Second lecture set Flashcards
Key ingredient(s) for controlling drug delivery
Coating
applied to the outside of solid dosage form to provide the following
- protection of the agents from air or humidity
-mask taste
-special drug release
-aesthetic
Key ingredient(s) for controlling drug delivery
Disintegrates, coating, and lubricants
Aqueous film coating generally contain
film-forming polymer
plasticizer to produce flexibility and elasticity of coating
colorant and opafier
vehicle
Reasons for Enteric coating
It is added to prevent the release of an API in a region where it may undergo breakdown
1. to prevent API from gastic fluids
2. to prevent gastric distress from the API
3.Target API delivery to a site in the intestines
4.to provides a delayed release
5. to deliver the API in a higher local concentration in the intestines where it may be absorbed and have a higher bioavailability
What is sustained release
The onset of the pharmacologic action is delayed, but its therapeutic effect has a sustained duration
What is controlled release
It implies a reproducibility and predictability in the drug release kinetics
Allows us to maintain a narrow drug plasma concentration-steady state
Examples of controlled release formulations
- Coated beads (controlles release by programed erosion)
-Multitablet system (tablet in gelatin)
-Microencapsulated (solid,liquid, or gas are encapulated in wall material which allows spreading on micriparticles across absorbing surface.)
-Drug Embedding in a hyrophilic matric/ slowly eroding (Release is controlled by erosion rate)
What is Steady state
The rate going into the body must be equal to the disposition
what are the characteristics needed for best oral controlled release formulation
- Must exhibit neither slow or fast absorption or excretion
- Uniformly absorbed from the gastrointestinal tract
-Administered in relatively small doses
-Have good safety/therapeutic window
-Chronic therapies better suited than acute
What are physiological factors affecting absorption
- absorbing surface area
-residence time at absorption site - pH changes in Lumen
-permeability/(perfusion) - dietary effects
-Protein binding
-biliary uptake and clearance
Different types of epithelia
- simple squamous
- simple columnar
-translational-comprised - stratified squamous
where can simple squamous epithelia be found?
This thin layer of flattened cells mostly line blood vessels-placenta
Where can simple columnar epithelia be found?
This is usually found in the GI tract
Where can translational- comprised epithelia be found?
comprised of several different layers with different shapes and usually found in areas that stretch
Where can Stratified squamous epithelia be found?
Comprised of layers of squamous cells
Usually found in areas subject to wear and tear-skin is one type that the barrier function comes from keratinization
Explain the composition of biological membranes
- All living cells are enclosed by one or more membranes, this defines the cells as the living unit
- the membrane isolates the cellular contents from the environment (The membrane forms a barrier)
-Membrane is semi-permeable, this helps to permit the rapid passage of some chemicals while preventing the passage of others
-cellular lipid composition is polarized
-intracellular membrane lipids are different then extracellular lipids
Does cholesterol only have harmful effects on membranes?
NO
-cholesterol provides fluidity at lower levels
- When it exceeds a certain level the membrane undergoes a phase transition and forms a liquid crystalline state (known as atherosclerosis when occuring in the vasculature)
Membrane and Cell-Based assays
P(app)= ((delta)Q/(delta)t)/(AC(o)60)
(cm*sec)^-1
deltaQ/delta t = amount of compound appearing on the receiver side as a function of time
A= surface area of the filter support
Co = initial concentration of compound applied to the donor side
Explain 2 types of intestinal transport mechanisms
Passive (non-saturable)
- paracellular (between cells)
-Transcellular (through cells)
Carrier Mediated (saturable)
- Active (energy dependent)
- Facilitated diffusion (energy independent)
What are drug transporters and what are their roles
- Drug transporters are membrane bound proteins widely distributed throughout the body, prominently on apical and basolateral surfaces of organs involved in clearance
- They are used to move important molecules across the membrane ( like drug molecules)
- Crucial determinant of tissue and cellular distribution of drugs not only for drug clearance but also sanctuary organs
- variations in drug transporter activity can be major determinants of drug response and drug safety
Solute Carriers
- these are nutrient and xenobiotic transporters
- contain 43 subfamilies
- > 300 members identified
- generally influx or secretory efflux transporters
- PepT1, OATs, OATPs
ATP-Binding cassette (ABC)
-7 subfamilies
- 50 membrers presently identified
- generally efflux-multidrug resistant transporters
- P-glycoprotein, MRPs
Absorption
What are the routes of permeability
-Influx transporter mediated
-Passive transcellular
-Passive transcellular and efflux
-passive paracellular
-metabolism
-Efflux of the metabolites
- Metabolism generally works to deactivate a compound and make it more polar so it can be excreted by the body
IMPORTANT TO NOTE
- many potential different combinations of these parallel routes of metabolism that can contribute to net absorption of a drug
- Drug physiochemical properties will dictate the number of potential permeation routes that may govern absorption
Define influx
Transporters that transfer substrates into a cell
Define Efflux
Transporters that transfer substrates out of a cell
Define Absorptive
Transporters transfer substrates from the lumen into the systemic blood circulation or vice-versa from the blood into an organ when discussing endothelia and organ distribution
Define Secretory
- Transporters transfer their substrates from the blood circulation into bile, urine. and/or the GI lumen for excretion
Characteristics of Passive paracellular permeation
- hydrophilicity
- Molecular size and shape
- pKa of the ionizable groups
- linear increase in permeability with increasing concentration
-Adjuvants can open tight junctions and increase transport
Characteristics of facilitative/ Active transcellular permeation
-Affinity (Km), Capacity (Vmax/ J max)
- Concentration dependent saturation
- Expression level (constitutive, induced)
Function (Drug- drug & drug nutrient interactions, competitive inhibition)
Excipients like surfactants can limit the effects of efflux by Pgp or BCRP
Characteristics of Passive Transcellular Permation
- lipophilicity ( hydrogen bonding potential, Hydrophobicity)
- Molecular size and shape
- pKA of the ionized groups
-Linear increase in permeability with increasing concentration - Dissolution/ solubility limited with high lipophilicity
GI Tract epithelia
Oral cavity
buccal (Stratified squamous epithelium) and sublingual (simple squamous epithelium)
GI Tract epithelia
Esophagus
comprised of stratified squamous epithelium
Trachea is comprised of psuedostratified squamous epithelial cells
GI Tract epithelia
Stomach
comprised of predominantly columnar epithelial cells, mixed with other cell types like mucus producing goblet cells, and parietal (acid secreting) and enterochromaffin-like (histamine secreating) cells
GI Tract epithelia
Small and large intestines
lined with predominantly columnar epithelial cells. These cells are mixed with many different cell types
GI Tract epithelia
Rectum
upper (simple columnar)
Lower (stratified squamous non-kertinized region transitioning to stratified squamous keratinized region near the anal sphincter) half.
What is the role of the stomach
To digest food and control the flow of its contents into the intestine
- regulates food delivery to intestine
-pH protects against most bacteria, allows pepsin to function
-Acts as food reservoir
Characteristics of the stomach
Fasted pH is normal, healthy adults <3
Fed pH is the range of 5 to 7
Gastric emptying half-time is about 30min
Fasted emptying cycles through 4 phases culminating with a “housekeeper” wave.
Fed state, no defined cycle
What are the Three regions of the stomach and explain them
Fundus- Contains gas and produces contrations to move stomach contents
Body- reservoir for ingested food and fluids
Antrum- lowest part of the stomach, funnel shaped, contains the pyloric region and controls flow into the small instestine
Characteristics of the Intestine
Most transporters are located in SI
Upper SI= mixing
Lower SI= electrolyte
Colon= fluid and electrolyte absorption
What is the Mouth to anus transit time
24-32 hours
What is the small intestinal transit time
3 hours
Where does most absorption occur
Small intestine
what is the small intestinal pH
5.0-6.5
where does colon drug absorption mainly occur
the ascending region nearest to the SI
what causes increased surface area in the small intestine
villi and folding in the small intestine
describe columnar epithelium
Form a single continuous layer of absorptive cells covering each villus
columnar epithelium Crypt region
3x more crypt then villi, comprised of undifferentiated cells that proliferate
- goblet cells, paneth cells, argentaffin cells
Columnar epithelium Villus region
Absorptive enterocytes
few goblet cells do appear as well as M cells
cells from the crypt migrate to the villus top and are extruded-sloughed off at the tip enterocyte lifetime
Characteristics of the colon
125 cm long
- ascending (20cm)
-traverse colon (45cm)
-Descending (45)
- rest is sigmoid
-varies in thickness from 2.5cm in the sigmoid region to 8.5cm in the caecum
-ileocaecal valve limits food flow from the ileum into the caecum and vice versa
- Colon is responsible for water and electrolyte absorption (caecum, ascending colon)- prevents dehydration and leads to formation of solid fecal matter
describe the Colon structure
-serosa-squamous epithelium covered with adipose tissue
- Muscularis Externa-inner circular muscle layer and incomplete outer longitudinal layer
Colonic mucosa- Three layers
- muscularis mucosae
-lamina propria
- epithelium
Proximal colon is usually where enteric coated formulations target by oral administration
- Distal colon- rectal administration, e.g. suppositories
describe the Colon structure
-serosa-squamous epithelium covered with adipose tissue
- Muscularis Externa-inner circular muscle layer and incomplete outer longitudinal layer
Colonic mucosa- Three layers
- muscularis mucosae
-lamina propria
- epithelium
Proximal colon is usually where enteric coated formulations target by oral administration
- Distal colon- rectal administration, e.g. suppositories
Slide 70
relationship between stomach emptying rates and colonic retention
stomach and colonic region appear to correlate quite well over fairly extened time periods
describe the rectum
upper - simple columnar
lower- stratified squamous non-keratinized region which becomes keratinized near the anal sphincter
The stratified squamous non keratinized epithelium allows high drug absorption
multiple drugs that can be delivered rectally
residence time
GI characteristics in Man
what is biorelevant dissolution time?
GI characteristics in Man
What are the mean residence times?
GI Transit time variation
Absorption of a drug varies through out population
gastic residence differs dramatically
Gastric emptying controls colonic absorption, where greater GI residence leads to higher absorption
characterization of GI luminal fluids
Jejunum - pH 7.08(+-) o.54 | Buffer capacity - 3.23(+-)1.26 | Bile salt content - 2.88 (+-) 1.8
Ileum - pH 7.8 | Buffer capacity - 6.4
Colon - pH 8.1(+-) 0.53 | Buffer capacity - 36.2+-)7.92
What are factors that influence drug solubility
- buffer capacity
-bile salts - regional fluids
- other drugs
- potential issues from endogenous substrates
What are the challenges that arise from assumptions of the GI physiology
- the transporters and enzymes along the GI tract vary
- Diet and chemical exposure varies
- variability is enormous in GI fluid composition
-drug- nutrient and drug-drug interactions are common - microbiome
-pharmacogenetics and genomics are a huge issue
ADME(T)
Absorption
Distribution
Metabolism
Excretion
Toxcicity
Critical points:
- disposition is comprised of distribution and elimination
- elimination describes the removal of the drug from the body and includes ME
what is the nature of pharacokinetic processes
simple PK analyses often treat the different compartments as kinetically simple tissues or spaces. This is not always true, and advance PK analyses beyond the scope of this module can then be applied.
- Process can be reversible or irreversible
- process can be linear or nonlinear
Define Bioavailability
Refers to the rate and extent of drug absorption
Define Absolute Bioavailability
The AUC of a given dosage form compared with the AUC of the same dose injected intravenously
AUC= Plasma level vs. Time curve
Define relative bioavailability
Refers to the AUC of a given dosage form compared to an arbitrary reference standard
Define Bioequivalent
does not mean that the therapeutic effect of two dosage forms are equivalent
True or False
Bioavailability is the fraction of an administered dose that reaches the systemic circulation intact.
True
True or false
Dosage forms are designed to convey performance by balancing the composition of the excipients, the drug’s physicochemical properties and to overcome the physiological barriers required for a safe and efficacious response.
True
True or False
When blinding clinical trials, it is often important to mask the organoleptic properties of the comparator and the drug being tested. These senses include sight, smell, taste, touch, and sound.
True
True or False
The stomach has a significantly increased surface area due to villi, folds of Keckring, and microvilli.
False
True or False
Drug levels observed in the therapeutic window can be governed in part by transporters and metabolism, based on the compound being studied. Therefore, transporters and enzymes do not play an important role in drug product performance.
False
True or False
The microenvironmental pH at the membrane surface may be different than the lumen based on the fact that the mucus and the glycocalyx have buffering effects.
True
All of the following can reduce the bioavailability of an orally administered drug EXCEPT:
1.Poor dissolution in the GI tract
2.Poor penetration of the blood-brain barrier
3.Chemical degradation in the GI tract
4.Poor solubility in the GI fluids
5.Poor absorption across the GI mucosa
2
Which is NOT included in the acronym of ADMET?
1.Excretion
2.Toxicity
3.Metabolism
4.Dissolution 5.Distribution
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