advanced drug delivery oral route

Question 1

what are the aims and objectives of new technology in oral drug delivery?

Answer 1

aims:

Deliver drugs at time of peak clinical need

Deliver drugs in the part of the GIT where they are best absorbed

deliver drugs continuously along the GIT: sustained release to maintain drug concentration in the blood for a long period of time.

Objectives to achieve the aim:

develop a technology that introduces a lag period before drug release: e.g. If we need a drug to be released in a specific area in the GI tract , we would need to introduce a lag time that is long enough to overcome the transit in the stomach.

identify triggers for drug release after a lag period: developing tricks to control the release.

Question 2

which area in the GI tract should be targeted the most for oral drug absorption and why is this?

Answer 2

portal vein - because 31.5 percent of the drug can be absorbed here

jejunum 1 - because 20 percent of the drug can be absorbed here

duodenum - because 9 percent of the drug can be absorbed here

Question 3

what is the main function of the:

stomach

small intestine

large intestine

Answer 3

stomach: digestion

small intestine: absorption of nutrients

large intestine: reabsorption of water, formation and elimination of faeces.

Question 4

what are the Physiological factors affecting oral bioavailability?

Answer 4

Transit time

pH

Microflora

Enzymes

Redox potential

Presence of solids and liquids

Question 5

explain how transit time affects oral bioavailability?

which part of the GI tract is the transit time most stable?

Answer 5

the transit time is important because it corresponds to the amount of time that the drug delivery system and the drug would be in contact with the mucosa and therefore in contact with the surface for absorption.

stability:

stomach (very variable): 30 minutes for d<2mm and liquids. 3 hours for d>7mm, up to 10hours with a heavy meal.

small intestine: 3-5hours

colon: 8-15 hours (this is because food is retained in the colon for a prolonged period of time due to contractions)

Question 6

what other variables affect drug transit time in the stomach?

Answer 6

size
 density
 dietary intake (fat)
 posture
 gender
 age
 exercise
 emotional state
 stress
 disease

Question 7

what is the relative pH for these different regions of the GI tract:

stomach

small intestine

large intestine

Answer 7

stomach:

fasted - 1.5-3
fed - 2-5

small intestine :

duodenum fasted- approx 6.1

duodenum fed- approx 6.1

ileum - approximately 7-8

large intestine (result of polycarbohydrate fermentation):

caecum and colon- 5.5-7
rectum - approx 7

Question 8

what is the microflora numbers along the oral route?

saliva

stomach

duodenum:

colon

Answer 8

saliva - 10^7 (aerobes=anaerobes)

stomach - 10^4 - 10^8; 0 when fasted (because pH drops)

duodenum: 10^3 - 10^4 (because peristalsis and bile acid reduce the number)

colon 10^11, only anaerobes ( not much oxygen in the colon)

Question 9

why are majority food absorption and breakdown in the small intestine?

explain how enzymes affects oral bioavailability?

Answer 9

because majority of the enzymes that breakdown food like proteins, lipids and sugars are present in the small intestine.

if the drug target is usually the small intestine because that is where the drug is absorbed into the body and we have to consider the different enzymes when formulating an oral drug

Question 10

how does redox potential affect oral drug bioavailability?

what is the redox potential in the small intestine and colon?

Answer 10

Differences in redox potential between the small intestine and the colon can be used to develop colon specific drug delivery systems.

small intestine = -69 +/- 90mV
colon = -415 +/- 72 mV

Question 11

how does presence of food and liquid affect oral drug bio availability?

Answer 11

Presence of food:

Delayed drug gastric emptying

Drug interactions or binding and complexation (tetracyclines + Ca2+ from dairy products)

Splanchnic blood flow increased 🡪 reduced 1st pass metabolism

Presence of liquids

The amount of liquid present in the lumen decreases along the GIT and it is minimum in the colon

Question 12

what are the advantages of the oral route.

Answer 12

Patient Familiarity 🡪convenience and compliance

Large surface area 🡪 drug absorption

Rich blood supply 🡪 increased drug distribution

Peristaltic movements 🡪 increased mixing

Great volume of fluid 🡪 improves drug dissolution

Prolonged retention for better transit time (see transit time)

Versatility- vast range or formulations available

Question 13

what are the disadvantages of the oral route?

Answer 13

Variability - drug bioavailability depends on so many things

Adverse reactions 🡪local irritation, sensitisation

High enzymatic activity

1st pass metabolism

Extreme pH

Question 14

within the colon describe the following:

_______________ in the proximal colon result in retaining and mixing of the luminal content for a prolonged time, thus causing eventual dosage forms retention in the caecum and ascending colon.

___________divide up the faecal mass in the transverse tract (Watts and Illum, 1997).

In the distal and descending tracts of the colon ____________ prevail. The contraction of circular muscles allows a thorough mixing of the luminal material and confers to the large intestine its sacculated appearance.
_________________ associated with defecation normally occur only three or four times a day and are due to the contraction of longitudinal muscles.

Retrograde contractions
Annular contractions
Segmenting movements
Propulsive movements

Answer 14

Retrograde contractions in the proximal colon result in retaining and mixing of the luminal content for a prolonged time, thus causing eventual dosage forms retention in the caecum and ascending colon.

Annular contractions divide up the faecal mass in the transverse tract (Watts and Illum, 1997).

In the distal and descending tracts of the colon segmenting movements prevail. The contraction of circular muscles allows a thorough mixing of the luminal material and confers to the large intestine its sacculated appearance.
Propulsive movements associated with defecation normally occur only three or four times a day and are due to the contraction of longitudinal muscles.

Question 15

what are the Current Technologies in Oral Drug Delivery

Answer 15

Conventional dosage forms: tablets, capsules, supensions, emulsions, solution, etc.

Prodrugs

Advanced tablet formulations

Advanced pellet formulations

Advanced capsule formulations

pH responsive formulations

Question 16

explain prodrugs as a Current Technologies in Oral Drug Delivery? why are they prepared?

Answer 16

Prodrug: compound resulting from the modification of a biologically active compound.

Prodrugs are prepared in order to:

increase absorption (adding lipophilic moieties)

protect from enzymatic degradation

avoid premature absorption (colonic delivery)

Question 17

give examples of Advanced tablet formulations

as a Current Technologies in Oral Drug Delivery? OGET

Answer 17

1. Osmotic tablets
2. Gellable barrier layers
3. Erodible barrier layers
4. Tablet rupture

Question 18

explain Osmotic tablets as an Advanced tablet formulation

Answer 18

One way of delaying and controlling drug release from a tablet is by exploiting osmotic pressure.

Elementary osmotic pump: The core is a single layer tablet containing a water soluble drug with or without osmotic agents that are excipients able to recall water from the outside.

Water from the GI enters though the membrane to the core, the drug is dissolved and pumped out through the exit orifice.

This system is very simple but it is good only for soluble drugs.

Question 19

osmotic tablets is only good with soluble drugs, meaning it has problems with non soluble drugs, how is this problem solved?

Answer 19

Another way of overcoming the problems encountered in the delivery of poorly soluble drugs is by using the push-pull system.

where the Tablet is divided into:

DRUG LAYER containing the poorly soluble drug, osmotic agent and suspending agent

PUSH LAYER containing and osmotic agent and swellable polymer

Question 20

explain the use of Gellable barrier layers in an Advanced tablet formulation.

what is the typical barrier used for this?

Answer 20

Delayed drug release can be obtained by using a gellable layer.
Drug release can start only after complete hydration of the outer layer when the water reaches the core dissolves the active and transports it outside by diffusion, the delay will depend on:
the nature of the polymer
the thickness of the layer

Drug release profile will be sustained release after a lag time

the typical barrier used is HMPC or Hypromellose

Question 21

explain the use of erodible barrier layers in an Advanced tablet formulation.

Answer 21

same with gellable barrier except that the barrier would erode away and the drug will then release as normal.

only induces a lag time but not sustained release

Question 22

where can the principle of Gellable and erodible barriers be applied?

Answer 22

in biphasic drug release

Question 23

explain biphasic drug release

Answer 23

Biphasic delivery systems are designed to release a drug at 2 different rates or in 2 different periods of time: they are either quick/slow or slow/quick. A quick/slow release system provides an initial burst of drug release followed by a constant rate (ideally) of release over a defined period of time.

Question 24

the tablet that has swellable-erodible layers with the drug +HMPC at the core; how is the drug released all through out the GI tract?

Answer 24

Stomach: swelling increases gastric residence time up to 6h, 30% of drug released by diffusion and erosion

Small intestine: constant dissolution for further 6h (40%)

Colon: complete tablet disintegration in 8h, 100% release

Swellable-erodible layers: control surface area diffusion of the drug, the swelling of the hydrophilic core

Question 25

explain tablets that rupture as an Advanced tablet formulation

Answer 25

The tablet core contains a disintegrant

This works as an osmotic agent absorbing water

When the internal pressure is too high the coating ruptures releasing the drug

Question 26

explain Advanced pellet formulations as a Current Technology in Oral Drug Delivery

Answer 26

pellets are normally released into a capsule that opens and releases a number of little pellets, these pellets can be designed in different ways using some of the principles that we have already seen.
we can fill one capsule with pallets of different types, we can therefore obtain different types of release.

Question 27

what are the types of pallet release in advanced pallet formulations

Answer 27

pallets that are designed to provide a sigmoidal shape of drug release: which works by using a combination of a matrix and reservoir, where there is a polymer in the core of the pellet and there is a membrane on the outside. the important pare of the pellet is the membrane which is formed by two different polymers.

the polymers are ethyl cellulose (soluble) + eudragit RS (insoluble).

2. pellets that have a pulsatile release after a lag time depending on the thickness of the coating.
   here the only polymers used in the coating is ethyl cellulose, the core is the drug and a sugar head.
   in this case the drug is released as soon as the coating is dissolved and eroded.

Question 28

what is eudragit and eudragit RS?

Answer 28

eudragit is a polymer that is used for enteric coating.

eudragit RS is a polymer that becomes more and more soluble as the pH incrreases

Question 29

explain Advanced capsule formulations as a Current Technology in Oral Drug Delivery

Answer 29

capsules are called the pulsincap: where there is the capsule, the drug, a swelling agent and a plug
similar to the osmotic system: where there is an area in the system that draws water inside of the system, the area is filled with a swelling agent that will increase in size pushing against the drug compartment.

the plug is formed by a crosslinked gel the gel is absorbing water and is increasing in volume to a point where the plug actually comes off the capsule and the drug is released.

Hydrogel composition and wall thickness control water diffusion and delays drug release
Swelling agent absorbs water and pushed the plug out

Time delay depends on:
Composition and thickness of the wall
Osmotic contents
Length of the plug

this system is used for delayed release.

Question 30

list the components of advanced capsule formulation

how does it work

Answer 30

the cap: is soluble gelatin

the content: is the soluble hydrogel plug, the drug formulation and the expulsion agent

the capsule shell: is water-impermeable ethylcellulose-coated gelatin capsule

gelatin capsule dissolves and the plug swells when in contact with fluids, and starts to slide out of the capsule

Question 31

explain pH responsive formulations as a Current Technology in Oral Drug Delivery

Answer 31

Most used polymers: METHACRYLATES (pH responsive) changes in solubility depending on the pH

it is important for the polymer to be:
pharmacologically inactive
excreted unchanged

Trade name EUDRAGIT®🡪 esters of acrylic and methacylic acid

Different grades of polymers are obtained by mixing monomers in different ratios, acidic+neutral+alkaline

Question 32

what are the different polymers used in pH responsive formulations and what are their applications?

Answer 32

Methacrylic copolymers -COOH (anionic):
Gastro resistance
Delivery to the colon

Aminoalkyl methacryate copolymers -COO-CH2-CH2N(CH3)2:
Taste, odour and moisture protection (dissolves in the stomach)

Methacrylate copolymers -COOCH3 or COOC4H9 (neutral):
Delayed and sustained drug release (insoluble)

Aminoalkyl methacryate copolymers -COO-CH2-CH2N+(CH3)3 3Cl- :
Delayed and sustained drug release

Question 33

describe the controlled release strategy used in the design of Concerta® as an osmotic tablet?

clue: (explain the diagram in slide 20 for lecture 4 9oral drug delivery).

Answer 33

The water dispersible colour overcoat contains and initial dose of drug that is immediately released to establish the initial effective plasma drug concentration. Water build up in the push compartment causes internal pressure to increase and drug (in low concentration) to be initially released from drug compartment 1. The drug at higher concertation from compartment 2 gradually mixes with drug in compartment 1 and provides a middle concentration that is then released at a constant rate.

Question 34

what are the things that researches are looking in oral drug delivery?

Answer 34

Increasing the retention time of DDS in the GIT
🡪 MUCOADHESIVES

Increasing the absorption of poorly absorbed drugs
🡪 ABSORPTION ENHANCERS

Targeted drug delivery
🡪 COLONIC DRUG DELIVERY

Question 35

where is the main target of oral drug delivery?

Answer 35

the colon

Question 36

what are the reasons behind the colon being the target site for oral drug delivery?

Answer 36

Opportunities for drug delivery:
6.0 < pH < 7.4

long residence / low mixing

prevention of nausea and vomiting

Opportunities for development of new systems:

local bacteria provide possibility for specific targeting

low activity of peptidases and proteases good for administration of peptides and proteins

high efficacy of absorption enhancers

treatment of
topical conditions
local diseases (ibs)
colonic cancer

site for delivery of proteins and peptides

Question 37

what are the strategies for colonic targeting

Answer 37

pH-controlled systems : pH in the colon is at about 6 or 7

Time-controlled systems:

Pressure-controlled systems

Enzyme-controlled systems

Question 38

explain how pH-controlled systems is used in colonic targeting

Answer 38

Eudragit soluble at pH 6 or 7 can be used for enteric coating of colon targeted systems

pH =7.5 in the small intestine 🡪 can cause early release of drug

Eudragit soluble at pH 7.5 and slowly swelling can be used: in vivo some dosage froms were found not to break down at all

Intra- and inter-individual changes in pH make this systems not reliable

Question 39

explain how Time-controlled systems is used in colonic targeting

Answer 39

refers to transit time, make use of introducing a lag time to get the drug to be released only in the colon even if it sits in the stomach for a long time.

one of the systems is the use of the pulsincap:
These systems are programmed to release the drug after a set lag time

Pulsincap™ was the fisrt system developed

Variability limits the efficacy of these systems

Enteric coating counteracts high inter- and intra-patient variability in transit time.

Question 40

explain how Pressure-controlled systems is used in colonic targeting

Answer 40

Muscular contractions in the gastrointestinal tract generate an internal pressure that varies depending on the location

Higher pressure in the colon can be exploited for specific delivery

Ethylcellulose capsules of different size and thickness have been evaluated

Promising approach but still under development

High pressure in the fed stomach could lead to premature drug release

not a very good strategy

Question 41

explain how Enzyme-controlled systems is used in colonic targeting

Answer 41

Colon (400 species, 1011 CFU, all anaerobes)
(specific enzymes to digest the material not yet digested in the Small Intestine)

structures to coat the drug with in order to be successful in reaching the colon before being degraded and avoid the drug releasing in the stomach:
Di-tri-saccharidases, mucoplysaccharidases, β-gucuronidases, β-xylosidases, α-arabinosidases, β-glucosidases, nitroreductases, azoreductases, deaminases, hydroxylases

the drug sulfasalazine uses enzyme controlled system, it can only be degraded once it gets to the colon.

Question 42

What would be the best strategy to target an anticancer drug to treat colonic cancer?

Answer 42

Orally administered capsule coated with a pH sensitive polymer that dissolves at pH > 6.5 and containing particles (diameter = 200 nm) functionalised with an antibody specific to the tumour

Question 43

You are tasked with proposing a delivery system for the efficacious and safe delivery of a cytotoxic drug for the treatment of colonic cancer. Describe in detail 2 suitable systems:

An oral formulation for local delivery of the drug (50%)
A systemic formulation to be administered parentally (50%)
Each system must be described in detail covering the following points as a minimum:

• How it is designed (diagram) and rationale behind its development.
• Mechanism of drug release/targeting as appropriate.
• Classes of excipients employed and their role.

Answer 43

The student will need to consider targeted drug delivery in both cases, suggesting:

• a colon specific drug delivery system in the case of oral delivery (pH controlled, time controlled, enzymatic degradation, pressure controlled or a combination of these), very importantly the systems should address the need to avoid early release and should rely on a specific targeting moiety as antibodies, and a specific release trigger such as pH of the tumour tissue.
• a system that follows active and/or passive targeting to the tumour for the parenteral formulation, EPR effect should be considered, the system could be particulate or soluble system.

Common mistakes:

• use of oral absorption enhancers: you do not want systemic absorption but local effect in the colon
• description of EPR effect in the GIT: this is not relevant as EPR refers to endothelial permeability not epithelial