Oral Drug Delivery

• Bioavailability

  The rate and extent of the drug reaching the systematic circulation (blood)
• Intravenous route offers direct administration of the drug into the systemic circulation and the all dose administrated become available into the plasma to be distributed to the tissues
• Oral route is considered the most popular route of drug delivery as around 80% of medicines are delivered orally in the form of tablets, capsules, solution, suspensions and emulsions
• Advantages of oral drug delivery

  • Patient: convenience, not invasive and higher compliance
  • Manufacture: well established processes, easy to manufacture and cheap process
  • High surface area available for absorption
• Traditional oral delivery systems

  • Tablets
  • Capsules
  • Soft gelatin capsules
  • Suspensions
  • Emulsions
• Controlled oral delivery systems (sustain and extend drug release)

  • Osmotic delivery devices
  • Controlling drug through membrane control
• Rate-limiting step

  The slowest step in the processes that determine the rate and extent of appearance of the drug into the systemic circulation
• Very poorly water-soluble drugs will require long time to dissolve and hence dissolution is the rate limiting step, while highly soluble drugs has high dissolution and the rate limiting step could be their permeation across the intestinal membrane
• Other potential rate limiting steps, could be the gastric emptying or it could be the rate at which the drug is metabolised (either in intestinal mucosal cells or in liver)
• GIT

  • Muscular tube that extends from mouth to anus, 6 m in length with varying diameter
  • Luminal surface is very rough due to the presence of microstructures known as villi and microvilli, which are finger-like projections that help to improve surface area, leading to increased absorption
  • Change in pH across the tract: very acidic in the stomach, slightly more alkaline in the small intestine, and even more alkaline in the large intestine
• Mucus

  A viscoelastic, translucent gel that acts as a protective layer and is a mechanical barrier, with a large water content of 95% and the other 5% are other ingredients including a glycoprotein called mucin
• Oesophagus

  • Thick muscular layer that joins the oral cavity to stomach, 250 mm long and 20 mm in diameter
  • Has mucus glands, allowing the secretion of mucus, which plays a role in lubricating food and helping it to move down into the stomach
  • Has a pH between 4-6 and rapid transit (1-4 seconds), meaning the drug doesn't stay in the oesophagus for long, so there's less chance for the drug to be absorbed into it
• Stomach

  • Most dilated part and consist of four anatomical regions fundus, body, antrum and pylorus, which is connected to the small intestine
  • Has a capacity of 1.5 L, its main function is storage: when food is eaten, it can be stored in the stomach until it slowly moves into the small intestine
  • Under fasting conditions, it contains 50 mL of fluids, which is mainly gastric fluid
  • Hydrochloric acid, which is secreted by parietal cells, maintain the pH of the stomach between 1-3.5
  • Has a number of enzymes that are in the stomach and start the food degradation process, including pepsin which is secreted by chief cells and helps to break down proteins into peptides
• Pepsin is a challenge for drugs that are nucleotide or polypeptides in nature: hormones such as insulin can't be taken orally as once it reaches the stomach, it'll be broken down by pepsin into amino acids, meaning it won't be effective for the diabetic patient
• Small intestine

  • Longest (4-5 m) and most convoluted part, with a diameter of 25-30 mm
  • Divided into the duodenum (200-300 mm length), jejunum (2 m length), and ileum (3 m in length)
  • Surface area (~200m2) is increased enormously by folds of Kerckring, villi (finger-like projections that are 0.5-1.5 mm in length and 0.1 mm diameter, containing arteriole, venule and lymphatic vessels/lacteal) and microvilli (around 600-1000 brush-like structures that cover each villus)
• GI pH

  • Oesophagus: 6.8, 30 seconds
  • Stomach: 1.8-2.5, 15 hours
  • Duodenum: 5-6.5, 5 minutes
  • Jejunum: 6.9, 1-2 hours
  • Ileum: 7.6, 2-3 hours
  • Colon: 5.5-7.8, 15-48 hours
• Effect of pH on drugs

  • Chemical stability, such as hydrolysis which might result in incomplete bioavailability
  • Rate and extent of dissolution is also affected by pH as extent of ionisation changes throughout the GI tract
  • Absorption characteristics of the drug according to the ionisation status will also change
• Luminal enzymes that can affect oral drug bioavailability

  • Pepsin and protease (might cause degradation to drugs which are protein in nature such as nucleotides)
  • Lipase (might affect the release of drug from fat/oil containing dosage forms)
  • Esterase enzymes (can hydrolyse ester drugs)
• Ways food can affect oral drug bioavailability

  • Alteration of pH (food can act as a buffer, which increases the pH)
  • Simulation of gastric secretions (can degrade the drugs)
  • Competition for absorption (food can compete with drugs for absorption)
  • Increased viscosity of gastrointestinal contents (might result in reducing the dissolution rate)
  • Increased blood flow to the GIT and liver (can result in lower metabolism for some drugs)
• Physiological disorders of the GIT can affect the absorption and hence the bioavailability of orally administrated drugs
• Pre-systemic metabolism

  One of the major challenges that faces the oral drugs is degradation/metabolism by liver enzymes such as cytochrome P450. After the drug absorption from stomach, small intestine and upper colon, it passes into the hepatic portal system prior to reaching the systemic circulation.
• Intensive drug metabolism might result in an ineffective drug, e.g. propranolol is well absorbed but only 30% of oral dose are available to systemic circulation because of the first pass effect
• Mucus and unstirred water layer

  The water content in mucus can act as a barrier, especially for drugs that are lipophilic, so they would be unable to penetrate this water layer. Unstirred water layer is around 30-100 μm in thickness and is created by the incomplete mixing of the luminal contents near the intestinal mucosal surface.
• Mechanisms of drug uptake

  • Transcellular (through the cell membrane): passive diffusion, active transport, endocytosis
  • Paracellular (between the cells)
• Passive diffusion

  For small lipophilic molecules, doesn't require any energy: molecules pass from a region of high concentration (lumen) to region of low concentration (blood), moving along the concentration gradient
• Active transport (carrier mediated transport)

  Drug molecules form a complex with the carrier on the apical side and this complex moves across the membrane to liberate the drug on the other side of the membrane. Drugs are transported against the concentration gradient, facilitated by the energy generated by ATP hydrolysis.
• Endocytosis

  Plasma membrane invaginates and the invagination pinches off to form membrane-bound vesicles that enclose the drug. The materials is usually transferred to other vesicle or lysosomes and digested.
• Paracellular pathway

  Drug molecules are transported through the aqueous pores between the cells, suitable for small hydrophilic molecules with molecular weight of 200Da
• Efflux

  After absorption, some of the drugs molecules get expelled back into the lumen of the gastrointestinal tract via efflux transporters such as p-glycoprotein