Neelam Presentation
-
Upload
neelam-singh -
Category
Documents
-
view
217 -
download
0
Transcript of Neelam Presentation
-
8/11/2019 Neelam Presentation
1/60
-
8/11/2019 Neelam Presentation
2/60
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.
2
-
8/11/2019 Neelam Presentation
3/60
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.
3
-
8/11/2019 Neelam Presentation
4/60
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.
4
-
8/11/2019 Neelam Presentation
5/60
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
5
-
8/11/2019 Neelam Presentation
6/60
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 .
6
-
8/11/2019 Neelam Presentation
7/60
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.
7
-
8/11/2019 Neelam Presentation
8/60
EXCIPIENTS PROFILE
Intestinal absorption enhancers used-
*Sodium deoxycholate
*Sodium taurocholate
*Polyoxy ethylene 20cetyl ether and
*Oleic acid
Polymer- Sodium alginate
Crosslinking agent- Zinc chloride
8
-
8/11/2019 Neelam Presentation
9/60
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.
9
-
8/11/2019 Neelam Presentation
10/60
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.
10
-
8/11/2019 Neelam Presentation
11/60
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.
11
-
8/11/2019 Neelam Presentation
12/60
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
12
-
8/11/2019 Neelam Presentation
13/60
PLAN OF WORK
Preformulation Study
Permeability enhancement of the drug
Formulation development and Optimization
Evaluation of ceftriaxone beads
Stability studies
13
-
8/11/2019 Neelam Presentation
14/60
-
8/11/2019 Neelam Presentation
15/60
IR Spectrum of Pure drug
15IR Spectrum of drug with sodium taurocholate
-
8/11/2019 Neelam Presentation
16/60
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
pH 6.8 Freely soluble
pH 7.4 Freely soluble
In different pH
16
-
8/11/2019 Neelam Presentation
17/60
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
drug and polymers.17
-
8/11/2019 Neelam Presentation
18/60
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
18
-
8/11/2019 Neelam Presentation
19/60
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
-
8/11/2019 Neelam Presentation
20/60
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
20
-
8/11/2019 Neelam Presentation
21/60
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
21
-
8/11/2019 Neelam Presentation
22/60
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
22
-
8/11/2019 Neelam Presentation
23/60
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
23
-
8/11/2019 Neelam Presentation
24/60
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
24
-
8/11/2019 Neelam Presentation
25/60
Permeation rate of ceftriaxone sodium (g/cm2) using biological membrane
25
-
8/11/2019 Neelam Presentation
26/60
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
26
-
8/11/2019 Neelam Presentation
27/60
-
8/11/2019 Neelam Presentation
28/60
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
28
-
8/11/2019 Neelam Presentation
29/60
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
29
-
8/11/2019 Neelam Presentation
30/60
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
30
-
8/11/2019 Neelam Presentation
31/60
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
31
-
8/11/2019 Neelam Presentation
32/60
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
32
-
8/11/2019 Neelam Presentation
33/60
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
33
-
8/11/2019 Neelam Presentation
34/60
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
34
-
8/11/2019 Neelam Presentation
35/60
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
35
-
8/11/2019 Neelam Presentation
36/60
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
36
-
8/11/2019 Neelam Presentation
37/60
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
37
-
8/11/2019 Neelam Presentation
38/60
-
8/11/2019 Neelam Presentation
39/60
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
39
S C
-
8/11/2019 Neelam Presentation
40/60
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
40
-
8/11/2019 Neelam Presentation
41/60
-
8/11/2019 Neelam Presentation
42/60
Batches having good drug content & entrapment efficiency
42
-
8/11/2019 Neelam Presentation
43/60
-
8/11/2019 Neelam Presentation
44/60
Swelling behavior of beads after 8h44
-
8/11/2019 Neelam Presentation
45/60
-
8/11/2019 Neelam Presentation
46/60
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 (%)
-
8/11/2019 Neelam Presentation
47/60
S.No Time(min)
Cum drug release (%)
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
47
-
8/11/2019 Neelam Presentation
48/60
Drug release profile of beads in pH-7.4 buffer
48
Drug release study in pH 1.2 buffer
-
8/11/2019 Neelam Presentation
49/60
g y p
S.No Time(min)
Cum drug release (%)
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
49
CONTIN
-
8/11/2019 Neelam Presentation
50/60
S.No Time(min)
Cum drug release (%)
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..
50
-
8/11/2019 Neelam Presentation
51/60
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
51
-
8/11/2019 Neelam Presentation
52/60
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
52
-
8/11/2019 Neelam Presentation
53/60
Drug Permeation profile of Batches D1, J1, & J2
53
-
8/11/2019 Neelam Presentation
54/60
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.
Higuchi model54
-
8/11/2019 Neelam Presentation
55/60
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
55
-
8/11/2019 Neelam Presentation
56/60
-
8/11/2019 Neelam Presentation
57/60
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.
57
-
8/11/2019 Neelam Presentation
58/60
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.
58
-
8/11/2019 Neelam Presentation
59/60
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.
59
-
8/11/2019 Neelam Presentation
60/60