Formulation and Evaluation of Isoniazid Mucoadhesive nanospheres embedded micro particulates inhalable dry power Gnanaprakash PhD Associate Professor Department of Pharmaceutics P Rami Reddy Memorial College of Pharmacy India ID: 525419
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Lungs alveolar targeted drug delivery: Formulation and Evaluation of Isoniazid Mucoadhesive, nanospheres embedded micro particulates inhalable dry power
Gnanaprakash
Ph.D
Associate Professor
Department of Pharmaceutics
P. Rami Reddy Memorial College of Pharmacy, IndiaSlide2
Introduction
Tuberculosis (TB) is a highly contagious persistent infection caused by
Mycobacterium tuberculosis
and
Mycobacterium
bovis
and has highest mortality rate than any other infectious disease.
Treatment of active TB is
becoming
more and more complex with the emergence of multidrug-resistant tuberculosis (MDR
).
Available
TB treatment involves daily administration of four oral antibiotics for a period of six months or more.
Due to the high percentage of side effects (like ototoxicity and nephrotoxicity) and the extended duration of treatment results in low patient adherence.Slide3
Lungs Alveolar Targeted Drug Delivery
Because of limitations associated with the conventional treatment of
lung diseases a growing
attention has been given to the development of targeted drug delivery systems
.
Pulmonary
route of drug delivery gaining much importance in the present day research field as it enables to target the drug delivery directly to lung both for local and systemic treatment
.
The important attention to be given in the development of pulmonary drug delivery system is the compatibility of polymers used in the design of particulate carriers.
The
safety of these polymers must be first determined and their compatibility with lung fluid is of great concern. Slide4
Concept of Lung TargetingSlide5
Challenges in Lung Targeting
The polymers used to prolong the release rate for chronic use may accumulate in the lung, especially in the lung periphery, which is not served by
mucociliary
clearance.
The
chance of presence of residual solvent in the final product leads to pulmonary toxicity.
Carriers used in the design of dry powder inhalation formulations, such as sugars, and
cyclodextrins
can cause bronchoconstriction in many of the hypersensitive individuals.
Chronic
use of proteins and other carriers, such as absorption enhancers and enzyme inhibitors, can produce immunogenicity, local irritation, and toxicity.
Increased
permeability may also allow transport of other toxins and antigens across the epithelial barrier.
Slide6
Nano in Lung Targeting
Nanotechnology is
now promising to create drug
nanospheres
that can be
developed
in a various innovative
ways.
Nano
spheres
drug
delivery pathways can be used to increase drug efficacy and
reduce
the side effects
.
Polymeric
nanocarriers
such as polymeric
nano
spheres
,
polymeric
nanocapsules
and polymeric
nanoparticles have
been evaluated for oral drug
delivery.
The
most commonly used polymers for
nanocarriers
are
polylactide
-co-
glycolic acid
(PLGA),
polymethylmethacrylates
(
Eudragits
) and
chitosan.Slide7
Background (Literature
Survey)
Literature survey revealed that the following problems have been observed from the previous works done on the DRY POWDER
INHALERS.
Low therapeutic drug concentration at blood plasma.
Not suitable polymers were used to achieve drug release mechanism.
More difficult methods have been adopted to design the dosage form.
More numbers of synthetic polymers and less numbers of natural polymers were used to develop controlled drug delivery systems.
The natural polymers provide many advantages which are not studied well.Slide8
Aim of the present study
The present investigation is to predict the impact of different formulation and process variables on designing of
nanospheres.
Conduct some physicochemical evaluations
to conclude the optimized method for the formulation of
nanospheres. Slide9
Selection of drug for oral inhalation
Isoniazid, also known as
isonicotinylhydrazide
(INH), is an antibiotic used as a first-line agent for the prevention and treatment of both latent and active tuberculosis.
It
is effective against mycobacteria, particularly
Mycobacterium
tuberculosis
and
Mycobacterium
bovis
.
Isoniazid has
low bioavailability
(20-50%),
Protein binding (0-10%)
and
short biological half-life (0.5-1.6h
) when
oral administration.
Traditional immediate release solid dosage forms need to be administered three times a day.
All above criteria
favours
us to develop lung targeted drug delivery system.Slide10
Plan of work
Pre formulation
Trial formulations
Optimization of formulation by factorial design
Physicochemical and in vitro characterization
In vivo studies Slide11
Drug polymer interaction studyFTIR
Isoniazid + Chitosan
Isoniazid + Lectin
Isoniazid + PLGA
S.No.
Functional group
Frequencies of drug
as
per IP (cm
-1
)
Frequencies of
procured
drug (cm
-1
)
1
C=O
stretching (
Ketone, Ester)
1725 (s) 1700 (s)
1725.42 (s),1702.92 (s).
2
C-O stretching (Alcohol)
1240 (s)
1243.64 (s).
3
C-O stretching (Alcohol)
1100 (s)
1102.15 (s)
4
C-O stretching (Ester)
1160 (s)
1153.38 (s)
5
C-O stretching (Ester)
1130 (s)
1128.53 (s)Slide12
Drug polymer interaction studyDSC
Isoniazid + Chitosan
Isoniazid + Lectin
Isoniazid + PLGA
Name of test sample
Enthalpy
(J/g)
Peak temperature
(
o
c)
Inference
Pure Drugs
125.9
244.2
Not applicable
(NA)
INH+
CHN
125.9
244.2
Compatible
INH+
LEC
149.9
248.0
Compatible
INH+
PLG
145.2
238.3
CompatibleSlide13
Materials used in the formulation
Main
Polymer: PLGA
Mucoadhesive
Polymers: Chitosan and Lectin
Stabilizer: Polyvinyl Alcohol (PVA)
Surfactant:
Pluronic
F68Slide14
Emulsion solvent evaporation method
Drug
loaded PLGA
NSs
were prepared by dissolving
drug and polymers
in 300
μL
of chloroform
.
The organic phase was emulsified in 2 mL of 9% PVA by
micro tip
sonicator for
10-20 min.
The emulsion was added drop wise into 8 mL of stirring 9% PVA solution (continuous phase).
The emulsion was left on gentle stirring for 3 h to allow for solvent evaporation. Then, suspended
NSs
were collected by ultracentrifugation at 40,000
rpm for
15 min at
12°
C.
The
NSs
were washed three times with cold double-de-ionized water and then freeze-dried for 48
h to get
discrete
particles.Slide15
Box Behnken Experimental Design
A three factor, three levels Box-
Behnken
design was used for the optimization procedure.
The
design consists of a replicated center points and a set of points lying at the midpoint of each edge of the multidimensional cube that defines the region of interest.
(
+1, +1, 0)
(0, -1, -1) Slide16
Experimental Design
The non-linear computer generated quadratic model is given as:
Y = b
0
+ b
1
X
1
+ b
2
X
2
+ b
3
X
3
+ b
12
X
1
X
2
+ b
13
X
1
X
3
+ b
23
X
2
X
3
+ b
11
X
12
+ b
22
X
22
+ b
33
X
32
+ E
Where
Y is the measured response associated with each factor level
combination
;
b
0
is an intercept; b
1
to b
33
are regression coefficients computed from the observed experimental values of Y;
X
1
, X
2
and X
3
are the coded levels of independent variables and E is the error term Slide17
Experimental DesignSlide18
Trial run for formulation Slide19
3D response surface plots displaying effect of Polymer Concentration, surfactant and sonication timeSlide20
Conclusion
It was concluded that an appropriate statistical design and optimization technique could be successfully used in the development of lung targeted drug delivery for INH with predictable drug release properties.
Response
surface methodology optimization enabled formulation of INH loaded NSs with release rate. Validation of the optimization technique demonstrated the reliability of the model.
Works in progress
Physicochemical evaluation
In vitro
Characterization
Ex vivo In vivo
studiesSlide21
Thank youQuestions?