Dosage Exam 3 Flashcards
What kind of curve represents a polydispersed molecular weight?
A broad curve
What kind of curve represents a monodispersed molecular weight?
A narrow curve
What does Mn stand for?
Number average
What does Mw stand for?
Weight average
How is a molecular weight distribution determined?
By dividing Mw/Mn
What number polydispersity represents a “monodispersed” weight distribution?
Mw/Mn is about equal to 1
What number polydispersity represents a “polydispersed” weight distribution?
Mw/Mn»_space;> 1
What are the characteristics of a crystalline polymer?
-Linear
-Can pack together at T < Tm
-Sharp Tm
Good barrier to drug diffusion, durable
*Hard to dissolve
*Uniform molecular structure in straight rows
What are the characteristics of an amorphous polymer?
-More common
*Irregular structure
-Forms “glass” at T < Tg (low temperatures)
-Softens over a wide temperature range (Tg)
**Rubbery at high temperatures
*Transition temperature is where it goes from being glass to rubbery
What does Tg stand for?
Glass transition temperature
What is the Glass Transition temperature (Tg)?
The temperature range where a polymer changes from a hard, rigid (glassy) state to a more pliable, compliant (rubbery) state
At T«Tg what state is a polymer in?
The polymer is hard, stiff, and glassy
At T»Tg what state is a polymer in?
Polymers are rubbery and may flow
What is an example of a drug that utilizes the Tg in its release?
Chewable dosage forms like Nicotine gum have Tg’s close to the body temperature so that they become rubbery upon chewing and release nicotine quickly
What are the 3 factors that affect Tg?
-Polymer length (longer = higher Tg)
-Side chains (bulkier = Higher Tg)
-Crosslinking (More crosslinked = Higher Tg)
What are plasticizers?
Molecules that increase the entropy and mobility of polymer chains
**Ultimately lowers Tg
What is the most common example of a plasticizer?
Water
In a stress-strain curve, what does the “slope” represent?
Slope is a measure of modulus (stiffness)
–the greater the slope, the less likely a polymer is to bend (more likely to stay stiff)
In a stress-strain curve, what does the “area under the curve” represent?
Toughness
(energy required to break the polymer)
What is the difference between chemical gels and physical gels?
Chemical gels are crosslinked by covalent bonds
Physical gels are crosslinked by hydrogen bonds, hydrophobic interactions, or complexation
What are hydrogels?
Crosslinked networks of hydrophilic polymers
*swell rapidly when in water
*retain large volumes of water in structure
What are biologics?
Medications derived from or produced by living organisms
*these are large molecule drugs
What are the 6 kinds of biologics?
-Recombinant proteins
-Peptides
-Blood Factors
-Vaccines
-Oligonucleotides
-Cell-based therapies
What is the most common type of biologic drug?
Monoclonal antibodies
What are the structural features of MAbs?
-high beta-sheet content
-quaternary structure (two light chanins and two heavy chains linked by disulfide bonds)
-molecular weight about 150,000 daltons
Where does antigen binding occur on MAbs?
Through the variable domain (V), at the complementarity determining region (CDR)
What drugs are MAb derivatives?
-Remicade
-Humira
-Simponi
-Cimzia
-Enbrel
What is an antibody drug conjugate (ADC)?
A MAb-based drug where an antibody is linked to a cytotoxic agent
-the antibody is specific for a tumor-associated antigen with restricted expression on normal cells (target specific)
-the cytotoxic agent kills target wells when internalized and released
(efficacious killing)
-these are connected by a linker
What are three examples of cytokines?
-Interleukins
-Interferons
-Erythropoeitins
What are some structural features of cytokines?
-High alpha-helix content (4-helix bundles)
-Molecular weight is about 30,000 daltons (smaller than MAbs)
What are some structural features of insulins?
-Forms hexamers and dimers
-Small peptides or proteins
-Have BOTH A-chains and B-chains linked by SS bonds
-Molecular weight is 5800 daltons (very small)
What kind of insulin analog is Lispro insulin?
Fast acting insulin analog
-Lys and Pro on C-terminus are reversed and block dimer and hexamer formation
What kind of insulin analog is Insulin aspart?
Fast acting insulin analog
-Pro on C-terminus of B-chain is mutated to Asp
What kind of insulin is Insulin glargine?
Long-Acting insulin analog
-Microcrystals form on injection causing slow release of drug
What are peptides?
Short proteins (less than 50 amino acids)
-Some secondary structure but no higher order structure
What is an important note about vaccine size?
They can be much larger than other biologics
What are the first living drugs?
CART-cell therapy
What is an example of an oligonucleotide?
Spinraza
-used to treat spinal muscular atrophy
**nucleotide chemical structure
What are the 3 types of coronavirus vaccines?
-Protein-based
-Viral vector
-mRNA
What is the route typically used for biologics?
parenteral
What are the typical dosage forms for biologics?
-Solution for injection
-Pen or autoinjector
-Pre-filled syringe
-Lyophilized powder for reconstitution
What are the benefits to solution formulations for biologics?
-Simple
-Least expensive
-Convenient
-Do not require reconstitution
-Can be inspected visually prior to administration
What are the clinical concerns for biologics in solution?
-Efficacy
-Sterility
-Side effects
-Pain on injection
What are the formulation concerns for biologics in solution?
All Clinical Concerns and:
-Stability
-Manufacturability
What are the formulation variables for biologics in solution?
-Solution properties
-Container/closure
-Storage conditions
What is the affect of additives on stability?
They make stability worse
What is the affect of higher concentration on aggregation?
Higher concentration = higher aggregation
What is the relationship between turbidity and aggregation?
More aggregation = more turbidity
How does subcutaneous delivery (SC) affect MAb aggregation?
Since SC delivery requires small volumes, MAb concentration is pushed to 100mg/mL which increases its aggregation risk
(need a higher concentration of MAb in a smaller about so it increases risk of aggregation)
What are the three ways that proteins aggregate?
Chemical reactions
—Cross-linking between protein molecules
Colloidal Interactions
—Molecules stick together without change in structure
Unfolding
—Molecules unfold which puts them at risk of undergoing a chemical reaction or colloidal interactions
What are excipients used for?
To stabilize the protein
What is a necessary feature of excipients in order for them to stabilize a protein?
Excipients that are preferentially excluded from the protein surface promote interactions with water and stabilize the native protein structure
What is the effect of preferential binding by excipients on proteins?
Excipients that bind to proteins can lead to denaturation of the protein
What is the one exception with protein and excipient binding?
Protein binding to ligands can result in a stabilized native structure
Should you shake biologics before use?
NO, never shake/agitate biologics
(Can lead to aggregation)
What is an important point about prefilled syringes, pens, and autoinjectors?
They are NOT formulations
The pen (physical device) is the “medical device”
The solution inside the pen is the “formulation”
Together they are the “combination product”
What are the advantages of pre-filled syringes, pens, and autoinjectors?
-Convenient and easy to use
-Easy to transport
-Discrete
-Increased patient compliance
-Reduced risk of dosage error
-Reduced risk of product contamination
What are the disadvantages of pre-filled syringes, pens, and autoinjectors?
-High cost
-Cannot mix two drugs
-Drug waste from priming
-Large surface-to-volume ratio and lubricants can induce aggregation of proteins
What are the special concerns associated with pre-filled syringes, autoinjectors, and pens?
-High surface-to-volume ratio
-Low total volume
-Syringe lubricant and oils
Proteins are surfactants, what does this mean?
Proteins can unfold when exposed to surfaces or interfaces
What are the advantages of lyophilized powders?
-Lower rates of chemical and physical degradation
-Better stability and longer shelf-life
-Do not need to be refrigerated
-Can be used in pre-filled syringes, pens, and auto-injectors (dual-chamber)
What are the disadvantages of lyophilized powders?
-Require reconstitution
-Expensive and time-consuming to manufacture
What is lyophilization and what is its benefit?
AKA freeze-drying
-Is gentler than other methods at removing water
What is the process that lyophilization uses to remove water called?
sublimation
In what conditions does sublimation occur?
-Low temperature
-Low pressure
What are the four stages of lyophilization and in what conditions do they occur?
- Freezing
(high pressure (atmospheric) is maintained, temperature decreases) - Vacuum
(pressure decreases, low temperature maintained) - Sublimation
(low pressure maintained, low temperature but increasing) - Dry powder to ambient
(increase pressure back to atmospheric, increase temperature back to atmospheric)
What are the ways that lyophilization can cause instability?
-Freeze-concentration can promote aggregation
-Disulfide bond scrambling can be accelerated
-Protein structure can be perturbed
-Aggregated or degraded protein can be seen with reconstitution
What does lyophilization tell us about the stability of a protein?
If a protein is lyophilized, this means it IS NOT STABLE IN SOLUTION
What excipients can be used to prevent a protein structure from being perturbed during lyophilization?
-Lyoprotectants
-Cryoprotectants
What is the outermost layer of skin?
stratum corneum
What are the “bricks” and “mortar” in the stratum corneum?
Bricks: dead cells
Mortar: lipid
Are dead cells permeable?
No
How does permeation of the skin occurs and how does this relate to hydration?
Permeation occurs by partitioning through the lipids (mortar) between dead cells (bricks)
-State of hydration is directly related to the ease of permeation
What is the second layer of the skin (moving from outward to in)?
living epidermis
What distinguishes the epidermis from the dermis?
The epidermis is living cells without capillaries
*also the source of skin color and tanning
What layer of skin much drug reach to have systemic action?
Dermis
What characteristics distinguish the dermis from the other layers of skin?
-Contains capillaries**
-Contains pain, thermal, and tactile sensors
-Injury must reach dermis to scar!
What is the purpose of hair follicles and sweat glands in absorption?
They are a secondary route of absorption that bypasses the stratum corneum
What is emolliency?
The softening of horny tissue
(stratum corneum topical effect)
What is keratolysis?
Chemical digestion and removal of horny tissue
(stratum corneum topical effect)
What is an example of an antiperspirant and how does it work?
Aluminum Chloride
-irritates and closes the orfices of eccrine glands to impede sweat flow
What is an example of a topical medication used for acne treatment?
Retinoids
-reset the process of epidermal proliferation and differentiation
-prevent lesion formation
Rank the bases of ointments from most hydrophobic to most hydrophilic
Hydrophobic
-Hydrocarbon bases
-Silicone bases
-Absorption bases
-Water bases
Hydrophilic
What are examples of hydrocarbon bases?
-Petrolatum
-Polyethylene dissolved in mineral oil
What do silicone bases contain?
Polydimethylsiloxane oil
What do absorption bases contain?
W/O emulsifiers
(emulsion with aqueous solution of drug)
What is an example of a water soluble base?
Polyethylene glycol ointment
What is a paste?
An ointment with a high concentration of insoluble particulate solids added
What are the two types of creams?
O/W or W/O emulsion
What is a gel?
A liquid phase trapped in a matrix of natural or synthetic polymer
What is a rigid foam?
Air or other gas emulsified in a liquid phase
*liquid phase may contain drug
Ex: aerosol shaving cream, antiseptic foam
How does hydration affect drug permeability?
More hydrated = more drug permeability
How does iontophoresis work to enhance penetration?
Uses low voltage electrical current to drive charged drugs through skin
How does electroporation work to enhance penetration?
Uses high voltage to create transient pores in skin
How does ultrasound work to enhance penetration?
Uses low frequency ultrasonic energy to disrupt the stratum corneum
How do ionic surfactants work as penetration enhancers?
Disorder the lipid layer of the stratum corneum to swell and leach out structural components, reducing diffusional resistance
How do reducing agents work as penetration enhancers and what are some examples?
Disrupt disulfide bonds of proteins in keratinized cells
-Ascorbate and Dithiothreitol
What is azone and how does it work as a penetration enhancer?
-Nonpolar oily liquid that fluidizes the lipid region of the stratum corneum
What is DMSO and how does it work as a penetration enhancer?
-Dipolar solvent
It enters the aqueous region of the stratum corneum and interacts with the lipid polar heads to expand the hydrophilic region between the polar heads
What are microneedles used as?
-Pretreatment to increase skin permeability before a drug patch is applied
-Coated with drug that is released from the needles after they are embedded into the skin
What is it called when microneedles are used right before applying a drug-loaded patch?
“poke with patch”
What is it called when microneedles are coated with a drug and then embedded into the skin?
“coat and poke”
What are some common errors in transdermal patch administration?
-Preparation
-Removal
-Application
-Monitoring
-Storage and disposal
What are the black box warnings for the Xulane patch?
-Cigarette smoking and serious cardiovascular risk
-Risk of venous thromboembolism
-PK profile of ethinyl estradiol
Compared to women that take oral contraceptives:
-Higher steady state concentration and lower peak concentration
-AUC and Css are 60% higher
-Cmax is 25% lower
What factors affect drug solubility?
-Hydration (more hydrated, greater permeability)
-Solubility of drug in stratum corneum
-Excipients
-pH
