DESIGN AND ASSESSMENT OF COLON SPECIFIC DRUG DELIVERY OF CELECOXIB USING PULSINCAP TECHNIQUE

DESIGN AND ASSESSMENT OF COLON SPECIFIC DRUG
DELIVERY OF CELECOXIB USING PULSINCAP TECHNIQUE

Dissertation submitted to
Jawaharlal Nehru Technological University,
Anantapur.

Presented by
LAKSHMI K
Regd. No. (11421S0304)
M. Pharm (Pharmaceutics) IInd year

Under the guidance of
Mr. RAJESH KAZA, M. Pharm., (Ph.D.)
Associate professor
Dept. of pharmaceutics
SRI PADMAVATHI SCHOOL OF PHARMACY
MOHAN GARDENS, TIRUCHANOOR, TIRUPATHI-517503
JUNE-2013
1

PULSATILE DRUG DELIVERY SYSTEM
 Pulsatile drug delivery system delivers drug in a rapid and burst manner within a
short time period immediately after a programmable lag phase.
 Pulsatile drug delivery aims to release drug in a programmed pattern i.e., at
appropriate time and appropriate site of action.

Drug release profile of pulsatile drug delivery system
A: Ideal sigmoidal release
B and C: Delayed release after a lag time
2

ADVANTAGES
Drug
targeting to
specific site
Improved
patient
compliance

Bypassing first
pass metabolism

ADVANTAGES
No risk of
dose dumping

Drug adapts to
suit circadian
rhythms of
diseases

Limited risk
of local
irritation

Reducing
dose
frequency

3

disADVANTAGES
Large number
of process
variables
Lack of
manufacturing
reproducibility
and efficacy

Multiple
formulation
steps

ADVANTAGES
Need of
advanced
technology

Higher cost
of production
Trained/skilled
personal needed
for
manufacturing

4

Drug release mechanism from pulsincap system

5

RHEUMATOID ARTHRITIS
 Rheumatoid arthritis is an autoimmune disorder in
which various joints in the body are inflamed which
leads to swelling, pain, morning stiffness and severe

pain at joints.
 It is a chronic disease which initially attacks the
synovium, a connective tissue membrane that lines the
capsule around joints and secretes a lubricating fluid.
 In rheumatoid arthritis, an abnormal immune system
response produces destructive molecules that causes
continuous inflammation to the synovium and thereby

narrowing the joint space and eventually damaging the
bone.
6

ETIOLOGY OF RHEUMATOID ARTHRITIS

GENETIC
FACTORS

AGE

GENDER

SMOKING

FAMILY
HISTORY

7

Treatment FOR RHEUMATOID ARTHRITIS
• Celecoxib

• Joint replacement surgery

• Prednisone

• Unicondylar knee arthroplasty

• Methotrexate

• Synovectomy

• Infliximab

• Arthroscopy

Surgery

Life Style
Changes
• Regular exercise
• Managing psychological and
emotional conditions

Drug
Therapy

Alternative
Therapies
• Acupuncture,
• Mineral baths (Balneotherapy)

• Proper dietary intake
8

LITERATURE REVIEW
Punitha et al., (2009) have worked on increasing the solubility of poorly water soluble drug celecoxib with solid dispersion
technique using urea as water soluble carrier by physical mixture, solvent evaporation and fusion method. Solid dispersions
were prepared by using 1:1, 1:3 and 1:5 ratios of drug and polymer respectively. The dissolution studies were carried out
using USP paddle type dissolution apparatus. Solid dispersion of drug and polymer in 1:5 ratio prepared by fusion method
showed faster dissolution rate i.e., 79.08% when compared to that of other formulations prepared by physical mixture and
solvent evaporation method. The FT-IR studies revealed that no interaction of drug with carrier. Finally solid dispersions of
drug and polymer in 1:5 ratios respectively prepared by fusion method showed excellent physicochemical characteristics and
was found to be described by first order release kinetics.

Ram Mohan Gupta et al., (2011) carried out an experiment to increase the solubility and dissolution rate of celecoxib by
preparing the spherical crystals of celecoxib using polymers like polyethylene glycol 4000, sodium carboxy methylcellulose,
sodium alginate and polyvinyl pyrrolidone K30 in different ratios i.e., 1:1, 1:2, 1:3 and 1:4 respectively. All the formulations
were characterized for micromeritic properties. FT-IR spectra and differential scanning calorimetry studies revealed that
compatibility between drug and polymer. X-ray diffraction studies revealed the occurrence of decrease in crystallinity of
spherical agglomerates of celecoxib. From the results of dissolution study, spherical agglomerates of celecoxib prepared with
polyvinyl pyrrolidone K30 in 1:4 ratio respectively showed maximum drug release when compared to that of pure drug and
9

other batches of spherical agglomerates.

LITERATURE REVIEW
Gohel et al., (2002) studied a programmed drug delivery of ketoprofen from hard gelatin capsules containing a hydrophilic

plug made up of polymers like HPMC K15M or guar gum. The significance of factors such as plug thickness and the
formulation of fill material on the release pattern of diltiazem hydrochloride were investigated. In order to accelerate the drug
release after a lag time of 4 hrs, an effervescent blend, sodium bicarbonate and citric acid in the capsules were added. The
plugs of HPMC K15M in tablet form, were used for obtaining immediate drug release after lag time. The results indicated
that the drug release was dependent on the type of swellable hydrophilic agent, HPMC K15M or guar gum for achieving

predetermined lag time.

Putta Rajesh Kumar et al., (2012) developed the pulsatile drug delivery system for verapamil hydrochloride to release the
drug after a predictable lag time. The verapamil hydrochloride pulsincaps were prepared by physical mixture with lactose by
varying drug to polymer ratio and evaluated for percentage yield, drug content, IR and in vitro drug release studies. Sodium
alginate and xanthan gum were used as hydrogel plugs to maintain a suitable lag period. The in vitro drug release studies
were carried out by using buffer of pH 1.2 for a period of 2 hrs, phosphate buffer of pH 7.4 for a period of 4 hrs and
phosphate buffer of pH 6.8 for a period of 6 hrs simultaneously. Results showed that the optimized formulation containing
guar gum as hydrogel plug releases 94.5% of drug at 12 hrs with 4 hrs lag time. Thus programmable pulsatile drug release
has been achieved from optimized formulation over a period of 12 hrs and is consistent with the demands of pulsincap drug
delivery system.

10

AIM OF the WORK

The aim of present work is to
improve the solubility of celecoxib
by rapid solvent change method and
the prepared microcrystals were
used for the development of
pulsatile drug delivery using
pulsincap technique.
11

OBJECTIVEs OF THE WORK
1.

2.

3.

4.

5.

6.

• To enhance the solubility of celecoxib by rapid solvent change method .

• To synchronize the drug delivery to the circadian rhythms of rheumatoid arthritis.

• To provide maximum drug release when sharp increase of symptoms of rheumatoid arthritis occurs .

• To bypass the gastric degradation and first pass metabolism of drug.

• To minimize the frequency of drug administration

.

• To improve the patient compliance.

12

DRUG PROFILE
CELECOXIB

• Molecular
formula:
C17H14F3N3O2
• Category: Selective COX-2
inhibitor (NSAID)
• Bioavailability: 25-30%
• Half life: 7.5-8 hrs
• Solubility: It is freely
soluble
in
methanol,
ethanol, PEG 400, DMSO
and acetone. It is poorly
soluble in water and nonpolar hydrocarbons.

• Melting point: 1571580C

• Dose: 100-200 mg
• Uses:Rheumatoid
 Used for the
treatment of
arthritis
 Osteoarthritis
 Ankylosing
spondylitis

13

POLYMER PROFILE
S. No.

1.

2.

3.

NAME OF THE
POLYMER

Guar gum

Maltodextrin

PVP K30

FUNCTIONAL CATEGORY

USES

 Stabilizing agent
 Suspending agent
 Tablet binder and
disintegrant
 Viscosity enhancer

 In colonic drug delivery
 Used in cosmetics, food
and pharmaceutical
formulations.






 Tablet film former in
aqueous film coating.
 Carrier to increase the
viscosity of solutions.
 Osmolarity regulator for
solutions.

Stabilizing agent
Tablet binder
Viscosity enhancer
Diluent

 Stabilizing agent
 Tablet binder and
disintegrant
 Dissolution enhancer
 Suspending agent

 Solubilizer
 Coating agent

14

EXCIPIENT PROFILE
S. No.

1.

NAME OF THE
EXCIPIENT

HPMC K100 M

FUNCTIONAL CATEGORY






Controlled release agent
Film former
Suspending agent
Viscosity enhancer
Sustained release agent

2.

Sodium starch
glycolate

 Tablet and capsule
disintegrant

3.

Lactose

 Dry powder inhaler
 Carrier

USES
 Emulsifier
 Used in oral, ophthalmic,
nasal and topical pharmaceutical formulations.
 Suspending agent in
topical gels and ointments

 Super disintegrant

 Tablet and capsule diluent

15

PLAN OF WORK

• Drug-polymer
compatibility
studies
• Preparation of
calibration curve
for drug
PREFORMULATION
STUDIES

PREPARATION AND
EVALUATION OF
CELECOXIB
MICROCRYSTALS

• Preparation of
microcrystals
• Evaluation of
microcrystals
• Characterization
of microcrystals

• Physicochemical
characterization of
formaldehyde
treated capsules
• Preparation of
pulsincaps
• Evaluation of
pulsincaps
PREPARATION AND
EVALUATION OF
CELECOXIB
PULSINCAPS

16

Experimental methodology
Pre-formulation studies

1.
2.

• Preformulation studies for drug

• Drug-excipient compatibility
studies by FT-IR

17

Preparation of celecoxib microcrystals BY
RAPID SOLVENT CHANGE METHOD
Drug solution

Hydrophilic
stabilizer

Non solvent

Crystallization

Drying at 500C
for 1 hr

Celecoxib
microcrystals
18

Working formula of celecoxib microcrystals
Formulation code
S. No.

Ingredients
F1

1.

2.
3.
4.

Celecoxib
(gms)
Guar gum
(gms)
Maltodextrin (gms)
PVP K30
(gms)

F2

F3

F4

F5

F6

F7

F8

F9

1.76

1.76

1.76

1.76

1.76

1.76

1.76

1.76

1.76

0.02

0.04

0.06

---

---

---

---

---

---

---

---

---

0.02

0.04

0.06

---

---

---

---

---

---

---

---

---

0.02

0.04

0.06

5.

Methanol (solvent) (ml)

10

10

10

10

10

10

10

10

10

6.

Water (anti-solvent) (ml)

20

40

60

20

40

60

20

40

60

19

EVALUATION OF microcrystals
Percentage
crystal
yield

Particle size
distribution

EVALUATION
STUDIES

Percentage
drug
content

In vitro
drug
release
studies
20

CHARACTERIZATION OF microcrystals

Differential
scanning
calorimetry
(DSC)

CHARACTERIZATI
ON STUDIES
X-Ray
diffractometry
(XRD)

Scanning
electron
microscopy
(SEM)

21

Preparation of celecoxib pulsincaps
Preparation of
cross-linked hard
gelatin capsule
bodies

Separation of cap and
bodies of capsules.

Treatment of capsule
bodies with 15% v/v
formaldehyde solution
for 12 hrs in dessicator.

Drying for a period of
3 hrs at 50 C.

Preparation of
hydrogel plug

Different weight
ratios (1:1, 1:2, 1:3
and 1:4) of HPMC
and guar gum
respectively were
taken

Subject to direct
compression method
using 6 mm punches
and dies on rotary
tablet punching
machine.

Capsule Filling

Sealing and coating
of capsules

200mg of optimized
celecoxib microcrystal
formulation were
taken.

Joint of capsule body and
cap was sealed with a
small amount of 3% ethyl
cellulose ethanolic
solution.

To this, add
appropriate quantities
of sodium starch
glycolate (super
disintegrant) and
lactose (diluent)

Coating of capsules with
3% ethyl cellulose
ethanolic solution by dip
coating method.

Filling of above
mixture in capsule
bodies

Coating was repeated until
8-12% increase in total
weight of capsule was
obtained.
22

Composition of pulsincaps
S. No.

Ingredients

Weight taken (per capsule)

1.

Optimized microcrystal formulation (mg)

Equivalent to 200 mg of drug (w/w)

2.

Sodium starch glycolate (mg)

(4%) (w/w)

3.

Lactose (mg)

Quantity sufficient (q.s)

Total weight (mg)

300 mg

Composition of different formulations of hydrogel plug
Formulation code
S. No.

Ingredients
H1

H2

H3

H4

1.

HPMC (mg)

150

100

75

60

2.

Guar gum (mg)

150

200

225

240

Total weight (mg)

300

300

300

300
23

evaluATION OF pulsincaps

Solubility test

Disintegration
test

EVALUATION
STUDIES

Evaluation of
hydrogel
plugs

In vitro drug
release
studies
24

EVALUATION OF hydrogel plugs
Thickness
test

Harness
test

EVALUATION
STUDIES

Friability
test

Weight
variation
test
25

RESULTS AND DISCUSSION
Standard curve of celecoxib
S. No.

Concentration (µg/ml)

Absorbance

1.

0

0

2.

2

0.085

3.

4

0.181

4.

6

0.275

5.

8

0.365

6.

10

0.450

26

Preformulation studies of celecoxib

Colour

• White crystalline

Taste

• Bitter

Melting point

• 1570C

27

Drug-excipient compatibility study by FT-IR .
Functional group

Celecoxib

CX:GG

CX:MD

C-C (Aromatic
bending)

792.84 cm-1

797.84 cm-1

796.84 cm-1

794.84 cm-1

C=C (Aromatic
stretching)

1446.79 cm-1

1443.79 cm-1

1445.79 cm-1

1442.79 cm-1

3098.05 cm-1

3099.98 cm-1

3097.98 cm-1

3094.98 cm-1

1228.81 cm-1

1230.73 cm-1

1233.73 cm-1

1232.73 cm-1

3343.04 cm-1

3341.12 cm-1

3339.19 cm-1

3342.04 cm-1

S=O (Stretching)

1165.15 cm-1

1162.15 cm-1

1164.15 cm-1

1163.15 cm-1

C-N (Stretching)

1348.41 cm-1

1346.48 cm-1

1347.41 cm-1

1350.34 cm-1

C-F (Stretching)

3233.09 cm-1

3235.02 cm-1

3234.02 cm-1

3236.95 cm-1

C-H (Aromatic
stretching)
C-H (Aromatic
bending)
N-H (Aromatic
stretching)

CX:PVP K30

 Same peaks of N-H, C-N, C-F and S=O bonds were present as that of pure
drug without much shifting in the spectra of celecoxib microcrystals suggested
that no chemical interaction between the drug and stabilizing agent.
28

0.4
0.8

0.3

0.6

1647.41, 0.27

0.4

0.2

3098.05, 0.3015
3343.04, 0.08878

0.2

3233.09, 0.08552

763.90, 0.1538

1228.81, 0.02133
1165.15, 0.0006996 1348.41, 0.00338

0.0

576.79, 0.09064
1155.50, 0.06075
1078.34, 0.04968

1446.79, 0.08247

792.84, 0.07979

1000

1458.36, 0.161

929.80, 0.154

0.1

1500

2000

2500

3000

600

800

1000

1200

1400

1600

FT-IR spectrum of maltodextrin

FT-IR spectrum of celecoxib
0.65
0.8

0.60
0.6

1655.13, 0.5447
0.55

870.00, 0.5693

0.4

0.50

812.13, 0.5192

673.24, 0.5179

0.2
3339.19, 0.05435

0.45

3235.02, 0.04854 3099.98, 0.2359
1230.73, 0.009505
1165.15, 0.0008563
1348.41, 0.001917

1155.50, 0.4384

605.72, 0.4378

0.0
792.84, 0.0495
1000

0.40

1446.79, 0.04871
1500

2000

2500

3000

600

FT-IR spectrum of celecoxib microcrystals
containing maltodextrin

800

1000

1200

1400

FT-IR spectrum of guar gum

1600

29

0.6

0.8

0.5

0.6
1016.61, 0.5022
846.85, 0.4899

0.4

0.4

733.04, 0.4388
1169.00, 0.4199
1371.55, 0.4082

3099.98, 0.4106

2955.31, 0.3278

3341.12, 0.171
1230.73, 0.3758

648.16, 0.3709

3235.02, 0.1632
0.2
0.3

792.84, 0.157
1165.15, 0.01194
0.0

1348.41, 0.02018

1446.79, 0.1692
1288.61, 0.2841

1230.73, 0.06457
1000

1500

1000

2000

2500

1500

2000

2500

3000

3000

containing guar gum

FT-IR spectrum of PVP K30

0.8

0.6

3099.98, 0.6003

3343.04, 0.3396
3236.95, 0.3268

0.4

1446.79, 0.325

792.84, 0.3178
0.2

1165.15, 0.03449
1230.73, 0.152
1350.34, 0.08314

0.0
1000

1500

2000

2500

3000

containing PVP K30

30

Evaluation of celecoxib microcrystals

S. No.

Formulation code

% Crystal yield

% Drug content

% Cumulative
drug release at 60
min

1.

F1

93.25

86.31

54.69 0.98

2.

F2

95.55

91.63

74.33 1.32

3.

F3

96.30

94.99

85.12 0.78

4.

F4

92.69

86.87

63.06 0.76

5.

F5

94.44

92.03

78.67 0.92

6.

F6

96.70

95.36

89.33 0.89

7.

F7

91.57

85.70

42.70 0.96

8.

F8

95.55

90.22

69.65 0.45

9.

F9

96.15

94.60

82.03 0.65
31

Particle Size Distribution
Celecoxib

F6 Formulation

F3 Formulation

F9 Formulation

32

Dissolution profile of celecoxib microcrystals

 From the results, it was revealed that the enhancement in the dissolution rate
of microcrystals occurs due the presence of stabilizing agent, which has the ability
to reduce the crystallinity of drug by adsorption onto the specific faces of the
growing crystal surface of crystalline drug which results in the passage of solvent
towards the faces and interiors of drug particles and leads to increased solubility
and subsequent dissolution.
33

DSC STUDIES

Celecoxib

CX:MD

CX:GG

CX:PVP K30

34

DSC STUDIES
From DSC thermograms, the melting point of pure celecoxib,
microcrystals containing guar gum, maltodextrin and PVP K30 showed a
sharp melting endothermic peak at 170.01, 163.08, 161.70 and 162.370C
respectively.
Melting endotherm is not appreciably changed in celecoxib
microcrystals prepared in the presence of hydrophilic stabilizing agents
i.e., guar gum, maltodextrin and PVP K30 but with a slight reduction that
did not seem to be significant.
This observation confirmed the absence of chemical interaction of drug
with stabilizing agents during crystallization process.
35

XRD STUDIES

Celecoxib

CX:MD

CX:GG

CX:PVP K30

36

XRD STUDIES
Characteristic peaks appeared in the XRD for celecoxib showed sharp
intensity peaks at 2θ values of 10, 22, 27, 29, 31, 36, 41, 46, 49, 54 and 74.
 In case of celecoxib microcrystals containing guar gum, sharp intensity
peaks were exhibited at 25, 31, 36, 39 and 46. In case of celecoxib
microcrystals containing maltodextrin, sharp intensity peaks were exhibited
at 41, 53, 59 and 74. In case of celecoxib microcrystals containing PVP K30,
sharp intensity peaks were exhibited at 31, 41, 49 and 74.
The lack of numerous distinctive peaks of the drug in case of celecoxib
microcrystals indicates the reduced crystallinity when compared to that of
pure drug.

This may be due to partial conversion of the drug to amorphous state from
crystalline state and thus enhances the solubility
37

SEM STUDIES

20KV
20KV

9.7mm×500SE
9.7mm×500SE

28µm
100µm

17/06/2013
17/06/2013

SEM of celecoxib

12:39
10:43

SEM of celecoxib microcrystals
38

SEM STUDIES
 Microcrystals containing maltodextrin as stabilizing agent at
0.1% w/v concentration with 1:6 ratios of solvent to anti-solvent
(v/v) respectively (F6 formulation) showed small platy crystals
with particle size of 28µm diameter.
From the results, it was observed that the particle size of drug
decreases three folds by rapid solvent change method. This may
be due to face specific adsorption of stabilizing agent alters the
growth rate of the crystal faces where adsorption takes place and
thus changes the morphology of the crystal.
Modification of crystal habit can improve the dissolution rate
by promoting the growth of more hydrophilic faces or inhibiting
the growth of more hydrophobic faces.
39

Evaluation of celecoxib pulsincaps
Physico-chemical characterization of capsules:
Color

S. No.

Capsule type

1.

Dimensions

Odor

Length
(mm)

Diameter
(mm)

Red

Odorless

21.6 0.20

3.24 0.03

Blue

Red

Odorless

19.8 0.15

3.22 0.11

White

White

Odorless

19.9 0.20

3.27 0.06

Body

Cap

Untreated capsules without
coating

Blue

2.

Formaldehyde treated
capsules without coating

3.

Formaldehyde treated
capsules with coating

Solubility and disintegration time:
S. No.

Capsule type

Solubility test

Disintegration time

1.

Untreated capsules without coating

Whole capsule-≤15 min

Whole capsule-3 min

2.

Formaldehyde treated capsules
without coating

Cap-≤15 min

Cap-3 min
Body-2 hrs

Body-10 hours

40

Evaluation of hydrogel plugs
Hydrogel
S. No.

Plug code
(HPMC:Guar gum)

Mean thickness
(mm)

Mean hardness
(kg/cm2)

% Friability

% Weight
variation test

1.

H1 (1:1)

2.99

4.50

0.78

Passes the test.

2.

H2 (1:2)

3.06

4.50

0.74

Passes the test.

3.

H3 (1:3)

2.82

4.50

0.63

Passes the test.

4.

H4 (1:4)

3.11

4.50

0.81

Passes the test.

41

Dissolution data of celecoxib pulsincap formulations
Percent cumulative drug release (mean±S.D.)

Time
S. No.

(Hr:min)

PH1

PH2

PH3

PH4

1.

00:30

0.00

0.00

0.00

0.00

2.

01:00

0.00

0.00

0.00

0.00

3.

01:30

0.00

0.00

0.00

0.00

4.

02:00

0.00

0.00

0.00

0.00

5.

02:30

0.00

0.00

0.00

0.00

6.

03:00

6.32±0.13

0.00

0.00

0.00

7.

03:30

14.35±1.04

0.00

0.00

0.00

8.

04:00

29.73±0.34

5.93±1.02

0.00

0.00

9.

04:30

45.65±0.45

17.35±0.32

0.00

0.00

10.

05:00

57.76±0.14

30.73±0.44

6.11±0.67

0.00

11.

05:30

68.34±0.67

45.65±1.32

22.72±1.18

0.00

12.

06:00

76.88±1.32

60.76±0.89

45.77±0.44

0.00

13.

06:15

79.05±1.15

64.34±0.37

51.23±0.63

0.00

14.

06:30

79.92±0.44

67.88±1.29

55.48±1.23

9.30±1.22

15.

06:45

80.32±1.38

70.95±0.44

59.61±1.32

22.49±1.42

16.

07:00

81.11±1.29

72.89±1.06

64.42±0.12

56.03±0.38

17.

07:15

81.89±0.54

73.99±0.42

67.38±1.27

67.35±1.17

18.

07:30

82.12±0.25

74.96±0.23

68.03±0.21

86.17±0.23

19.

07:45

82.46±0.36

76.83±0.18

70.01±0.32

87.36±0.61

20.

08:00

82.86±0.41

78.32±0.53

72.83±0.22

87.89±0.38

42

Dissolution profile of celecoxib pulsincap formulations
100

% Cumulative drug release

90
80
70
60

PH1

50
PH2

40
30

PH3

20
PH4

10

0
0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

5

5.5

6

6.5

7

7.5

8

Time (hrs)

 Out of four pulsincap formulations prepared (PH1-PH4), PH4
formulation showed highest percentage drug release i.e., 87.89% at the
end of 8th hr and maximum lag time of 6 hrs when compared to other

pulsincap formulations.

43

Lag time profile of celecoxib pulsincap formulations

Formulation code

PH4

PH3

PH2

PH1

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

5

5.5

6

Lag time (hrs)

 Increase in lag time of pulsincap formulation with increased
concentration of guar gum occurs may be due to the presence of high
viscosity for guar gum which further retards the release of drug by
increasing the erosion time of hydrogel plug.
 Therefore, in case of PH4 pulsincap formulation, due to the presence of
higher amount of guar gum in hydrogel plug, plug possesses high viscous
nature and takes more time for complete erosion. Hence it maintains a
maximum lag time of 6 hrs when compared to other pulsincap
formulations
44



Celecoxib microcrystals were prepared by rapid solvent change method using guar gum, maltodextrin and
PVP K30 as a hydrophilic stabilizing agents. 1:6 ratio of solvent to antisolvent (methanol/water) and 0.1%
stabilizing agent were optimum parameters for microcrystallization of celecoxib.



The optimized microcrystals were exploited in the development of pulsincaps. Amongst the pulsincap
formulations prepared (PH1-PH4), PH4 formulation containing hydrogel plug made of HPMC and guar

gum in 1:4 ratio respectively was considered as optimized formulation in which percentage drug release
was found to be 87.89% at the end of 8th hour and maximum lag time of 6 hrs when compared to that of
other pulsincap formulations.


The studies have clearly indicated that pulsatile drug release of celecoxib from time dependent pulsincaps
can be helpful for chronomodulated therapy for treating rheumatoid arthritis as well as declining the
frequency of dose administration by preventing the drug from gastric degradation and first pass metabolism.
45

Publications
 “Design and Characterization of Microcrystals for Enhanced

Dissolution Rate of Celecoxib” Lakshmi K, Pranav Kumar Reddy and
Rajesh Kaza. Current Drug Discovery Technologies, 2013, 10(4), 305314.
 “Design and Assessment of Colon Specific Drug Delivery of
Celecoxib Microcrystals Using Pulsincap Technique” . Rajesh Kaza and
Lakshmi K. Current Drug Delivery. [Accepted and Article in Press].

46

 Gothoskar A.V and Joshi N.H. A review on pulsatile drug delivery systems. Drug Delivery
Technology, 2004; 4(5): 1-11.
 Shiva kumar H.G, Pramod kumar T.M and Kashyapa G.D. Pulsatile drug delivery system.
Indian J Pharm Educ., 2003; 37(3): 125-128.
 Sarasija, S and Hota, A. Colon-specific drug delivery systems. Indian J Pharm Sci., 2000;
62(1): 1-8.

 Jain N.K, Krishnaiah Y.S.R and Satyanarayana S. Colon-specific drug delivery systems.
Advances in controlled and novel drug delivery (1st edition). CBS publishers and
distributors, New Delhi, 2000; pp. 89-119.
 http://www.drugs.com/celecoxib.html

 http://www.rxlist.com/cgi/generic/coxib.html
 Smolinske S.C. Handbook of food, drug and cosmetic excipients. Boca Raton, CRC
Press, New York, 1992; pp. 303–305.
47

 Rajesh A Keraliya, Tejal G Soni, Vaishali T Thakkar, Tejal R Gandhi and Rajanikant C Patel.
Formulation and physical characterization of microcrystals for dissolution rate

enhancement of tolbutamide. Int J Pharm Sci Res., 2010; 1(1): 69-77.
 Nighute A.B and Bhise S.B. Enhancement of dissolution rate of rifambutin by preparation.
of microcrystals using solvent change method. Int J Pharm Tech Res., 2009; 1(2): 142-148.
 Hancock B and Zografi G. Characterization and significance of the amorphous state in

pharmaceutical systems. Int J Pharm Sci.,1997; 8(6): 1–12.
 Franenkel Conrat H and Olcott H.S. Reaction of formaldehyde with proteins II participation
of guanidyl groups and evidence of crosslinking. J American Chem Soc., 1946; 6(8):34-38.
 Kikuchi A and Okano T. Pulsatile drug release control using hydrogel plugs. Adv Drug Del
Rev., 2002; 54: 53-77.
 Meena A, Kumar B, Surya Prakash T.N.K and Senthamarai R. Development and evaluation of
of pulsatile drug delivery system of lornoxicam. Int J Pharm world Res., 2011; 2(2): 1-14.
48

DESIGN AND ASSESSMENT OF COLON SPECIFIC DRUG DELIVERY OF CELECOXIB USING PULSINCAP TECHNIQUE

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