Neelam Presentation

8/11/2019 Neelam Presentation

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INTRODUCTION

MULTIPARTICULATE DOSAGE FORMS

are

pharmaceutical formulations in which the active substance is

present as a number of small independent subunits, each

exhibiting some desired characteristics. They can be in many

forms such as granules, pellets, beads, mini tablets .

To deliver the recommended total dose, these subunits are filled

into a Capsule or compressed into a tablet.

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ADVANTAGES OF MULTIPARTICULATE DOSAGES

FORMS

Multiparticulate provide many advantages over single-unitsystems because of their small size. They are also better

distributed and less likely to cause local irritation & are less

dependent on gastric emptying.

After disintegration, the individual subunit particles passes

rapidly through the GI tract & they are able to leave the

stomach continuously.

Drug safety may also be increased by using multiparticulatedosage forms, e.g. Multiparticulate reduces dosedumping.

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MULTIPARTICULATE SYSTEM OF BEADS

Gelation techniques are used for the preparation of beads .

THERMAL GELATION:

Agar and agarose Polymer.

Beads are prepared by extruding a warm agar cell suspension

drop wise into ice chilled buffer. The extruded droplets gel

rapidly upon cooling .

IONOTROPIC GELATION:

Chitin, chitosan, alginates Polymer used .

Gelation is carried out at room temp, making this the most

widely used gelation procedure.Cations used to trigger the gelation of alginate includes Ca+2,

Ba+2, Cu +2, Pb +2, Mn +2, Zn+2, Ni+2, Al+3.

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DRUG PROFILE OF CEFTRIAXONE SODIUM

Category - Antibacterial ( BCS Class III drug)

Structure

N

NN

S

N

O

NH

N

S

S

O

ONaCH3

O

O ONa

H H

OCH3

NH2

Molecular formula - C18H16N8Na2O7S3.3.5H2O

Molecular weight - 662.0

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Description: white or yellowish, crystalline powder, slightly

hygroscopic.

Melting point: 1560c

Half life - 8 hrs

Dose - 200mg to 2.0g.

Elimination: 50-60% excreted unchanged in urine,

40-50% excreted unchanged in bile.

Mode of action - The bactericidal activity of ceftriaxone

results from inhibition of bacterial cell wall

synthesis .

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Uses

Ceftriaxone is valuable for multi drug resistant Typhoid fever,

also used for gonorrhea, meningitis, septicemia. Infection of

the bones, joints, skin and wounds. Renal, urinary and

respiratory tract infections.

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EXCIPIENTS PROFILE

Intestinal absorption enhancers used-

*Sodium deoxycholate

*Sodium taurocholate

*Polyoxy ethylene 20cetyl ether and

*Oleic acid

Polymer- Sodium alginate

Crosslinking agent- Zinc chloride

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PERMEABILITY ENHANCEMENT

Low permeability of ceftriaxone sodium is a result of

The molecule displays a high degree of polarity .

Ceftriaxone sodium is an ionized molecule, and as such is

resistant to lipid dissolution, thus establishing an immediatebarrier to the necessary lipid diffusion of ceftriaxone across the

mucosal bilayer.

Ceftriaxone molecule presents a high degree of electrical

resistance to the lipid bilayer due to its level of polarity.

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APPROACHES TO ENHANCE THE ABSORPTION OF

DRUGS THROUGH INTESTINAL MUCOSA

such as

By using Absorption enhancers absorption enhancers were

mixed with drug in different molar ratio, to enhance the

lipophilicity of drug.

Prodrug design -by introducing hydrophobic moieties which

could directly improve drug permeability, it can form a

physically associated complex with the drug and alter the

physical properties of the active substance.

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AIM AND OBJECTIVE

The Aim of the present study is Development and evaluation of

polymeric beads of Ceftriaxone sodium by using Absorptionenhancers.

Ceftriaxone sodium is low permeable drug, hence

To enhance the permeability of the drug, intestinal absorption

enhancers were used in varied molar ratios with drug and effect of

different absorption enhancers on permeability of the drug was

studied.

Blend of permeation enhancers, drug and excipients wereincorporated into beads, these beads were filled into capsules to

create the final dosages form.

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METHODOLOGY OF THE RESEARCH WORK

The methodology used for the preparation of beads was ionotropic gelation

method, in which aqueous solution of polymer and drug was added drop

wise in the solution of zinc chloride to prepare beads.

DrugPolymer solution

Precision device

Crosslinking solution

Beads

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PLAN OF WORK

Preformulation Study

Permeability enhancement of the drug

Formulation development and Optimization

Evaluation of ceftriaxone beads

Stability studies

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IR Spectrum of Pure drug

15IR Spectrum of drug with sodium taurocholate


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Parameter Result

Solubility analysis(I.P.)

In different solvents

a. Water

b. Methanol

c. Ethanol

d. Glycerole. Acetone

Freely soluble

Slightly insoluble

Very Slightly soluble

Very Slightly solublePractically insoluble

Phosphate Buffer ResultspH 1.2 Freely soluble

pH 5.5 Freely soluble



In different pH

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Parameter Results

Micromeritics

Carrs Index

Angle of repose

Partition coefficient

In octanol-water system

In octanol-7.4 pH system

Particle size range

pH

Drug polymer interaction

Very poor flow

Drug is hydrophilic

Fine

Neutral

No significant interaction between

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PERMEABILITY ENHANCEMENT OF THE DRUG

Following steps were carried out

oDetermination of o/w partition profile of the drug with

selected permeation enhancers

oIn vitro permeation studies using excised animal

intestinal tissue

oCalculation of permeation rate and permeability

coefficient:

FORMULATION AND EVALUATION

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Partition coefficient of the drug with Permeation enhancers

S. No Permeation

enhancer

Drug : Permeation

enhancer ratio

(mM)

Po/buffer Batch

code

1 Sodium

deoxycholate

1:0.2 0.026 P1

1:0.3 0.026 P2

1:0.4 0.029 P3

2 Sodium taurocholate 1:1 0.042 P4

1:2 0.046 P5

1:3 0.058 P6

1:4 0.054 P7

1:5 0.048 P8

1:6 0.040 P919


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S. No Permeation

enhancer

Drug : Permeation

enhancer ratio

(mM)

Po/buffer Batch

code

3 Polyoxyethylene

20 cetyl ether

1:0.030.024 P10

1:0.04 0.035 P11

1:0.05 0.039 P12

1:0.06 0.042 P131:0.07 0.078 P14

1:0.08 0.081 P15

1:0.09 0.052 P16

1:0.1 0.040 P17

1:0.2 0.032 P18

1:0.3 0.030 P19

1:0.4 0.039 P20

1:0.5 0.039 P21

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Partition coefficient of drug with Combination of absorption

enhancers

S.No Batch code Drug: SD: ST Po/buffer

1 P22 1 : 0.4 : 3 0.043

S.No

Batch code Drug: S.T: O.A. Po/buffer

1 P23 1:3:0.5 0.177

2

P24

1:3:1

0.507

3 P25 1:3:1.5 0.390

4 P26 1:3:2 0.125

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S.No Batch code Drug: Brij 58 : O.A. Po/buffer

1 P27 1 : 0.08 : 0.5 0.107

2 P28 1 : 0.08 : 1 0.121

3 P29 1 : 0.08 : 1.5 0.130

4 P30 1 : 0.08 : 2 0.093

5 P31 1 : 0.08 : 2.5 0.099

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IN VITRO PERMEATION STUDIES USING EXCISED

ANIMAL INTESTINAL TISSUE

The permeability studies were conducted using the static Franz cell

system

Intestinal tissue is clamped between donor and receiver compartment

Transport medium was HanksBalanced Salt Solution (HBSS) buffer (pH-

7.4).

sample solution (2mg/ml) was placed in donor compartment and buffer

sol. was filled into the acceptor compartment

The acceptor medium was continuously stirred and the experiment wasperformed at 37oC.

Samples were periodically removed from the acceptor compartment over

4 h

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Permeability study of Batches having good Po/buffer value.

Time(min) Cum amt permeated (g/cm2)

CTZ

Batch

P23

Batch

P24

Batch

P25

Batch

P26

Batch

P28

Batch

P29

0 0 0 0 0 0 0 0

30 71.419 211.75 285.42 250.59 150.35 136.57 190.45

60 150.35 362.11 566.34 446.06 306.98 310.73 349.58

90 220.52 582.63 801.90 701.66 463.60 444.80 541.28

120 302.21 726.72 1024.43 908.15 584.89 562.33 706.68

150 389.67 917.18 1289.06 1112.64 739.25 722.96 864.55

180 451.07 1102.62 1535.65 1303.09 877.06 855.78 1022.43

210 516.22 1303.099 1746.15 1503.57 1039.97 1002.38 1182.81

240 599.92 1505.0 1970.68 1684.005 1202.86 1174.29 1347.20

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Permeation rate of ceftriaxone sodium (g/cm2) using biological membrane

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PERMEABILITY COEFFICIENT / APPARENT PERMEABILITY

COEFFICIENTPermeability coefficient of Batches having good Po/buffer value

S No. Batch code Papp(cm/sec)

1 CTZ 1.5510-4

2 P 23 3.8610-4

3 P 24 5.0510-4

4 P 25 4.1410-4

5 P 26 3.0810-4

6 P 28 3.0110-4

7 P 29 3.4510-4

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FORMULATIONS

S.No Con. of sod.

alginate

Drug: Alginate

ratio (mM)

Con of

ZnCl2(mM)

Curing time

(min)

Batch

code

1 0.5:1 A1

2 2% 1:1 0.4 2 A2

3 1.5:1 A3

4 2:1 A4

5 0.5:1 B1

6 3% 1:1 0.4 2 B2

7 1.5:1 B3

8 2:1 B4

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S.No Con. of sod.

alginate

Drug: Alginate

ratio

Con of

ZnCl2(mM)

Curing time

(min)

Batch

code

9 0.5:1 C1

10 4% 1:1 0.4 2 C2

11 1.5:1 C3

12 2:1 C4

130.5:1 D1

14 5% 1:1 0.4 2 D2

15 1.5:1 D3

16 2:1 D4

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S.No Con. of sod.

alginate

Drug:

Alginateratio

Con of

ZnCl2(mM)

Curing

time (min)

Batch

code

17 0.5:1 E1

18 6% 1:1 0.4 2 E2

19 1.5:1 E3

20 2:1 E4

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S.No Con. of sod.

alginate

Drug:

Alginate ratio

Con of

ZnCl2(mM)

Curing time

(min)

Batch

code

21 0.5:1 2 F1

22 5% 1:1 0.5 2 F2

23 1.5:1 5 F3

24

2:1 5

F4

25 0.5:1 5 G1

26 5% 1:1 0.3 5 G2

27 1.5:1 2 G3

28 2:1 2 G4

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S.No Con. of

sod.

alginate

Drug:

Alginate

ratio

Con of

ZnCl2(mM)

Curing

time (min)

Batch

code

29 0.5:1 2 H1

30 6% 1:1 0.5 2 H2

31 1.5:1 5 H3

32 2:1 5 H4

33 0.5:1 5 I1

34 6% 1:1 0.3 5 I2

35 1.5:1 2 I336 2:1 2 I4

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S.No Absorption

enhancers

Sodium

alginate

con.

Drug:

A.E.:

Alginate

(mM)

Con of

Zn Cl2

Curing

time

(min)

Batch

code

37 Sodiumtaurocholate

and oleic acid

5% 1:3:1:2 0.4 2 J1

38 Polyoxy

ethylene 20

cetyl ether and

oleic acid

5% 1:0.8:1.5:2 0.4 2 J2

OPTIMIZED BATCHES

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EVALUATION OF BEADS

Size and morphology of beads

drug content and entrapment efficiency

Swelling studies

In vitro drug release

Permeability study

Study of drug release Kinetics

Stability studies

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S. No. Batch code Mean diameter (mm)

S.D. (n=20)

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

B1

B2

B3

B4

C1

C2

C3

C4

D1

D2

D3

D4

E1

E2

E3

E4

1.3120.07

1.3140.06

1.3400.06

1.5570.08

1.3410.05

1.3300.09

1.4100.08

1.4420.06

1.3330.02

1.3810.05

1.2120.11

1.3600.12

1.3280.1

1.4000.07

1.3970.04

1.3640.1

Mean diameter of

beads

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S. No. Batch

code

Mean diameter

(mm) S.D.

(n=20)

17

18

19

20

21

22

23

24

F1

F2

F3

F4

G1

G2

G3

G4

1.2900.13

1.3110.11

1.3200.14

1.3750.09

1.2990.01

1.3100.15

1.3980.13

1.3720.14

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S. No. Batch

code

Mean diameter

(mm) S.D.

(n=20)

25

26

27

28

29

30

31

32

33

34

H1

H2

H3

H4

I1

I2

I3

I4

J1

J2

1.2820.01

1.2990.09

1.3630.12

1.3000.13

1.3400.13

1.3710.10

1.2900.13

1.3770.08

1.3680.12

1.3790.10

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S.No Batch Code Drug content

(%)

Entrapment

efficiency

(%)

1

2

3

4

5

6

7

8

9

10

B1

B2

B3

B4

C1

C2

C3

C4

D1

D2

23.86

21.15

11.17

13.11

24.21

10.21

8.44

8.70

39.99

23.15

68.19

66.0

43.53

44.57

70.30

45.90

30.0

29.19

75.33

63.60

Drug content and entrapment efficiency

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S.No Batch Code Drug content

(%)

Entrapment

efficiency

(%)

11

12

13

14

15

16

17

18

19

20

D3

D4

E1

E2

E3

E4

F1

F2

F3

F4

11.13

12.95

26.98

21.59

13.57

12.78

17.20

12.83

16.23

12.11

38.03

34.0

68.52

65.28

49.2

39.12

56.36

45.46

52.53

42.13

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Batches having good drug content & entrapment efficiency

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Swelling behavior of beads after 8h44


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In vitro drug release- in Phosphate buffer pH 7.4

S.No Time(min)

Cum drug release (%)

Batch B1

Batch

B2 Batch C1 Batch D1 Batch D2

1 0 0 0 0 0 0

2 15 32.38 34.82 30.14 29.59 29.68

3 30 34.98 36.41 33.73 37.82 39.54

4 45 36.00 38.15 36.36 43.54 45.935 60 37.29 43.03 40.08 49.52 47.72

6 90 44.46 48.34 45.52 52.73 51.44

7 120 50.92 55.95 56.30 58.81 54.94

8 180 54.08 61.68 56.36 65.10 61.79

9 240 62.97 65.55 63.70 73.34 68.37

10 360 69.86 71.58 69.16 81.90 74.53

11 480 76.17 76.45 76.51 87.80 80.89

12 720 81.19 82.48 82.02 93.86 87.85

13 1440 82.05 83.2 83.53 94.52 88.4546

C d l (%)


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S.No Time(min)


Batch E1Batch

E2Batch J1 BatchJ2

1 0 0 0 0 0

2 15 27.27 28.01 29.81 30.12

3 30 31.84 32.92 34.40 34.85

4 45 38.88 37.67 39.48 38.03

5 60 43.32 39.98 42.10 42.40

6 90 48.91 43.41 45.86 46.51

7 120 55.81 44.88 47.17 49.95

8 180 61.65 52.25 57.66 57.77

9 240 64.68 59.80 62.90 64.004

10 360 70.72 69.29 76.99 76.06

11 480 78.03 77.48 83.54 83.08

12 720 83.05 85.34 92.88 91.30

13 1440 86.06 86.33 93.21 92.09

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Drug release profile of beads in pH-7.4 buffer

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Drug release study in pH 1.2 buffer


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g y p

S.No Time(min)


Batch B1 BatchB2

Batch C1 Batch D1 Batch D2

1 0 0 0 0 0 0

2 15 2.73 2.47 3.13 2.60 3.91

3 30 5.60 4.82 4.69 4.82 6.39

4 45 8.21 6.91 7.82 7.17 9.39

5 60 10.43 9.13 10.30 9.52 11.60

6 90 14.34 13.04 14.34 14.21 15.91

7 120 16.95 17.08 17.60 17.86 18.52

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CONTIN


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S.No Time(min)


Batch E1 Batch E2 Batch J1 BatchJ2

1 0 0 0 0 0

2 15 2.73 3 2.60 2.70

3 30 5.34 5.36 4.82 4.43

4 45 7.82 7.85 6.91 6.39

5 6010.17 10.17 8.86 8.21

6 90 14.34 14.34 12.65 12.26

7 120 16.82 17.08 16.95 15.78

CONTIN..

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Drug release profile of beads in pH1.2buffer

0

2

46

8

10

12

14

1618

0 50 100 150

cumd

rugrelease(%)

Time (min)

batchE1

batchE2

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PERMEABILITY STUDY OF OPTIMIZED BATCHES OF

CEFTRIAXONE BEADS

Permeability study of batches D1, J1 and J2

Time(min)Cum amt permeated (g/cm2)

Batch D1 Batch J1 Batch J2

0 0 0 0

30 70.10 283.42 187.45

60 147.91 563.98 346.64

90 217.54 798.89 538.71

120 300.21 1020.20 701.60

150 376.72 1286.1 862.20

180 449.61 1532.99 1018.90

210 523.10 1743.20 1178.61

240594.91 1964.67 1340.20

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Drug Permeation profile of Batches D1, J1, & J2

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STUDY OF DRUG RELEASE KINETICS OF

OPTIMIZED BATCH J1)

Kinetics models were fitted to dissolution data of optimized

batch, using linear regression analysis.

Release of drug from beads occur by Higuchi model

following non-Fickian transport mechanism.

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The optimized formulation J1 was stored at40oc/75%RH

The color of beads from each batch had become

somewhat darker in comparison to previous condition.

There was no significant change in shape and size of

beads.

No significant change was found in drug content.

TIME DRUG CONTENT(%)

0 99.98

30 99.10

60 98.68

STABILITY STUDY OF OPTIMIZED BATCH

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CONCLUSION

It can be concluded from this dissertation work that the

objective of the proposed project has been fulfilled, permeability of

the drug has improved and it was successfully formulated in to

beads.

Ceftriaxone sodium, a hydrophilic drug containing many polar

groups, exhibited very small Po/buffer value (0.026). However, the

combination with absorption enhancers led to improvement in the

Po/buffer value ( 0.507)up to many folds.

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The extent of enhancement was found to be highly

dependent on the absorption enhancers species used. The

combination of sodium taurocholate and oleic acidprovided the highest permeability of the drug(three

times). Although the drug permeation was less when

sodium taurocholate, sodium deoxycholate and

Polyoxyethylene 20 cetyl ether were used individually.

Alginate beads of ceftriaxone sodium were successfully

prepared by using combination of sodium taurocholate

and oleic acid as a absorption enhancer and evaluated in

vitro.

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The higher and more rapid release of ceftriaxone in

intestinal pH and low % release of drug in gastric pH due to

limited swelling in acidic medium. This situation is helpful in

the protection of ceftriaxone from the acidic environment ofstomach when administered orally.

Further in vivo studies are required to explore possibilities

of obtaining more predictable results.

The future prospects of absorption enhancers is

promising. However, a number of safety concerns and

formulation design issues must be considered before the

application of absorption enhancers to routine oral drug

delivery in humans.

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