PULSATILE DRUG DELIVERY

PULSATILE DRUG DELIVERY

A K Dhadwe1*, C P Rathod, S M Vadvalkar, G R Shendarkar, P H Bhosale and Patil K G.

Department of Pharmaceutics and Pharmaceutical Technology Nanded Pharmacy College,

Shyam Nagar Nanded, Maharashtra, India.

ABSTRACT

The release of the drug as a pulse after a lag time has to be designed in

such a way that a complete and rapid drug release follows the lag time.

Various systems like capsular systems, osmotic systems, single and

multiple-unit systems based on the use of soluble or erodible polymer

coating and use of rupturable membranes have been dealt with in the

article. It summarizes the latest technological developments,

formulation parameters, and release profiles of these systems.In the

present work Eudragit S 100 alone is used for coating. Batches were

coated in different percent weight gain from 1-7 percent. These coated

tablets showed increase in the lag time with increase in the coating

level. The lag time increases from 2 to 8 hrs for the coating of 1-7 %

respectively. This study was utilized to optimize the formulation. The

present work concludes that there is a constant need for new delivery

systems that can provide increased therapeutic benefits to the patients. Pulsatile drug delivery

is one such system that, by delivering drug at the right time, right place, and in right amounts,

holds good promises of benefit to the patients suffering from chronic problems like arthritis,

asthma, hypertension, etc.

KEYWORDS: Modified release oral tablet; Single pulsatile drug; Sustain action; Challenges; Approaches; Market status.

INTRODUCTION

Modified release dosage forms represent the most popular form of controlled drug delivery

systems due to the obvious advantages of oral route of drug administration. Modified release

product can be defined as a system where his principle rationale for the use of pulsatile

Volume 4, Issue 5, 2599-2613. Research Article ISSN 2277– 7105

Article Received on 19 March 2015,

Revised on 08 April 2015, Accepted on 29 April 2015

*Correspondence for Author

A K Dhadwe

Department of

pharmaceutics and

pharmaceutical

technology Nanded

Pharmacy College, Shyam

Nagar, Nanded,

release is for the drugs where a constant drug release, i.e., a zero-order release is not desired.

“The drug release characteristic of time. Course and/or location are chosen to accomplish therapeutic or convenience objective not offered by conventional dosage forms” Terbutaline

Sulphate should be delivered when it is needed in minimum required dose. For Terbutaline

Sulphate to follow the circadian rhythm in asthma the reasonable and acceptable delivery

system capable of releasing the drug in a pulsatile fashion is needed. Therapy with modified

release dosage form with zero order release theoretically leads to controlled and constant

levels of drug in plasma throughout the day.

Advantages of pulsatile drug delivery

1. Extended day time or nighttime activity.

2. Reduced side effects.

3. Reduced dosage frequency.

4. Reduction in dose size.

5. Improved patient compliance.

6. Lower daily cost to patient due to fever dosage units are required by the patient in

therapy.

7. Drug adducts to suit circadian rhythm of body function or disease.

8. Drug targeting to specific sites like colon.

9. Protection of mucosa from irritating drugs.

1. Commercial products

Table no.I Commercial products of Pulsatile DDS

Technology Mechanism Proprietary name and

dosage form API Disease

OROS® Osmotic mechanism Covera-HS®; XL tablet Verapamil HCl Hypertension

CODAS® Multi particular pH dependent system

Verelan® PM; XL

release capsule Verapamil HCl Hypertension

DIFFUCAPS® Multi particulate system Innopran®; XL tablet Verapamil HCl,

Propranolol HCl Hypertension

Table no.II Name of Material & supplied company

Sr.no. Chemical Ingredient Supplier

1 Drug [ Terbutaline Sulphate ] Shimoga Chemicals Pvt. India. 2 Microcrystalline cellulose Ideal Cures Ltd., Mumbai.

3 Sodium starch glycolate Signet Chemicals Pvt Ltd, Mumbai.

4 Eudragit S 100 Evonik Pvt.Ltd.Mumbai.

5 Magnesium stearate Loba Chemicals, Mumbai

7 Potassium dihydrogen phosphate S. D. Fine chemicals, Mumbai

8 Acetone S. D. Fine chemicals, Mumbai

2. Formulation of core tablet

Table .no. III Formulation of core tablet (Formula) Formulation

Code

Ingredient in %

TBS MCC SSG Lactose Mg Stearate Talc

F1 10 60 1 26 2 1

F2 10 60 2 25 2 1

F3 10 60 3 24 2 1

F4 10 60 4 23 2 1

F5 10 60 5 22 2 1

F6 10 60 6 21 2 1

F7 10 60 7 20 2 1

F8 10 60 8 19 2 1

F9 10 60 9 18 2 1

F10 10 60 10 17 2 1

F11 10 60 11 16 2 1

F12 10 60 12 15 2 1

F13 10 60 13 14 2 1

F14 10 60 14 13 2 1

F15 10 60 15 12 2 1

The core tablets were prepared with selected excipients by direct compression on single

punch tablet compression machine. Accurately weighed quantities of drug and other

ingredients like sodium starch glycolate, lactose, and magnesium stearate were mixed by

triturating in glass mortal-pestle. The blend was directly compressed at weight of 150 mg

using 7 mm diameter punch. The compositions of the formulation batches containing

different ratios of polymers chosen on trial and error basis. (Swarbrick, J. 2005).

3. Physical Evaluation of Powder Blend used for Preparation coare Tablet

Table no. IV Physical evaluation of powder blend used for preparation of core tablet Formulation Angle of

Repose

Bulk Density (g/cm2)

Tap Density g/cm2)

%

Compressibility

F 1 26.110.04 0.420.06 0.470.03 7.540.03 F 2 26.880.03 0.480.06 0.510.05 6.120.04 F 3 28.450.03 0.470.04 0.480.03 8.920.03 F 4 28.670.02 0.510.05 0.580.06 7.940.05 F 5 27.020.03 0.430.06 0.570.06 9.090.03 F 6 27.780.03 0.520.04 0.540.05 11.110.05 F 7 28.290.04 0.510.04 0.440.03 10.630.07 F 8 30.890.05 0.480.05 0.580.06 7.540.03 F 9 29.230.04 0.380.05 0.640.05 8.770.03

F 11 28.770.02 0.510.05 0.580.06 7.950.05 F 12 28.320.04 0.490.04 0.440.03 10.430.07 F 13 26.020.04 0.410.06 0.470.03 7.340.03 F 14 29.230.04 0.380.05 0.640.05 8.770.03

F 15 28.900.03 0.40.04 0.70.06 8.020.03

n=3

Table no. V Evaluation of core tablets

Formu-lation

Hardness Weight

Uniformity Friability Thickness Uniformity of content

Disintegration time (sec.)

(kg/cm2) (mg) ± SD (%)

F1 4.8 148±1.12 0.621 1.5±0.3 100±1.02 63

F2 4.9 152±1.123 0.554 1.6±0.3 101±1.12 60

F3 4.8 156±1.09 0.741 1.40±0.4 101±1.04 57

F4 4.5 151±0.05 0.358 1.55±0.5 98±0.98 55

F5 4 .6 145±0.97 0.558 1.54±0.5 99±0.94 53

F6 4 .3 158±1.34 0.658 1.5±0.3 102±1.26 51

F7 4 .7 160±1.56 0.554 1.6±0.3 100±1.01 47

F8 4 .4 155±0.06 0.741 1.40±0.4 101±1.02 42

F9 4 .3 148±1.12 0.358 1.55±0.5 97±1.12 40

F10 3.9 152±1.123 0.558 1.5±0.3 98±0.99 36

F11 4.5 156±1.09 0.721 1.5±0.3 100±1.04 33

F12 4.3 151±0.05 0.348 1.6±0.3 99±0.98 31

F13 4.4 161±0.05 0.598 1.40±0.4 98±0.94 24

F14 4.6 156±1.09 0.657 1.55±0.5 100±1.26 20

F15 4.2 151±0.05 0.553 1.6±0.3 99±1.01 15

n=3

4. Dissolution study

Table no.VI Dissolution profile of core tablet formulation

Batch code % Cumulative Release/ Min.

0 1 2 3 4 5

F1 0 20±0.98 47±0.65 78±0.98 89±0.99 99±0.99

F2 0 27±0.59 59±0.95 86±1.01 91±1.05 98±0.82

F3 0 29±0.85 41±0.68 73±1.02 84±1.05 99±0.88

F4 0 35±0.86 67±0.87 79±1.9 97±0.97 -

F5 0 21±0.68 59±0.69 80±0.99 98±0.86 -

F6 0 33±0.67 52±0.95 79±0.96 98±0.98 -

F7 0 37±0.95 66±0.87 83±0.89 99±1.04 -

F8 0 35±0.96 74±0.57 89±0.95 98±1.09 -

F9 0 45±0.92 78±0.65 99±1.08 - -

F10 0 38±0.94 69±0.54 93±1.02 - -

F11 0 42±1.09 77±0.89 99±1.0 - -

F12 0 47±0.83 81±0.97 98±1.05 - -

F13 0 68±0.87 99±0.92 - - -

F14 0 79±0.97 97±0.98 - - -

Fig.no.I Dissolution profile for core tablet 5. FORMULATION OF COATING SOLUTION

Table no.VII Formulation of coating solution.(Formula)

Coating Material CT 1 CT 2 CT 3 CT 4 CT 5 CT6 CT7

Eudragit S100 (%) 1 2 3 4 5 6 7

Avg.% Wt Gain 1 2 3 4 5 6 7

Di-butyl phthalate

(%) 2 2 2 2 2 2 2

Solvent (ml) 100 100 100 100 100 100 100

The core tablets were coated with a polymethacrylate co-polymer with pH dependent

solubility.

A. COATING OF TERBUTALINE SULPHATE CORE TABLET

Coating was carried with help of spray gun .The parameter are shown in following tablet.

Table no.VIII Parameter for Coater (perforated pan)

Parameter Formulations-

CT1 CT2

Inlet temp (o C) 55 55

Outlet temp (o C) 40 40

Nozle diameter (mm.) 1 1

Automization pressure (bar) 1 2

Spray rate (g/min.) 20 17

Pan Speed/min. 25 25

6. RESULT DISCUSSION

A. FTIR studies: The FT-IR spectra of pure drug was taken by preparing KBr pellets. (Disk method) Scanning Range: 4000 – 500 cm -1

Table No.IX: Interpretation IR

Fig. no.II FT-IR Spectrum of Terbutaline Sulphate.

C. Drug-polymer compatibility study: The FT-IR spectra of pure drug was taken by preparing KBr pellets. (Disk method) Scanning Range: 4000 – 500 cm –

1.SSG,MCC

Fig.no. III FT-IR Spectrum of SSG & MCC. Interpretation of FTIR data

Wave number (cm-1) Assignments

1716 C=N Stretching

1670 C=O Stretching

1568 NH Bending

2. TBS, SSG, MCC

Fig.no IV. FT-IR Spectrum of TBS,SSG & MCC. 3. Core Tablet

Fig no. V FT-IR Spectrum of Core Tablet. 4. Eudragit S 100

B. Determination of λmax

Determination of λmax in pH 1.2 , 7.4 and 8.1

The solution of Terbutaline sulphate in above medium was scanned from 200 to 400 nm in

order to determine the λmax for its estimation in the respective media. The UV spectrum

obtained is shown in Figure. The wavelength of maximum absorbance (λ max) was found to be

275 nm in simulated gastric fluid and 276 nm in pH 7.4 and 8.1

Fig.No.VII Scanning of Terbutaline Fig. No.VIII Scanning of Terbutaline Sulphate in gastric fluid (pH 1.2) sulphate in intestinal fluid (pH 7.4 & 8.1) C. Calibration curve

Calibration curve of Terbutaline in pH 1.2

Absorbance data for calibration curve of Terbutaline Sulphate in simulated gastric fluid PH

1.2

Table no. X Calibration curve Value

Figure No. IX Calibration curve of TBS in simulated gastric fluid Calibration curve of TBS

in pH 7.4 (intestinal fluid) Sr. Concentration

(µg/ml) Absorbance

1 0 0

2 2 0.1023

3 4 0.2046

4 6 0.3036

5 8 0.3996

6 10 0.5055

7 12 0.6035

8 14 0.6991

275nm 276

Table no.XI Absorbance data for calibration curve of Terbutaline sulphate in intestinal fluid:

Fig.X Calibration curve of Terbutaline

Sulphate in intestinal fluid pH 7.4

Table no.XII Absorbance data for calibration curve of Terbutaline sulphate in pH 8.1

Fig.XI Calibration curve of Terbutaline Sulphate in in pH 8.1

Table no.XIV Evaluation of coated tablet Coated

Formulation Hardness

Weight

variation Disintegration

time (in hr.) Thickness Friability

Uniformity of content (mg) ± SD

CT 1 4 .3 152±1.12 1 2.8±0.02 0.554 98±0.98

CT 2 4 .7 153±1.123 2 2.9±0.02 0.741 99±0.94

CT 3 4 .4 155±1.09 3 3.0±0.04 0.358 102±1.26

CT 4 4 .3 157±0.05 4 2.9±0.03 0.558 100±1.01

CT 5 3.9 159±0.97 5 3.0±0.03 0.658 101±1.02

CT6 4 159±0.98 6 3.1±0.05 0.554 987±1.12

CT 7 4 .2 162±.58 7 3.0±0.03 0.554 98±0.98

S.N. Concentration

(µg/ml) Absorbance

1 0 0

2 2 0.13

3 4 0.225

4 6 0.363

5 8 0.481

6 10 0.611

7 12 0.711

8 14 0.865

Sr.No. Concentration

(µg/ml) Absorbance

1 0 0

2 2 0.14

3 4 0.285

4 6 0.419

5 8 0.55

6 10 0.698

7 12 0.838

Table no. XV: Dissolution study of coated tablet formulation Time in

Hrs. _{CT 1 CT2 CT3} % Cumulative Release _{CT4 CT5 CT 6 CT7}

0 0 0 0 0 0 0 0

1 16.85±0.98 0 0 0 0 0 0

2 97.37±0.97 21.24±0.95 0 0 0 0 0

3 96.85±0.87 96.67±.85 14.71±0.86 0 0 0 0

4 95.92±0.91 97.87±0.65 19.29±0.88 0 0 0

5 97.08±0.78 96.75±0.87 0 0 0

6 95.96±0.98 0 0 0

7 9.24±0.45 11.45±0.5 16.47±0.5

8 90.78±0.56 93.34±0.56 98.74±0.99

Fig.no. XII Dissolution profile of Coated tablet. D. Scanning electron microscopy

The coating of optimised batch were examined by scanning electron microscopy as shown in

figures Fig No, a illustrating the microphotographs of formulation CT 7 at lower and higher

magnification. The coated surface was spherical with no visible major surface irregularity.

Few wrinkles and inward dents were appeared on the surface of tablet . It may due to collapse

Fig. No.XIII: SEM of CT 7 Fig. No.XIV: SEM of CT 7

formulation at (50 X) magnification formulation at (200 X) magnification 7. Stability study

Accelerated stability studies (AST) was carried for optimized formulation CT5 by exposing

to 40°C/75% RH for one month and analyzed the sample at the interval of 7,14,21,28 days.

The sample was analyzed.

Table No.XVI: AST of CT 7 formulation.

Table Sr.N0. Days % Drug remaining

% Drug remaining2

% Drug remaining3 5-8C 272 C 402 C

1 0 100  0.010 100  0.14 100  0.17

2 15 99.97 0.13 99.86  0.21 99.63  0.20

3 30 99.80  0.05 99.81 0.16 99.46 0.16

4 45 99.74  0.12 99.79  0.11 99.29  0.09 5 60 99.68  0.15 99.75  0.12 99.13  0.18

6 75 99.85±0.02 99.78±0.12 99.45±0.04

7 90 99.45±.23 99.58±0.13 99.65±0.15

CONCLUSION

Literature review of pulsatile drug delivery reveals that the dosage form releases the drug

immediately after a period of time lag. And this can be achieved by developing various

systems like capsular systems, osmotic systems, pH sensitive drug delivery system, single-

and multiple-unit systems based on the use of soluble or erodible polymer coating and use of

reputable membranes, systems with reputable coating layer, systems with erodible coating

layers. In such systems the drug release is controlled by the dissolution or erosion of the

outer coat which is applied on the core containing drug. It is useful tool for delivering

The preclinical studies have shown that pulsatile approach of delivering antibiotic is

more effective.

ACKNOWLEDGMENT

This dissertation would not have been possible without the guidance and the help of several

individuals. Would like to thanks for excellent guidance of Dr. S. M.Vadvalkar, Principal of

Nanded Pharmacy College, Nanded. Whose encouragement I will never forget.

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