Pulsatile Viva

Presented byMr. Sumit A. Abnawe

Guided byProf. Vishnu P. Choudhary

In partial fulfillment of the degree of Master of Pharmacy in

Quality Assurance Techniques MAEER’s Maharashtra Institute of Pharmacy,

MIT campus, Kothrud, Pune - 411 038.

2009 - 20101

Development and Evaluation of Time – Based Rupturable Pulsatile Drug

Delivery System

CONTENTS

2

IntroductionLiterature ReviewResearch Envisaged and Plan of WorkDrug ProfileExcipients ProfileExperimental Work & ResultSummary and ConclusionIndustrial ApplicabilityAcknowledgementReferences

INTRODUCTION

3

Pulsatile Drug Delivery System It is the one type of drug delivery system, where the delivery device is capable of releasing drug after predetermined time delay (i.e. lag time).

4

Chronopharmaceutical Drug Delivery It is the delivery of drugs in accordance with the circadian rhythms of the disease.

Diseases and Chronological Behaviour

5

Disease Chronological behaviour Drugs used

Peptic ulcer Acid secretion is high in the afternoon and at night

H2 blockers

Asthma Precipitation of attacks during night or at morning hour

Early β2 agonist, Antihistaminics etc.

Cardiovascular diseases

BP is at its lowest during the sleep cycle and rises steeply during the early morning awakening period

Nitroglycerin, Calcium channel blocker, ACE inhibitors etc.

Arthritis Pain in the morning and more pain at night

NSAIDs, Glucocorticoids etc.

Diabetes mellitus Increase in the blood sugar level after meal

Sulfonylurea, Insulin, Biguanide etc.

Attention deficit syndrome

Increase in DOPA level in afternoon

Methylphenidate etc.

Hypercholesterolemia

Cholesterol synthesis is generally during night than during day time

Higher HMG CoA reductase inhibitors

6

PULSATILE DRUG

DELIVERY SYSTEM

Time controlled pulsatile drug

delivery

Single unit systems

1. Capsule based Capsular 2. Capsular system based on Osmosis3. System with erodible barrier coatings4.System with rupturable coating

Multiple unit systems

1. System with rupturable coating2. Osmotic based rupturable coating system3. Pulsatile delivery by change in membrane permeability

Stimuli induced

pulsatile drug delivery

1. Temperature induced systems2. Chemical stimuli induced pulsatile systems

Externally regulated

pulsatile drug delivery

Classification:

LITERATURE REVIEW

7

Journals and Articles review1. R. Bodmeier et al. investigated swelling characteristics

as follows: Croscarmellose sodium > Low-substituted

hydroxypropyl cellulose > sodium starch Glycolate > crospovidone > hydroxypropyl methylcellulose.

1. Andrei Dashevsky, Ahmad Mohamad studied and concluded that: For complete repture, amount of (Ac-Di-Sol®)

required was 48% (w/w). To use ethyl cellulose of lower molecular weight Addition of talc led to increase brittleness of

membrane

1. T.Y. Fan et al. studied and concluded that: DILTIAZIM atblet containing 8 mg SSG and coating

levels 5.7 %, 7.4 % and 9.5 % of Ethyl cellulose and Eudragit L (1:2) shows lag time of 1, 3 and 4 hours respectively.

8

4. Ahmad Mohamad and Andrei Dashevsky concluded that:

Rupturable top-coating was successfully performed using an aqueous dispersion of ethylcellulose.

A higher coating level was required, when aqueous dispersion was used, compared to organic coatings.

5. Raghavendra Rao N. G and Suryakar V. B prepared

Montelukast sodium buccal patches.

9

Patents Review Hrakovsky, Julia et al. has taken patent for:

“Stable pharmaceutical formulations of montelukast sodium.”

The invention encompasses stable pharmaceutical compositions in film coated tablet form comprising montelukast or salts thereof and methods of preparing the same. Preferably, the salt is the sodium salt.

RESEARCH ENVISAGED AND PLAN OF WORK

10

In a large study involving 8,000 asthmatics, it is observed that,

1. 75% awakened one night per week,

2. 64% awakened 3 nights per week and

3. 39% had their sleep disturbed on a nightly basis.

The patients who self-characterized their asthma as mild,

1. 26% had nightly awakenings and

2. 53% of asthma deaths occurred during the night time hours.

3. Lung function is usually highest at 4 pm and lowest at 4 am the latter time is generally when asthma symptoms are most prevalent.

4. Based on these findings it was planned to modify drug delivery and therapy to achieve an effective drug level at the required time. This can be achieved by adapting a pulsatile drug delivery system of a suitable drug.

11

LiteratureSurvey

Selection of Drug &Excipients

Formulation development of trial batches (TD & TS)

Formulation Development

Preformulation Study

Evaluation of trial batches

Coating of trial batches

Results and Discussion

Evaluation of SA1 to SC4 batches

Formulation development of SA1 to

SC4 batches

Coating of SA1 to SC4 batches

Summary and Conclusion

LiteratureSurvey

DRUG PROFILE

12

Montelukast Sodium

Sr. no.

Parameter Comments

1 Mechanism of action

Selective leukotriene receptor antagonist of the cysteinyl leukotriene CysLT1 receptor.

2 Absorption Rapid absorption, BA is not affected by a standard meal

3 Half-life 2.7 to 5.5 hours

4 Tmax 3 to 4 hours

5 Dose >15 yrs, 10 mg daily

N

OCOO-Na+

HO

CH3

H3C

Cl

13

Marketing and Patent status

14

Innovetor

15

Patent Status

EXCIPIENTS PROFILE

16

Sr. no.

Excipient Use

1 Cellulose, microcrystalline

Diluent

2 sodium starch glycolate

Disintegrant.

3 Doshion P 544 C Disintegrant.

4 Colloidal silicon dioxide

Glidant

5 Magnesium stearate Lubricant

6 Sodium lauryl sulfate

Solubilizer in concentrations greater than critical micelle concentration

7 Ethylcellulose Sustained-release tablet coating

8 Talc To increase brittleness of coat

9 Titanium dioxide Opacifier

10 Castor oil Plasticizer

11 Dichloromethane Coating solvent

12 Isopropyl alcohol Coating solvent

EXPERIMENTAL WORK AND

RESULT

17


18

Sr. no.

Test Limit Result

1 Appearance Light yellow coloured powder,

hygroscopic in nature.

2 Identification by IR - -

3 Determination of BD & TD - 0.769 &

0.9094 Test for sodium

0.1 gm sample + 20 ml water + 2 ml 15 % Potassium carbonate + boil No ppt + 4 ml potassium pyroantimonate TS + boil + cool in ice water

Sodium is present.

5 Loss on drying (% w/w) 3 2.5

6 Determination of flow property -

7 Drug analysis by UV/Visible spectrophotometer

- 346 nm

8 Drug-excipient interaction - Compatible

9 Assay by HPLC (% w/w ) 98.0 - 102.0 99.78

Drug analysis by UV/Visible spectrophotometer

19

Sr. no.

Parameter Observation

1. Wavelength of detection (nm) 3462. Beer’s law limit (μg/ml) 6 - 163. Regression Equation (y = mx + c)4. Slope (m) 0.08535 Intercept (c) 0.16966 Correlation coefficient 0.9994


20

Sr. no.

Test Limit Result



Light yellow coloured powder,



3 Determination of BD & TD - 0.769 & 0.9094 Test for sodium


- Sodium is present.




- 346 nm

8 Drug-excipient interaction - -

9 Assay by HPLC (% w/w ) 98.0 - 102.0 99.78

21

VialNo. Drug + Excipients Ratio

Initial Observat

ion

Observation after 15 days under

following conditions

55°C

55°C, 5%

moisture

1. Pure Montelukast Sodium 1.0 White powder

Liquification

Liquification

2. Montelukast Sodium + Microcrystalline Sodium 1:1 White

powderNo

change

Brownish white cake

3.Montelukast Sodium + Microcrystalline Sodium + Doshion P 544 C

1:1:1 White powder

No change

Brownish white power

4.

Montelukast Sodium + Microcrystalline Sodium + Doshion P 544 C + Magnesium Stearate

1:1:1:1

White powder

No change


5.

Montelukast Sodium + Microcrystalline Sodium + Doshion P 544 C + Magnesium Stearate + Hydrophobic Colloidal Anhydrous Silica

1:1:1:1:1

White powder

No change

No changeAbove observations shows that Montelukast Sodium is

compatible with selected excipients in presence and absence of 5 % moisture.

22

VialNo. Drug + Excipients Ratio

Initial Observati

on

Observation after 15 days under

following conditions

55°C 55°C, 5% moisture

1. Pure Montelukast Sodium 1.0 White powder

Liquification

Liquification

2. Montelukast Sodium + Microcrystalline Sodium 1:1 White

powderNo change

Brownish white cake

3.Montelukast Sodium + Microcrystalline Sodium + Sodium Starch Glycolate

1:1:1 White powder

No change

Brownish white cake

4.

Montelukast Sodium + Microcrystalline Sodium + Sodium Starch Glycolate + Magnesium Stearate

1:1:1:1 White powder

No change


5.

Montelukast Sodium + Microcrystalline Sodium + Sodium Starch Glycolate + Magnesium Stearate + Hydrophobic Colloidal Anhydrous Silica

1:1:1:1:1

White powder

No change

No change

Above observations shows that Montelukast Sodium is compatible with selected excipients in presence and absence of 5 % moisture.


23

Sr. no.

Test Limit Result




3 Determination of BD & TD - 0.769 &

0.9094 Test for sodium


Sodium is present.




- 346 nm

8 Drug-excipient interaction - -

9 Assay by HPLC (% w/w ) 98.0 - 102.0 99.78

24

Assay of pure drug was carried out by ADL department of Elder pharmaceuticals using INH developed and validated HPLC method.

Montelukast sodium chromatogram by using optimized chromatographic conditions.

MO

NT

E -

6.2

50

AU

0.00

0.05

0.10

0.15

0.20

Minutes

0.00 1.00 2.00 3.00 4.00 5.00 6.00 7.00 8.00

Formulation design of core tablets

25

Formulation of Montelukast sodium core tablets of trial batches TD and TS

Sr. No.

IngredientWeight (mg) /

tablet Formulation code

TD TS

1.Montelukast Sodium (equivalent to 10 mg of Montelukast)

10.38 10.38

2. Microcrystalline Cellulose (PH 102) 102.47 102.07

3. Sodium Starch Glycolate - 10.4

4. Doshion P 544C 10 -

5. Hydrophobic Colloidal Anhydrous Silica 0.65 0.65

6. Magnesium Stearate 6.5 6.5

Final Weight 130 130

Manufacturing Process

26

1. All the ingredients were weighed accurately.

2. Weighed quantity of Montelukast sodium was passed through # 40 and mixed with microcrystalline cellulose PH 102 (previously passed through # 30) in geometrical proportion in dark room.

3. Weighed quantity of sodium starch glycolate or doshion P 544C was passed through # 30 and mixed with step 2.

4. Hydrophobic colloidal anhydrous silica was passed through # 60 and mixed with step 3 in polybag.

5. Magnesium stearate was passed through # 60 and mixed with step 4 in polybag for one minute.

6. The tablets were compress at average weight of 130 mg/tab.

7. Physical evaluation of tablets was carried out.

Evaluation of Montelukast sodium core tablets of TD and TS trial batches

27

Sr. No.

ParameterResult

LimitTD TS

1 Hardness (mm) 4.0 - 5.0 4.0 - 5.0 -

2 Thickness (mm) 3.85 3.86 -

3 Diameter (mm) 7.04 7.05 -

4 Friability (%) 0.437 0.537 < 1

5 Disintegration Time (min.) 2 - 4 10 - 12 < 15

min.

6 Weight variation (%) ±1.5 ±1.45 < 10

7 Content of active ingredient (%)

99.43 - 100.75

99.54 - 100.92

90 - 110

8 Uniformity of content (%)

99 - 10199 - 101 85 -

115

9 Dissolution Study (%) 100.02 98.21 NLT 70%

28

Dissolution Study

Experimental Conditions Apparatus - USP Dissolution Apparatus, Type

II (Paddle) Dissolution Medium - 0.5% SLS Volume - 900 ml Temperature - 37 ± 0.5ºC RPM - 50 Limit - NLT 70 % drug should be

dissolves in 30 minutes in 0.5 % SLS.

29

The tablets of batches TD and TS shows 98-101% drug dissolved in 30 min so it passes the dissolution test, as it is specified by FDA that NLT 70 % drug should be dissolves in 30 minutes in 0.5 % SLS.

Release profile of Montelukast sodium core tablets of TD and TS batches

Coating of Montelukast sodium tablets of TD and TS trial batches

30

Sr. No. Component Use Quantity

1.Ethyl cellulose 20 cps

Coating polymer 70 % w/v

2. TalcAnti-adherent 10 % w/v

3. Castor oil Plasticizer 15 % w/v

4. Titanium dioxide Opecifier 5 % w/v

5. Methylene chloride Solvent65 % of total

solvent

6. Isopropyl alcohol Solvent35 % of total

solvent

Coating parameters

31

Coating solution was prepared to have 5 % reconstitution level for ease of spray through the nozzle.Sr.

No.Parameter Quantity

1. Weight of tablets 100 gms

2. Coating level 20 %

3. Coating material 20 gm

4. Loss during process 2 %

5. Reconstitution level 5 %

6.Isopropyl alcohol (35 %)

(solvent)133 gm

7.Methylene chloride (65 %)

(solvent)247 gm

Total solvent 380 gm

Coating process conditions

32

Sr. No. Parameter Conditions

1. Inlet air temperature 400C

2. Product bed temperature 300C - 350C

3. Outlet temperature 360C - 380C

4. Pump RPM 1

5. Pan RPM 35

6. Spray rate 2.1 gm/min/gun

7. Process time 3 hrs.

Coating formula for trial batches

33

STAGE

FORMULA (mg)

TD TSI CORE TABLET PREPARATION

` Montelukast Sodium (equivalent to 10 mg of Montelukast) 10.38 10.38

2 Microcrystalline Cellulose (PH 102) 102.47 102.07

3 Sodium Starch Glycolate - 10.4

4 Doshion P 544C 10 -

5 Hydrophobic Colloidal Anhydrous Silica 0.65 0.65

6 Magnesium Stearate 6.5 6.5

Total weight 130 130II COATING OF ETHYL CELLULOSE

1 Ethyl cellulose 20 cps 9.1 13.65

2 Talc 1.3 1.95

3 Castor oil 1.95 2.9254 Titanium dioxide 0.65 0.975

Total weight 140.00 149.50

Weight gain on core tablets 10 % 15%

Evaluation of coated TD and TS batches

34

Sr. No.

Parameter

Result

LimitTD TS

1 Hardness (mm) 6 - 8 9 - 10 -

2 Thickness (mm) 3.96 4.12 -

3 Diameter (mm) 7.32 7.48 -

4 Weight variation (%) ±1.0 ±1.0 < 10


99.38 -

101.20

99.46 -

100.83 90 - 110

6 Uniformity of content (%) 99 - 101 99 - 101 85 - 115

7 Dissolution Study (%) 100.02 98.21 NLT 70 %

35

According to release profile it was concluded that amount of resin required was not economic so it was planned to exclude Doshion P 544C and to use economic superdisintegrant, SSG and the changes had been made in to the formula of TS batch to get the required pulsatile profile.

Dissolution study

Drug release profile of coated Montelukast sodium tablets of TD and TS batches

Formulation of Montelukast sodium core tablets of SA, SB and SC batches

36

Sr.

No.Ingredient

Weight (mg) /

tablet

Formulation code

SA SB SC

1.Montelukast Sodium (equivalent to10 mg of Montelukast) 10.38 10.38 10.38

2. Microcrystalline Cellulose (PH 102) 109.87107.2

7

104.6

7

3. Sodium Starch Glycolate 2.6 5.2 7.8

4.Hydrophobic Colloidal Anhydrous

Silica0.65 0.65 0.65

5. Magnesium Stearate 6.5 6.5 6.5

Final Weight 130 130 130

Evaluation of Montelukast sodium core tablets of SA, SB and SC batches

37

Sr. No. Parameter

Result

LimitSA SB SC

1 Hardness (mm) 3.5 - 4.5 3.5 - 4.5 3.5 - 4.5 -

2 Thickness (mm) 3.65 3.69 3.7 -

3 Diameter (mm) 7.05 7.05 7.05 -

4 Friability (%) 0.217 0.253 0.221 < 1

5 Disintegration Time (min.) 3 - 4 5 - 6 6 - 8 < 15

min.

6 Weight variation (%) ±1.5 ±1.4 ±1.5 < 10


100.05 -101.00

100.19 -100.94

99.87 - 100.58 90 - 110

8 Uniformity of content (%) 99 - 101 99 - 101 99 - 101 85 -

115

9 Dissolution Study (%) 99.46 99.59 99.76 NLT 70%

Dissolution study

38

The tablets of batches SA, SB and SC shows 99-100% drug dissolved in 30 min so it passes the dissolution test, as it is specified by FDA that NLT 70 % drug should be dissolves in 30 minutes in 0.5 % SLS.

Release profile of Montelukast sodium core tablets of SA, SB and SC batches

Coating of Montelukast Sodium tablets of SA, SB and SC batches Batch SA

39

STAGE FORMULA (Mg) BATCHE CODE

I CORE TABLET PREPARATION SA1 SA2 SA3 SA4

1Montelukast Sodium (equivalent to 10 mg of Montelukast)

10.38 10.38 10.38 10.38

2 Microcrystalline Cellulose (PH 102)109.8

7109.8

7109.8

7109.8

7

3 Sodium Starch Glycolate 2.6 2.6 2.6 2.6

4 Hydrophobic Colloidal Anhydrous Silica 0.65 0.65 0.65 0.65

5 Magnesium Stearate 6.5 6.5 6.5 6.5

Total weight 130 130 130 130

II COATING OF ETHYL CELLULOSE

1 Ethyl cellulose 20 cps 4.55 6.37 9.1 10.92

2 Talc 0.65 0.91 1.3 1.56

3 Castor oil 0.975 1.365 1.95 2.34

4 Titanium dioxide 0.325 0.455 0.65 0.78

Total weight136.50

139.10

143.00

145.60

Weight gain on core tablets (% w/w) 5 7 10 12

Batch SB

40

STAGE FORMULA (Mg) BATCH CODE

I CORE TABLET PREPARATION SB1 SB2 SB3 SB4


10.38 10.38 10.38 10.38

2 Microcrystalline Cellulose (pH 102)107.2

7107.2

7107.2

7107.2

7




Total weight 130 130 130 130



2 Talc 0.65 0.91 1.3 1.56

3 Castor oil 0.975 1.365 1.95 2.34


Total weight136.50

139.10

143.00

145.60


Batch SC

41

STAGE FORMULA (Mg) BATCH CODE

I CORE TABLET PREPARATION SC1 SC2 SC3 SC4


10.38 10.38 10.38 10.38

2 Microcrystalline Cellulose (PH 102)104.6

7104.6

7104.6

7104.6

7




Total weight 130 130 130 130



2 Talc 0.65 0.91 1.3 1.56

3 Castor oil 0.975 1.365 1.95 2.34


Total weight136.50

139.10

143.00

145.60


Evaluation of batches SA1 to SC4

42

Sr. No.

Formulation code

ParameterHardnes

s (kg/cm2)

Thickness (mm)

Diameter

(mm)

Weight variation

(%)1. SA1 5.2 3.85 7.20 ± 1

2. SA2 6.1 3.90 7.24 ± 1

3. SA3 6.3 3.95 7.33 ± 1

4. SA4 7.5 4.03 7.39 ± 1

5. SB1 5.1 3.85 7.21 ± 1

6. SB2 6.2 3.92 7.25 ± 1

7. SB3 6.3 3.96 7.31 ± 1

8. SB4 7.6 4.05 4.39 ± 1

9. SC1 5.2 3.84 7.20 ± 1

10. SC2 6.2 3.91 7.23 ± 1

11. SC3 6.4 3.96 7.32 ± 1

12. SC4 7.6 4.05 7.39 ± 1

43

Sr. No. Formulation code

Content of active ingredient (%)

1. SA1 99.83 - 100.86

2. SA2 99.89 - 100.53

3. SA3 99.93 - 100.32

4. SA4 99.23 - 100.10

5. SB1 99.53 - 99.98

6. SB2 99.91 - 100.98

7. SB3 99.84 - 100.64

8. SB4 99.96 - 100.82

9. SC1 99.79 - 100.90

10. SC2 99.76 - 100.11

11. SC3 99.78 - 100.20

12. SC4 99.79 - 100.78

Dissolution study: Batch SA

44

Montelukast release from tablet containing 2% (w/w) Sodium starch glycolate and coated with 5% (w/w) coating level shows the lag time of 1.5 hours then follow the sigmoidal release pattern with 100% drug release at 4.5 hours. As the concentration of coating level increases from 7 to 12 % (w/w) the lag time extended to 4 hours and then follows the delayed release profile with the 100 % drug release at the 5.5 to 6 hours.

Drug release profile of coated Montelukast sodium tablets of SA1 to SA4 batches

Batch SB

45

Montelukast release from tablet containing 4 % (w/w) Sodium starch glycolate and coated with 5% (w/w) coating level shows the lag time of 1.5 hours then follow the sigmoidal release pattern with 100% drug release at 3.5 hours. As the concentration of coating level increases from 7 to 12 % (w/w) the lag time extended to 4.25 hours and then follows the delayed release profile with the 100 % drug release at the 4 to 6 hours.

Release profile of coated Montelukast sodium tablets of batches SB1 to SB4

Batch SC

46

Montelukast release from tablet containing 6 % (w/w) Sodium starch glycolate and coated with 5% (w/w) coating level shows the lag time of 1.5 hours then follow the sigmoidal release pattern with 100% drug release at 4th hours. As the concentration of coating level increases from 7 to 12 % (w/w) the lag time extended to 4 hours and then follows the delayed release profile with the 100 % drug release at the 3.5 to 6 hours.

Release profile of coated Montelukast sodium tablets of batches SC1 to SC4

Stability study of selected batch

47

INTERMEDIATE STABILITY:Storage conditions: 30 ± 2o C and RH 65 % ± 5%

Product: Pulsatile drug system of Montelukast sodium tablets

Batch no. – SC2

Pack Size - 10 tablets packed in alu-alu pouch

Batch size - 400 tabs

Kept for stability on - April 2010

Label claim - Each coated tablet contains:

Montelukast sodium equivalent to Montelukast..........10 mg

Colour - Titanium dioxide

48

Sr. No.

Parameter

Specification Initial 1 M 2M 3M

1. Description

Pale yellow, circular, biconvex

Pale yellow, circular, biconve

x


x


x


x

2. Assay 90 - 110 % 99.76 - 100.11

99.74 - 99.99

98.52 - 100.07

98.62 - 99.91

3. Dissolution NLT 70% 99.72 99.70 99.71 99.68

49

Montelukast release from batch C tablets after 1st and 2nd months does not shows significant change in lag time and cumulative % drug release but after 3rd month it shows drastic change in lag time from initial value 2 hrs to 1.5 hrs and shows 100 % drug release at 4th hr showing instability of coat after 3 months.

Drug release profile of coated Montelukast sodium tablets of SC2 batch after 1, 2 and 3 monthswhich were kept for Intermediate Stability study

50

ACCELARATED STABILITY Storage conditions: 30 ± 2o C and RH 65 % ± 5% Product: Pulsatile drug system of Montelukast sodium tabletsBatch no. – SC2Pack Size - 10 tablets packed in alu-alu pouchBatch size - 400 tabsKept for stability on - April 2010Label claim - Each coated tablet contains:Montelukast sodium equivalent to Montelukast..........10 mgColour - Titanium dioxide

51

Sr.

No.

Paramet

er

Specificat

ion

Initial 1 M 2M 3M

1 Descriptio

n

Pale

yellow,

circular,

biconvex

Pale

yellow,

circular,

biconve

x

Pale

yellow,

circular,

biconve

x

Pale

yellow,

circular,

biconve

x

Pale

yellow,

circular,

biconve

x

2 Assay 90 - 110 % 99.76 -

100.11

99.63 -

99.97

98.32 -

99.51

98.11 -

99.28

3 Dissolutio

n

NLT 70%99.72 99.73 99.68 99.64

52

Montelukast release from batch C tablets after 1st month does not shows significant change in lag time and but shows 100 % drug release after 4th hr but after 2nd and 3rd month it shows drastic change in lag time from initial value 2 hrs to 1.5 hrs and shows 100 % drug release after 4th hr showing instability of coat after 2 months.

Drug release profile of coated Montelukast sodium tablets of SC2 batch, after 1, 2 and 3 months which were kept for Accelerated Stability study

SUMMARY AND CONCLUSION

53

The main objective of the study was to develop rupturable pulsatile drug delivery system to treat asthma. Lung function (e.g., peak expiratory flow rate or FEV1) is usually highest at 4 pm and lowest at 4 am the latter time is generally when asthma symptoms are most prevalent. So, the intension was that the formulation should be administered in the evening at 10.00 pm which will rupture after 2 hours and will reach to its C max at around 3.00 pm to around 3.30 pm and will be available at the site of action for at least 4 to 5 hours.

54

For batch TD, The release profile of batch TD containing 10 mg Doshion P 544 C and coated with 10 % Ethyl cellulose shows lag time of 3.5 hours and 100% drug release at 4.25 hour. According to release profile it was concluded that amount of resin required was not economic so it was planned to exclude Doshion P 544 C and to use economic superdisintegrant.

For batch TS, Montelukast sodium release from batch TS containing 8 % Sodium starch glycolate and coated with 15 % coating level showed lag time of 4 hours and 56 % drug release at 4.5 hour. According to the release profile of control batch, the changes were done in the formula to required pulsatile release profile.

55

Montelukast sodium release from batches A1 to A4 containing 2% (w/w) Sodium starch glycolate and coated with 5% (w/w) coating level shows the lag time of 1.5 hours and 100% drug release at 4.5 hours. As the concentration of coating level increases from 7 to 12 % (w/w) the lag time extended to 4 hours and then follows the delayed release profile with the 100 % drug release at the 5.5 to 6 hours.

Montelukast sodium release from batches B1 to B4 containing 4% (w/w) Sodium starch glycolate and coated with 5% (w/w) coating level shows the lag time of 1.5 hours and 100% drug release at 3.5 hours. As the concentration of coating level increases from 7 to 12% (w/w) the lag time extended to 4.25 hours and then follows the delayed release profile with the 100% drug release at the 4 to 6 hours.

56

Montelukast sodium release from batches C1 to C4 containing 6% (w/w) Sodium starch glycolate and coated with 5% (w/w) coating level shows the lag time of 1.5 hours and 100% drug release at 4th hours. As the concentration of coating level increases from 7 to 12 % (w/w) the lag time extended to 4 hours and then follows the delayed release profile with the 100 % drug release at the 3.5 to 6 hours.

Therefore the present study indicates that, to get pulsatile drug release profile, Montelukast sodium core tablets with average weight of 130 mg containing 6 % of sodium starch glycolate with minimum coating level of 7 % Ethyl cellulose with addition of 15 % castor oil and 10 % talc, showing lag time of 2 hours and 100% drug release, was achieved.

INDUSTRIAL APPLICABILITY

57

Not a single pulsatile release tablet of Montelukast Sodium is available in the domestic, regulated and non regulated market.

Patent expiration date is Aug. 13, 2013.After expiration of the drug exclusivity and

patents of innovator or before that the pulsatile formation can be commercialized in the choice of market.

ACKNOWLEDGEMENT

58

I would like to acknowledge here Proff. V. P. Choudhari, my Research

guide Dr. Prof. B. S. Kuchekar for giving me a

chance to be a part of this prestigious institute.

Dr. Miss. Swati Jagdale for helping me during the project work

Elder Pharmaceuticals Ltd for giving me a valuable training and

last but not the least, my Friends.....

REFERENCES

59

B.U Janugade, S. S. Patil, S.V. Patil, P. D. Lade, Pulsatile drug delivery system for chronopharmacological disorders: an overview, Journal of Pharmacy Research Vol.2, Issue 1, January 2009, Pages: 132 – 143.

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