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A PRESENTATION ON

DEVELOPMENT AND EVALUATION OF POLYMERIC


BEADS OF CEFTRIAXONE SODIUM BY USING
ABSORPTION ENHANCERS

Submitted for partial fulfillment of requirement for the award of Master of
Pharmacy Degree in Pharmaceutics








UTTAR PRADESH TECHNICAL UNIVERSITY,
LUCKNOW, INDIA
10 JAN, 2010

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
ADVANTAGES OF MULTIPARTICULATE DOSAGES
FORMS

Multiparticulate provide many advantages over single-unit
systems 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 multiparticulate
dosage forms, e.g. Multiparticulate reduces dose dumping.


3
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
DRUG PROFILE OF CEFTRIAXONE SODIUM

Category - Antibacterial ( BCS Class III drug)

Structure


N
N
N
S
N
O
NH
N
S
S
O
ONa C H
3
O
O ONa
H
H
OCH
3
N H
2





Molecular formula - C
18
H
16
N
8
Na
2
O
7
S
3
.
3.5H
2
O


Molecular weight - 662.0
5
Description: white or yellowish, crystalline powder, slightly
hygroscopic.

Melting point: 156
0
c

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
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
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
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 immediate
barrier 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
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
AIM AND OBJECTIVE

The Aim of the present study is Development and evaluation of
polymeric beads of Ceftriaxone sodium by using Absorption
enhancers.

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 were
incorporated into beads, these beads were filled into capsules to
create the final dosages form.





11
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.


Drug
Polymer solution
Precision device
Crosslinking solution
Beads
12
PLAN OF WORK


Preformulation Study

Permeability enhancement of the drug

Formulation development and Optimization

Evaluation of ceftriaxone beads

Stability studies




13


S.No

1.


2.
Parameter

Physical characteristics
Color
Taste

Identification
Analytical method




Infra-Red Analysis

R
f
value
Assay
Melting Point
Result/ Observation


Off-White
Bitter


(i) max 265.0 nm ( buffer
pH 1.2 )
(ii) max 241.0 (In
phosphate buffer pH 7.4)

showed all characteristic
peaks
0.69
99.89 %
156
0
C

Inference

On the basis of
these tests it
could be
confirm that the
drug sample
was pure and
authentic


PREFORMULATION
14
IR Spectrum of Pure drug
15
IR Spectrum of drug with sodium taurocholate
Parameter Result
Solubility analysis(I.P.)
In different solvents
a. Water
b. Methanol
c. Ethanol
d. Glycerol
e. Acetone



Freely soluble
Slightly insoluble
Very Slightly soluble
Very Slightly soluble
Practically insoluble

Phosphate Buffer Results
pH 1.2 Freely soluble
pH 5.5 Freely soluble
pH 6.8 Freely soluble
pH 7.4 Freely soluble
In different pH
16
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


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
Partition coefficient of the drug with Permeation enhancers

S. No Permeation
enhancer
Drug : Permeation
enhancer ratio
(mM)
P
o/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 P9
19
S. No Permeation
enhancer
Drug : Permeation
enhancer ratio
(mM)
P
o/buffer
Batch
code
3 Polyoxyethylene
20 cetyl ether
1:0.03
0.024 P10
1:0.04
0.035 P11
1:0.05
0.039 P12
1:0.06
0.042 P13
1:0.07
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
Partition coefficient of drug with Combination of absorption
enhancers

S.No Batch code Drug: SD: ST P
o/buffer

1 P
22
1 : 0.4 : 3 0.043
S.N
o
Batch code Drug: S.T: O.A. P
o/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
S.No Batch code Drug: Brij 58 : O.A. P
o/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
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 Hanks Balanced 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 was
performed at 37
o
C.

Samples were periodically removed from the acceptor compartment over
4 h

23
Permeability study of Batches having good P
o/buffer
value.



Time(min) Cum amt permeated (g/cm
2
)
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
Permeation rate of ceftriaxone sodium (g/cm
2
) using biological membrane
25
PERMEABILITY COEFFICIENT / APPARENT PERMEABILITY
COEFFICIENT
Permeability coefficient of Batches having good P
o/buffer
value

S No. Batch code P
app
(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

FORMULATION DEVELOPMENT AND OPTIMIZATION

Preparation of beads by ionotropic gelation method

S.No. Parameters
1 Sodium alginate concentration (w/v)
2 Drug polymer ratio
3 Con. of zinc chloride (mM)
4 Curing time (min)

The parameters, which were to be optimized, are as follows
27
FORMULATIONS
S.No Con. of sod.
alginate
Drug: Alginate
ratio (mM)
Con of
ZnCl
2
(mM)
Curing time
(min)
Batch
code
1
0.5:1 A
1

2 2%
1:1
0.4 2
A
2

3
1.5:1 A
3

4
2:1 A
4

5
0.5:1 B
1

6 3%
1:1
0.4 2
B
2

7
1.5:1 B
3

8
2:1 B
4

28
S.No Con. of sod.
alginate
Drug: Alginate
ratio
Con of
ZnCl
2
(mM)
Curing time
(min)
Batch
code
9
0.5:1 C
1

10 4%
1:1
0.4 2
C
2

11
1.5:1 C
3

12
2:1 C
4

13
0.5:1 D
1

14 5%
1:1
0.4 2
D
2

15
1.5:1 D
3

16
2:1 D
4

29
S.No Con. of sod.
alginate
Drug:
Alginate
ratio
Con of
ZnCl
2
(mM)
Curing
time (min)
Batch
code
17
0.5:1 E
1

18 6%
1:1
0.4 2
E
2

19
1.5:1 E
3

20
2:1 E
4

30
S.No Con. of sod.
alginate
Drug:
Alginate ratio
Con of
ZnCl
2
(mM)
Curing time
(min)
Batch
code
21 0.5:1
2
F
1

22
5%
1:1
0.5 2
F
2

23 1.5:1
5
F
3

24 2:1
5
F
4

25 0.5:1
5
G
1

26
5%
1:1
0.3 5
G
2

27 1.5:1
2
G
3

28 2:1
2
G
4

31
S.No Con. of
sod.
alginate
Drug:
Alginate
ratio
Con of
ZnCl
2
(mM)
Curing
time (min)
Batch
code
29 0.5:1 2 H
1

30 6% 1:1 0.5 2 H
2

31 1.5:1 5 H
3

32 2:1 5 H
4

33 0.5:1 5 I
1

34 6% 1:1 0.3 5 I
2

35 1.5:1 2 I
3

36 2:1 2 I
4

32
S.No Absorption
enhancers
Sodium
alginate
con.
Drug:
A.E.:
Alginate
(mM)
Con of
Zn Cl
2

Curing
time
(min)
Batch
code
37 Sodium
taurocholate
and oleic acid
5% 1:3:1:2 0.4 2 J
1

38 Polyoxy
ethylene 20
cetyl ether and
oleic acid
5% 1:0.8:1.5:2 0.4 2 J
2

OPTIMIZED BATCHES
33
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
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

B
1

B
2

B
3

B
4

C
1

C
2

C
3

C
4

D
1

D
2

D
3

D
4

E
1

E
2

E
3

E
4


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
S. No. Batch
code
Mean diameter
(mm) S.D.
(n=20)
17
18
19
20
21
22
23
24
F
1

F
2

F
3

F
4

G
1

G
2

G
3

G
4

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
S. No. Batch
code
Mean diameter
(mm) S.D.
(n=20)
25
26
27
28
29
30
31
32
33
34

H
1

H
2

H
3

H
4

I
1

I
2

I
3

I
4

J
1

J
2

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
SEM micrograph of Bead (Batch J1)
38
S.No Batch Code Drug content
(%)
Entrapment
efficiency
(%)
1
2
3
4
5
6
7
8
9
10
B
1

B
2

B
3

B
4

C
1

C
2

C
3

C
4

D
1

D
2

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.No Batch Code Drug content
(%)
Entrapment
efficiency
(%)
11
12
13
14
15
16
17
18
19
20
D
3

D
4

E
1

E
2

E
3

E
4

F
1

F
2

F
3

F
4

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
S.No Batch Code Drug content (%) Entrapment
efficiency
(%)
21
22
23
24
25
26
27
28
29
30
31
32
33
34
G
1

G
2

G
3

G
4

H
1

H
2

H
3

H
4

I
1

I
2

I
3

I
4

J
1

J
2

18.70
17.4
10.9
14.10
15.3
18.5
14.23
17.53
13.8
7.14
9.78
9.20
39.90
39.00
56.03
41.07
58.0
45.11
48.97
38.80
47.92
37.49
38.70
27.03
40.0
31.12
76.02
77.10
41
Batches having good drug content & entrapment efficiency
42
Swelling study

Beads were studied for swelling characteristics, only those
batches were selected which have good drug content and
entrapment efficiency more than 50%.

43
Swelling ratio= wt of wet beads/ wt of dried beads

Swelling behavior of beads after 8h
44
Swelling behavior of beads after 8 h contd..
45
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 45.93
5 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 88.45
46
S.No Time(min)
Cum drug release (%)
Batch E1
Batch
E2
Batch 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

Drug release profile of beads in pH-7.4 buffer
48
Drug release study in pH 1.2 buffer
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 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
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 60
10.17 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
Drug release profile of beads in pH1.2buffer
0
2
4
6
8
10
12
14
16
18
0 50 100 150
c
u
m

d
r
u
g

r
e
l
e
a
s
e

(
%
)

Time (min)
batch
E1
batch
E2
51
PERMEABILITY STUDY OF OPTIMIZED BATCHES OF
CEFTRIAXONE BEADS

Permeability study of batches D1, J1 and J2
Time(min)
Cum amt permeated (g/cm
2
)
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
240
594.91 1964.67 1340.20
52

Drug Permeation profile of Batches D1, J1, & J2

53
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 model 54
The optimized formulation J1 was stored at
40
o
c/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

log % Drug remaining Vs Time , Batch J1

Degradation rate constant R was found to be 2.310
-4
day
-1

56
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 P
o
/
buffer
value (0.026). However, the
combination with absorption enhancers led to improvement in the
P
o
/
buffer
value ( 0.507)up to many folds.








57
The extent of enhancement was found to be highly
dependent on the absorption enhancers species used. The
combination of sodium taurocholate and oleic acid
provided 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
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 of
stomach 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
60