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Absorption of drugs through non oral routes
Introduction
‘’The process of movement of unchanged drug from the site
of administration to systemic circulation is called as drug
absorption’’
The majority of drug are administered generally orally.
But in some cases it is not good route of administration.
For reason like patient non compliance, first pass effect,
immediate drug action etc.
There are more important biopharmaceutics and
pharmacokinetics principle that must be considered for non-
oral absoprtion.
Non invasive routes of drug drug
absorption
1) Buccal / Sublingual administration-
2) Rectal administration
3) Topical administration
4) Intramuscular administration
5) Subcutaneous administration
6) Pulmonary administration
7) Intranasal administration
8) Intraocular administration
9) Vaginal administration
Buccal / sublingual administartion
Two sites for oral mucosal delivery of drug as
1) Sublingual route- Drug places between tongue incase of
sublingual.
2) Buccal route- Drug places between cheek and gum in case of
buccal.
• The barrier to drug absorption by this routes is the epithelium
of oral mucosa.
• Passive diffusion is the major mechanism for absorption of
most drugs; nutrients may be absorbed by career-mediated
processes.
• The buccal and sublingual route appear ideal for lipid soluble
drugs.
• Examples-
-Anti anginals- nitrites and nitrates
-Anti hypertensives- nifedipine
-Analgesics- morphine; bronchodilators- fenoterol
-Steroids- oestradiol
-Peptides- oxytocin
FACTOR TO BE CONSIDER
Lipophilicity of drug
Higher the lipophilicity greater the absorption. Eg clindamycin.
Salivary secretion
Absorption is slow in dry mouth
PH of saliva
PH of saliva is about 6, increases the PH of saliva promotes the absorption of weak
bases but reduces the absorption of weak acids. Eg. Flubiprofen (PH 5.5).
Binding to oral mucosa
Systemic availability is poor when drug is strongly bind to oral mucosa. Eg. Nicotin gum.
Storage compartment
Storage compartment in buccal mucosa appear to exit which is responsible for slow
absorption of drug. Eg – buprenorphine.
Thickness of oral epithelium
Advantages-
 Rapid absorption and higher blood levels
 No first pass metabolism
 No degradation of drugs such as that encountered in the GIT
 Presence of saliva facilitates both drug dissolution and
permeation.
Disadvantages:-
 Concern for taste and discomfort
 Limited mucosal surface- small doses are administered.
Rectal Administration
• Important route for children and older person.
• Drug given as suppositories or solution.
• Absorption from solution is better.eg - lincomycin.
• Presence of fecal matter in rectum retard absorption of drug.
• PH of rectal fluids also influence drug absoption.
• Absorption is slower because of limited surface area.
• Absoprtion occur by passive diffusion.
• Drug administered by this route includes Aspirin,
paracetamol, theophylline, barbiturates.
Advantages-
 Alternative route for administration of unpleasant drugs
 Avoids nausea, vomiting
 Can be used in case of unconscious patients
 Bypasses presystemic hepatic metabolism from lower
half of rectum.
Disadvantages-
 Absorption is sometimes irregular and incomplete and
many drugs cause irritation of rectal mucosa.
Topical Administration
• It is the largest organ of the body with the body weight
approximately 2kg and 2 sq m in area and received about 1/3
0f total circulation.
• Majority of drug applied topically are meant for local and
systemic effects.
• Dosage forms here are cream, ointments, lotion, gels,
transdermal patches and disks.
• When topically applied drug are meant exert their effects
systemically , the mode of administration is called as
Percutaneous or Transdermal delivery.
• Diffusion through the multiple lipid bilayers of dead hydrophilic
keratinized and horny cells of stratum corneum is the rate
limiting step.
• Topical drug application
1) systemic delivery – Clonidine, scopolamine, nicotine, fentanyl .
2) Local delivery – Antimiotics , Antiinflammatories , Anaesthetics.
3) Deliver to appendages- Antiinfective, Antiacne, Antiperspirant.
• Topical route is useful for drug with low oral bioavailability and
short duration of action.
Transdermal route-
•This route of administration achieves systemic effects by
application of drugs to the skin, usually via a transdermal
medicated adhesive patch.
•The rate of absorption can vary markedly, depending on the
physical characteristics of the drug (lipid soluble) and skin at the
site of application.
•This route is most often used for the sustained delivery of
drugs, such as the antianginal drug nitroglycerin, the antiemetic
scopolamine.
• Site – Upper arm, chest, abdomen, mastoid region
• First pass effect avoided
• Absorption- increase by oily
base, occlusive dressing,
rubbing preparation
Percutaneous absorption of drug by novel
techniques
Iontophoresis :- movement of ionic drug into
body by means of an electric current.
Cortisol , methacoline, lidocaine, salicylates.
Phonophoresis :- movement of drug molecules
through the skin under the influence of ultra
sound.
Skin structure
Anatomically skin made of 3 distinct layer as
Epidermis
Dermis
Subcutaneous
 There are three pathways postulated for the diffusion of
solutes through the skin:
Transcellular (passive diffusion)-
cross keratinized cells.
Accessible to non-polar molecules.
hydrophilic drug show penetration through this layer.
Intercellular (paracellular)-
Across the lipid matrix.
Accessible to non-polar molecules
Lipophilic drugs show penetration through this layer.
Transappendageal–
Accessible to polar molecules
Across hair follicles, sweat gland, sebaceous glands.
DRUGS
Epidermis
PERMEATION
BLOOD
CIRCULATION
UPTAKE
Dermis Sub dermal tissue
STRATUM CORNEUM CAPILLARY LAYER
16
Factors influence the percutaneous absorption
1) Skin condition-
 Thickness of stratum corneum
 Presence of hair follicles
 Hydration of skin
 Age
 Skin microflora
 Skin PH
 Skin surface lipids
 Anatomical site
2) Composition of topical vehicle-
 Vehicle or base
 Permeation enhancers
3) Appliction condition-
 Rubbing
 Occlusion
 Loss of vehicle
3) External factors-
 Env humidity and temp
 Grooming
 Exposure to chemicals
 Chronic use of certain drugs
Intramuscular Administration
• Absorption of drug from i.m site is relatively rapid
but much slower in comparision to I.v injection.
• Absorption of lipophilic drugs occurs by passive
diffusion into blood circulation and lymphatic
system.
• Hydrophilic and ionic drugs are absorbed into
blood circulation via the capillary pores.
ADVANTAGES-
 Oily suspensions for depot and slow release
preparations.
 For drugs which degrade after oral route- insulin
 Rapid onset of action.
DISADVANTAGES-
 Metabolism of drugs in muscle tissues.
 Precipitation of drug at the injection site.
 Irritating drugs may be very painful.
Factors determine rate of drug absorption
from i.m
1. Vascularity of the injection site.
Buttocks<thigh<arm . Eg – 4.5mg/kg lidocain
1. Lipid solubility and ionization of drug.
2. Molecular size of drug.
3. Volume of injection and concentration.
4. PH , composition and viscosity of injection
vehicle.
Subcutaneous administration
• Absorption of drug from subcutaneous site slower
than the intramuscular site.
• Administration of drug that degrade when taken
orally eg- insulin, sod heparin.
• Absorption occur by passive diffusion
• Rate of absorption depends upon blood flow and
injection volume
• It is used only when drug does not cause irritation,
otherwise severe pain, necrosis or tissue damage
may occur.
• Rate of absorption from this site can increase by-
1) Enhancing blood flow to the injection site-
By massage, application of heat, co-administration of vasodialator.
2) Increasing drug tissue contact area-
Co-administration of enzyme Hyaluronidase.
Pulmonary administration
• The drug are generally administered by inhalation
either as gases or aerosol which are rapidly
absorption just like exchange of gases between the
blood and inspired air.
• Absorption of hydrophilic drugs occur by diffusion
through aqueous membrane pores.
• Lipophilic drugs are absorbed by passive diffusion.
• Bronchodilators (salbutamol), anti-inflamatory
(bechlomethasone), anti-allergics (cromolyn).
• Avoids first –pass hepatic metabolism and Produce
rapid action with reduced systemic side effects.
Drug delivery to lungs is dependent upon the particle
size of the aerosolised droplets-
• Particles > 10µ impact on the mouth, throat or upper
respiratory tract mucosa and do not reach the
pulmonary tree.
• Very small particles- 0.6 µ from which drug
absorption is rapid.
• Particles 1-5µ deposit within the lower respiratory
tract.
Intranasal administration
• Drug absorption by this route is as rapid as
parenteral administered because of its high
permeability and rich vasculature.
• Popular for administration of peptides and protien
drugs.
• Route treat local symptoms like nasal congestion ,
rhinitis.
• Absorption depend upon drug lipophilicity and
molecular weight.
• Rapid absorption by diffusion is observed up to 400 -
1000 dalt.
• Lipophilic drugs shows rapid absorption by diffusion
and Hydrophilic drugs are absorbed by pore
transport.
• Permeation of drugs is influenced by pH of nasal
secretions (5.5 to 6.5), viscosity and Pathological
conditions such as common cold
• Mechanisms for the drug delivery from nose to the
brain:
 By cross the blood-brain barrier.
 By cross the olfactory epithelium via simple diffusion,
receptor mediated transcytosis or paracellular
transport.
 By neuronal cell of the olfactory nerve undergo
intracellular axonal transport.
Intraocular administration
• Topical application of drug to the eye is mainly for
local effects such as mydriasis , miosis, anaesthesia
or tretament of infection glaucoma.
• Sterile aqueous solutions of drugs are administered
in the conjunctival cul-de-sac.
• The barrier to intraocular prnetration of drug is the
cornea which posses both hydrophilic and lipophilic
characteristics.
• absorption of drug by passive diffusion into the
systemic circulation.
Corneal absorption:-
 Transport via corneal epithelium and stroma of small ionic
and lipophilic drugs.
 Outer epithelium is rate limiting barrier with pore size 60 A .
Non-corneal absorption:-
Transport via sclera and cojuctiva into intra ocular tissues by
passive diffusion of hydrophilic drugs.
• Various factors influence the absoprtion and
bioavailability.
 Hydrophilicity and lipophilicity
 Solubility in lacrimal fluid
 PH of lacrymal fluid
 Rate of blinking
 Volume of instilled fluid
 Viscosity of formulation
Vaginal administration
• Drugs meant for intravaginal action are
generally intended to act locally in the
treatment of bacterial or fungal infections or
prevent conception.
• The drugs are absorbed by passive diffusion
into the systemic circulation.
• Factors inluence the absorption-
 PH of lumen fluid (4-5)
 Vaginal secretion
 Microorganism present in vaginal lumen.
Comparison of different routes
ROUTE/ONSET OF ACTION ABSORPTION
MECHANISM
DRUGS
Buccal/
Sublingual
(3-5mins)
Passive diffusion, carrier
mediated transport
Nitrites and nitrates-
antianginals, nifedipine,
morphine, etc
Rectal (5-30mins) Passive diffusion Aspirin, paracetamol,
theophylline, etc
Transdermal
(minutes-hours)
Passive diffusion Nitroglycerine,
lidocaine, scopolamine,
testosterone, etc.
Subcutaneous
(15-30mins)
Passive diffusion Insulin, heparin
ROUTE/ ONSET OF
ACTION
ABSORPTION
MECHANISM
EXAMPLES
Inhalation
(2-3mins)
Passive diffusion,
pore transport
Salbutamol,
cromolyn,
Beclomethasone
Intramuscular
(10-20mins)
Passive diffusion,
endocytosis, pore
transport
Phenytoin, digoxin,
steroids and
antibiotics, etc.
Intranasal
(3-5mins)
Passive diffusion,
pore transport
Phenylpropylamine,
antihistamines
Intraocular Passive diffusion Atropine, pilocarpine,
adrenaline, etc.
Intraocular Passive diffusion Atropine, pilocarpine,
adrenaline, etc.
References:-
1. Milo Gibaldi; Biopharmaceutics and Clinical
Pharmacokinetics; PBS Publishers; 4th
Edition, 2005; Page No: 80-118
2. D.M.Brahmankar, Sunil B.Jaiswal;
Biopharmaceutics and Pharmacokinetics-A
Treatise; Vallabh Prakashan Publishers; 1st
Edition; 1995; Page No: 81-92.
Absorption of drugs through non oral routes

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Absorption of drugs through non oral routes

  • 2. Introduction ‘’The process of movement of unchanged drug from the site of administration to systemic circulation is called as drug absorption’’ The majority of drug are administered generally orally. But in some cases it is not good route of administration. For reason like patient non compliance, first pass effect, immediate drug action etc. There are more important biopharmaceutics and pharmacokinetics principle that must be considered for non- oral absoprtion.
  • 3. Non invasive routes of drug drug absorption 1) Buccal / Sublingual administration- 2) Rectal administration 3) Topical administration 4) Intramuscular administration 5) Subcutaneous administration 6) Pulmonary administration 7) Intranasal administration 8) Intraocular administration 9) Vaginal administration
  • 4. Buccal / sublingual administartion Two sites for oral mucosal delivery of drug as 1) Sublingual route- Drug places between tongue incase of sublingual. 2) Buccal route- Drug places between cheek and gum in case of buccal.
  • 5. • The barrier to drug absorption by this routes is the epithelium of oral mucosa. • Passive diffusion is the major mechanism for absorption of most drugs; nutrients may be absorbed by career-mediated processes. • The buccal and sublingual route appear ideal for lipid soluble drugs. • Examples- -Anti anginals- nitrites and nitrates -Anti hypertensives- nifedipine -Analgesics- morphine; bronchodilators- fenoterol -Steroids- oestradiol -Peptides- oxytocin
  • 6. FACTOR TO BE CONSIDER Lipophilicity of drug Higher the lipophilicity greater the absorption. Eg clindamycin. Salivary secretion Absorption is slow in dry mouth PH of saliva PH of saliva is about 6, increases the PH of saliva promotes the absorption of weak bases but reduces the absorption of weak acids. Eg. Flubiprofen (PH 5.5). Binding to oral mucosa Systemic availability is poor when drug is strongly bind to oral mucosa. Eg. Nicotin gum. Storage compartment Storage compartment in buccal mucosa appear to exit which is responsible for slow absorption of drug. Eg – buprenorphine. Thickness of oral epithelium
  • 7. Advantages-  Rapid absorption and higher blood levels  No first pass metabolism  No degradation of drugs such as that encountered in the GIT  Presence of saliva facilitates both drug dissolution and permeation. Disadvantages:-  Concern for taste and discomfort  Limited mucosal surface- small doses are administered.
  • 8. Rectal Administration • Important route for children and older person. • Drug given as suppositories or solution. • Absorption from solution is better.eg - lincomycin. • Presence of fecal matter in rectum retard absorption of drug. • PH of rectal fluids also influence drug absoption. • Absorption is slower because of limited surface area. • Absoprtion occur by passive diffusion. • Drug administered by this route includes Aspirin, paracetamol, theophylline, barbiturates.
  • 9. Advantages-  Alternative route for administration of unpleasant drugs  Avoids nausea, vomiting  Can be used in case of unconscious patients  Bypasses presystemic hepatic metabolism from lower half of rectum. Disadvantages-  Absorption is sometimes irregular and incomplete and many drugs cause irritation of rectal mucosa.
  • 10. Topical Administration • It is the largest organ of the body with the body weight approximately 2kg and 2 sq m in area and received about 1/3 0f total circulation. • Majority of drug applied topically are meant for local and systemic effects. • Dosage forms here are cream, ointments, lotion, gels, transdermal patches and disks. • When topically applied drug are meant exert their effects systemically , the mode of administration is called as Percutaneous or Transdermal delivery.
  • 11. • Diffusion through the multiple lipid bilayers of dead hydrophilic keratinized and horny cells of stratum corneum is the rate limiting step. • Topical drug application 1) systemic delivery – Clonidine, scopolamine, nicotine, fentanyl . 2) Local delivery – Antimiotics , Antiinflammatories , Anaesthetics. 3) Deliver to appendages- Antiinfective, Antiacne, Antiperspirant. • Topical route is useful for drug with low oral bioavailability and short duration of action.
  • 12. Transdermal route- •This route of administration achieves systemic effects by application of drugs to the skin, usually via a transdermal medicated adhesive patch. •The rate of absorption can vary markedly, depending on the physical characteristics of the drug (lipid soluble) and skin at the site of application. •This route is most often used for the sustained delivery of drugs, such as the antianginal drug nitroglycerin, the antiemetic scopolamine. • Site – Upper arm, chest, abdomen, mastoid region • First pass effect avoided • Absorption- increase by oily base, occlusive dressing, rubbing preparation
  • 13. Percutaneous absorption of drug by novel techniques Iontophoresis :- movement of ionic drug into body by means of an electric current. Cortisol , methacoline, lidocaine, salicylates. Phonophoresis :- movement of drug molecules through the skin under the influence of ultra sound.
  • 14. Skin structure Anatomically skin made of 3 distinct layer as Epidermis Dermis Subcutaneous
  • 15.  There are three pathways postulated for the diffusion of solutes through the skin: Transcellular (passive diffusion)- cross keratinized cells. Accessible to non-polar molecules. hydrophilic drug show penetration through this layer. Intercellular (paracellular)- Across the lipid matrix. Accessible to non-polar molecules Lipophilic drugs show penetration through this layer. Transappendageal– Accessible to polar molecules Across hair follicles, sweat gland, sebaceous glands.
  • 17. Factors influence the percutaneous absorption 1) Skin condition-  Thickness of stratum corneum  Presence of hair follicles  Hydration of skin  Age  Skin microflora  Skin PH  Skin surface lipids  Anatomical site
  • 18. 2) Composition of topical vehicle-  Vehicle or base  Permeation enhancers 3) Appliction condition-  Rubbing  Occlusion  Loss of vehicle 3) External factors-  Env humidity and temp  Grooming  Exposure to chemicals  Chronic use of certain drugs
  • 19. Intramuscular Administration • Absorption of drug from i.m site is relatively rapid but much slower in comparision to I.v injection. • Absorption of lipophilic drugs occurs by passive diffusion into blood circulation and lymphatic system. • Hydrophilic and ionic drugs are absorbed into blood circulation via the capillary pores.
  • 20. ADVANTAGES-  Oily suspensions for depot and slow release preparations.  For drugs which degrade after oral route- insulin  Rapid onset of action. DISADVANTAGES-  Metabolism of drugs in muscle tissues.  Precipitation of drug at the injection site.  Irritating drugs may be very painful.
  • 21. Factors determine rate of drug absorption from i.m 1. Vascularity of the injection site. Buttocks<thigh<arm . Eg – 4.5mg/kg lidocain 1. Lipid solubility and ionization of drug. 2. Molecular size of drug. 3. Volume of injection and concentration. 4. PH , composition and viscosity of injection vehicle.
  • 22. Subcutaneous administration • Absorption of drug from subcutaneous site slower than the intramuscular site. • Administration of drug that degrade when taken orally eg- insulin, sod heparin. • Absorption occur by passive diffusion • Rate of absorption depends upon blood flow and injection volume • It is used only when drug does not cause irritation, otherwise severe pain, necrosis or tissue damage may occur.
  • 23. • Rate of absorption from this site can increase by- 1) Enhancing blood flow to the injection site- By massage, application of heat, co-administration of vasodialator. 2) Increasing drug tissue contact area- Co-administration of enzyme Hyaluronidase.
  • 24. Pulmonary administration • The drug are generally administered by inhalation either as gases or aerosol which are rapidly absorption just like exchange of gases between the blood and inspired air. • Absorption of hydrophilic drugs occur by diffusion through aqueous membrane pores. • Lipophilic drugs are absorbed by passive diffusion. • Bronchodilators (salbutamol), anti-inflamatory (bechlomethasone), anti-allergics (cromolyn). • Avoids first –pass hepatic metabolism and Produce rapid action with reduced systemic side effects.
  • 25. Drug delivery to lungs is dependent upon the particle size of the aerosolised droplets- • Particles > 10µ impact on the mouth, throat or upper respiratory tract mucosa and do not reach the pulmonary tree. • Very small particles- 0.6 µ from which drug absorption is rapid. • Particles 1-5µ deposit within the lower respiratory tract.
  • 26. Intranasal administration • Drug absorption by this route is as rapid as parenteral administered because of its high permeability and rich vasculature. • Popular for administration of peptides and protien drugs. • Route treat local symptoms like nasal congestion , rhinitis. • Absorption depend upon drug lipophilicity and molecular weight. • Rapid absorption by diffusion is observed up to 400 - 1000 dalt.
  • 27. • Lipophilic drugs shows rapid absorption by diffusion and Hydrophilic drugs are absorbed by pore transport. • Permeation of drugs is influenced by pH of nasal secretions (5.5 to 6.5), viscosity and Pathological conditions such as common cold • Mechanisms for the drug delivery from nose to the brain:  By cross the blood-brain barrier.  By cross the olfactory epithelium via simple diffusion, receptor mediated transcytosis or paracellular transport.  By neuronal cell of the olfactory nerve undergo intracellular axonal transport.
  • 28. Intraocular administration • Topical application of drug to the eye is mainly for local effects such as mydriasis , miosis, anaesthesia or tretament of infection glaucoma. • Sterile aqueous solutions of drugs are administered in the conjunctival cul-de-sac. • The barrier to intraocular prnetration of drug is the cornea which posses both hydrophilic and lipophilic characteristics. • absorption of drug by passive diffusion into the systemic circulation.
  • 29. Corneal absorption:-  Transport via corneal epithelium and stroma of small ionic and lipophilic drugs.  Outer epithelium is rate limiting barrier with pore size 60 A . Non-corneal absorption:- Transport via sclera and cojuctiva into intra ocular tissues by passive diffusion of hydrophilic drugs. • Various factors influence the absoprtion and bioavailability.  Hydrophilicity and lipophilicity  Solubility in lacrimal fluid  PH of lacrymal fluid  Rate of blinking  Volume of instilled fluid  Viscosity of formulation
  • 30. Vaginal administration • Drugs meant for intravaginal action are generally intended to act locally in the treatment of bacterial or fungal infections or prevent conception. • The drugs are absorbed by passive diffusion into the systemic circulation. • Factors inluence the absorption-  PH of lumen fluid (4-5)  Vaginal secretion  Microorganism present in vaginal lumen.
  • 31. Comparison of different routes ROUTE/ONSET OF ACTION ABSORPTION MECHANISM DRUGS Buccal/ Sublingual (3-5mins) Passive diffusion, carrier mediated transport Nitrites and nitrates- antianginals, nifedipine, morphine, etc Rectal (5-30mins) Passive diffusion Aspirin, paracetamol, theophylline, etc Transdermal (minutes-hours) Passive diffusion Nitroglycerine, lidocaine, scopolamine, testosterone, etc. Subcutaneous (15-30mins) Passive diffusion Insulin, heparin
  • 32. ROUTE/ ONSET OF ACTION ABSORPTION MECHANISM EXAMPLES Inhalation (2-3mins) Passive diffusion, pore transport Salbutamol, cromolyn, Beclomethasone Intramuscular (10-20mins) Passive diffusion, endocytosis, pore transport Phenytoin, digoxin, steroids and antibiotics, etc. Intranasal (3-5mins) Passive diffusion, pore transport Phenylpropylamine, antihistamines Intraocular Passive diffusion Atropine, pilocarpine, adrenaline, etc. Intraocular Passive diffusion Atropine, pilocarpine, adrenaline, etc.
  • 33. References:- 1. Milo Gibaldi; Biopharmaceutics and Clinical Pharmacokinetics; PBS Publishers; 4th Edition, 2005; Page No: 80-118 2. D.M.Brahmankar, Sunil B.Jaiswal; Biopharmaceutics and Pharmacokinetics-A Treatise; Vallabh Prakashan Publishers; 1st Edition; 1995; Page No: 81-92.