Transcript 1 - Physical Pharmacy Laboratory

DRUG ABSORPTION
Overview
1. The structure and function of biological membranes and the factors influencing the
transport of drugs though them
2. The special features of routes for drug administration
- oral route and oral absorption
- buccal and sublingual absorption
- intramuscular and subcutaneous injection
- transdermal delivery
- eye and ear
- vaginal absorption
- lung and respiratory tract
- nasal and rectal routes
- intrathecal drug administration
Biological membranes and drug transport
Biological membranes
1. Function
- to contain the aqueous contents of cells and separate them from an aqueous exterior
phase
2. Nature
- lipoidal
- selectively permeable
3. Structure
- composed of bilayers of phospholipids and cholesterol or related structures
- embodied hydrophbic proteins in the matrix of lipid molecules
- exterior: hydrophilic, negatively charged
interior: hydrophobic
Biological membranes and drug transport
3. Structure - Cholesterol
- major component of most mammalian biological membranes
- to fit closely in bilayers with the hydrocarbon chains of unsaturated fatty acids
- remove of cholesterol causes the membrane to lose its structural integrity and to
become highly
- complexes with phospholipids and reduces the permeability of phospholipid
membranes
Biological membranes and drug transport
3. Structure : fluid mosaic model
Biological membranes and drug transport
4. Drug absorption through biological membrane
- controlled by the nature of membrane ( its degree of internal bonding and rigidity,
Its surface charge) and by physicochemical properties of drugs
- passive diffusion : lipid-soluble drugs
- transport system : water-soluble drugs
Biological membranes and drug transport
Lipophilicity and absorption
Log P : partition coefficient
ratio of the concentrations of the un-ionized solute in solvents
used to calculate lipophilic efficiency
ex)
Log P
organic
acqueous
Dissolution solvent
1
10
1
hydrophobic
0
1
1
both
-1
1
10
hydrophilic
Organic
Acqueous
Biological membranes and drug transport
Lipophilicity and absorption
Drug with high log P values
- protein bound
- low aqueous solubility
- bind extraneous sites
Drug with low log P values
- too hydrophilic
- have any affinity for the membrane
- poorly absorbed
Typical activity – log P plot
Biological membranes and drug transport
Molecular weight and drug absorption
-
The larger MW drug: poorer absorption
-
A rule of five by Lipinski
good oral adsorption is when:
the drug molecules has fewer than 5 hydrogen bond donor
( -OH or –NH groups)
the molecular weight is less than 500
log P of the drug is less than 5
there are fewer than 10 H-bond acceptor
Biological membranes and drug transport
Permeability and the pH-partition hypothesis
-
Assumption
only unionised form (U) of drug can pass through membranes by diffusion and
ionsied forms (I) will be rejected
-
Calculation of percentage inoisation
weakly acidic drug
weakly basic drug
Biological membranes and drug transport
Discrepabcies between expected and observed absorption
Explanations
- Absorption and ionisation are dynamic process
- The difference between the bulk pH and actual pH
Biological membranes and drug transport
Problems in the quantitative application ot the pH-partition hypothesis
1. Viability in pH condition
- variation in the stomach pH (1-3 vs upto 7): variable dissolution rate of drug
- variation in the small intestine by its pathological stauts
Biological membranes and drug transport
Problems in the quantitative application ot the pH-partition hypothesis
2. pH at a membrane surfaces
- pH at the membrane surfaces is lower than that of the bulk pH due to higher
hydrogen concentration at the surface
 the solubility of drug will be changed in the vicinity of the membrane
- the secretion of acidic and basic substances in the gut wall
Biological membranes and drug transport
Problems in the quantitative application ot the pH-partition hypothesis
3. Convective water flow
- factors that can make water movement
: difference in osmotic pressure between blood and the contents of the lumen
difference in hydrostatic pressure between lumen and perivascular tissue
- The movement of water molecules affects the rate of absorption of small molecules
- if the drug and water are using same route, absorption of water-soluble drug will
be increased.
Biological membranes and drug transport
Problems in the quantitative application ot the pH-partition hypothesis
4. Unstirred water layers
- lies adjacent to all biological membranes
- additional barrier for absorption of drug
Biological membranes and drug transport
Problems in the quantitative application ot the pH-partition hypothesis
5. Effects of the drug
- the drug must be in its molecular form before absorption
- basic drugs are expected to be more soluble than acidic drug in stomach
Biological membranes and drug transport
Problems in the quantitative application ot the pH-partition hypothesis
6. Other complication factors
- the very high area of the surface of the small intestine
- co-administration of drugs
- drugs are unstable in the gastrointestinal tract
metabolised on their passage through the gut wall
hydrolysed in the stomach to active form (prodrug)
bound to mucin to form complexes with bile salts
in charged form
Routes of Administration
The special features of routes for drug administration
- oral route and oral absorption
- buccal and sublingual absorption
- intramuscular and subcutaneous injection
- transdermal delivery
- eye
- ear
- vaginal absorption
- lung and respiratory tract
- nasal
- rectal
- intrathecal drug administration
The oral route and oral absorption
- The oral route is the most popular and convenient
route of drug administration
- The drugs for oral administration can survive the acid of
the stomach, which are resistant to enzymatic attack, and
which are absorbed across gastrointestinal membranes
The oral route and oral absorption
The gastrointetinal tract and drug absorption
1. Function
digestion and absorption of foods and nutrients
2. Factors affecting absorption from oral dosage forms
: the extent and rate of dissolution of the drug
the rate of gastric emptying
the site of absorption
The oral route and oral absorption
Structure of the gastrointestinal tract
Stomach
- is not an organ designed for absorption
- its volumes varies with the food content
- HCl liberated from parietal cell
The oral route and oral absorption
Structure of the gastrointestinal tract
Small intestine
- main site of absorption
- three sections: duodeum, jejunum, ileum
- involved in food digestion and absorption
- enlarged absorbind area by surface folds
in the intestinal lining : villi and microvilli
- surface area : 100 cm2
The oral route and oral absorption
Structure of the gastrointestinal tract
Large intestine
- site for water absorption
- secrete the mucus to aid the intestinal
- no villi
The oral route and oral absorption
Passive, carrier-mediated and specialised transport
Possible ways for drug absorption
: tight junction ( the paracellular route )
carrier-mediated uptake mechanisms
endocytosis
The oral route and oral absorption
Bile salts and fat absorption pathways
Bile salts
- ampiphilic compounds
- secreted into the jejunum
- efficient emulsifier and disperse fat globules
 allowing the action of lipase at the increased globule surface
The oral route and oral absorption
Bile salts and fat absorption pathways
Fat absorption
medium chain
directly hydrolys
Fatty acid
Glycerol
Fatty acid
Fatty acid
Fatty acid
long chain
Hydrolysis
OH
Bile salts
OH
Fatty acid
Micelle
The oral route and oral absorption
Bile salts and fat absorption pathways
Drug absorption
- lipid-soluble drugs may be absorbed by fat absorption pathway
- the administration of drugs in an oily vesicle can significantly affect absorption
The oral route and oral absorption
Gastric emptying, motility and volume of contents
- The volume of the gastric contents will determine the concentration of a drug
- The time the drug resides in the stomach will determine many aspects
- drug absorbed in intestine : emptying rate determine the delay before absorption
- acid-labile drug : residence time in the stomach determines the level of breakdown
- non-disintegrating drug : retention in stomach can influence absorption pattern
- The stomach empties liquids faster than solids
- Acids show slow gastric emptying
high MW acids are less effective than low MW acids
The oral route and oral absorption
Gastric emptying, motility and volume of contents
- Natural triglycerides inhibit gastric motility
- The nature of dose form may influence gastric emptying
: solid or liquid, acid or alkaline, aqueous or oily
- Food affects not only transit but also pH in the GI tract
Routes of Administration
The special features of routes for drug administration
- oral route and oral absorption
- buccal and sublingual absorption
- intramuscular and subcutaneous injection
- transdermal delivery
- eye
- ear
- vaginal absorption
- lung and respiratory tract
- nasal
- rectal routes
- intrathecal drug administration
Buccal and sublingual absorption
- The absorption of drugs through the oral mucosa
provides a route for systemic administration
- avoids exposure to the gastrointestinal system
- drugs bypass the liver and have direct access to the
systemic circulation
Buccal and sublingual absorption
Mechanism of absorption
- Function of the oral mucosa: barrier
- Structure : a mucosa layer
a keratinised layer
an epithelial layer
a basement membrane
connective tissue
a submucosal region
Buccal and sublingual absorption
Mechanism of absorption
- Most of drugs are absorbed by simple diffusion
- Linear relationship between percentage absorption and log P
- With increasing pH, absorption of basic drug increases and acidic drugs decreases
- The buccal route has the advantages of the sublingual route
→ the buccal mucosa is similar to sublingual mucosal tissue
→ a sustained-release tablet can be held in the cheek
Routes of Administration
The special features of routes for drug administration
- oral route and oral absorption
- buccal and sublingual absorption
- intramuscular and subcutaneous injection
- transdermal delivery
- eye
- ear
- vaginal absorption
- lung and respiratory tract
- nasal and rectal routes
- intrathecal drug administration
Intramuscular and subcutaneous injection
- Efficient routes for drug administration because
drug can bypass the problems encountered in the
stomach and intestine
- Drug can diffuse through tissue and pass across
the capillary walls then enter the circulation via
capillary supply
- Molecular size is important factor for releasing
- Hydrophobic drugs show prolongation of action
due to its binding to muscle protein
Intramuscular and subcutaneous injection
- Molecular size is important factor for releasing
- muscle fiber → capillary wall → blood
- transport through the capillary wall is the ratelimiting step
- the larger the molecule the more slowly it diffuses
and the greater difficulty it has in traversing the
aqueous pore in the capillary walls or the cell
junction
Intramuscular and subcutaneous injection
- Hydrophobic drugs show prolongation of action due to its binding to muscle protein
- Dicloxacillin is 95% bound to protein, ampicillin is bound to the extent of 20%
→ dicloxacillin is absorbed more slowly from muscle than is ampicillin
dicloxacillin
ampicillin
Intramuscular and subcutaneous injection
Site of injection
- Composed of aqueous and lipid components
- The pH of the region will determine whether
drugs will dissolve in the tissue fluids or
precipitate from formulations
- Muscle tissue is more acidic
- The rate of injection determines : how quickly
the drug begins to act & how long it acts
Intramuscular and subcutaneous injection
Vehicles
- Water-miscible solvents are used for formulation
ex) PEG 300 or 400, propylene glycol or ethanol mixture
- Dilution by the tissue fluid may cause a drug to precipitate
- Three main type of formulation
1. aqueous solution – rapid removal
2. aqueous suspensions
3. oily solution – slow diffusion for long action
Intramuscular and subcutaneous injection
Blood Flow
- The rate of blood flow is different in different muscle
→ site of i.m. injection can be crucial
Intramuscular and subcutaneous injection
Formulation effects
- Crystalline suspensions of fluspirilene, certain steroids and procaine benzylpenicillin can be
prepared in different size ranges to produce different pharmacokinetic profiles following
i.m. or s.c. injection
- Different nature of the formulation
→ variability in response to a drug
or, differences in response to a formulation from different manufacturers
- The depth of the injection is significant
→ The blood supply to the region is limited , there will be an additional restriction to
rapid removal
- The additives can influence dispersion, the solubiliser undoubtedly reducing precipitation at
the site of injection and increasing the rate of solution
Routes of Administration
The special features of routes for drug administration
- oral route and oral absorption
- buccal and sublingual absorption
- intramuscular and subcutaneous injection
- transdermal delivery
- eye
- ear
- vaginal absorption
- lung and respiratory tract
- nasal
- rectal routes
- intrathecal drug administration
Transdermal delivery
- Stratum corneum
: barrier layer of the skin
behaves like a passive diffusion barrier
- Drug formulation can change rapidly once they have been spread on the skin due to
absorption of some excipients and evaporative loss of water
Transdermal delivery
Route of skin penetration
- The major pathway for transporting water-soluble molecules
: transcellular ( passage through cells and cell walls )
- The pathway for lipid –soluble molecules
: intercellular ( passage through endogenous lipid )
- Passage through damaged skin is increased over normal skin
Transdermal delivery
Route of skin penetration
- The physicochemical factors that control drug penetration
: the hydration of the stratum corneum
pH
temperature
drug concentration
the molecular characteristic of the penetrant
the vehicle
Transdermal delivery
Influence of drug
- Factors that determine the diffusion coefficient of the drug
: molecular size, shape and charge
- The partition coefficient is determined by the properties of drug and vehicle
: vehicles represents the donor phase
the skin represents the acceptor phase
- The peak activity in a drug series coincides with an optimal partition coefficient
- Not all drugs are suitable for transdermal delivery
Transdermal delivery
Formulations
- Oil-in-water systems : most general formulation
- Simple aqueous lotions : cooling effect on the skin
- Aqueous creams : combined characteristics of the lotion and ointment
- Ointments : composed of single-phase hydrophobic base
used for the application of the insoluble or oil-soluble medicaments
- Absorption bases : have capacity to facilitate absorption by the skin
have ability to take up considerable amounts of water to from
water-in-oil emulsions
Transdermal delivery
Drug release from vehicles
- In emulsions, the relative affinity of drug for the external and internal phases of the
emulsion is an important factor
- A drug dissolved in an internal aqueous phase of a w/o emulsion must be able to diffuse
through the oily layer to reach the skin
- Three cases can be considered : solution, suspension and emulsion systems
Transdermal delivery
Drug release from vehicles
- Solutions : release rate is proportional to the square root of the diffusion coefficient
release is slower from a viscous vehicle
- Suspension : release rate is proportional to the square root of the total solubility of the
drug in the vehicle
- Emulsion : release rate is proportional to the diffusion coefficient of the drug in the
continuous phase inversely proportional to partition coefficient between phase
Transdermal delivery
Transdermal medication: patches and devices
- Advantages
: elimination of the vagaries that influence gastrointestinal absorption
direct introduction into the systemic circulation without entering the portal circulation
constant and continuous administration by simple application
rapid termination when needed
Transdermal delivery
Transdermal medication: patches and devices
- Patches
: four basic forms of patches (matrix, reservoir, multilaminate and drug-in-adhesive)
- Ionophoresis
: the process by which the migration of ionic drugs into tissue
enhanced by the use of an electrical current
possible source of enhancement : ion-electric field interaction, convective flow,
current
Transdermal delivery
Transdermal medication: patches and devices
- Ultrasound and transdermal penetraration through cavitation
cavitation : ultrasound expands and then collapses air bubble in the stratum corneum
liquefy the solid fat and allow molecules to pass through the skin
permeability increases as the frequency of ultrasound decreases
- Jet injector
: based on the high velocity ejection of particles through an orifice
drug is delivered though either or both skin failure and convective flow
Routes of Administration
The special features of routes for drug administration
- oral route and oral absorption
- buccal and sublingual absorption
- intramuscular and subcutaneous injection
- transdermal delivery
- eye
- ear
- vaginal absorption
- lung and respiratory tract
- nasal
- rectal routes
- intrathecal drug administration
The eye
- A wide range of drug are placed in the eye
: antimicrobials, antihistamines, decongestant,
mydriatics, miotics and cycloplegic agents
- Formulation : drops or oinments
The eye
- Drugs are absorbed by the
conjuctiva enters the systemic
circulation
- covered with a thin fluid film, the
tear film, which protects the cornea
from dehydration and infection
- absorbing surface
- Two barrier system
: a blood-aqueous barrier
a blood-vitreous barrier
The eye
Tear
- Components
: electrolytes- sodium, potassium and some calcium ions, chloride and other counter ions
and glucose
macromolecules- albumin, globulins and lysozyme
- Lipid form a monolayer over the tear fluid surface
- Drugs may interact with components of the tear fluid, so that tear coverage is disrupted
The eye
Absorption of drugs applied to the eye
- Cornea
: main barrier of absorption comprises an epithelium, a stroma, and an endothelium
- Epithelium and endothelium
: high lipid content penetrated by unionized
lipid-soluble form of drug
- Stroma
: high water content
drug which have both lipid-soluble and water
-soluble to some extent can penetrate
The eye
Aqueous Humour
- Both water-soluble and lipid soluble drugs can enter the aqueous humour
- The pH- partition hypothesis accounts only imperfectly for different rates of entry into
aqueous humour
The eye
Influence of formulation
- Some ingredients of eye medications may increase the permeability of the cornea.
- Surface-active agents are known to interact with membranes to increase the permeability
The eye
Influence of formulation : to increase permeability
- Eye drops : formulated to be isotonic with tear fluid
less than 5% in administered drops acts on ocular tissue
- Prodrugs : modified drug substances to increase its ability to penetrate the corneal
barrier
- Reservoir systems : soft lenses,
the alza ocusert device for controlled release of pilocarpine
Routes of Administration
The special features of routes for drug administration
- oral route and oral absorption
- buccal and sublingual absorption
- intramuscular and subcutaneous injection
- transdermal delivery
- eye
- ear
- vaginal absorption
- lung and respiratory tract
- nasal
- rectal routes
- intrathecal drug administration
The ear
- Medications are administered to the ear
only for local treatment
- Drops and other vehicles administered to
the ear will occupy the external auditory
meatus, which is separated from the middle
ear by the tympanic membrane
- The acidic environment of the ear skin surface
is thought to be a defence against invading
microorganism
Routes of Administration
The special features of routes for drug administration
- oral route and oral absorption
- buccal and sublingual absorption
- intramuscular and subcutaneous injection
- transdermal delivery
- eye
- ear
- vaginal absorption
- lung and respiratory tract
- nasal
- rectal routes
- intrathecal drug administration
Absorption from the vagina
- Not a route for the systemic administration of drugs
- Steroids, prostaglandins, iodine and some antibiotics and antifungals are appreciably
absorbed
- Variable absorption due to constant change of absorbing surface
- Mucus may retard absorption
Absorption from the vagina
Formulations : vaginal tablets, foams, gels, suspensions, and pessaries
- Tablets : contain excipients to increase viscosity and are bioadhesive
- hydrogel-based vaginal pessaries : for delivering prostagladin E and bleomycin
- Micropatches will gel on contact with vaginal mucosal surfaces and adhere
→ made of starch, gelatin, albumin, collagen or dextran
Routes of Administration
The special features of routes for drug administration
- oral route and oral absorption
- buccal and sublingual absorption
- intramuscular and subcutaneous injection
- transdermal delivery
- eye
- ear
- vaginal absorption
- lung and respiratory tract (Inhalation theraphy)
- nasal
- rectal
- intrathecal drug administration
Inhalation Therapy
- The respiratory system is a route for medication
- Used to avoid systematic side effects
- The respiratory track epithelium : similar characteristics with biological membrane
→ lipid-soluble compounds rapidly absorbed
- High permeability to water soluble molecules of pulmonary epithelium than gastrointestinal mucosa
- The difficulty in targeting particles to the sites of maximal absorption
→ low efficiency
Inhalation Therapy
Physical factors affecting deposition of aerosols
- Deposition of particles is dependent
on particle size
Inhalation Therapy
Physical factors affecting deposition of aerosols
- The major process that influence deposition of drug particles
: interception
impaction
gravitational settling
electrostatic attractions
brownian diffusion
- Factors that affect particle size and particle size distribution
: nature of the aerosol-producing device and formulation
Physicochemical principles of pharmacy 4th edition,
Alexander T Florence and David Attwood
Inhalation Therapy
Delivery devices
- Pressurised aerosols : single-phase and two-phase system
single phase : the liquid propellant is the liquid phase containing drug in solution or
suspension
two-phase : the propellant forms a separate liquid phases
- Nebulisers
: generate aerosols continuously for chronic therapy of respiratory disorders
the particle size distribution varies with the design and mode of use
Routes of Administration
The special features of routes for drug administration
- oral route and oral absorption
- buccal and sublingual absorption
- intramuscular and subcutaneous injection
- transdermal delivery
- eye
- ear
- vaginal absorption
- lung and respiratory tract (Inhalation theraphy)
- nasal
- rectal
- intrathecal drug administration
The nasal route
- Three main classes of medicinal agents
: drugs for the alleviation of nasal symptoms
drugs that are inactivate in the GI track following oral administration
where the route is an alternative to injection
The nasal route
- Feasible for the delivery of peptides and proteins
- Considerable factors
: droplet or particle size ( by aerosol)
nasal vascularity and mucus flow
- Formulation factors : the volume
concentration
viscosity
pH
tonicity
Routes of Administration
The special features of routes for drug administration
- oral route and oral absorption
- buccal and sublingual absorption
- intramuscular and subcutaneous injection
- transdermal delivery
- eye
- ear
- vaginal absorption
- lung and respiratory tract (Inhalation theraphy)
- nasal
- rectal
- intrathecal drug administration
Rectal absorption of drugs
- The rectal mucosa : lipoidal barrier
contact site for suppository form of drugs
- Rectal fluids have buffering capacity
- Factors can affect bioavailability of suppository
: formulation
retention time in the rectal cavity
the size and shape
melting point
- Important features of excipient materials
: melting point
speed of crystallization
emulsifying capacity
Rectal absorption of drugs
The Rectal cavity
- Rectum : the terminal 15-19cm of the large intestine
- The rectal ampulla
: suppository contact site
made up of a layer of cylindrical epithelial cells without villi
- Blood supply to rectum
: superior rectal artery
veins of the submucous plexus → rectal vein
- Drug absorption though venous network
: absorbed in superior vein → portal vein → liver
absorbed in inferior vein → interior vena cava
→ bypass liver
Rectal absorption of drugs
Absorption from formulations
- Rate limiting step in drug absorption for suppositories made from a fatty base
: partitioning of the dissolved drug from the molten base
- Diffusion rate from base : water soluble < water- insoluble substances
- Absorption form the rectum depends on the concentration of drug in absorbable form
in the rectal cavity
- Additional surfactants
: increase the ability to spread and the extent of absorption
Routes of Administration
The special features of routes for drug administration
- oral route and oral absorption
- buccal and sublingual absorption
- intramuscular and subcutaneous injection
- transdermal delivery
- eye
- ear
- vaginal absorption
- lung and respiratory tract (Inhalation theraphy)
- nasal
- rectal routes
- intrathecal drug administration
Intrathecal drug administration
- Used to deliver drugs to the brain and spinal cord
- More invasive than i.v., i.m. or s.c. routes
- Percutaneously implanted catheters
and subcutaneous implantable pumps are used
 reduce the risk of infection
- Activity determining factor
: diffusion by bulk flow mechanism