NOVEL DRUG DELIVERY SYSTEM(NDDS) FOR NASAL

2. AURHOR:- NILESH S.JAWALKAR
E-MAIL:-nilesh.jawalkar91@gmail.com

3. Nasal drug delivery is attractive not
because it is BETTER than injectable
therapy……
BUT
…Because it is SAFER!
...No needle
…NO needle stick risk!
Nasal drug delivery is receiving much attention from the
pharmaceutical industry.
About 2% of the overall drug delivery is administered via the
nasal route.
Topical decongestants or anti-inflammatory drugs used to
treat a rhinitis or allergy related indications are well-known
drug products.
The nasal route is an attractive alternative to invasive
administrations, and pr

4. Nasal
Epithelial Characteristics
Surface
Sections
Cells / Functions
Stratified squamous and keratinized
epithelial cells with nasal hairs /
Support and protection
Stratified squamous cells / Support
Area
Vestibule
Atrium
Respiratory
region
Olfactory
region
Vascularization
Permeability
≈ 0.6 cm2
Low
Poor
NF
Low
Reduced
Very high
Good
Pseudostratified cells / Support
Columnar non ciliated cells / Support
≈ 130 cm2
Columnar ciliated cells / Support and
muciliary clearance
Globet cells / Mucus secretion
Basal cells / Progenitors of other cell
types
Sustentacular cells / Support and
≈ 15 cm2
synthetic
Olfactory receptor cells / Olfaction
perception
Basal cells / Progenitors of other cell
types
High
Direct access

5. The nose actively contributes
to two major functions of the
human system.
•The first function is the
sense of smell (olfaction)
•The second is respiration
or breathing.
The nasal septum divides the
nasal cavity into left and right
halves.
The nasal septum is never a
straight vertical separation of
the two cavities.

6. (1) Spheno palatine artery
(2) Greater palatine artery
(3) Superior labial artery
(4) Anterior and posterior ethmoidal artery

7. 1) Drugs that are orally not absorbed can be delivered to
the systemic circulation by means of nasal drug delivery.
2) Hepatic first pass metabolism is avoided.
3) Easy accessibility and needle free drug application
without the necessity of trained personnel facilitates self
medication, thus improving patient compliance compared to
parenteral routes.
4) Drug degradation that is observed in the gastrointestinal
tract is absent.
5) The bioavailability of large drug molecules can be
improved by means of absorption enhancer or other
approach.
6) Rapid drug absorption and quick onset of action can be
achieved.
7) The nasal bioavailability for smaller drug molecules is
good.

8. 8) Drug possessing poor stability in GIT fluids are given by nasal route.
9) Studies so far carried out indicate that the nasal route is an
alternate to parenteral route, especially, for protein and peptide drugs.
10) Polar compound exhibiting poor oral absorption may be
particularly suited for this route of delivery.
11) Convenient for the patients, especially for those on long term
therapy, when compared with parenteral Medication.

9. 1) Nasal cavity provides smaller absorption surface area
when compared to GIT.
2) Relatively inconvenient to patient when compared to oral
delivery system since there is a
possibility of irritation.
3) There is a risk of local side effects and irreversible
damage of the cilia on the nasal
mucosa, both from the substance and from constituents
added to the dosage form.
4) There could be a mechanical loss of the dosage form into
the other parts of the respiratory
tract like lungs because of improper technique of
administration.
5) Certain surfactants used as chemical enhancers may
disrupt and even dissolve the
membrane in high concentration.

11. Nasal Drug
Absorption
Characteristis
of the drug
Properties
of the
formulation
Nasal Drug
Absorption
Prodrugs,
Enzymatic
Inhibitors
Absorption
enhancers
Mucoadhesive
drugdelivery
systems
Novel
formulation
forms

12. STRATEGIES TO INCREASE NASAL
DRUG ABSORPTION………..
Strategy
Examples
1. Nasal enzyme inhibitors
Bestatin, amastatin, boroleucine, fusidic acids and
bile salts
2. Nasal permeation enhancers
Cyclodextrins, surfactants, saponins, phospholipids
3. Prodrug approach
Cyclic prodrugs, esters, derivatization of C and N
termini
4. Nasal mucoadhesive drug delivery
Carbopol, polycarbophil, cellulose derivatives,
lecithin, chitosan
5. Particulate drug
Microspheres, nanoparticles, liposomes

13. STRATEGIES TO INCREASE NASAL
DRUG ABSORPTION CONT….
Problem
Challenge
Solution
Poor physicochemical
Improve physicochemical
Prodrugs
properties of drug and/or
properties of drug
Cosolvents
formulation
and/or formulation
Cyclodextrins
Pharmaceutical excipients
Novel drug formulations
Enzymatic degradation
Reduce drug affinity to nasal
Prodrugs
enzymes
Enzymatic inhibitors
Inhibit
nasal
enzymes Protect drugs from
Prodrugs
nasal enzymes
Cosolvents
Low permeability through
Increase drug permeability
Prodrugs
nasal membrane
and dissolution
Cosolvents Absorption
Modify nasal membrane
enhancers
Absorption enhancers
Mucoadhesive systems
Enhance drug residence time
Gelling/Viscosifying agents
in nasal cavity

14. Name of compound
Surfactants
Example
Sodium dodecyl sulphate (SDS),
Polyoxy ethylene-9-lauryl ether,
Phosphatidylcholines
Complexing and
Ethylene diamine tetraacetic acid
Chelating agents
(EDTA)
Cyclodextrins and
α-, β-, γ-cyclodextrin, DMβ-, HPβ-
derivatives
cyclodextrin
Fusidic acid
Sodium tauradihydrofusidate
derivatives
(STDHF)
Bile salts
Sodium taurocholate,
Sodium glycocholate
Dry microspheres
Degradable starch microsphere,
Dextran microspheres

15. MECHANISM OF NASAL ABSORPTION

17. Pathways for nasal absorption
Nose brain pathway
Absorption through the olfactory neurons
- transneuronal absorption. Olfactory
epithelium is considered as a portal for
substances to enter CNS
 The olfactory mucosa (smelling area in nose) is in
direct contact with the brain and CSF.
 Medications absorbed across the olfactory mucosa
directly enter the CSF.
 This area is termed the nose brain pathway and
offers a rapid, direct route for drug delivery to the
brain.
Brain
Brain
CSF
CSF
Brain
CSF
Highly
vascular
mucosa
nasal

18. Lipophilicity
Non-lipophilic
Lipophilic molecules
Cell Membrane
“Lipid Loving”

Cellular membranes are composed of
layers of lipid material.

Drugs that are lipophilic are easily and
rapidly absorbed across the mucous
membranes.

19. Absorption through
the supporting
cells & the
surrounding
capillary bed
- venous
drainage

20. •Cytochrome P 450 dependent onooxygenases, Lactate
dehydrogenase, Oxidoreductase, Hydrolases, Esterase, lactic
dehydogenase, malic enzymes, lysosomal proteinases, steroid
hydroxylases., etc.,
•Cytochrome P450 dependent mono oxygenases has been reported
to catalyse the metabolism of xenobiotics, nasal decongestants,
nocotine, cocaine, phenacetin, nitrosamine progesterone etc.,
•Insulin zinc free was hydrolysed slowly by leusine aminopeptidase,
•PG of E series was inactivated 15 hydroxyprostaglandin
dehydrogenase
•Progesterone and testosterone were metabolized by several steroid
hydroxylases in the nasal mucosa of rats

21. •Nasal secretion of adult : 5.5-6.5
•Infants and children: 5-6.7
•It becomes alkaline in conditions such
as
acute rhinitis, acute sinusitis.
•Lysozyme in the nasal secretion helps
as
• antibacterial and its activity is
diminished in alkaline pH

22. Designing of nasal formulation depends upon the therapeutic need of the
particular drug molecule, duration of action and duration of therapy. Both
controlled release and conventional release drug delivery are possible through
nasal route.(38)
1. Nasal drops
2. Nasal powders
3. Nasal sprays (solution/suspension)
4. Nasal mucoadhesive particulate delivery (micro/nanoparticles, liposomes)
5. Nasal gel
6. Nasal ointments
7. Nasal microemulsions

23. Drug Molecule
* Molecular weight and size: <1000 Da
* Solubility: Higher to get dissolved in the nasal fluid and thereby to
get permeated (important for particulate drug delivery).(29)
* Compound lipophilicity: Should be high for better absorption
(through transcellular route), although hydrophilic small molecular
weight compounds absorb through aqueous channels.(30)
* Partition coefficient and pKa: Unionized molecules easily
permeate, although ionized species also permeate through different
pathways.
* Therapeutic dose: <25 mg per dose(31)

24. Drug concentration: Higher the concentration, higher the
permeation
(up to certain extent)(32)
* Dose volume: 0.05 - 0.15 ml per dose
* Formulation pH: 4.5 – 6.5 to avoid nasal irritation.
(nasal surface pH is 7.39 and pH of nasal secretions is 5.5 –
6.5)(33)
* Osmolarity: Isotonic formulation (less irritant), higher salt
concentration increases permeability but is irritant to nasal
mucosa.(34)
* Viscosity: Higher the viscosity, longer the residence time of
formulation.
But it also hinders normal physiological functions like ciliary
beating and mucociliary clearance, thus affecting
permeability.(35)

25. Nasal gels are high-viscosity thickened solutions or suspensions. Until the
recent development of precise dosing devices, there was not much interest in
this system. The advantages of a nasal gel include the 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 and target delivery to mucosa
for better absorption. The deposition of the gel in the nasal cavity depends on
the mode of administration, because due to its viscosity the formulation has
poor spreading abilities. Without special application techniques it only
occupies a narrow distribution area in the nasal cavity, where it is placed
directly. Recently, the first nasal gel containing Vitamin B12 for systemic
medication has entered the market.

26. Nanoparticles may offer an improvement to nose to brain drug delivery
since they are able to protect the encapsulated drug from biological and/or
chemical degradation, and extracellular transport by P-gp efflux proteins.
This would increase CNS availability of the drug. A high relative surface
area means that these vectors will release drug faster than larger
equivalents, a property desirable where acute management of pain is
required. Their small diameter potentially allows nanoparticles to be
transported transcellularly through olfactory neurones to the brain via the
various endocytic pathways of sustentacular or neuronal cells in the
olfactory membrane. Surface modification of the nanoparticles could
achieve targeted CNS delivery of a number of different drugs using the
same ‘platform’ delivery system which has known and well characterised
biophysical properties and mechanism(s) of transit into the CNS.

27. POLYMER USED IN N ASAL GEL
PREPARATION
Pluronic PF 127(Poloxamer 407 )
Pluronic (PF 68)
HPMC K4M
PVP-K-30
Carbopol 934P

28. POLYMER USED IN N ASAL GEL
PREPARATION
Sr No.
Polymer
Category
1
Pluronic PF
127(poloxamer 407
)
Thermoreversible
polymer
2
Pluronic (PF 68)
Thermoreversible
polymer
3
Hpmc K4m
Bioadhesive
polymer
4
Pvp-k-30
Bioadhesive
polymer
5
Carbopol 934P
Bioadhesive
polymer
6
7

29. Pluronics
are
surfactants
(oxyethylene-polyoxypropylene)
exhibiting
each
copolymers
–
poly
thermoreversible
of
poly
(oxyethylene)
property.
(BASF
Wyandotte, Product brochure). Pluronic has been
accorded GRAS status and has high solubilizing
capacity. (Schmolka et al., 1991). Aqueous pluronic
dispersions
(20
–
35
%)
are
solutions
at
low
temperature and are converted into semisolid gel at
higher
(or
body)
temperature.
There
useful
physiochemical properties of pluronics have been
evaluated for controlled release of drugs for topical,
rectal and ophthalmic routes.

30. Preparation of nasal gel formulations:
Nasal gel using different concentration of pluronic F-127 and
pluronic F-68 and various formulation additives were prepared
by cold method described by schomolka et al. (Schomolka et al.,
1972). Briefly, the method involved slow addition of polymer,
drug and other additive in cold water with continuous agitation.
The formed mixtures were stored overnight at 4oC. The nasal gel
formulation showing satisfactory gelation temperature (30oC 37oC) were selected as optimized formulation. On this optimized
formulation further study was carried out and additional
amount of bioadhesive polymer namely methyl cellulose and
hydroxy propyl methyl cellulose (HPMC K 4 M) were added in the
concentration 0.5,1, and 1.5 % w/w.

31. Preformulation studies
1)Determination of λmax of API
A stock solution of 100 μg/ml of MCP HCl was prepared by
dissolving 10 mg in 100 ml of deionized distilled water. The
resulting solution was scanned between 200 nm to 400 nm
using double beam UV-visible spectrophotometer.
2)Differential scanning calorimetry
Differential scanning calorimetry (DSC) was used to evaluate
the thermal behavior of pure drug and physical mixture of the
drug and excipients. Five-ten milligrams of samples were
weighed and sealed in standard aluminum pans and then
scanned over a temperature range from 50 to 300°C at a
heating rate of 10°C/min.

32. Characterization OF NASAL GEL
1)Gelation point
2)pH of the gels
3)Content uniformity
4)Rheological studies (Viscosity)
5)Gel strength determination
6)Determination of mucoadhesive strength
7) Spreadability