Oral drug delivery Flashcards

1
Q

What are the advantages of oral drug delivery?

A

for the patient

  • convenience
  • not invasive
  • higher compliance

for manufacture

  • well established processes
  • easy to manufacture
  • cheap process.

high surface area available for absorption.

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2
Q

What are the types of formulations for oral drug delivery?

A

traditional

  • tablets
  • capsules
  • soft gelatin capsules
  • suspensions
  • emulsions

controlled

  • sustained
  • extended
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3
Q

What is bioavailability? What are the factors affecting oral drug availability?

A

bioavailability

  • the rate and extent of appearance of the drug into the systemic circulation
  • depends on a series of process

rate limiting step - determines bioavailability

  • dissolution
  • absorption/permeation
  • gastric emptying rate
  • drug metabolism rate
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4
Q

What is the GIT? What are its properties?

A

gastrointestinal tract

  • muscular tube extend from mouth to anus
  • is ~ 6 m in length with varying diameter
  • the luminal surface is very rough
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5
Q

What is mucus?

A

mucus = majority of GI epithelium is covered with mucus

  • is a viscoelastic translucent gel
  • has large water content = 95%
  • acts as protective layer and mechanical barrier
  • is removed by abrasion and the acidic or enzymatic breakdown

a primary component is a glycoprotein called mucin

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6
Q

What are the components of the GIT?

A
oesophagus 
stomach 
duodenum
jejunum
ileum
colon, pH 5.5-7.8 , transit time 15-48 hours

small intestine = duodenum, jejunum, ileum
large intestine = colon

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7
Q

What is the oesophagus? What are its properties?

A

is a thick muscular layer join the oral cavity to stomach
- 250 mm long and 20 mm diameter

has mucus glands to secret mucus to lubricate food and protect lower part from gastric acid.

has pH between 6.8 and rapid transit (10-14 seconds)

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8
Q

What is the stomach? What are its properties?

A

is the most dilated part and consist of four anatomical regions
- fundus, body, antrum and pylorus.
- has a capacity of 1.5 L
- transit time = 1-5 hours
- pH = 1.8-2.5
under fasting conditions contains 50 mL of fluids
- mainly gastric fluid

contains

  • hydrochloric acid = secreted by parietal cells to maintain the pH
  • gastrin hormone = released by G cells to stimulate gastric acid and pepsinogen secretion
  • pepsin = secreted by chief cells in the form of its precursor pepsinogen, once activated it breaks down proteins to peptides
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9
Q

What is the function of the stomach?

A

temporary reservoir for ingested food

reduce ingested solids to chyme by the action of acid and enzymatic digestion.
- chyme = semi-fluid mass of partially digested food that is expelled from the stomach into the duodenum

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10
Q

What is the small intestine? What are its properties?

A

small intestine = duodenum, jejunum, ileum
- main site of absorption
properties
- is the longest and most convoluted part = 4-5 m
- has a diameter of 25- 30 mm.

divided into:
duodenum = 200-300 mm in length, pH 5-6.5 , transit time > 5 mins
jejunum = 2 m in length, pH 6.9 , transit time > 1-2 hours
ileum = 3 m in length, pH 7.6 , transit time > 2-3 hours

the surface area of the small intestine increases by

  • folds of Kerckring = inner circular folds
  • villi = contain arteriole, venule and lymphatic vessels/lacteal
  • microvilli = brush like structure that coves each villus
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11
Q

What are the barriers of oral absorption?

A
Gastrointestinal pH
Luminal enzymes
Food
Physiological disorders
Pre-systemic metabolism
Mucus and unstirred water layer
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12
Q

How is gastrointestinal pH a barrier for oral absorption?

A

pH varies along the GIT

  • starts with lower pH of 1-3.5 for the gastric fluid which increases to 3-7 after a meal and gets back to normal after 2-3 hours.
  • intestinal pH is higher than gastric pH due to neutralisation with bicarbonate secreted by pancreas into small intestine

effect of pH on drugs

  • can cause chemical instability = hydrolysis
  • affect rate and extent of dissolution
  • can affect absorption characteristics of the drug according to the ionisation status = must be unionised to pass the lipid bilayer
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13
Q

What are the luminal enzymes? How are luminal enzymes a barrier for oral absorption?

A

pepsin and protease, lipase, esterase, colonic bacteria secrete enzymes

pepsin and protease
- cause degradation to drugs which are protein in nature = nucleotides
lipase
- affect the release of drug from fat/oil containing dosage forms

ester drugs
- susceptible to hydrolysis by esterase enzymes in the lumen

colonic bacteria
- secretes some enzymes that could break drugs = sulfasalazine

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14
Q

How is food a barrier for oral absorption?

A

presence of food can also affect the rate and extent of absorption either directly or indirectly

effect
alteration of pH
- food acts as a buffer = increases the pH which would reduce the dissolution of weak basic drugs and increase it for acidic drugs.

cause stimulation of gastric secretions
- gastric secretions would degrade the drugs
= bile secretion cause by fatty foods forms complexes with neomycin and nystatin

competition for absorption.

increase viscosity of gastrointestinal contents
- result in reducing the dissolution rate.

increase blood flow to GIT and liver
- resulting in lower metabolism for drugs due to saturation of metabolising enzymes
= propranolol

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15
Q

How are physiological disorders a barrier for oral absorption?

A

GIT physiological disorders affect the absorption and hence the bioavailability of orally administrated drugs.

  • local diseases can alter the gastric pH and hence affect the stability, dissolution and absorption of drugs

example

  • patients with ulcerative colitis and Crohn’s disease have lower pH
  • AIDS causes over secretion of gastrin and hence low pH
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16
Q

How is pre-systemic metabolism a barrier for oral absorption?

A

after drug absorption from stomach, small intestine and upper colon, it passes into the hepatic (liver) portal system prior to reaching the systemic circulation.
- the liver is the primary metabolic site and the last barrier for orally absorbed drugs

propranolol

  • well absorbed but only 30% of oral dose are available to systemic circulation because of the first pass effect
  • sustained-release propranolol is even less
17
Q

What are the different enzymes involved in pre-systemic metabolism? What drugs are susceptible to pre-systemic metabolism?

A

enzymes

  • cytochrome P450 - liver enzyme
  • CYP3A4 - gut walls

drugs

  • propranolol
  • atorvastatin
  • lignocaine
  • diazepam
18
Q

How are mucus and unstirred water layer a barrier for oral absorption?

A

before the drug get into the epithelial surface it has to pass across the mucous layer and unstirred water layer.

  • unstirred water layer is around 30-100 μm in thickness - unstirred water layer is created by the incomplete mixing of the luminal contents near the intestinal mucosal surface.
19
Q

What are the main mechanisms for drug uptake?

A

trancellular = can be divided into

  • passive diffusion
  • active diffusion = carrier mediated
  • endocytosis

paracellular

20
Q

What is the process for passive diffusion?

A

transcellular = passive diffusion

  • for small lipophilic molecules
  • molecules pass from a region of high concentration (lumen) to a region of low concentration (blood)

low concentration is maintained by the blood
- concentration in blood, with a large volume of 4-5L in comparison, is very small compared to the lumen concentration

21
Q

What describes passive diffusion? What drugs can be moved by passive diffusion?

A

Fick’s First Law

drugs

  • steroids
  • sex hormones = oestradiol
22
Q

What is the process for active transport?

A

drug molecules form a complex with the carrier on the apical side = carrier mediated
complex moves across the membrane to liberate the drug on the other side of the membrane = released
carrier becomes free and is ready to transfer another drug molecule.

drugs are transported against concentration gradient
- this is facilitated by the energy generated by ATP hydrolysis.

the rate of absorption is proportional with the concentration only at law concentration
- at high concentration the carrier become saturated

23
Q

What drugs can be moved by active transport?

A

amino acid

peptide like drugs

  • penicillin
  • cephalosporins

nuceloside like drugs

  • antiviral
  • anticancer
24
Q

What is the process for endocytosis?

A

primary mechanism of transport for macromolecules

plasma membrane invaginates and the invagination pinch off to form membrane-bound vesicles that enclose the drug
- takes the drug within the cell and the vesicle is transported within the cell

the materials is usually transferred to other vesicle or lysosomes and digested.

25
Q

What are the different types of endocytosis? What is their process?

A

pinocytosis
- engulfment of the extracellular small droplets by membrane vesicles
- fluid and droplets (small macromolecules)
= usually fat soluble vitamins - Vitamin A,D, E and K

phagocytosis

  • engulfment of particles larger than 500 nm (large particles)
  • digested by the lysosomes

transcytosis
- material is internalized by membrane domain and transported across the cell and secreted on the opposite side.

26
Q

What is the process for paracellular transport?

A

drug molecules is transported through the aqueous pores between the cells.
- these intracellular spaces occupy only 0.01% of the total surface area.

suitable for small hydrophilic molecules with molecular weight of 200Da
- calcium ions, mannitol and paracellular markers (bisphosphonate)

27
Q

What is the process for efflux?

A

after absorption of some of the drugs molecules, they get expelled back into the lumen of the gastrointestinal tract via efflux transporters
- p-glycoprotein = p-gp

drugs effluxed

  • digitoxin
  • paclitaxel.