lipids are dissolved in ethanol
2. mRNA are disolved in aqueous buffer
3. The two mixtures are pumped into the two primary inlets of the microfluidic mixer using syringe pumps
4. The herringbone structure induce chaptic advection in the laminar flow that enables rapid mixing of ethanol and the aqueous phase
5. Approx. 15 cycles are needed to complete mixing
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What is the dosage form of an mRNA vaccine?
Suspension
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What is the route of administration of the mRNA vaccine?
Intramuscular injection
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What is the physical appearance of the mRNA vaccine?
* White to off-white
* Frozen
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What is the packaging of the mRNA vaccine?
* Clear glass 2mL vial
* Rubber stopper (not made with natural rubber, latex)
* Aluminium overseal
* Flip-off cap
BPS 4
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