Development of specialized delivery system for nasal administration

DEVELOPMENT OF
SPECIALIZED DELIVERY
SYSTEM FOR NASAL
ADMINISTRATION OF DRUGS
Mr. Rajendra Dafal
Under the guidance of
Dr. (Mrs.) Ujwala. A. Shinde
Bombay College of Pharmacy, Mumbai
By

OVERVIEW
Rajendra Dafal, Bombay College of Pharmacy, Mumbai
1) Introduction
2) Analytical Method Development
3) Screening of excipients
4) Optimization and characterization of microemulsion and mucoadhesive
microemulsion
5) Nasal ciliotoxicity
6) Stability studies
7) Summary and Conclusion

Introduction
 Schizophrenia occurs with regular frequency
nearly everywhere in the world in 1 % of
population and begins mainly in young age
(mostly around 16 to 25 years).
 Schizophrenia is defined by
 a group of characteristic positive and negative
symptoms
 deterioration in social, occupational, or interpersonal
relationships
 continuous signs of the disturbance for at least 6
months

Paliperidone
 Paliperidone (PPN) is a second-generation atypical antipsychotic
 Therapeutic activity in schizophrenia is mediated through a
combination of central dopamine Type 2 (D2) and serotonin Type
2 (5HT2A) receptor antagonism
 Physicochemical and Biopharmaceutical properties
Parameter Values
Log P 1.8
BCS Classification Class II
Elimination half-life (t1/2) 23h
Clearance route Liver
Daily dose (oral) 3-12 mg
Number of doses per day Once a day
Bioavailability 28%

Need of a new
drug delivery
system which
will overcome
these
disadvantages
Side effect
due to non-
targeted
delivery
Dose
reduction
To have fast
onset of
action
Low
bioavailability

RAJENDRA DAFAL, BOMBAY COLLEGE OF PHARMACY, MUMBAI
BRAIN
Systemic Drug
Delivery
ANS route
Novel Drug
Delivery
Biotechnology
Based
Chemistry Based Direct CNS Delivery
Intra-
arterial
Intravenous
BBB
Disruption
Liposomes,
SLN,
Nanogels,
Nanoemulsion,
Nanaosphere
mAbs,
Genomics,
Trojan
horses
Cationic
proteins
Intracerebral
Intra-nasal
Intrathecal
Transcranial
Chimeric
peptide
Prodrug
Approaches for Brain Drug Delivery

Blood
Olfactory part
Nose
Clearance
Brain CSF
Organ tissue Elimination
Drug
Pathways for reaching brain after Intranasal Delivery
Intranasal Delivery
 Non- invasive method
of bypassing the BBB
 Direct movement of
drug from sub mucosa
space of nose to brain
& CSF
Rajendra Dafal, Bombay College of
Pharmacy, Mumbai

Olfactory bulb
Pharmacy, Mumbai

Microemulsion
Microemulsion Structure
 Microemulsions are thermodynamically stable colloidal dispersion of
water and oil stabilized by a surfactant and cosurfactant
 Microemulsion act as vehicle for poorly water soluble drugs
Pharmacy, Mumbai

Rationale
Why
microemulsion
Systems
Why Nasal
Drug
Delivery
Why
paliperidone
Pharmacy, Mumbai

Specific aims
 In vitro studies
 Standardization and analytical method development
 Screening of oils, surfactants and co-surfactants
 Preparation and optimization microemulsion formulation for PPN
 Characterization of optimized microemulsion formulation of PPN
 Formulation and evaluation of mucoadhesive microemulsion of PPN
 In vivo studies
 Nasal ciliotoxicity
 Stability studies


Standardization and
analytical method
development
Pharmacy, Mumbai

Standardization of Drug
 Melting point
 UV spectroscopy
 IR spectroscopy
 DSC
 X-ray diffraction

Uv absorption spectrum of PPN in methanol

Standardization of Drug
Parameter Value
Melting point 168 - 173 0C
Absorption maxima 278 nm
Linearity Range (μg/mL) 8-36
Standard regression equation y = 0.0256x - 0.0254
Correlation Coefficient (R2 ) 0.9997

Solubility studies
Shake flask method
Drug
0.5 g Vehicle
( excipient)
Supernatant
analyzed by
UV Jasco v-
530
Baka E et al., J Pharmaceut Biomed Anal. 2008;46(2):335-341. Rajendra Dafal, Bombay College of Pharmacy, Mumbai

Selected systems for microemulsion
formulation
 Oily Phase-
 Oleic acid- eq. solubility of 11.95±0.43 mg/mL
 Surfactant-
 Labrasol- eq. solubility of 4.88±0.18 mg/mL
 Co-surfactant-
 Transcutol-P eq. solubility of 6.24±1.57mg/mL

Optimization and
characterization of
microemulsion and
mucoadhesive microemulsion

Construction of pseudo ternary
phase diagrams
Surfactant:
cosurfactant
mixture
(Smix)
Turbidity
is the
end point
Oil: surfactant and cosurfactant mixture (Smix) ratios: 1:9 to 9:1

Phase diagrams for Labrasol and
Transcutol-P by water titration method
Figure. The pseudo-ternary phase diagrams with various surfactant:
cosurfactant weight ratios[ Smix ] 1:2(a), 1:1(b), 2:1(c), 3:1(d) Labrasol (Lab)
to Transcutol P (TNS-P) by water titration.
(a) (b)
(c) (d)

Compositions of microemulsion
formulations
Formulations Oleic acid (%) Smix (%) Water (%) Total (%)
1 6 55 39 100
2 6 60 34 100
3 8 55 37 100
4 8 60 32 100
5 10 60 30 100
6 12 60 28 100
7 14 60 26 100
8 30 60 10 100
9 35 60 5 100
10 40 55 5 100
11 45 50 5 100

Method of preparation
Drug
+
Oleic acid
Cyclomixing
follwed by
ultrasonication
Addition of
surfactant and
cosurfactant
Cyclomix and
add required
quantity of DD
water
Microemulsion

Drug loading efficiency, globule size and
P.I. of microemulsion formulation
formulations
Globule
size(nm)
Blank
PI
Globule
size(nm) PPN
loaded
PI
Max Drug
loading
(mg/ml)
1 324.4±1.91 0.281±0.055 434.6±2.333 0.092±0.004 15.15±0.022
2 320.3±3.11 0.171±0.016 320.6±0.283 0.189±0.059 14.93±0.017
3 427.3±1.20 0.116±0.025 320.3±3.041 0.267±0.104 15.01±1.262
4 390.0±6.15 0.247±0.028 444.5±4.031 0.068±0.065 15.86±0.058
5 383.7±2.26 0.357±0.046 458.3±4.243 0.208±0.235 19.41±0.006
6 307.8±1.27 0.340±0.075 544.1±3.394 0.347±0.165 25.57±0.017
7 282.9±2.90 0.394±0.012 574.7±4.455 0.090±0.050 21.86±0.171
8 256.2±2.12 0.290±0.009 226.1±3.889 0.292±0.069 55.23±0.801
9 214.9±3.82 0.350±0.040 219.4±2.758 0.272±0.056 56.88±0.124
10 192.1±3.54 0.284±0.021 185.2±4.101 0.435±0.045 59.56±0.041
11 177.7±6.31 0.337±0.025 181.5±4.172 0.380±0.033 57.35±0.069

Characterization of PPN microemulsion
system
Formul
ations
Components (% w/w)
Oleic
acid
Labrasol Transcutol P Water PPN
A 30 30 30 10 5
B 35 30 30 5 5
C 40 27.5 27.5 5 5
D 45 25 25 5 5
Compositions of optimized microemulsion formulations
 Microscopic appearance
 Optical isotropicity and visual
appearance
 Percent transmittance
 Globule size analysis
 Zeta potential and Conductivity
 pH
 Determination of drug content
 Thermodynamic stability studies
 Viscosity
 Refractive Index

Formulation and evaluation of
Mucoadhesive microemulsion
Microemulsion
Mucoadhesive
Agent
Continuous
Stirring
Mucoadhesive
Microemulsion
Characterization
PPN Mucoadhesive
microemulsion
PPN Mucoadhesive
microemulsion containing 1%
of PHE
Globule size (nm) 185±4.54 199.3±5.32
P.I. 0.332±0.021 0.261±0.0261
Zeta potential (mV) -37±2.54 -36.8±4.33
pH 5.585±0.021 5.610±0.032
Drug content (%) 97.85±0.38 97.07±0.63
Mucoadhesive agent=HPMC K4M, Carbopol 971 NF and Carbopol 974 NF

Ex- vivo skin permeation study
Apparatus: Franz diffusion cell
Release media: 20 % methanol in SNES pH 5.5
Volume of release media: 17 ml in a Franz diffusion cell
Quantity of formulation: formulations equivalents to 5 mg
of PPN.
Study duration: 24 hrs.
Temperature: 34°C±1°C
Stirring speed: Moderate stirring with magnetic stirrer
Membrane: Nasal mucosa of the sheep
Volume of aliquot withdrawn: 1 ml
Time interval of aliquot withdrawal: 1, 2, 4, 6, 8, 12and 24
hrs.
Analysis: by UV [278 nm].

Ex- vivo skin permeation study
Formulation
Flux (Jss) in
mg/cm2/hr
Permeability coefficient (Kp) in
cm/hr×10-3
Enhancement ratio (Er)
Carbopol 974 NF MME 49.02±4.65 0.02775±0.004 12.01
Microemulsion 52.25±4.27 0.0295±0.005 12.80
PPN suspension 11.55±2.13 0.00231±0.0002 ------
In ex-vivo permeation studies
were carried out using sheep
nasal mucosa to assess the
permeation of selected PPN
suspension, microemulsion
and compared with MME.

Experimental protocol
 Experimental protocol was approved
by CPCSEA Local Institutional Animal
Ethics Committee before the study was
started
 Strain of rat used: SD rats
 Gender of rats: Either sex
 Weight of the animals: 250-300 g
 Age: 6-8 weeks
 Number of rats / group: 5
 Dosage used – 0.4mg/kg for PPN
 Site of administration: Nasal for all
the formulation.
 Animals were were dosed as per
schedule for 7 days and sacrificed to
nasal mucosa were observed under
SEM
Sr. No Group Description
No. of
animals
1 I Group
MME containing
only PPN
5
2 II Group
MME containing
PPN and 1% PHE
5
3 III Group
Blank formulation /
Placebo
5
4 IV Group
Saline
(Negative Control)
5
5 V Group
1%(w/v) Sodium
Deoxycholate
Solution
( Positive Control)
5
Study protocol of Nasal ciliotoxicity

Group
Observations
Inflammation Infiltration (I)
Neutrophilic
exudates
Suppurative
inflammation (SI
with neutrophilic
exudates
Degeneration
(D)
Erosion
(E)
Negative control + NAD NAD NAD NAD NAD
Positive control NAD +++ +++ NAD NAD NAD
Blank MME NAD ++ NAD NAD NAD NAD
Test Formulation-I
(PPN)
NAD ++ NAD NAD NAD NAD
Test Formulation-II
(PPN+PHE)
NAD ++ ++ NAD NAD NAD
Where, (+)=Mild (++)=Moderate (+++)=Severe NAD=No abnormality detected

Rajendra Dafal, Bombay College of Pharmacy,
Mumbai

Storage conditions
 5° C ± 2°C for 3 months (Refrigerator)
 25°±2°C/60% RH (Room temperature)
 The samples in duplicate were withdrawn at
0 month (initial), 1 month, 2 month and 3
month time intervals and evaluated for the
following parameters.
 Appearance, globule size, zeta potential, pH
and drug content

Effect of temperature on drug content of PPN
MME

Summary
 Solubility studies play important role in the selection of
suitable excipients for microemulsion formulation
 km ratio has great influence on microemulsion region of
pseudoternary phase diagrams
 Globule size, P.I. and drug loading efficiency are the
important criteria in optimization of microemulsions
 Ex-vivo skin (sheep nasal mucosa) permeation study
revealed that microemulsion and mucoadhesive
microemulsion formulations had a higher permeability
coefficient than the PPN suspension

Conclusion
Mucoadhesive microemulsion formulation would
be promising delivery systems to enhance the
nasal permeability of paliperidone by avoiding
first pass effect with advantage of brain targeted
delivery.

R A J E N D R A D A F A L , B O M B A Y C O L L E G E O F P H A R M A C Y ,
M U M B A I

Development of specialized delivery system for nasal administration

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