Workshop: Biopharmaceutics of Oral Dose Formulation

Question 1

how much gastric fluid is in an emptying stomach?

Answer 1

100mL

Question 2

what is dissolution?

Answer 2

dose form -> disintergration of granules -> deaggregation into fine particles -> solubilised molecules absorbed

Question 3

what is a simple model of dissolution?

Answer 3

• When a drug is rapidly absorbed or partitioned into another compartment, the concentration [C] decreases with distance
• As drug molecules diffuse away from the saturated diffusion layer into the bulk fluids, new drug molecules replace them, rapidly saturating the diffusion layer (sink conditions)
• The rate of dissolution is the rate limiting step under these conditions
• Where we have sink conditions, we can assume first order kinetics: C] intestine > [C] blood

Question 4

what is permeation?

Answer 4

• Small hydrophilic compounds permeate through paracellular water channels  few drugs actually do this
• Lipophilic compounds permeate by partition into and through the lipid bilayer of biological membranes (transcellular route)  in some circumstances
• Some compounds permeate via membrane transporters  this is increasingly being observed and includes drug efflux transporters
• Transport through other epithelial and endothelial barriers (e.g. BBB) relies on more advanced understanding and novel drug delivery methods
• Large compounds e.g. synthetic peptides and protein-based biologics raise a number of problems

Question 5

what is carrier mediated transport/

Answer 5

• Carrier mediated facilitated and active transport: the absorption rate is assumed to be the rate of carrier mediated membrane transport
Absorption rate = VmaxC/(Km+C)
• C is the free (un-complexed) drug concentration at the site of absorption (ie GI luminal side of the bio membrane of the epithelial cell)
• Km is a constant relating to the affinity of the carrier binding the drug (cf enzymes kinetics)
• Vmax is a ‘constant’ relating to the maximum rate of transport or saturation of the carrier (cf enzyme kinetics)

Question 6

how does a change in solubility in different gut regions affect its absorption?

Answer 6

decrease in solubility as you move from stomach to duodenum, it does decrease hundred-fold but it would still be okay, but after duodenum is increase again – this is because it is ionised again at these pH as it has two ionisation points. We have a biphasic pH solubility profile  due to drug possessing two pKa values, acidic pKa 1.7 and basic pKa 7.9. Lowest solubility seen at pH 3.5.

Question 7

what is the consquence of food on absorption?

Answer 7

drug solubility differs by a factor of 100 over pH range 1-3 hence this may cause variable absorption, depending on the pH of the fasted or fed stomach of the patient

Question 8

what is the consequence of formulation on absorption?

Answer 8

wide difference in drug solubility over the pH range 1-3 may cause difference in the rate or extent of dissolution from different formulations

Question 9

how does permeabiluty and logD affect absorption/

Answer 9

Permeability and drug LogD
• In highly acidic conditions (stomach)  drug exhibits high solubility yet unfavourable logD/ permeability due to lower surface area in the stomach
• In less acidic conditions (duodenum 4-6)  drug exhibits a moderate but lower solubility yet a greater absorption in this region – due to an increased logD value and high permeability, when absorption provides sink conditions due to an increase surface area
• In basic conditions (colon 6-8)  the moderate solubility and permeability in the ileum and the increased solubility and lower logD/permeability, in the colon are also expected to contribute to bioavailability.

Question 10

what is a class i?

Answer 10

high sol

high perm

Question 11

what is a class ii?

Answer 11

low sol

high perm

Question 12

what is a class iii?

Answer 12

high sol

low perm

Question 13

what is a class iv?

Answer 13

low sol

low perm

Question 14

A weakly basic BCS class II drug has decreased bioavailability when administered in an immediate release oral dosage form. Which is a possible cause of the decreased bioavailability?

Answer 14

The dose was taken on an empty stomach – decreased solution and therefore decrease bioavailability

Question 15

what are drug solubility issues?

Answer 15

• BCS class I drugs are generally clinically effective in immediate release or controlled release formulations
• Poorly soluble Class II and IV drugs cause problems for pharmaceutical development
• Increased use of combinatorial chemistry and high throughput drug screening means that up to 40% of new compounds are poorly soluble or lipophilic
• There is a greater reliance on patented formulation processes to address poor solubility
• In addition, more poorly soluble drugs are now off patent and require more cost-effective formulation solutions to make the products financially viable in a competitive and price-sensitive market

Question 16

what are drug solubiluty issues in formulation?

Answer 16

Low solubility compounds create many problems during formulation, including:
• Severely limited choice of delivery technologies
• Increasingly complex dissolution testing
• Limited or poor correlation with in vivo absorption
The difficulties of achieving predictable and reproducible in vivo/in vitro correlations are often severe enough to halt product development

Question 17

Newly synthesised drug compounds may have solubility and permeability issues that halt drug development. Which =would be LEAST likely in the case of a drug with poor solubility and high permeability?

Answer 17

Increased bioavailability – this drug is poorly soluble so you might not get much absorption in the stomach

Question 18

what factors affect solubily and permeability?

Answer 18

• Wettability – measurement of contact angle
• Surfactants – wetting, solubilisation and permeability enhancing
• Particle size – smaller size increase effective surface area
• Solid dispersions – eutectic mixture with water soluble carrier
• Polymorphs – different solubility, melting point and dissolution rate
• pH solubility – weak acid and bases vary as a function of pH
• Soluble prodrugs – of poorly soluble drug eg nordiazepam replaced with clorazepate, acid degraded to nordiazepam
• Complexation – by excipients, GI mucin, food etc
• Adsorbents – reduce drug available, unless readily reversible
• Viscosity- enhancing agents, complex drug, increase residence time
• Degradation – acid or enzymatic hydrolysis (eg Penicillin G, erythromycin) reduce drug available for absorption
• Diluents – hydrophilic diluents for hydrophobic drugs

Question 19

what major issues are caused by poor solubility?

Answer 19

• Poor oral bioavailability
• Suboptimal dosing
• Food effects: variation in bioavailability in fed vs fasting states
• Lack of dose response proportionality
• Inability to optimise lead compounds
• Harsh excipients required e.g. excessive use of co solvents
• Use of extreme basic or acidic conditions to enhance solubilisation
• Uncontrollable precipitation after dosing
• Patient non-compliance due to inconvenience of formulation and/or dosing regimen

Question 20

what are cyclodextrins?

Answer 20

• CD have a hydrophobic interior and hydrophilic exterior, so form complexes with hydrophobic compounds
• They are formed by
• Supersaturating a CD solution with drug, with agitation
• Kneading a drug/CD/solvent slurry to a paste, which is dried and sieved
• Hydrophilic polymers e.g. HPMC improve the solubilising effect of CDs, so less CD is needed to solubilise the same amount of drug
• Few oral CD-based drug products are on the market because they have toxicity and stability issues

Question 21

what are amorphous solid dispersions?

Answer 21

• Amorphous compounds are more soluble, but are more unstable and prone to recrystallization
• Amorphous compounds can be created by formulation with polymers
• Spray dry using solvents or replace with supercritical fluids
• Hot melt extrusion: soften polymer, add drug and mix as the dispersion flows through the extruder; rapidly cool and extrude to form strands of polymeric glass with embedded API; mill glass strands into a powder

Question 22

what are polar excipients?

Answer 22

• polyethylene glycol
• gelatin
• sugar glass
• lipids

Question 23

what is polyethylene glcyol

Answer 23

• Liquid PEG can be used as a co-solvent in liquid-based dosage forms to prevent precipitation of compounds that are poorly soluble in aqueous formulations
• Suitable for topical and parenteral administration
• Acts as a wetting agent or enhances dispersion of solid dosage forms; incorporated by solvent evaporation or freeze drying
• Can be used in combination with other excipients e.g. stearic acid, sodium lauryl sulfate

Question 24

what is gelatin?

Answer 24

• A naturally derived collagen extract with both positive and negative charges , which bind to the poorly soluble compound
• Can be used to improve the wettability of hydrophobic compounds when used as a granulating agent

Question 25

what is sugar glasses?

Answer 25

• A naturally occurring fructose polymer, safe for parenteral and pulmonary use, GRAS status for oral formulations
• Mixing an inulin solution with a drug solution, followed by freeze drying, creates a sugar glass
• Sugar glasses improve the dissolution profile of the drug and protect it from physical and chemical degradation, increasing stability
• Sugar glasses are used in the formulation of cyclosporin, diazepam, amoxicillin, bacitracin, tetrahydrocannabinol

Question 26

what is particle engineering?

Answer 26

• Reducing particle size increases surface area and usually improved dissolution properties, enabling the use of a wider range of formulations and delivery approaches
• Recrystallization of poorly soluble materials using liquid solvents and anti-solvents to reduce particle size requires organic solvents for processing, increasing the complexity of manufacture
• Conventional comminution and spray-drying rely upon mechanical stress to disaggregate the active compound
• This puts significant amounts of stress on the drug product and may induce degradation or thermal stress
• This approach is therefore not suitable for thermo-sensitive or unstable compounds

Question 27

how does particle size and surface area affect absorption?

Answer 27

Higher absorption in small intestine because of higher surface to mass ratio of small particle suspension, and greater dissolution in the transit time through the small intestine – window of absorption.
Nanoparticles have a much higher surface to volume ratio. The smaller particles will dissolve much more quickly

Question 28

what is nanoparticulation?

Answer 28

• Traditional methods of comminution, such as grinding and milling, are often incapable of reducing the particle size sufficiently for nearly insoluble drugs (<0.1mg/ml)
o Micro-milling may operate down to sub-micron sizes, with physical and thermal stresses
o Piston gap methods create drug nanoparticles through hydrodynamic cavitation
• Supercritical fluids (SCFs) create nanoparticles by control of solubility using pressure and temperature in solvents such as carbon dioxide

Question 29

what is supercritcal fluids?

Answer 29

Supercritical fluids are used in manufacture as an effective means of producing different sizes and shapes of drug particles.
Supercritical fluids (eg carbon dioxide, water) at a temperature and pressure above their thermodynamic critical points, assume the properties of both a liquids and a gas.

Question 30

Supercritical fluid processes are emerging as alternatives to produce small drug particles by re-crystallization and precipitation processes.

Answer 30

SCFs are highly compressible, allowing small changes in temperature and pressure to alter density and solvation power

Question 31

what are self emulsifying systems?

Answer 31

• Dosage forms are often liquids, which are packaged in soft- or hard-shelled capsules
• Non-ionic surfactants improve drug solubilisation and prevent drugs from precipitating out of the micro-emulsion
• Tweens (polysorbates) and Labrafil (polyoxyethylated oleic glycerides) with high hydrophile-lipophile balances (HLB) are used to ensure an immediate formation of oil-in-water droplets during production
• Co-solvents/surfactants e.g. ethanol, PEG, propylene glycol are used to increase the amount of drug dissolved into the lipid base
• Solid products are suspension-dried to obtain stable drug particles in powder form e.g. Eurand’s nanolipispheres – a stable colloidal micro-emulsion suspension of sub-micron drug particles in a solid lipid matrix

Question 32

1. Why is itraconazole prescribed after a full meal?

Answer 32

Increase gastric retention time and increase pH (weakly basic drug). It is protonation and dissolution in stomach is important in determining absorption. Higher gastric emptying results in insufficient dissolution in the stomach before the drug is emptied into the intestine for absorption. Absorption improved by slower gastric emptying rates after a full meal.

Question 33

Why may IV itraconazole be considered in seriously ill and chemotherapy patients?

Answer 33

• Reduced GI blood flow in those who are seriously ill.
• Iv works faster
• Difficulties in swallowing oral dose and eating a mea
• Avoids first pass metabolism and upregulation activation of PGP
• Gastric hypochlorhydria increase pH in stomach and this would lead to porr absorption of weak bases, common issue in seriously ill people/cancer patients

Question 34

Why may itraconazole not be prescribed with H2 antagonists (famotidine), proton pump inhibitors (omeprazole), antacids or didanosine tablets?

Answer 34

These drugs are prescribed to prevent stomach acid secretion, if you have less acid then this drug will be dissolved slower and decrease absorption of itraconazole.

Question 35

Why may an acidic beverage be recommended?

Answer 35

Acidic drinks could help because they decrease gastric pH and make itraconazole more soluble. Doesn’t really happen in practice mainly evidence based in labs

Question 36

Why may the itraconazole dose be increased or not prescribed with rifampin, rifabutin, phenytoin, phenobarbital, carbamazepine?

Answer 36

All these drugs induce CYP3A4 decreasing absorption, these effects may last 1-2 weeks after interacting drugs are stopped.

Question 37

Why may intestinal absorption of itraconazole vary in the same patient and between different patients?

Answer 37

• Anything that is poorly soluble you will get patient variation
• The close location of PGP and CYP 3A4 in enterocyte cells and the overlapping substrate results in intestinal barrier to a variety of xenobiotics. Person to person variation in expression
• GI tract may have different expression
• Patient diet, underlying disease, drug therapy, pharmacogenetics can play a role in PGP expression resulting in variation.
• Itraconazole is both an inhibitor and substrate of PGP, therefore absorption can change over a period over a prolonged exposure.
• Intestinal CYP 3A4 metabolism produces both active and inactive metabolites. People may produce different rates of this metabolite.

Question 38

Why is there a 60% higher AUC for the oral cyclodextrin-itraconazole solution under fasting conditions, compared to the sugar-coated itraconazole capsule under fasted conditions, and only 30% higher AUC under fed conditions?

Answer 38

• Sugar coated drug has poor dissolution in the stomach under faster conditions, improved after meal
• Encapsulation in lipophilic pocket of cyclodextrin improves water solubility
• Improved solubility means less reliance on weak base protonation and dissolution in the stomach resulting in a large increase in AUC under fasted conditions, a smaller increase seen under fed conditions
• Little cyclodextrin is absorbed from gut in healthy adutls, 50-60% is excreted unchanged in the faeces, the rest is broken down by gut microflora into molecules of glucose.
• Cyclodextrin passing through the gut stimulates intestinal secretion and gastrointestinal propulsion, and may cause nausea and osmotic diarrhoea.

Question 39

Explain the dissolution profiles in 0.1M HCl of the different itraconazole formulations shown below

Answer 39

Sugar spheres dissolves more rapidly that pure drug powder
Amount of drug release from nanoparticles suspension formulation was 90% within 10 mins compared to 10% from pure drug and 17% from sugar spheres.
Increase in accessible surface area couples with the hydrophilic surfactant coating of the smaller nanoparticles may be the reasons for the 6x increase in dissolution rate.

Question 40

what would increase solubilty within a drug?

Answer 40

• reducing surface area
• add a surfactant
• pro drug
• salt form
• cyclodextring

Question 41

what would increase permability?

Answer 41

• permeation enhancers
• efflux inhibitors
• liquid filled capsules
• GI motility??