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BY
V. SANDEEP KUMAR
M.PHARMACY II ASEMESTER
2010
DEPARTMENT OF PHARMACEUTICS,
UNIVERSITY COLLEGE OF PHARMACEUTICAL SCIENCES,
KAKATIYA UNIVERSITY, WARANGAL.
Clinical testing of IN Morphine gluconate compared
with traditional IM and oral products
CONTENTS
INTRODUCTION
ANATOMY AND PHYSIOLOGY OF NASAL CAVITY
BARRIERS TO NASAL ABSORPTION
FACTORS INFLUENCING NASAL DRUG ABSORPTION
STRATEGIES TO INCREASE NASAL DRUG ABSORPTION
NOSE TO BRAIN DELIVERY
INTRANASAL DELIVERY OF VACCINES
INTRANASAL DELIVERY OF PEPTIDE AND PROTEINE DRUGS
ANIMAL MODELS FOR NASAL ABSORPTION STUDIES
THERAPEUTIC AREAS SUTIABLE FOR INTRANASAL DELIVERY
CONCLUSION
REFERENCES
Avoidance of hepatic first-pass metabolism
Avoids degradation of drug in gastrointestinal tract resulting
from acidic or enzymatic degradation
Rate of absorption comparable to IV medication
Results in rapid absorption and onset of effect
Non-invasive, Painless, needle-free administration mode
Easily accessible (even easier to access than IM or IV sites)
Self-medication is possible through this route
Results in higher bioavailability thus uses lower dose & hence
lower side effects
Useful for both local & systemic drug delivery
Direct transport into systemic circulation and CNS is possible .
Offers lower risk of overdose
Drugs that are orally not absorbed can be delivered to the systemic
circulation by nasal drug delivery
Adversely affected by pathological conditions(cold or allergies may
alter significantly the nasal bioavailability)
Irritation of nasal mucosa by drugs
Volume that can be delivered into nasal cavity is restricted to
25–200 μl
Normal defence mechanisms like mucocillary clearance and ciliary
beating affects the permeability of drug
Enzymatic barrier to permeability of drugs
Interspecies variability is observed in this route
Absorption enhancers cause irritation.
NASAL CAVITY :ANATOMY, PHYSIOLOGY
Major functions of the nasal cavity are breathing and olfaction.
Nasal vasculature is richly supplied with blood to fulfill the basic functions
such as heating and humidification, mucociliary clearance and immunological
functions.
Relatively large surface area (~150 cm2) because of the presence of ~400
microvilli per cell.
It is divided by middle (or nasal) septum into two symmetrical halves, each
one opening at the face through nostrils and extending posterior to the
nasopharynx.
Cross-sectional View
a – nasal vestibule
d – middle turbinate
b – palate
e – superior turbinate
c – inferior turbinate
f – nasopharynx
Nasal secretions
Nasal secretion contains sodium, potassium, calcium, mucus glycoproteins,
albumins, immunoglobulins IgA, IgG, lysozymes, cytochrome P450
dependent
monooxygenases,
lactate
dehydrogenase,
oxidoreductases,
hydrolases like steroid hydrolases
Nasal pH
It varies between 5.5–6.5 in adults and 5.0–7.0 in infants.
Nasal epithelium is covered with a thin mucus layer (5 μm thick) and organized in
two distinct layers: an external, viscous and dense(gel), and an internal, fluid and
serous(watery).
 Nasal mucus layer consists of 95% of water, 2.5-3% of mucin, and 2% of electrolytes,
proteins, lipids, enzymes, antibodies, sloughed epithelial cells and bacterial products
MUCOCILIARY CLEARANCE(MCC)
Nasal mucosal lining
Enzymes present in nasal cavity
Mucociliary clearance (MCC)
•Lipophilic drugs are generally well absorbed with the pharmacokinetic
profiles identical to those obtained after an I.V injection and bioavailabilities
approaching 100%.
•Ex: fentanyl where the Tmax for both i.v and nasal administration is 7 min or
less and the bioavailability was near to 80%.
• Nasal permeability of polar drugs especially large mol.wt polar drugs such
as peptides and proteins is low.
•Polar drugs with mol.wt below 1000 Da will generally pass the membrane
using paracellular route.
Tight junctions can open and close to a certain degree, when needed.
Proteins through endocytotic transport process but only in low amounts.
Clearance of the administered formulation from the nasal cavity due to the
mucociliary clearance mechanism.
Especially for drugs that are not easily absorbed and formulations that are
not mucoadhesive.
Aldehyde dehydrogenase, glutathione transferase, epoxide hydrolases,
cytochrome P-450-dependent monooxygenases, carboxyl esterases ex: nasal
decongestants, alcohols, nicotine and cocaine.
Aminopeptidases, exopeptidases, endopeptidases are involved in in pre
systemic degradation of peptides and proteins
Transport Of Drugs Across Nasal Epithelium
A- Transcellular passive diffusion, B- Paracellular passive diffusion,
C-Carrier mediated , D- Transcytosis , E- Effluxt ransport
NASAL PHYSIOLOGICAL FACTORS
 Blood flow and neuronal regulation
Huang et al showed that phenylephrine, a vasoconstrictor agent, inhibited the
absorption of acetylsalicylic acid in nasal cavity. Kao et al. stated that nasal
absorption of dopamine was relatively slow and incomplete probably due to its own
vasoconstrictor effect.
 Nasal secretions
• Viscosity of nasal secretion
• Diurnal variation
pH of nasal cavity
 Mucociliary clearance (MCC)
The clearance of a drug product from the nasal cavity is influenced by the site of
deposition.
Polar drugs are the most affected by MCC.
Inter-individual variability observed in MCC.
Enzymatic degradation
Transporters and efflux systems
Physicochemical properties of drugs
Molecular weight
Lipophilicity
pKa
Lipophilic drugs well absorbed through transcellular mechanisms with nasal
bioavailability near to 100%( lower than 1 kDa).
Absorption of lipophilic drugs bigger than 1 kDa is significantly reduced.
Rate of permeation of polar drugs is highly sensitive to mol.wt if it is higher
than 300 Da.
For some small polar molecules only a 10% bioavailability is suggested.
The value may go down to 1% for large molecules such as proteins.
Huang, C.H. et al. studied absorption of benzoic acid at pH 7.19 (99.9% of
the drug existed in ionized form) it was found that >10% of drug was
absorbed.
Solubility
Drugs poorly soluble in water and/or requiring high doses may constitute a
problem as allowable volume of drug solution is low for intranasal drug
administration
PROPERTIES OF THE FORMULATION
pH
Viscosity
Osmolarity
Pharmaceutical excipients
Area of nasal mucus membrane exposed
Dosage form
Device related factor
Particle size of the droplet or powder
If the particle size is <10 μm, then particles will be deposited in the upper
respiratory tract, whereas if particle size is <0.5 μm then it will be exhaled.
Size between 5–7 μm will be retained in the nasal cavity.
Site and pattern of deposition
STRATEGIES TO INCREASE NASAL DRUG ABSORPTION
Prodrugs
To improve the solubility of poorly soluble drugs. Ex: the l-dopa has a low
water solubility of 1.65 mg/Ml, Testosterone, Estradiol
Kao et al. produced various prodrugs of L-Dopa and the solubility was
increased to 660 mg/mL with butyl ester prodrug.
To improve its lipophilic character, ultimately increasing its transport
across a biological membrane
To improve enzymatic stability of drugs. For example, Yang et al. stated that
L-aspartate- β-ester prodrug of acyclovir was more permeable and less labile
to enzymatic hydrolysis than its parent drug.
It is a a powerful strategy to increase the bioavailability of peptides.
Choice of salt form
Cancer patients treated with nasally administered morphine gluconate
experienced rapid onset of pain relief and good pain scores (Fitzgibbon et al.,
2003; Pavis et al., 2002).
Co-solvents
Diazepam and Clonazepam are administered to suppress epileptic
convulsions requires rapid onset of action. However, these are poorly soluble
and nasal formulations comprised of cosolvents demonstrated a Tmax of <5
min, and a pharmacodynamic response was seen in 1.5 min in a rabbit model
(Li et al.,2000)
Enzymatic inhibitors
Proteases and Peptidases inhibitors - bestatine, amastatin, boroleucin,
borovalin, and comostate amylase, puromycin, bacitracin (Ex: leucine
enkephalin and human growth hormone)
Trypsine inhibitors – leupeptine and aprotinin (against degradation of
calcitonin).
Certain absorption enhancers - bile salts and fusidic acid.
Absorption enhancers
They improve the absorption of
poorly permeable molecues across nasal
epithelium.
Physicochemical effects
By alterig the physicochemical properties of a drug in the formulation.
Membrane effects
Induce reversible modifications of the structure of epithelial barrier.
oModifying the phospholipidic bilayer,
oIncreasing membrane fluidity by
a) Extraction or leaching of membrane components ( proteins)
b) Creating disorders in the phospholipids domain in the membrane.
oReversed micelle formation between membranes.
oOpening tight junctions between epithelial cells.
Nasal Absorption Promoting Systems
Chitosan
Due to its biodegradability, biocompatibility and bioadhesive property, lower
toxicity, it is widely used in intranasal formulations.
 It interacts with protein kinase C system and opens the tight junctions between
epithelial cells.
It also enhances the dissolution rate of low water soluble drugs.
Most studied drugs are insulin and morphine
Cyclodextrins
As complexing agents to improve nasal drug absorption by increasing drug
solubility and stability. (2-hydroxypropyl-cyclodextrin increased the solubility of
progesterone 88-fold.)
They interact with the lipophilic components of membranes changing their
permeability.
A nasal product (Aerodiol) containing 17-estradiol solubilized in dimethylcyclodextrin is marketed for menopausal symptoms.
Mucoadhesive drug delivery systems
Mucoadhesion implies the attachment of the drug delivery system to the
mucus, involving an interaction between mucin and a synthetic or natural
polymer is called mucoadhesive.
Mucoadhesives mostly used in IN delivery are chitosan, alginate and
cellulose or its derivatives.
Carbapol 934P and polycarbophil are mucoadhesive polymers that inhibit the
trypsin proteolytic enzyme and therefore, increase the stability of peptide drugs.
NOVEL DRUG FORMULATIONS
Liposomes
They can effectively encapsulate small and large molecules with a wide
range of hydrophilicity and pKa values .
They enhance nasal absorption of peptides such as insulin and calcitonin by
increasing their membrane penetration (attributed to the increasing nasal
retention of peptides, protection of the entrapped peptides from enzymatic
degradation ).
Novel mucoadhesive multivesicular liposomes for transmucosal insulin
delivery has been investigating.
Lliposomal drug delivery systems were also reported as useful for influenza
vaccine and non-peptide drugs such as nifedipine.
Microspheres
Microspheres based on mucoadhesive polymers (chitosan, alginate) present
advantages for IN delivery.
Microspheres may also protect the drug from enzymatic metabolism.
Wang et al. have investigated gelatin microspheres as a IN delivery system
for insulin .
Positive results are found for nasal delivery of
Metoclopramide microspheres of alginate/chitosan
Carbamazepine chitosan microspheres
Carvedilol alginate microspheres
New and developing approach to deliver drugs to the brain.
Improved delivery to the brain via the IN route has been reported for some
low-mol.wt drugs as well as therapeutic peptides and proteins .
Nose to brain delivery has been reported either in humans or animal models
of Alzheimer’s disease, brain tumours, epilepsy, pain and sleep disorders .
Nose to the CNS may occur via olfactory neuroepithelium.
Since central nervous bioavailability of drugs, transported by the olfactorypathway is estimated to be 0.01% to 0.1%, only very potent drugs may reach
therapeutic levels
Possible routes of transport between the nasal cavity and the brain and CSF
Efflux transporters impair drug concentration in the brain after IN administration [Graff
and Pollack 2003].
P-glycoprotein, an ATP-dependent efflux pump, preventing the influx of a drug (D) from nasal
membrane to CNS
Human clinical testing of IN Apomorphin, Sublingual and
subcutaneous dosing in 12 subjects
INTRANASAL DELIVERY OF VACCINES
Nasal mucosa houses lymphatic tissues involved in the first line defense
against airborne microorganism.
In humans the NALT is known as the Waldeyer´s Ring.
Reasons for exploiting the nasal route for vaccine delivery.
• The nasal mucosa is the first site of contact with inhaled pathogens.
• The nasal passages are rich in lymphoid tissue.
• Creation of both mucosal and systemic immune responses.
• Low cost, patient friendly, non-injectable, safe.
The majority of the invading pathogens enter the body via mucosal surfaces.
Therefore, mucosal sites have a potential as first line of defense against entering
pathogens.
Nasal secretions are known to contain immunoglobulins (IgA, IgG, IgM, IgE),
and neutrophils and lymphocytes in the mucosa .
Nasal vaccine delivery stimulates the production of local secretory IgA and
IgG
Nasal vaccine systems based on live or attenuated whole cells, split cells,
proteins or polysaccharides and with and without various adjuvants were
investigating.
Nasal Drug Products for Vaccination Available in the Market
The chitosan nasal delivery system has been tested for influenza, and
diphtheria vaccine in various animal models and in man.
Bioadhesive property and transient effect on the tight junctions of chitosan
lead to an improved immune response.
It has been reported that Ab levels were similar for IM conventional
influenza vaccine and nasal administration of the chitosan-influenza vaccine.
Due to its positive charge chitosan gets complexed with negatively
charged DNA plasmids and self-assembling into nanoparticulate systems for
improved delivery of DNA.
Nasal delivery of DNA plasmid expressing epitopes of respiratory
syncytial virus (RSV) to produce an effective vaccine.
INTRANASAL DELIVERY OF PEPTIDE AND
PROTEIN DRUGS
•Being hydrophilic polar molecules of relatively high molecular weight, are
poorly absorbed across biological membranes with low bioavailabilities .
•This low uptake may adequate for some commercial products such as
desmopressin and calcitonin ( 3432 Da, 3% (Novartis Pharmaceuticals, 2006).
•Novel formulation strategies
Absorption enhancers
 Bioadhesive agents
•Absorption enhancing effect of different cyclo-dextrins (rats,rabbits),
medium chain fatty acid (rats), sodium tauro-24, 25-dihydrofusidate (sheep)
on intranasally administered insulin in rats and rabbits was obsrved.
Bioavailabilities of peptides and proteins administered IN in the presence of
absorption enhancers
The clearance half- life can be increased with starch microspheres of insulin
(SMS).
 Insulin administered in combination with SMS resulted in 497% increase in
AUC for plasma insulin as compared to insulin solution.
The AUC increased by 1657% compared to insulin solution when an
enhancer lysophosphatidyl choline was used with insulin and SMS.
Successfully intranasally administered proteins include oxytocin, buserelin,
desmopressin, luteinizing hormone releasing hormone, growth hormone and
adrenocorticotrophic hormone.
Nasal Drug Products (Proteins and Peptides) for Systemic Drug Delivery on
the Market
Nasal Drug Products (Non-Peptide) for Systemic Drug Delivery on the Market
In Vivo Nasal Absorption studies
Rat Model
Rabbit Model
Dog Model
Sheep Model
Monkey Model
Ex Vivo Nasal Perfusion Models
The surgical procedure of
Nasal absorption in the rat
Experimental set-up for exvivo Nasal perfusion
Nasal Dosage forms
Nasal Drops
Simple and convenient systems .
Disadvantage is the lack of dose precision.
Nasal Sprays
Both solution and suspension can be formulated into nasal sprays.
They can deliver an exact dose of 25 to 200 µl by metered dose pumps and
actuators.
The choice of pump and actuator assembly depend on the particle size and
morphology (for suspensions) and viscosity of the formulation.
 Solution and suspension sprays are preferred over powder sprays because
powder results in mucosal irritation .
Nasal Gels
Nasal gels are high-viscosity thickened solutions or suspensions.
Advantages
 Reduction of post-nasal drip due to high viscosity
 Reduction of taste impact due to reduced swallowing
 Reduction of anterior leakage of the formulation
 Reduction of irritation by using soothing/emollient excipients
Nasal Powders
If solution and suspension dosage forms cannot be developed e.g.due to lack
of drug stability
Advantages
Absence of preservative
Superior stability
Local application
Diadvantages
Nasal mucosa irritationa, metered dose delivery
NASAL DELIVERY DEVICES
Common devices are
Droppers
Squeeze bottles
Spray pumps / atomizers (Accuspray Nasal Atomizer,
MAD (Mucosal Atomization Device, nasal)
Gel applicators
Nasal Nebulisers (Sinus Nebuliser Rhino Clear)
Pressurised Metered Dose Inhalers (pMDIs) Nasal (Ex:
Landmark®)
Disposable Unit/Bi-dose dispensing devices
Powder Dispensing Systems
MAD
Mechanical Basic Pump
The unit-dose
and
the bi-dose system
Powder unit-dose system.
Powder bi-dose system.
Novel Nasal spray pumps
Patient-independent Pumps
To minimise dose and spray variations
related to the patient's hand actuation
mode. (Equdel by Valois Pharma)
Preservative Free Systems (PFS)
To accommodate preservative-free drug formulations.
Preservatives may induce itching in chronic use
Can generate some formulation instabilities
Affect the smell and/or taste of the drug product.
(Freepod by Valois Pharma)
Side-actuation Spray Pumps
Eliminate any risk of the nasal nozzle entering the nostril too deeply
Avoids contact between fingers and nostrils which improves hygiene
during treatment.
LEADING PUMP SUPPLIERS
Valois, France
Pfeiffer, Germany
Becton Dickinson,
France
Nemo, Spain
BREATH ACTUATED BIDIRECTIONAL NASAL DRUG DELIVERY
Developed by OptiNose
Based on two nasal anatomical features
First, during exhalation against a resistance the soft
palate closes, separating the nasal and oral cavities.
So small particles in nasal spray can be used and still
avoid lung deposition by exhaling through the
mouth during nasal administration.
Single-use bi-directional
delivery device
Second, during closure of the soft palate there is a communication pathway
between the two nostrils, located behind the nasal septum. It is possible for air
to enter via one nostril, turn through 180˚ passing through the communication
pathway, and leave by the other nostril.
Bidirectional Nasal Drug Delivery Principle
Comparing Deposition patterns of traditional spray pump and bidirectional delivery device
incorporating the same spray pump (Gamma scintigraphy images from the same subject;
Cumulative distribution during 32 minutes)
White areas in the nose: 20-100% of maximum intensity
Orange areas in the nose: 0-20% of maximum intensity
Green areas in the nose: no deposition
Gamma-scintigraphy
images from the same subject; Cumulative distribution during 32 minutes
THERAPEUTIC AREAS SUTIABLE FOR INTRANASAL DELIVERY
CONCLUSION
In a nut shell, the advantages of IN delivery are numerous and very
importantly it is rapid and non-invasive.
An alternative to parenteral and oral route.
IN delivery suitable for both topical or systemic delivery and to treat both
acute and chronic diseases.
 It also bypasses the BBB and delivers the drug directly into the CNS. It
reduces systemic exposure and thus reduces the side effects.
IN delivery can be utilized for high molecular- weight drugs such as
peptides and proteins, however, bioavailability is dependent upon the
presence of absorption enhancers.
Another application for IN dosing is vaccine therapeutics.
However, still some research needs to be conducted in delivery of peptide and
protein and vaccines through nasal delivery and delivery of drug from nose to
brain.
Further, extensive research at the molecular level is required to increase the
permeation of drugs through the nasal mucosa without compromising normal
function.
Taking into consideration the current research interest in nasal delivery and
positive outcomes from the clinical trials throughout the world it is expected a
wide range of nasal products reaching the market in the near future.
REFERENCES
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• Talegaonkar S, Mishra PR. Intranasal delivery: An approach to bypass the blood brain barrier. Indian J
Pharmacol 2004; 36(3): 140-147
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(1987) 67
• S. Hirai, T. Yashiki, T. Matsuzawa, H. Mima, Absorption of drugs from the nasal mucosa of rat, Int. J. Pharm. 7
(1981) 317–325.
• H.D. Kao, Enhancement of delivery of L-Dopa by the administration of it’s prodrugs via the nasal route,
University of Kentucky, Lexington, Kentucky, 1995.
• .N. Geurkink, Nasal anatomy, physiology, and function, J Allergy Clin. Immunol. 72 (1983) 123 128.
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