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Lungs alveolar targeted drug delivery: Lungs alveolar targeted drug delivery:

Lungs alveolar targeted drug delivery: - PowerPoint Presentation

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Lungs alveolar targeted drug delivery: - PPT Presentation

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

delivery drug polymers design drug delivery design polymers lung isoniazid formulation inh treatment plga tuberculosis release stretching optimization targeted nss polymeric nanospheres

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Slide1

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?