Biopharmaceutics Flashcards
Difference between a drug and a medicine?
Drug = active pharmaceutical ingredient on its own
Medicine = API in dosage form, formulation, drug delivery system, drug and excipients etc.
What are the early stages of drug development?
- Study drug molecules in solution
- Interacting with isolated target cells
What requirements must dosage forms satisfy?
Manufacture Handling Cost Stability Convenience Marketing
Bioavailability is about absorption only. True or false?
True. Pharmacokinetics concerns the complete fate of the drug in the body (ADME)
Absorption –> is the rate and extent at which drugs reach the systemic circulation
Distribution –> includes the processes that are involved after absorption until it leaves the body
Metabolism –> includes all processes that involve changes to the drug in the body. These can take place in the gut wall, liver or elsewhere
Excretion –>is the process by which the drug is eliminated from the systemic circulation. These include the biliary, urinary, faeces or by sweat or breath
What is bioavailability and absolute bioavailability?
Bioavailability = Extent to which the active ingredient is absorbed from a drug product and becomes available at the site of action
Absolute bioavailability = defined as the fraction of the drug in the dosage form that arrives in the systemic circulation
Why does “available at the site of action” translate to arrives to the systemic circulation?
1) Practical reason – blood can be sampled easily. Most tissues are not accessible for sampling.
2) Pharmacokinetic theory – Blood is the central compartment from which drug is distributed.
3) Pharmacokinetic theory – Absorption is the process of drug entering the central compartment by a route of administration.
4) Pharmaceutics – once the drug is in the central compartment, the formulation is irrelevant; drug is now dissolved in blood plasma. Formulation is only relevant to absorption.
What are the two routes of administration?
1) Across epithelial layers
- Skin
- Small intestine (Gastrointestinal tract)
- Buccal, Gastric, Rectal (other parts of GI tract)
- Nasal, Bronchial, Pulmonary
2) Bypass epithelial layer via injection (parenteral route)
Intravascular – directly into the blood
- ->intravenous, IV, (bolus or infusion over time)
- –>intra-arterial (less common)
Extravascular – into other body tissues, from which drug must be absorbed into local capillaries (or by lymphatic system, discussed later)
- -> subcutaneous, SC
- -> intramuscular, IM
- -> intraperitoneal, IP
- > other less common routes, e.g. intrathecal (spinal canal to cerebrospinal fluid
Why injection? (as they can be more expensive, dangerous, inconvenient)
- Produce a rapid response (immediate to within seconds/minutes)
- Patient may be unconscious and cannot swallow
- Drug may be removed by vomiting
- Drug may be destroyed in G.I. tract (zero oral bioavailability)
- Low epithelial permeability
Where does absorption occur in transdermal delivery?
- Absorption occurs in the capillary bed of the dermis
- Drug must penetrate the avascular epidermis to reach the dermis where it can be absorbed by capillaries
- Absorption rate is low due to limited permeability and low surface area
What is the stratum corneum?
Complex structure formed of dead cells
What is the epidermis?
Avascular, tightly packed living cells
Transdermal drug absorption factors?
- Low permeability – limited to low MW, lipophilic drugs
- ->glyceryl trinitrate, nicotine, fentanyl
- ->Estradiol, testosterone, anti-nausea agents
- Low surface area (patch size)
- No transporter systems to exploit
Advantage – long timescale (hours, days)
Advantage – no “first-pass” metabolism
Gastrointestinal drug absorption factors?
- Large surface area of the small intestine
- ->Approximately ~100 m2
- ->Microvilli on the cell surface
- High permeability
- ->Designed for nutrient absorption
- ->No stratum corneum barrier
- ->Various absorption mechanisms
The permeability of the intestinal wall is potentially very high because of:
- Lipid bilayer of the epithelial cells lining the GI lumen allows absorption of lipophilic drugs – most of the surface area
- Gaps between cells in the epithelial lining allows for absorption of hydrophilic drugs – only a small fraction of total surface area
- Specific carrier systems can be exploited (e.g., for uptake of amino acids, other hydrophilic nutrients)
Potential influences on drug availability for absorption?
Physiological factors:
- Surface area
- Gastric emptying
- pH and viscosity of lumen fluid
- Intestinal transit time
- Epithelial transport processes
- Metabolism
- Blood flow
Drug and dosage form:
- Drug (pKa, Log P, solubility, stability)
- Dosage form (disintergration time and dissolution rate, size, excipients)
- Pharmacological effects of drug or other agents
Total transit time of sections of the GI tract:
Total transit time ~ 12 to 36 hours
Buccal & sublingual administration? Mouth
Mouth–>
- Low surface area, but permeability greater than skin.
- Appropriate for lipophilic, low molecular weight drugs (GTN, fentanyl, midazolam)
Advantage: convenient, fast, avoid “first pass” metabolism by liver
Example: GTN sublingual tablets and spray
Buccal & sublingual administration? The Stomach
- Low surface area - epithelial layer is comparatively smooth (no folds or villi)
- Tight junctions (limited paracellular transport)
- No transporters for nutrient absorption
- Hence, very little absorption occurs here
- Partial exceptions:
- ->Drugs with very high permeability e.g. ethanol
- ->Drugs that are weak acids e.g. aspirin
Factors of the small intestine?
- Very large surface area ~100 m2
- ->due to folds, villi, microvilli
- ->extra surface area claimed to be up to ~600 times the surface area of a smooth tube
- Extensive blood supply
- Nutrient transporters
- Paracellular transport
- First pass metabolism
- Transit time is typically 3-4 hours –> Not sensitive to dosage form, fed/fasted state
What is splanchnic circulation?
- Intestinal veins flow into portal vein of the liver
blood rich in absorbed material is filtered through the hepatic sinuses - Collected in hepatic vein and enters systemic circulation
What are the different pathways of absorption:
1) Transcellular
2) Paracellular
3) Carrier mediated
4) Transcytosis
Different absorption characteristics?
1) Lipid bilayer of the epithelial cells lining the GI lumen (route for lipophilic drugs)
- ->Drugs that obey “Lipinski’s rules” – small, lipophilic, logP > 0
- ->Un-ionised drug able to diffuse across epithelial layer into blood
2) Gaps between cells in the epithelial lining (route for hydrophilic drugs)
- ->Drugs with low molecular weight and logP < 0 may cross the gaps between epithelial cells (paracellular)
3) Specific carrier systems (e.g., for uptake of amino acids, other hydrophilic nutrients)
- -> Saturation of carrier proteins may be a problem.
- ->Therefore absorption (bioavailability) may be nonlinear (depends on the dose)
Case study of Gabapentin?
- Used for a number of neurological indications e.g. epilepsy
- Bioavailability decreases as dose incresases
- Prodrug – now a substrate for multiple nutrient transporters
Hydrolysed to gabapentin in the blood
Linear absorption (constant bioavailability)
Key steps in absorption:
1) Dissolution - drug must arrive at epithelial surface as a dissolved molecule
2) Permeation - across epithelial (gut) wall into blood or lymphatics
Key competing processes:
1) Transit - Removal of dosage form before absorption
2) Stability – break-down of drug in the gut lumen, gut wall, or by the liver before mixing with systemic blood
How is it determined what Classification system a drug falls into?
Relevance:
- Predict bioavailability problems during development of new drugs
- Suggest formulation approaches
- Indicates drugs for which formulation is not critical
Criteria:
- Solubility – maximum dose strength in 250 mL or less, over the pH range 1 - 8
- Permeability – over 90% absorption predicted by an “established laboratory method”
Limitations -
does not consider factors such as:
- Stability (e.g., at different pH values)
- Binding interactions with gut or its contents
Potential sources of variability in extent and rate of absorption
Physicochemical factors such as:
- Size & wettability of drug particles
- Solubility & pKa of drug molecule
- Lipophilicity (logP) of drug molecule
- Chemical reaction rates affecting stability
Interact with biological factors such as:
- Transit times in each section of gut (gut motility)
- Local pH
- Local enzymes, surfactants
- Epithelial surface area, mucus, gut contents
Biological factors may vary due to:
- Individual variations
- Health
- Meals, diet, fluid intake
- Activity
The importance of pH:
- Solubility – often critical
- -> extremely important for drugs that are weak acid or weak base
- Stability – possibly critical
- > Drug subject to acid hydrolysis?
- Permeability – rarely critical*
- -> Although the pH-partition hypothesis predicts that permeability is affected by the local pH
- ->Variation in surface area is the dominant effect (presence of villi)
- -> So weak acids are still better absorbed in intestine despite having high ionised fraction compared to stomach.
What is the pH in the Gastric fluid? (fed and fasted)
- Gastric fluid
pH 1 - 3.5 fasted, 3 – 7 fed
Residence time longer in fed state
What is the pH in the intestinal fluid?
Intestinal fluid
- pH varies along length from 5 to 8;
- affected by fed/fasted state
pH implications:
Drugs unstable in gastric fluid?
- Take with/after meal (higher pH)
- Large particle size to delay dissolution
- Convert to salt form to alter dissolution rate
- Enteric coating - delay disintegration until in intestine
- Prodrug – molecule with better solubility (or permeability) properties is metabolised into active drug after absorption
How do we account for the effect of DME?
We need to perform a control measurement:
Intravascular administration
IV injection =
–> No absorption
–> But drug in central compartment is subject to the same DME processes
Calculate Drug Exposure
- Area under the curve (AUC) of drug concentration versus time
- Units of exposure (AUC) are concentration x time ((𝒎𝒈∙𝒉)/𝑳)
Definition of absolute bioavailability?
𝑭= (𝑨𝑼𝑪)𝒐𝒓𝒂𝒍 / (𝑨𝑼𝑪)𝒊𝒗
Important measures for working out bioequivalanece of two dosage forms:
Bioequivalence of two dosage forms = no significant difference in
- AUC (i.e. relative bioavailability ~ 100%)
- Tmax
- Cmax
Bioequivalent’ suggests that the test dosage form will have the same therapeutic effectiveness as the standard form.
Examples of sweeteners used to improve appearance and palatability:
- Traditionally sucrose was used to sweeten oral formulations, but the use of sugar is now severely restricted
- Several sweeteners are available - all are much sweeter than sugar and are used in much lower concentrations including saccharin and aspartame
What caution comes with using aspartame as a sweetener?
The degradation products of aspartame include phenylalanine so it should not be ingested by patients with the condition phenylketonuria
How do you increase the sweetness in an organic compound?
An increase in the number of hydroxyl groups (—OH) in an organic compound increases its sweetness
Why use coatings?
Drugs inside capsules or coated tablets are easily swallowed with no contact between the drug and the taste buds
Coating tablets with polymer films or sugar coatings – barrier, thickness and composition will determine drug release
Sugar coating – tablet core is sealed with a thin film of poorly water-soluble polymer e.g. shellac or cellulose acetate phthalate – this retards drug release
Hydrophobic, water insoluble films e.g. ethylcellulose delay or reduce drug release, influencing absorption
Enteric coatings resist the low pH of the stomach but is disrupted by the higher pH of the duodenum e.g. cellulose acetate phthalate and polyvinyl acetate phthalate, which dissolve at pH 5
What characteristics should diluents have?
Diluents should be inert, non-hygroscopic, biocompatible, cheap, have good compactibility and dilution capacity, good water solubility and acceptable taste
Examples: Lactose, sucrose, mannitol, sorbitol, calcium phosphate, calcium carbonate, cellulose
Can hydrophilic diluents can increase the rate of dissolution?
Yes
What are disintergrants?
Disintegrants are natural, synthetic or chemically-modified polymers
When disintegrants come in contact with intestinal fluid they absorb liquid, and start to swell, dissolve, or form gels
This causes the tablet structure to rupture and disintegrate, increasing surface area for enhanced dissolution of the drug
Disintergrant function?
Disintegrants function by two or more of 4 mechanisms
i) capillary action (wicking
(ii) swelling,
(iii) deformation, or (iv) repulsion
Different polymers used as disintergrants?
Non-ionic polymers are natural or physically modified polysaccharides such as starches, celluloses or cross-linked polyvinylpyrrolidone (PVP)
Anionic polymers are mainly chemically-modified cellulose products or low-crosslinked polyacrylates
What are lubricants and how do they work?
Lubricants reduce the frictional forces between particles, and between particles and metal contact surfaces of manufacturing equipment, and can be solids or liquids
Boundary lubricants function by adhering to solid surfaces (granules and machine parts) to reduce friction
Examples: salts of long-chain fatty acids e.g. magnesium stearate or fatty acid esters e.g. sodium stearyl fumarate
Fluid film lubricants melt under pressure and create a thin fluid film around particles, but resolidify after the pressure is removed e.g. hydrogenated vegetable oil, glyceryl distearate or stearic acid
Liquid lubricants are released from the granules under pressure and create a fluid film. They do not resolidify when the pressure is removed but are reabsorbed or redistributed through the tablet matrix
Lubricants are often hydrophobic and retard liquid penetration into the capsule - this can be overcome by inclusion of a wetting agent and a hydrophilic diluent
What are binders? give examples
Tablet/capsule binders cause agglomeration of powder into granules during mixing with a granulating fluid, by altering inter-particle adhesion
Binders ensure that tablets can be formed with the required mechanical strength
The binder may be either dissolved or dispersed in the granulation liquid or blended in a dry state
Following evaporation of the granulation liquid, binders typically produce dry granules
Binders may be natural polymers, synthetic polymers or sugars
Examples: gelatin, PVP, hydroxypropyl methylcellulose, polyethylene glycol, sucrose, starch
What are chemical stabilisers:
Oxidation usually causes a colour change and may also cause precipitation or a change in odour
Oxidation is minimised by antioxidants, which delay the onset and/or significantly reduce the rate of complex oxidative reactions
Chelators such as EDTA are used to form soluble, stable complexes with certain metal ions e.g. copper, iron, manganese, lead, and calcium
This removes the ions from solution to prevent them reacting with other elements and/or precipitating
Chelators are used in oral, parenteral and topical formulations and are also referred to as chelants or sequestering agents
What is a buffering agent?
- A buffer is defined as a mixture of a weak acid or base and one of its salts
It is designed to maintain the pH of an aqueous system within very narrow limits
Buffers may be used
in suspension formulations, if a particular pH is required due to the route of administration
if the solubility of the drug is significantly affected by changes in pH
Due to its ionic nature, a buffer system will contribute charges to the formulation, which may affect
- -> flocculation behaviour
- -> the ionization state of other components
Buffers should not interfere with pharmacological activity of the drug or normal biological functions
What are anti-microbial preservatives?
- If water is present in a non-sterile formulation, an antimicrobial preservative is required to prevent microbial contamination
- Preservatives include sorbic acid, benzoic acid, parabens and benzalkonium chloride
- Sorbic acid and benzoic acid are both weak acids used in oral formulations
- Parabens are used in topical and parenteral preparations
- Benzalkonium chloride is used in aqueous eye drop formulations
- It is a cationic surfactant and will dissociate in aqueous solutions to produce Cl− ions and a long chain ionized surfactant moiety
- Benzalkonium chloride is not a ‘pure’ product – it comprises of a range of molecules with varying hydrocarbon chain lengths
What are viscosity enhancing agents and what are they used to control
Viscosity-enhancing agents are used to control:
- Palatability
- Ease of pouring
- Rate of sedimentation of dispersed particles
- -> Complex formation between a drug and a hydrophilic polymer could reduce the concentration of drug in solution that is available for absorption
- –> These agents may also increase the viscosity of the gastrointestinal contents, decreasing dissolution and/or uptake rates of the drug
- -> The target viscosity needed to maintain the particles in their suspended state must be balanced against the ease of use of the product
Different types of viscosity enhancing agents?
Viscosity-enhancing agents can be:
- hydrophilic polymers (e.g. tragacanth, gum arabic) or
- insoluble inorganic materials (e.g. clays - bentonite)
Cellulose-based compounds are commonly used as viscosity enhancers in suspension formulations
Cellulose ethers are obtained from native cellulose by chemical treatment, replacing the hydrogen of the –OH group on the glucose residues with a different functional group
All are water-soluble, except ethylcellulose and provide a range of solution viscosities
These polymers do not interfere with the flocculation behaviour of the system
What are surfactants?
- Surfactants are used as emulsifying agents, wetting agents, suspension stabilisers
- Surfactant monomers can potentially disrupt the integrity and function of a biological membrane enhancing absorption, but may also have toxic side effects
What are wetting agents?
- Wetting agents improve the flow of the liquid vehicle across the particle surface
- They reduce the interfacial tension between the solid particle and liquid medium, promoting dissolution
- Wetting agents are typically surfactants below their critical micelle concentration
- The wetting effect aids penetration of GI fluids into the mass of a solid capsule
- Wetting agents approved for use in oral liquid dosage forms include sodium lauryl sulfate, lecithin and polysorbate (Tween)
- Wetting agent are also used to increase the ease of skin spread for topical lotions and sprays
What are flocculation modifiers?
- May promote or prevent flocculation, depending on the relative extent of the attractive and repulsive energies
- Materials which deposit onto the surface of the particle, such as surfactants, will affect the surface potential
- Materials which ionize in solution, such as preservatives and buffers, will contribute charges to individual particles which generally leads to increased flocculation behaviour
The flocculation modifier is the last excipient to be added to the suspension formulation, its function is to adjust the flocculation status of the particles
Flocculation modifiers are ionic materials which ionize once in solution in the suspension medium e.g. sodium chloride
Excipients can directly interact with drugs via physical and chemical interactions:
Physical:
- Adsorption of drug molecules onto the surface of excipients can make the drug unavailable for dissolution and reduce bioavailability
- -> the antibacterial activity of cetylpyridinium chloride is decreased when it adsorbs to magnesium stearate
Chemical:
- a chemical reaction between drug and excipient alters bioavailability or stability
- ->Tetracyclines can interact with the Ca2+ ion of di-calcium phosphate, forming poorly soluble complexes with reduced bioavailability
