Targeted Drug Delivery

Question 1

What does a drug need to be to enter the GI tract?

Answer 1

Soluble
Permeable

Question 2

Name and describe the BCS classification:

Answer 2

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

Question 3

When is a drug considered to be highly soluble?

Answer 3

When the highest dose strength is soluble in < 250 ml water over a pH range of 1 to 7.5

Question 4

When is a drug considered to be highly permeable?

Answer 4

When the extent of absorption in humans is determined to be > 90% of an administered dose, based on mass-balance

Question 5

When is a drug considered to be rapidly dissolving?

Answer 5

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

Question 6

How long does gastric emptying approximately take?

Answer 6

2 hours

Question 7

What is the duodenum?

Answer 7

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

Question 8

What are the 2 types of control release and give an example?

Answer 8

Constant release e.g SR
Targeted release e.g target a particular part of the gut e.g enteric coated

Question 9

What does the onset mean?

Answer 9

The time where the drug gets into the therapeutic window

Question 10

What does the offset mean?

Answer 10

The time where the drug just about comes out of the therapeutic window

Question 11

Name 4 types of controlled release systems:

Answer 11

*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

Question 12

Describe monolith devices:

Answer 12

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

Question 13

Describe a monolith excipient:

Answer 13

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

Question 14

Give an example of a monolith device and how it works:

Answer 14

Geomatrix technology
DIFFUSION
-SWELLS in stomach, 30% released 6 hrs
-EROSION in SI, 40% released 6hrs
-erode in colon, 30% disintegrate 8 hrs

Question 15

What is the drug kinetics for CR drugs?

Answer 15

Zero order
Amount release is proportional to time

Question 16

Give the equation to calculate drug release kinetics:

Answer 16

Mt/M∞ = k √t
M= amount at time
M= total release
k= proportionality constant

Question 17

Describe Membrane limited systems:

Answer 17

Water in, drug out
Core coated with a film

Question 18

Name some typical membrane limited polymers:

Answer 18

Ethylcellulose (water insoluble)
Acrylic copolymers (eudragits, pH responsive)

Question 19

What would need to be added to membrane limited polymers to aid function:

Answer 19

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)

Question 20

What is a danger of membrane limited systems and why?

Answer 20

Danger of dose dumping
If the film becomes compromised

Question 21

What can be added to membrane limited systems to control the release?

Answer 21

Can have many layers, the more the layers the slower the release

Question 22

Name and describe an example of a membrane release system:

Answer 22

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

Question 23

Give the advantages and disadvantages of osmosis controlled systems:

Answer 23

+Wide range of drugs compatible
+Coating is cheap
+Zero order release possible
- Size of hole important so precise size to make is expensive

Question 24

What are advantages and disadvantages of multiple-particulate systems?

Answer 24

+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

Question 25

What are multiple-particulate systems and give an example?

Answer 25

Small granules which are coated in similar to membrane limited, typically loaded into capsule shells
e.g Micropump

Question 26

What are gastro-retentive dosage forms used for?

Answer 26

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

Question 27

What are the types of approaches for gastro-retentive delivery?

Answer 27

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

Question 28

Describe an example floating systems in gastro-retentive systems:

Answer 28

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

Question 29

Describe bioadhesive systems in gastro-retentive systems:

Answer 29

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

Question 30

Describe swelling and extendable systems in gastro-retentive systems:

Answer 30

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

Question 31

What is the colon and its function?

Answer 31

The large intestine
Primarily to remove water

Question 32

Is there any enzymatic activity in the colon and describe?

Answer 32

Yes, associated with carbohydrate breakdown, using anaerobic bacteria

Question 33

What is the pH in the colon?

Answer 33

Fairly neutral
Can be slightly above or below depending on location and individuals

Question 34

Why would you need a controlled targeted delivery to the colon?

Answer 34

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

Question 35

Name different types of approaches for colonic delivery:

Answer 35

Rectal delivery
pH controlled systems
Utilisation of colonic bacterial azoreduction
Utilisation of colonic bacterial polysaccharidases
Timed-release systems

Question 36

Describe rectal delivery as an approach for colonic delivery:

Answer 36

Only reach the descending colon, not the proximal colon, so not good for treatment in that area
Cultural bias

Question 37

Describe pH controlled systems as an approach for colonic delivery:

Answer 37

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

Question 38

Describe one way how the utilisation of colonic bacterial azoreduction is an approach for colonic delivery:

Answer 38

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

Question 39

Describe the structure of sulphasalazine:

Answer 39

Consist of a molecule of 5-aminosalicylic acid (5-ASA) linked via an azo bridge (-N=N-) to a sulphapyridine molecule

Question 40

Describe a second way how the utilisation of colonic bacterial azoreduction is an approach for colonic delivery:

Answer 40

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

Question 41

Describe a third way how the utilisation of colonic bacterial azoreduction is an approach for colonic delivery:

Answer 41

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

Question 42

Describe a way how the utilisation of colonic bacterial polysaccharides is an approach for colonic delivery:

Answer 42

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

Question 43

Describe one way how the timed-release system is an approach for colonic delivery:

Answer 43

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

Question 44

Describe another way how the timed-release system is an approach for colonic delivery:

Answer 44

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

Question 45

How do you measure what the dosage form is doing in the body?

Answer 45

Measure blood levels as a function of time
Gamma scintigraphy- image dose form in the body