Design of gastroretentive bilayer floating films of

propranolol hydrochloride and rosuvastatin calcium.Presented by,

Mr. Namdeo G. ShindeB. Pharm.

Under the guidance of,

Dr. N. H. AloorkarM. Pharm. Ph. D

Satara College of Pharmacy, Degaon-Satara.

2013-2014.

CONTENTS

Introduction

Need of present investigation

Literature survey

Material and methods

Results and discussion

Conclusion

Future perspectives

References

INTRODUCTION

The goal of any drug delivery system is to provide a therapeutic

amount of drug to proper site in the body to achieve and maintain

therapeutic concentration within range and to show pharmacological

action with minimum incidence of adverse effects.

To achieve this goal one should maintain dosing frequency and suitable

route of administration.

-Oral, parenteral, topical, nasal, rectal, vaginal, ocular etc.

Out of these routes, oral route of drug delivery is considered as the

most favored route of drug delivery, because of ease of

administration, more flexibility in designing, ease of production

and low cost.

-Physiological difficulties:

Inability to restrain and locate the controlled drug delivery system

within the desired region of the GIT due to variable gastric emptying

and motility.

Phases of migrating myoelectric cycle (MMC)

Phase I Phase lasts for 40-60 min. with rare contractions.

Phase II (Pre-burst phase)

Phase lasts for 40-60 min. Intensity and frequency increases gradually.

Phase III (burst phase)

Phase lasts for 4-6 min. It includes intense and regular contractions for short period. It is also known as the housekeeper wave.

Phase IV Phase lasts for 0-5 min and occurs between phases III and I of two consecutive cycles

The real challenge in development of oral controlled release drug delivery system is to sustain the release as well as prolong the presence of dosage form in stomach or upper small intestine until drug is completely released in desired period of time from suitable formulation.

Gastroretentive system can remain in the gastric region for several hours and hence significantly prolongs gastric residence time of drug which improves bioavailability.

To provide good floating behavior in the stomach the density of system should be less than density of gastric contents (~ 1.004 g/cm3).

Advantages of GRDDS

Improved drug absorption

Controlled delivery of drugs

Treatment of gastrointestinal disorders

Site-specific drug delivery

Ease of administration and better patient compliance

Simple and conventional equipments are required for manufacturing

Limitations of GRDDS It is not a suitable system for drugs with stability or solubility

problem in stomach.

FDDS require sufficiently high level of fluid in the stomach.

Drugs having irritant effect on gastric mucosa are not suitable.

Retention of high-density systems in the antrum part under the

migrating waves of the stomach is questionable.

STRATEGIES FOR GASTRORETENTION

Low density systems (<1.004 g/cm3)

High density systems (3 g/cm3)

Mucoadhesive systems

Superporous hydrogels

Expandable/swelling systems (12-18mm)

Magnetic systems

Superporous hydrogels

Swelling system Gastroretentive floating film

Gas generating system

Floating film delivery system

Emerged as an advanced alternative to traditional dosage forms

Floating film is drug loaded polymeric film consisting of an active

pharmaceutical ingredient, polymers, film forming agent, plasticizer

and suitable solvent.

Advantages-

Preparation of film is simple

Time saving

Chances of cross contamination are very less

Handling of film is easy

Preparation:

Solvent evaporation method

Drug release profile can be modified by using different polymers.

Layer-by-layer film formulation technique in which one layer is

of controlled release polymer and another layer is of sustained release

polymer can be prepared.

1• Polymeric dispersion of drug and

polymer

2• Poured in petriplate and dried

3• Thin layered film

Film forming polymers in floating films:

Provide quick disintegration and mechanical strength to the films.

Examples- pullulan, gelatin, guar gum, xanthan gum, hydroxyl propyl

methylcellulose, modified starches.

Ideal properties of the polymers used in the film drug delivery:

Non-toxic, non- irritant

Low density and readily available

Sufficient shear and tensile strength and shelf life.

Plasticizers used in floating films:

It helps to improve the flexibility of the film and reduces the

brittleness of the film.

Plasticizer significantly improves the film properties by reducing the

glass transition temperature of the polymer.

Examples-

Glycerol, propylene glycol, low molecular weight polyethylene

glycols, citrate derivatives like triacetin, acetyl citrate, phthalate

derivatives like dimethyl, diethyl, dibutyl derivatives, etc.

NEED OF PRESENT INVESTIGATION

Cardiovascular diseases (CVDs) are the number one cause of death.

According to the WHO Report 2012, CVDs will be the largest cause of

death and disability in India by 2020.

Hypertension and hyperlipidemia are the major disorders of the

cardiovascular system.

A strong need was recognized for the design of a single dosage form

which will give therapeutic effects on two or more diseases like

hypertension and hyperlipidemia simultaneously.

Hence to deliver propranolol HCl and rosuvastatin calcium

in the stomach, bilayer floating film was prepared.

Objectives

To formulate gastroretentive bilayer floating films of propranolol

HCl and rosuvastatin calcium.

To investigate the effect of polymer and plasticizer on the film.

UV-Spectroscopic simultaneous estimation of propranolol HCl and

rosuvastatin calcium in pure drug and in bilayer film.

To evaluate gastroretentive bilayer floating films of propranolol

HCl and rosuvastatin calcium.

Kumar MP et al (2010) have studied the gastroretentive delivery of

mucoadhesive films containing pioglitazone using ethyl cellulose as a

rate controlling polymer, HPMC and carbopol-934 were used as

mucoadhesive polymers.

They found that the polymer concentration was a major factor

affecting the drug release and mucoadhesive strength of film.

Literature review

Patel N et al (2011) have carried out formulation and evaluation of

floating tablets of metoprolol tartrate. They prepared tablets by using

MCC, HPMC K100M and HPMC K4M as polymers and sodium

bicarbonate as a gas-generating agent.

From this, they concluded that the floating tablets of metoprolol

tartrate could retard the release of drug upto a period of 8 hours.

Literature review

Literature review

Bhosale UV et al (2012) have studied the effect of concentration and

viscosity grade of polymer on drug release. They used hydroxypropyl

methylcellulose of different viscosity grades (HPMC K4M, HPMC

E5LV, HPMC K100M) as polymer and sodium bicarbonate as a gas-

generating agent to reduce floating lag time.

They concluded that as the viscosity and concentration of the

polymer was increased, drug release was decreased.

Brahmaiah B et al (2013) have formulated and evaluated of

gastroretentive floating drug delivery system of metoprolol tartarate.

They prepared floating tablets using HPMC K4M and HPMC K100M

as the release retardant polymers.

From this, they concluded that the floating tablets could control the

fluctuations in the plasma drug concentration, increased the

gastric residence time and eventually improved the bioavailability

of the drug.

Literature review

DRUG PROFILE

Propranolol Hydrochloride

Propranolol hydrochloride is non-selective beta-adrenergic receptor

blocking agent. It is white crystalline solid readily soluble in water and

ethanol.

Brandname Manufacturer Brandname Manufacturer

Beptazine MM Labs Inderal ® LA Wyeth pharmaceuticals

Betaprp- DZ Concern pharma. Pr Inderal ® LA Pfizer

Ciplar H Cipla Ltd. Propranolol hcl oral solution Roxane labs.

Corbetazine Nicholas piramal Inderal ® Akrimax pharmaceuticals

Dizepax Unimark pharma Tensyn plus Synokem pharmaceuticals

Syziral Psyco remedies Innopran XL Reliant pharmaceuticals

PKa: 9.4

Melting point: 162-165°C

Molecular formula: C16H21NO2.HCl

Molecular weight: 295.80

Pharmacokinetics-

Propranolol is completely absorbed after oral administration.

Due to first pass metabolism bioavailability is less (25%).

Peak plasma concentration occur about 1 to 4 h after an oral dose.

About 90 % of circulating propranolol is bound to plasma proteins.

Propranolol is extensively metabolized in kidney.

OCH2CHOHCH2NHCH(CH3)2 . HCl

2-Propranol,1-[(1-methylethyl)amino]-3-(1-napthalenyloxy)-hydrochloride

Rosuvastatin Calcium

Rosuvastatin calcium is a synthetic lipid-lowering agent.

Rosuvastatin is an inhibitor of HMG-CoA reductase. This enzyme

catalyzes the conversion of HMG-CoA to mevalonate, an early and

rate-limiting step in cholesterol biosynthesis.

Brandnames

Dose (mg) Manufacturers

Brandname

Dose (mg) Manufacturers

Bestor 5,10 Biocon Ltd. Rozavel 5,10 Sun pharmaceuticals

Fortius 5,10,20 Nicholas piramal Rozucor 5,10 Torrent pharmaceuticals

Ldnil FC 10,20 Saremed Ltd. Rostar 5,10 Vencare formulations Ltd.

Novastat 5,20 Lupin Turbovas 5,10 Microlabs Ltd.

Razel 5,10,20 Glenmark Zyrova 5,10 Zydus Cadila healthcare

Suvalip 5,10 Orchid chemicals Rovalip 10 Cadila pharmaceuticals

Rosuvas 5,10,20 Ranbaxy Rosuvastat 10 Dr. Reddys Lab.

Treatment LDL reduction HDL increase

Atorvastatin (10-80 mg) 37-51 % 5.7-2 %

Simvastatin (10-80 mg) 28-46 % 5.3 -6.8 %

Rosuvastatin (5-40 mg) 46-55 % 7.6-9.6 %

Pravastatin (10-40 mg) 20-30 % 3.2-5.5 %

Effect of drugs on LDL and HDL levels

PKa: 4.6

Melting point: 151-156°C

Molecular formula: (C22H27FN3O6S)2.Ca

Molecular weight: 1001.14°C

N

NNSO2Me

O-

OHOH O

F

Ca2+

Bis[(E)-7-[4-(flurophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl]-(3R,5S)-3-5-dihydroxyhept-6-enoic acid] calcium salt

2

MATERIALS AND METHODS

Propranolol hydrochloride and rosuvastatin calcium were supplied by

Watson Pharma, Mumbai and Okasa Pharma, Satara respectively. HPMC

K4M, HPMC E5LV, Eudragit RS 100, dibutyl phthalate were procured

from Research-Lab Fine Chemicals, Mumbai. Sr. No.

Name of Equipments Manufacturer

1. Electronic balance AW 220, Shimadzu, Japan

2. UV Spectrophotometer Pharmaspec 1700, Shimadzu , Japan

3. Hot air oven Singhla Scientific, Ambala Cantt

4. Magnetic stirrer Remi Equipments, Mumbai

5.USP tablet dissolution

apparatusElectrolab, TDT- 08L, Mumbai, India

6.Fourier transform infrared spectrophotometer (FTIR) Alpha Bruker, Germany

7.Differential scanning

calorimeterMettler- Toledo, Switzerland

Methods:

Selection of Drug:

Propranolol hydrochloride-

It was decided to formulate it in gastroretentive dosage forms because

it has short half-life (1-4 h), has less oral bioavailability (25%).

Rosuvastatin calcium-

From literature survey it was found that rosuvastatin calcium causes

more decrease in cholesterol than any other statins. Its absolute

bioavailability is 20 %. The half-life is 19 h.

Selection of Polymers and Excipients:

HPMC K4M polymer is hydrophilic in nature and has good gelling

properties hence suitable for use in sustained release layer.

HPMC E5LV mainly cause rapid release of drug because of its low

viscosity hence suitable for incorporation in immediate release layer.

Eudragit RS-100, a polymethacrylate, was used as water insoluble

film former in sustained release layer and drug release retardant.

Dibutyl phthalate was used as a plasticizer. Water and ethyl alcohol

were used as solvents.

Sr. No. Ingredients Category

1. Rosuvastatin calcium API

2. Propranolol hydrochloride API

2. HPMC K4M, HPMC E5LV Hydrophilic polymers

3. Eudragit RL-100 Film former and drug release retardant

4. Dibutyl phthalate Plasticizer

5. Ethanol Solvent for Eudragit RS-100

6 Water Solvent for HPMC K4M and HPMC E5LV

FORMULATION INGREDIENTS

Preformulation Study:

Characterization of drug:

Solubility profile

Melting point of drug

λ max determination and calibration curve of propranolol

hydrochloride and rosuvastatin calcium

Compatibility study between drug and excipients:

DSC Study

IR spectroscopy

IngredientsFormulation codes

RP1 RP2 RP3 RP4 RP5 RP6 RP7 RP8 RP9

Immediate Release layer R1 R2 R3 R4 R5 R6 R7 R8 R9Rosuvastatin calcium 5 5 5 5 5 5 5 5 5

HPMC E5LV 15 15 15 20 20 20 25 25 25

Dibutyl phthalate 0.50 0.50 0.50 0.50 0.50 0.50 0.50 0.50 0.50

Ethanol: Water 3:4 3:4 3:4 3:4 3:4 3:4 3:4 3:4 3:4

Sustained Release layer P1 P2 P3 P4 P5 P6 P7 P8 P9

Propranolol hydrochloride 40 40 40 40 40 40 40 40 40

HPMC K4M 20 20 20 25 25 25 30 30 30

Eudragit RS 100 04 06 08 04 06 08 04 06 08

Dibutyl phthalate 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5

Ethanol: Water 3:7 3:7 3:7 3:7 3:7 3:7 3:7 3:7 3:7

FORMULATION TABLE

Preparation of films

Films with single and double layer were prepared by solvent

casting method.

Preparation of solution for immediate release (IR) layer:

Polymeric dispersion were prepared by dissolving HPMC E5LV in

distilled water with constant stirring (300-350 rpm) on magnetic

stirrer.

Rosuvastatin calcium was separately dissolved in ethanol: water

(3:1) and added in polymeric solution followed by addition of

dibutyl phthalate as plasticizer.

Final solution was stirred vigorously on magnetic stirrer

(600-650 rpm) for 5 min.

Preparation of sustained release (SR) layer:

HPMC K4M and Eudragit RS 100 were individually dissolved in

distilled water and ethanol respectively.

Propranolol hydrochloride was dissolved in little quantity of water

and slowly added in polymeric dispersion followed by addition of

dibutyl phthalate as plasticizer with vigorous stirring on magnetic

stirrer (300-350 rpm).

Preparation of bilayer film:

Firstly solution of sustained release (SR) layer was casted on

petriplate and allowed to dry naturally (35-40 0C) at least for

40 min. then solution of immediate release layer (IR) was casted

on the dried film of CR layer and allowed to dry for at least 50

min. naturally followed by drying in hot air oven at 45-50 0C for

30-60 min.

On removal, the films were checked for possible imperfections

before being cut into 3×2 cm rectangles and stored.

Evaluation of gastroretentive drug delivery system

Visual appearance, thickness and weight of film

Folding endurance of film

Tensile strength of film

Percent moisture absorption study

Swelling index

Drug content and dissolution:

1 Apparatus USP Type II

2 Volume of medium 900 ml

3 Temperature 37±0.50C

4 Paddle Speed 50 rpm

5 Dissolution medium used 0.1 M HCl

Quantitative estimation of propranolol hydrochloride and rosuvastatin calcium by UV spectroscopy

If the sample contain two absorbing drugs each of which absorb at λmax of the other, it may be possible to determine both drugs by Vierodt’s method.

Simultaneous estimation of two drugs can be possible only when λmax of both drug components are reasonably dissimilar and two components do not interact chemically.

It is calculated by formula,

𝑪𝒑𝒓𝒐=𝑨𝟐𝒂𝒚𝟏− 𝑨𝟏𝒂𝒚𝟐

𝒂𝒙𝟐𝒂𝒚𝟏−𝒂𝒙𝟏𝒂𝒚𝟐

Where as,

ax1 and ax2 are absorptivities of PRO at λ1 and λ2 respectively.

ay1 and ay2 are absorptivities of ROS at λ1 and λ2 respectively.

A1 an A2 are absorbance of sample at λ1 and λ2 respectively.

𝑪𝒓 𝒐𝒔=𝑨𝟏𝒂𝒙𝟐−𝑨𝟐𝒂𝒙𝟏

𝒂𝒙𝟐𝒂 𝒚𝟏−𝒂𝒙𝟏𝒂𝒚𝟐

RESULTS AND DISCUSSION:

Preformulation Studies:

Solubility of drug:

Rosuvastatin calcium:

Freely soluble in ethanol, methanol, slightly soluble in water

Propranolol hydrochloride:

Freely soluble in water, ethanol, methanol etc.

Melting Point of propranolol hydrochloride and rosuvastatin

calcium: Name of drug Melting point in OC(Test compound)

Melting point in OC(Literature value)

Propranolol hydrochloride 159-161 162-165

Rosuvastatin calcium 152-154 151-156

λ max determination:

Propranolol hydrochloride(289 nm)

Rosuvastatin calcium(240.5 nm)

Calibration curve of propranolol hydrochloride

Concentration(µg/ml)

Absorbance

0 0.00004 0.15618 0.294612 0.445216 0.587420 0.744324 0.838928 0.954232 1.16336 1.289540 1.3726

λmax 289 nm

Slope 0.0347075

Intercept 0.019104545

Correlation coefficient 0.998617469

Beers range 4-40 µg/mi

0 4 8 12 16 20 24 28 32 36 400

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

Concentration (µg/ml)Ab

sorb

ance

Calibration curve of rosuvastatin calcium

0 6 12 18 24 30 360

0.2

0.4

0.6

0.8

1

1.2

1.4

Concentration (µg/ml)

Abso

rban

ce

Concentration(µg/ml)

Absorbance

0 0.000

6 0.223

12 0.4452

18 0.6129

24 0.7962

30 0.9876

36 1.2976 λmax 240.5 nm

Slope 0.034363

Intercept 0.004679

Correlation coefficient 0.996826

Beers range 6-36 µg/ml

Drug and polymer compatibility:Fourier transform infrared spectroscopy (FTIR):

Sr. No. Wave number(cm-1) for drug

Group responsible

Propranolol hydrochloride (E)

1. 798 Α-substituted naphthalene (790 cm-1)

2. 1264 Aryl O-CH2 asymmetric stretch

3. 1030 Aryl O-CH2 symmetric stretch (1035 cm-1)

4. 2962 C-H stretching (3000-2950 cm-1)

Rosuvastatin calcium (D)

5. 2822 N-H stretching

6. 1732.13 C=O stretching

7. 1544 C=C stretching

8. 2922.25 C-H stretching (3000-2950 cm-1)

9. 1433 N-H bending

10. 1430 Asymmetric bending vibration of CH3 group

11. 1379 Symmetric bending vibration of CH3 group

12. 1328 Asymmetric vibration for S=O

13. 774 , 588, 488 C=C of benzene ring

14. 1227 Bending vibration for C-H

15. 1150 C-F stretching vibrations

A) Eudragit RS100 B) HPMC K4M, C) HPMC E5LV D) Rosuvastatin calcium, E) Propranolol hydrochloride,F) Physical mixture of drug and polymer, G) Representative formulation

Differential Scanning Calorimetry (DSC):

Propranolol HCl

Peak point: 156.98°C

Representative formulationPeak point:149.26°C

Rosuvastatin calciumPeak point: 152.93°C

UV spectrophotometric method:UV spectrophotometric method was used for simultaneous quantitative determination of propranolol hydrochloride and rosuvastatin calcium in bulk and pharmaceutical dosage form.

Absorptivity of propranolol hydrochloride

Absorptivity of rosuvastatin calcium

289 nm(ax1)

240.5 nm(ay1)

240.5 nm(ax2)

289 nm(ay2)

Mean (n=3) 228.6 298.8 378.3 103.0

± SD 1.000 0.5859 1.336 1.261

Batch

code

Visual

appearance

Wt. of films

(mg)

Film thickness

(m)

Folding

Endurance

 

Tensile

strength (%)

Moisture

uptake study

RP1 Opaque 91.74±0.23 16.66±0.57 308±2.00 57.26 1.15±1.02

RP 2 Opaque 92.69±0.23 17.50±0.50 291±3.60 59.23 1.60±0.60

RP 3 Opaque 92.85±0.17 17.33±0.57 271±2.52 59.93 2.41±0.69

RP 4 Opaque 117.07±0.23 20.56±0.51 265±2.08 60.07 2.08±0.96

RP 5 Opaque 117.17±0.96 20.66±0.57 259±2.65 60.26 2.77±0.57

RP 6 Opaque 118.23±0.32 20.33±0.15 249±1.53 60.81 2.41±0.66

RP 7 Opaque 124.20±0.40 22.86±0.87 232±3.51 61.12 5.05±0.46

RP 8 Opaque 127.13±0.59 22.00±1.00 217±3.06 61.31 6.98±0.42

RP 9 Opaque 127.21±0.50 23.29±0.61 205±3.00 62.09 7.86±0.80

Evaluation of gastroretentive floating bilayer films

0 25 50 75 100 125 150

RP1

RP2

RP3

RP4

RP5

RP6

RP7

RP8

RP9

Film weight (mg)F

orm

ula

tio

n c

od

e

14 16 18 20 22 24 26

RP1

RP2

RP3

RP4

RP5

RP6

RP7

RP8

RP9

Film thickness (µm)

Fo

rmu

lati

on

co

de

Weight of film

Thickness of film

50

55

60

65

70

Formulation code

Ten

sil

e s

tren

gth

Folding endurance

Tensile strength

RP1 RP2 RP3 RP4 RP5 RP6 RP7 RP8 RP90

50

100

150

200

250

300

350

Formulation code

Fold

ing

endu

ranc

e

0

2

4

6

8

10

Formulation code

% M

ois

ture a

bso

rp

tio

n

Percent moisture absorption

0 2 4 60.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5 RP1RP2

RP3

RP4

RP5

RP6

RP7

RP8

RP9

Time (h)

Sw

elli

ng

ind

ex

Swelling index

Batch RP1 RP2 RP3 RP4 RP5 RP6 RP7 RP8 RP9

Immediate release (IR) layer: Rosuvastatin calcium

Batch R1 R2 R3 R4 R5 R6 R7 R8 R9

% content 97.5±0.74 101.6±0.25 103.1±0.57 100.26±0.92 104.34±0.81 102.3±0.66 100.12±0.11 102.33±0.53 104.27±0.34

Sustained release (SR) layer: Propranolol hydrochloride

Batch P1 P2 P3 P4 P5 P6 P7 P8 P9

% content 102.7±0.59 99.40±0.61 101.5±0.83 104.40±0.57 99.60±0.29 97.5±0.67 99.70±0.73 97.00±0.26 98.80±0.57

Drug Content:

In-vitro drug release:

Immediate release (IR) layer (Rosuvastatin calcium) Time R1 R2 R3 R4 R5 R6 R7 R8 R9

1min 4.4±0.56 10.8±0.6 10.0±0.57 4.2±0.66 30.0±0.42 10.4±0.2 12.6±0.5 16.4±0.5 10.4±0.5

2 min 28.8±0.44 26.4±0.5 38.6±0.66 30.0±0.6 42.0±0.57 31.4±0.6 43.4±0.6 46.8±0.3 33.2±0.8

3 min 44.0±0.66 58.8±0.2 51.2±0.54 37.6±0.7 71.0±0.66 52.2±0.4 76.8±0.2 59.6±0.7 78.2±0.6

4 min 48.6±0.58 66.0±0.4 75.41±0.5 55.2±0.6 76.8±0.24 75.4±0.6 79.6±0.5 74.6±0.6 93.6±0.4

5 min 77.4±0.66 97.6±0.66 97.6±0.42 90.4±0.84 97.0±0.23 94.6±0.57 93.8±0.45 87.2±0.82 100.8±0.4

6 min 94.0±0.57 99.4±.44 99.4±0.66 99.0±0.57 103.8±0.4 101.4±0.5 99.0±0.47 101.4±0.2 102.8±0.1

0.0 1.5 3.0 4.5 6.00

102030405060708090

100110

R1R2R3R4R5R6R7R8R9

Time (Min.)

% D

rug

rele

ase

Sustained release (SR) layer (Propranolol hydrochloride)

P1 P2 P3 P4 P5 P6 P7 P8 P9

1h 47.9±0.66 39.2±0.42 35.4±0.64 44.6±0.56 38.4±0.42 31.8±0.53 52.6±0.74 51.5±0.68 38.5±0.37

2h 51.40±0.2 49.2±0.92 42.1±0.57 51.5±0.37 51.7±0.57 46.5±0.14 62.7±0.42 60.6±0.94 45.4±0.66

3h 57.7±0.76 50.3±0.35 47.7±0.34 55.3±0.74 59.2±0.66 48.2±0.12 66.8±0.94 65.0±0.47 52.8±0.43

4h 61.8±0.38 61.1±0.57 59.6±0.84 66.0±0.42 62.5±0.24 52.2±0.46 73.8±0.35 74.3±0.57 60.2±0.34

5h 72.8±0.56 67.0±0.34 65.1±0.57 73.8±0.24 69.2±0.23 60.2±0.84 80.1±0.57 81.1±0.22 60.7±0.74

6h 82.8±0.27 71.2±0.64 73.1±0.66 86.6±0.77 76.08±0.4 51.0±0.35 89.8±0.66 81.3±0.66 73.9±0.33

7h 87.8±0.66 86.8±0.66 86.8±0.36 95.9±0.14 80.9±0.3 69.2±0.67 99.0±0.57 85.2±0.72 76.8±0.44

8h 101.6±0.5 95.7±0.72 88.7±0.57 101.8±0.5 93.5±0.4 87.2±0.57 99.65±0.35 89.2±0.66 85.5±0.37

0 2 4 6 80

102030405060708090

100110

P1P2P3P4P5P6P7P8P9

Time (Hours)

% D

rug

rele

ase

Data Analysis of Formulations

Responses X1 X2 TS (%) Rel8h (%) SI5h

RP1 -1 -1 57.26 101.6 1.54

RP2 -1 0 59.23 93.7 1.51

RP3 -1 +1 59.93 87.7 1.53

RP4 0 -1 60.07 101.8 2.49

RP5 0 0 60.26 93.5 2.52

RP6 0 +1 60.81 87.2 2.51

RP7 +1 -1 61.12 99.60 3.54

RP8 +1 0 61.31 89.2 3.42

RP9 +1 +1 62.09 85.5 3.40

Rel8h= +92.98889 -1.45X1 – 7.100X2 – 0.05000X12 -1.28333X2

2 + 1.76664X1X2 (R2 =

0.9920)

SI= +2.49444 + 0.96333X1 – 0.021667X2 (R2 = 0.9982)

TS (%) =+60.42+1.35X1+0.73 X2 (R2 = 0.9534)

ANOVA Study

Source Sum of Squares

Degree of Freedom

Mean Square F Value P Value

ModelSignificant/

Not significant

Model 324.62 5 64.92 74.12 0.0024

Significant

X1 12.61 1 12.61 14.40 0.0321X2 302.46 1 302.46 345.30 0.0003

X1X2 1.00 1 1.00 0.011 0.9217(X1)2 3.29 1 3.29 3.76 0.1478(X2)2 6.24 1 6.24 7.13 0.0757

Residual 2.63 3 0.88 - -

Core Total 327.254 8 - - -

Analysis of variance drug release

Source Sum of Squares

Degree of Freedom

Mean Square F Value P Value

ModelSignificant/ Not

significant

Model 5.58 5 1.12 713.98 ˂0.0001

Significant

X1 5.57 1 5.57 3564.62 ˂0.0001

X2 2.81 1 2.81 1.80 0.2719

Residual 4.68 3 1.56 - -

Core Total 5.58 8 - - -

Analysis of variance for swelling index at 5h

Analysis of variance for tensile strength

Source Sum of Squares

Degree of Freedom

Mean Square F Value P Value

ModelSignificant/

Not significant

Model 14.13 2 7.07 27.19 0.0010

Significant

X1 10.94 1 10.94 42.07 0.0006

X2 3.20 1 3.20 12.30 0.0127

Residual 1.56 6 0.26 - -

Core Total 15.69 8 - - -

Response Surface Plot:

Contour plot Response 3D surface plot

Contour plot Response 3D surface plot

Contour plot Response 3D surface plot

CONCLUSION

The gastroretentive floating bilayer films of rosuvastatin calcium and

propranolol hydrochloride were prepared using immediate and

controlled release polymers by solvent casting method.

Based on the % drug release, swelling index, folding endurance and

floating time formulation RP5 was selected as an optimized

formulation.

- Multilayer film DDS

- In-vitro buoyancy by string technique/endoscopy/gamma

scintigraphy

FUTURE PERSPECTIVES

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