Road Map 1 Oral Drug Delivery Flashcards
Disintegration
the breaking of a dosage forms into granules then into finer particles
First pass loss
the drug that is lost to metabolism and biliary elimination before reaching systemic circulation
Achlorhydria
disease that causes the stomach not to produce enough HCL
Gastric emptying
the evacuation of food from the stomach into the duodenum
Migration myoelectric (MMC)
electrical and mechanical activity that initiates in the stomach and propagates the length of the small intestine; cycle repeats every two hours until a meal is eaten
Intestinal transit
transit time from duodenum to large intestine (usually 3 to 4 hours); transit time through the colon is 10 to 36 hours
surface area and permeability of stomach
low surface area and poor permeability in comparison to small intestine
surface area and permeability of small intestine
very large surface area due to villi and microvilli; very good permeability due to single layer of columnar epithelium
surface area and permeability of large intestine
lower surface area than the small intestine due to lack of villi/microvilli; less permeable than small intestine
Identify the physiochemical properties needed to have good passive oral drug absorption.
a. Small MW (<500g/mol)
b. Sufficient water solubility to remain dissolved within GI fluids
c. Sufficient lipid solubility (ideally log P between 1 and 3) to permeate into a lipid membrane
d. If weak acid or weak base, some drug needs to be in the unionized state
e. Good stability in the fluids of the GI tract
Dissolution is rate-limiting
i. Drug will have limited water solubility, will dissolve slowly
ii. Results in a limited amount available to be absorbed
iii. The rate and extent of absorption will be greatly dependent upon the formulation of the dosage form
iv. Dissolution can be optimized by the addition of certain excipients or by exploiting certain physiochemical properties
Permeation is rate-limiting
i. Drug will have good water solubility, will dissolve quickly
ii. Results in lots of drugs in solution that is ready to be absorbed
iii. However, drug absorption is limited by the permeation of drug across the cell layer due to limited lipid solubility, high molecular weight, or high fraction of ionization
pH value of stomach and how pH changes
i. pH 1 to 3.5 in the fasted state
ii. Can be affected by
1. Time of day
2. Food (can act like a buffer and make it less acidic; will return to fasted state in 2 – 3 hours
3. Disease (achlorhydria / hypochlorhydria)
4. Drugs (PPIs and H2 antagonists)
pH value of small intestine and how pH changes
i. Duodenum = pH 5 to 6 (stomach acid neutralized by bicarbonate ions within the duodenum; pH gradually rises with progression down the small intestine)
ii. Jejunum = pH 5 to 6.5
iii. Ileum = pH 6.5 to 8
pH value of large intestine and how pH changes
Large intestine pH 6.5 (bacteria break down carbohydrates to short-chain fatty acids, which results in the lowering of pH)
How pH influences solubility
i. pH of the GI fluids greatly influences the solubility of weak acids and weak bases
ii. A drug will be more soluble in GI fluids when it is ionized
1. A weak acid will be more soluble at a basic pH
2. A weak base will be more soluble at an acidic pH
How pH influences permeability
i. Only the unionized fraction of drug can passively permeate across a membrane and be absorbed
1. Weak acids best absorbed from acidic conditions
2. Weak bases best absorbed from basic conditions
Solubility and permeability for weak bases
i. The low pH of the stomach would improve the solubility and dissolution of weak bases by increasing the fraction ionized
ii. Once the weak base reaches the small intestine, a supersaturated solution of drug may form as less of the drug will be ionized
1. Supersaturation occurs when the solution is at a higher concentration than what can be attained under normal circumstances
2. This can lead to some precipitation of the weak base
iii. The weak base will have improved permeability in the small intestine
Factors that increase gastric emptying/intestinal motility
i. Fasted state, more liquids, increase in temperature of food/drink, lying on right side, drugs (reglan, erythromycin, bethanchol), disease state (gastritis)
ii. Prokinetic drugs such as Reglan; results in shorter residence time and less time for dissolution and absorption
Factors that decrease gastric emptying/slow down intestinal motility
i. Fed state, large meal, high fat meal, lying on left side, drugs (anticholinergics, opiates), disease state (Parkinson’s, diabetes, hypothyroidism)
ii. A longer residence time in the small intestine allows more times for dissolution of dissolution-rate limited drugs and more time for absorption of permeability-rate limited drugs
Describe the transit time through the small intestine and large intestine. Explain how changes in intestinal transit influence drug absorption.
a. Transit time from the duodenum to large intestine is 3-4 hours
b. Transit time through the colon/large intestine is 10 to 36 hours
i. Transit time can increase or decrease with certain disease states (gastritis, IBD, IBS, GI surgery, etc)
rate
how quickly drug will be absorbed
extent
the total amount of drug absorbed
How the presence of food in the GI tract alters rate and extent of drug absorption
i. Delay gastric emptying
ii. Change gastrointestinal pH
iii. Change solubility
iv. Increase blood flow to GI tract
v. Change luminal metabolism of a drug substance
vi. Decrease transporter activity
vii. Physically or chemically interact with a dosage form or a drug substance
Possible food effects (dependent on the physiochemical properties of the drug molecule)
i. No change
ii. Decrease rate of absorption (increase Tmax)
iii. Decrease extent of absorption (decrease AUC, F)
iv. Increase extent of absorption (increase AUC, F)
Food effects on Class I Drugs
i. Administration with food may slow rate of absorption (increase Tmax) due to delaying gastric emptying
ii. Expect no effect on the extent of absorption
Food effects on Class II Drugs
i. Administration with food may slow rate of absorption (increase Tmax) due to delaying gastric emptying
ii. Can increase extent of absorption by improving solubility (secretion of bile salts and phospholipids in bile)
Food effects on Class III Drugs
Components in food and in the bile can inhibit intestinal uptake transporters needed for absorption (can result in a decrease in extent of absorption)
Class I Drugs
good solubility, rapid dissolution rate, good permeability
Class II Drugs
poor solubility and slow dissolution
Class III Drugs
good solubility, poor permeability/metabolism
