Targeted Drug Delivery Flashcards
What does a drug need to be to enter the GI tract?
Soluble
Permeable
Name and describe the BCS classification:
Class 1- high solubility/high permeability e.g verapamil
Class 2- low solubility/high permeability e.g ketoprofen
Class 3- high solubility/low permeability e.g ranitidine
Class 4- low solubility/low permeability e.g furosemide
When is a drug considered to be highly soluble?
When the highest dose strength is soluble in < 250 ml water over a pH range of 1 to 7.5
When is a drug considered to be highly permeable?
When the extent of absorption in humans is determined to be > 90% of an administered dose, based on mass-balance
When is a drug considered to be rapidly dissolving?
When > 85% of the labeled amount of drug substance dissolves within 30 minutes using USP apparatus I or II in a volume of < 900 ml buffer solutions
How long does gastric emptying approximately take?
2 hours
What is the duodenum?
Regulates the supply of material from the stomach to the small intestine
The diameter of the pyloric opening varies according to the nature of the gastric contents
What are the 2 types of control release and give an example?
Constant release e.g SR
Targeted release e.g target a particular part of the gut e.g enteric coated
What does the onset mean?
The time where the drug gets into the therapeutic window
What does the offset mean?
The time where the drug just about comes out of the therapeutic window
Name 4 types of controlled release systems:
*Monlith devices (solid ‘all in one’ matrix)
-Membrane limited systems (film coating) e.g pH responsive
-Multi-particulate systems
-Gastro-retentive systems (floating or bioadhesive) e.g stays floating on top of the stomach
Describe monolith devices:
Classical form of oral CR
A block of material through which drug is dispersed and releases slowly (hydrophobic/ hydrophilic excipient)
Hydrophilic more common
Hydrophobic used more for implants rather than oral
Describe a monolith excipient:
HPMC- hydroxypropyl methyl cellulose
Cheap, safe, can be compressed into tablet easily, hydrophilic
High degree of swelling with water and drug will slowly dissolve due to a viscous gel layer formed and slow release
Starts with a dry core and the longer it is exposed the more it grows and less is dry
Give an example of a monolith device and how it works:
Geomatrix technology
DIFFUSION
-SWELLS in stomach, 30% released 6 hrs
-EROSION in SI, 40% released 6hrs
-erode in colon, 30% disintegrate 8 hrs
What is the drug kinetics for CR drugs?
Zero order
Amount release is proportional to time
Give the equation to calculate drug release kinetics:
Mt/M∞ = k √t
M= amount at time
M= total release
k= proportionality constant
Describe Membrane limited systems:
Water in, drug out
Core coated with a film
Name some typical membrane limited polymers:
Ethylcellulose (water insoluble)
Acrylic copolymers (eudragits, pH responsive)
What would need to be added to membrane limited polymers to aid function:
Would need some plasitizers to lower the Tg of the polymer to make the film more flexible, or can add water soluble additives which will dissolve away to leave pores in film which drug can escape
e.g hydroxypropylmethylcellulose (SODAs)
What is a danger of membrane limited systems and why?
Danger of dose dumping
If the film becomes compromised
What can be added to membrane limited systems to control the release?
Can have many layers, the more the layers the slower the release
Name and describe an example of a membrane release system:
Osmosis controlled systems
Osmotic pressure can be used to pump a drug at a constant rate from delivery system
Only one pore where drug releases, can control diameter but expensive
Give the advantages and disadvantages of osmosis controlled systems:
+Wide range of drugs compatible
+Coating is cheap
+Zero order release possible
- Size of hole important so precise size to make is expensive
What are advantages and disadvantages of multiple-particulate systems?
+GI transit more consistent than single units
+dose dumping less likely as dose is spread
+decrease gastric irritation as less chance of single side of drug conc in GI
-expensive
What are multiple-particulate systems and give an example?
Small granules which are coated in similar to membrane limited, typically loaded into capsule shells
e.g Micropump
What are gastro-retentive dosage forms used for?
Good if needed to be retained in the stomach for a long period of time
Useful for drugs with a narrow absorption window in intestine
Local action
What are the types of approaches for gastro-retentive delivery?
Effervescent systems that generate gas and float
Low density systems or hydrodynamically balanced systems that float
Bioadhesive devices
Swelling or extendable systems that expand to a size larger than the pylorus
Describe an example floating systems in gastro-retentive systems:
e.g Gaviscon
Used to treat oesophageal reflux
Sodium alginate (guluronic, mannuronic acid natural polymer) with calcium carbonate
On contact with acid forms insoluble alginic acid, complexed with calcium, and carbon dioxide
Describe bioadhesive systems in gastro-retentive systems:
Materials that adhere to biological membranes, such as alginates, cellulose derivatives, chitosan and many others
Mucus composed of glycoproteins (mucins) which are crosslinked and heavily hydrated
Forms a protective layer on all internal epithelial surfaces of GI tract
Possibility of retaining dosage form in specific region of GI tract
Controversy on this
Describe swelling and extendable systems in gastro-retentive systems:
Must be swallowed
Expands to a larger size than the pylorus
Superporous hydrogels – swells in seconds/minutes from normal tablet size to a cylinder circa 4 inches by one inch
High porosity and low density result in large floating system
The hydrogel can be used to entrap slow release dosage forms
What is the colon and its function?
The large intestine
Primarily to remove water
Is there any enzymatic activity in the colon and describe?
Yes, associated with carbohydrate breakdown, using anaerobic bacteria
What is the pH in the colon?
Fairly neutral
Can be slightly above or below depending on location and individuals
Why would you need a controlled targeted delivery to the colon?
Local treatment e.g Crohn’s disease/ IBS
Systemic absorption of proteins as proteolysis is 20-60x less than in the ilea
The extended absorption of molecules
Chronopharmacology- dosing at specific times of day for symptom variation
Name different types of approaches for colonic delivery:
Rectal delivery
pH controlled systems
Utilisation of colonic bacterial azoreduction
Utilisation of colonic bacterial polysaccharidases
Timed-release systems
Describe rectal delivery as an approach for colonic delivery:
Only reach the descending colon, not the proximal colon, so not good for treatment in that area
Cultural bias
Describe pH controlled systems as an approach for colonic delivery:
Enteric coat can be applied
Eudragits- family of copolymers of methacrylic acid and methylmethacrylate
Insoluble in acidic pH, stomach but will be soluble at higher pH like colon e.g Eudragit®-S soluble at pH 7
Describe one way how the utilisation of colonic bacterial azoreduction is an approach for colonic delivery:
Sulphasalazine in treatment of inflammatory bowel diseases
Sulphasalazine shows only limited digestion in or absorption from the stomach or the small intestine and > 85 % is presented intact to the colon
The colonic bacteria then cleave the azo bond generating the independent 5-ASA and sulphapyridine molecules
5-ASA exerts its therapeutic effect locally and is essentially unabsorbed
Azo-polymers with the polymer being linked to the active drug via an azo link used
Describe the structure of sulphasalazine:
Consist of a molecule of 5-aminosalicylic acid (5-ASA) linked via an azo bridge (-N=N-) to a sulphapyridine molecule
Describe a second way how the utilisation of colonic bacterial azoreduction is an approach for colonic delivery:
An azo-linked polymer-drug complex was incorporated into a hydrogel system
As the pH of the GI tract increased, swelling of the gel increased, thus allowing access to the azo bonds, with subsequent cleavage and release of drug
Describe a third way how the utilisation of colonic bacterial azoreduction is an approach for colonic delivery:
Develop a formulation where the core contains the drug and the coat contains a molecule with the azo link, the drug could remain intact until the colonic bacteria would degrade the coat and drug would be released
Describe a way how the utilisation of colonic bacterial polysaccharides is an approach for colonic delivery:
In humans, the colon is the site of degradation of polysaccharides from the diet such as amylose, pectin, guar gum, chondroitin
By incorporating one or more of these materials into the dosage form, it would be expected that colonic targeting could be obtained
Describe one way how the timed-release system is an approach for colonic delivery:
The Pulsincap consists of an insoluble capsule body containing the drug formulation and is sealed with a hydrogel plug- only hydrogel plug is released once in colon
After oral administration the hydrogel plug slowly hydrates and swells until it is expelled from the capsule body, thus exposing the drug formulation for dissolution
Describe another way how the timed-release system is an approach for colonic delivery:
Egalet®
Two component system
A matrix is surrounded by a water-impermeable, non-eroding, hard shell made of polylactic acid (PLA) that creates a cylinder, with the API-containing matrix exposed at both ends
How do you measure what the dosage form is doing in the body?
Measure blood levels as a function of time
Gamma scintigraphy- image dose form in the body
