World Journal of Pharmaceutical Research et al. World ... · Venkataswamy et al. World Journal of Pharmaceutical Research PREPARATION AND EVALUATION OF BIPHASIC BILAYERED ... Transmucosal

www.wjpr.net Vol 7, Issue 11, 2018.

905

Venkataswamy et al. World Journal of Pharmaceutical Research

PREPARATION AND EVALUATION OF BIPHASIC BILAYERED

BUCCAL TABLET CONTAINING KETOROLAC IMMEDIATE

RELEASE LAYER AND DOMPERIDONE MALEATE SUSTAINED

RELEASE LAYER

M. Venkataswamy*1, M. Santhoshini

2, J. P. Priyanka

1, K. Prathyusha

1, Jaggareddy

Gari Manasareddy1 and Ramesh Alluri

3

1Department of Pharmaceutics,

3Department of Pharmacology,

Vishnu Institute of Pharmaceutical Education and Research, Vishnupur, Narsapur, Medak,

Telangana, India.

2Department of Pharmaceutics, Sri Indu institute of Pharmacy, Sheriguda Village,

Ibrahimpatnam Mandal, Ibrahimpatnam, Ranga Reddy District.

ABSTRACT

In the present study an attempt was made to design a biphasic Bilayer

buccal Tablet containing Ketorolac immediate release layer and

Domperidone maleate sustained release layer. FT-IR studies reveal that

there were no significant interactions between both the drugs and

between the drugs and their respective excipeints. For achieving

sustained release of Domperidone maleate, bucco adhesive polymers

Carbopol and CMC were used Formulations D6 and D7 gave drug

release 90.12±1.26 and 92.15±1.11 after 8hrs. Therefore D6 and D7

were considered as best formulations among D1 –D 11 for formulation

of bilayer buccal tablets. For achieving immediate result of Ketorolac,

from the results it was concluded that disintegration activity is good

with Crospovidone and SSG, K6 releasing 100.05±1.2, K9 releasing

99.51±1.21% after 14min. The bilayered tablets prepared by taking D6 and D7 of

Domperidone maleate and K6 and K9 formulations of Ketorolac as two layers (K6+D6,

K6+D7, K9+D6, K9+D7) have shown good post compression parameters like hardness,

friability weight variation, drug content etc which were within the limits. Hence they are

considered as optimized formulations.

World Journal of Pharmaceutical Research SJIF Impact Factor 8.074

Volume 7, Issue 11, 905-949. Research Article ISSN 2277–7105

Article Received on

09 April 2018,

Revised on 29 April 2018,

Accepted on 19 May 2018

DOI: 10.20959/wjpr201811-12447

*Corresponding Author

M. Venkataswamy

Department of

Pharmaceutics, Vishnu

Institute of Pharmaceutical

Education and Research,

Vishnupur, Narsapur,

Medak, Telangana, India.


906


KEYWORDS: Bilayer buccal Tablet, Domperidone maleate.

INTRODUCTION: The pharmaceutical industry has engendered considerable interest

making it a major participant in the healthcare industry. The advances and progress made by

pharmaceutical industry have greatly contributed in terms of treatment of disease, thereby

enhancing the quality of life.[1]

Over the time, scientists and researchers in the drug

development industries are focusing on alternate routes of administration to add to the

potential of approved drug products, or to overcome the drawbacks of the oral route.

Although oral route is preferred for administration of drugs, it is associated with some

restrictions for example: hepatic first pass metabolism, local GI toxicity and enzymatic

degradation within the GI tract. The Parenteral route having maximum bioavailability suffers

from poor patient compliance and various risks such as anaphylaxis and extravasation

infection these limitations have driven the alternate administration routes via the accessible

mucosal route as they offer many advantages including non invasive administration, rapid

onset of effect, good bio availability, elimination of hepatic first pass metabolism, reduced

amount of administered drug and low dose related side effects. Transmucosal routes of drug

delivery which comprise of the mucosal linings of the nasal, rectal, vaginal, ocular, and oral

cavity offer excellent opportunities and potential advantages over per oral administration for

systemic drug delivery. These advantages include possible bypass of first pass effect,

avoidance of presystemic elimination within the GI tract and depending on the particular

drug, a better enzymatic flora for drug absorption. Amongst the various mucosal routes the

mucosal lining of oral cavity offers distinct advantages like high vascularisation and

accessibility for the administration and removal of a dosage form in addition to high patient

acceptability compared to other non- oral routes of drug administration.[2,3]

The sites of drug

administration in the oral cavity include the floor of the mouth (sublingual), the inside of the

cheeks (buccal) and the gums (gingival). With the advances and progress in biotechnology,

hydrophilic high molecular weight therapeutic agents such as proteins and peptides are

readily available for therapeutic use. However, when administered by the oral route, these

agents suffer from problems such as degradation and poor absorption. To overcome these

obstacles and for successful delivery of proteins and peptides, the buccal route of drug

delivery has acquired significant attention.[4]

LITERATURE REVIEW: Vishnu M. Patel et al., (2007), formulated mucoadhesive

bilayer buccal tablets of propranolol hydrochloride using the bioadhesive polymers sodium


907


alginate (Na-alginate) and Carbopol 934P (CP) along with ethyl cellulose as an impermeable

backing layer. The tablets were evaluated for weight variation, thickness, hardness, friability,

surface pH, mucoadhesive strength, swelling index, in vitro drug release, ex vivo drug

permeation, ex vivo mucoadhesion, and in vivo pharmacodynamics in rabbits. Tablets

containing, Na-alginate and CP in the ratio of 5:1 (F2) had the maximum percentage of in

vitro drug release without disintegration in 12 hours. The swelling index was proportional to

Na-alginate content and inversely proportional to CP content. The surface pH of all tablets

was found to be satisfactory (7.0±1.5), close to neutral pH; hence, buccal cavity irritation

should not occur with these tablets. The mechanism of drug release was found to be non-

Fickian diffusion and followed zero-order kinetics.[93]

Luana Perioli et al.,(2007), formulated muco adhesive bilayer tablets for buccal sustained

release of flurbiprofen. The bilayered tablets, using mixtures of mucoadhesive polymers and

an inorganic matrix (hydrotalcite), for the topical administration of flurbiprofen in the oral

cavity. The first layer, responsible for the tablet retention on the mucosa, was prepared by

compression of a cellulose derivative and polyacrylic derivative blend. The second layer,

responsible for buccal drug delivery, was obtained by compression of a mixture of the same

(first layer) mucoadhesive polymers and hydrotalcite containing flurbiprofen. Nonmedicated

tablets were evaluated in terms of swelling, mucosal adhesion, and organoleptic

characteristics; in vitro and in vivo release studies of flurbiprofen-loaded tablets were

performed as well.[94]

Balamurugan et al.,(2008), formulated Mucoadhesive buccal tablet of Domperidone were

fabricated with objective of avoiding first pass metabolism and to improve its bioavailability

with reduction in dosing frequency. The mucoadhesive polymers used in the formulations

were Carbopol 934P, Methocel K4M, MethocelE15LV and Chitosan. Tablets were prepared

by direct compression method using polymer in different ratios. The formulations were

characterized for swelling index, in-vitro bioadhesion strength and in-vitro release studies.

The best mucoadhesive performance and invitro drug release profile were exhibited by the

tablet containing chitosan and Methocel K4M in ratio of 1:1. It was observed that the

optimized formulation follows Hixson Crowel release kinetics.[95]

Ashwini Madgulkar et al.,(2008), developed trilayered mucoadhesive tablet of itraconazole

with zero-order release. Itraconazole is practically insoluble in water; large interindividual

and intraindividual variations of its oral bioavailability are reported. A mucoadhesive drug


908


delivery system is useful to prolong the retention time of a dosage form in the stomach,

thereby improving the oral bioavailability of the drug. Solid dispersion of itraconazole with

Eudragit E100 was prepared by spray-drying method to improve dissolution. Trilayered

mucoadhesive tablet was prepared, with inner core containing solid dispersion of the drug

and with carbopol and HPMC sandwiched between two layers of hydrophilic mucoadhesive

polymer mixture of carbopol and Hydroxypropyl methyl cellulose (HPMC). Amounts of

Carbopol 934P (CP) and Methocel K4M (HPMC) were varied in the outer coat around the

solid dispersion. The drug-release pattern for all the formulation combinations was found to

be nonfickian, approaching zero-order kinetics. Suitable combination of two polymers

provided adequate bioadhesive strength and sustained-release profile with zero-order

kinetics.[96]

JG HIREMATH et al., (2009), prepared the buccoadhesive bilayered tablet of simvastatin

for the treatment of hypercholesterolemia, by using the mucoadhesive polymers such as

carbopol (CP), hydroxy propyl methyl cellulose (HPMC) and polyvinylpyrrolidone (PVP) in

different concentration. Ethyl cellulose is used in backing layer because of its water

impermeable nature. Tablets were prepared by direct compression method. The first layer

which adheres to mucosa was obtained by direct compression of mucoadhesive polymers and

drug. The second layer containing water impermeable agent was compressed on the first

layer. Tablets were subjected for physicochemical characterization tests such as FTIR, DSC,

hardness, weight variation, friability, mucoadhesive strength, in vitro drug release study, in

vitro drug permeation, and stability in human saliva. The FTIR and DSC analysis of drug,

polymers, physicalmixture and formulation indicated that the compatibility of drug with

excipients.[97]

MATERIALS AND METHODS

Table 1: Materials and their Sources.

SNO Name of the ingredient Source

1 Domperidone Gift sample from Aurobindo Pharma ltd, Hyderabad

2 Ketorolac Gift sample from Divis Pharmaceuticals ltd, Hyderabad

3 Mico crystalline cellulose Pioma Chemicals, Mumbai

4 Cross carmellose sodium Shreeji pharma international, vadodara

5 Crosspovidone Kores india ltd

6 Vanillin Wanbury ltd

7 Citric acid Wang Pharmaceuticals,New Delhi

8 Magnesium stearate Panchi chemicals,Hyderabad

9 Mannitol Provizer pharma ltd,Gujarat

10 Carbopol Provizer Pharma ltd,Gujarat

11 Carboxy methyl cellulose Akay organics ltd,India


909


Table 2: List of Equipment.

SNO EQUIPMENT MANUFACTURER MODEL

NUMBER

1 Electronic balance Shimadzu AUX 220

2 Sieves United engineering limited ASL00

3 FTIR Shimadzu,Japan model 840

4 Laboratory stirrer Remi RQT-124A

5 Rapid dryer Retsch Th-200

6 Digital PH meter Thermo Orion 2 star

7 Dissolution test apparatus ( U.S.P) Electrolab, india TDT-08L

8 Disintegration tester Thermolab ED-2L

9 Monsento Hardness tester Pharmatest PTB-311E

10 Roche Friabilator Thermolab EF-1N

11 Tablet compression machine 16 station Cadmech machinery co pvt ltd CMD3-16

12 Tap Density Tester (U.S.P.) Electrolab,India ETD-1020

13 Digital Vernier Caliper Mitutoyo Corp, Kawasaki, Japan

14 UV/Visible Spectrophotometer Lab india,Japan UV-3000

DRUG PROFILE

a) DOMPERIDONE MALEATE[110,111]

Name: Domperidone maleate,

Description: A specific blocker of dopamine receptors. It speeds gastrointestinal peristalsis,

causes prolactin release, and is used as antiemetic and tool in the study of dopaminergic

mechanisms.

Structure

Categories: Antiemetics, Dopamine Antagonists

IUPAC NAME: 5-Chloro-1-[1-[3-(2-oxo-1,3-dihydrobenzoimidazol-1-yl)propyl]-4-

piperidyl]-1,3- dihydrobenzoimidazol-2-one maleate.

Chemical name: C22 H24 ClN5O2. C4 H4O4


910


Trade names: Motilium, Nauzelin

Routes: Oral, intravenous, rectal

Classes: Benzimidazoles.

Pharmacology: Indication: For management of dyspepsia, heartburn, epigastric pain,

nausea, and vomiting.

Mechanism of action: Antiemetic: The antiemetic properties of domperidone maleate are

related to its dopamine receptor blocking activity at both the chemoreceptor trigger zone and

at the gastric level. It has strong affinities for the D2 and D3 dopamine receptors, which are

found in the chemoreceptor trigger zone, located just outside the blood brain barrier, which -

among others - regulates nausea and vomiting.

Dose and administration

Acute conditions (nausea, vomiting).

Adults: Two tablets (20mg) 3-4times per day, 15-30 min before meals.

Children: 5-12years old, one tablet (10mg) 3-4times per day,15-30min before meals.

Chronic conditions (mainly dyspepsia).

Adults: one tablet (10mg) taken 3times per day, 15-30min before meals.

Children: 5-12years old ½ tablet (5mg) 3-4 times per day, 15-30min before meals.

Pharmacokinetic data

Bio availability: High

Protein binding: 91-93%

Metabolism: Hepatic and Intestinal

Half life: 7hrs

Excretion: Breast milk, renal

Pharmacodynamics: Domperidone maleate is a specific blocker of dopamine receptors. It

speeds gastrointestinal peristalsis, causes prolactin release, and is used as antiemetic and tool

in the study of dopaminergic mechanisms.

b) KETOROLAC[112,113]

Name: Ketorolac

Description: A pyrrolizine carboxylic acid derivative structurally related to indomethacin. It

is an NSAID and is used principally for its analgesic activity.


911


Structure

Synonyms: Ketorolac, Ketorolac tromethamine, Ketorolaco(Spanish), Ketorolacum(Latin).

Brand names: Acular, Acular LS, Acular Preservative Free, Toradol.

Categories: Cyclooxygenase Inhibitors.

Chemical Formula: C15H13NO3.

IUPAC Name: 5-benzoyl-2, 3-dihydro-1H-pyrrolizine-1-carboxylic acid.

Classes: Pyrrolizines

Pharmacology: Benzoyl Derivatives

Indication: For the short-term (~5 days) management of moderately severe acute pain that

requires analgesia at the opioid level, usually in a postoperative setting.

Mechanism of action: Ketorolac is a nonsteroidal anti-inflammatory drug (NSAID)

chemically related to indomethacin and tolmetin. Ketorolac tromethamine is a racemic

mixture of [-] S- and [+] R-enantiomeric forms, with the S-form having analgesic activity. Its

antiinflammatory effects are believed to be due to inhibition of both cylooxygenase-1 (COX-

1) and cylooxygenase-2 (COX-2) which leads to the inhibition of prostaglandin synthesis

leading to decreased formation of precursors of prostaglandins and thromboxanes from

arachidonic acid. The resultant reduction in prostaglandin synthesis and activity may be at

least partially responsible for many of the adverse, as well as the therapeutic, effects of these

medications. Analgesia is probably produced via a peripheral action in which blockade of

pain impulse generation results from decreased prostaglandin activity. However, inhibition of

the synthesis or actions of other substances that sensitize pain receptors to mechanical or

chemical stimulation may also contribute to the analgesic effect. In terms of the ophthalmic

applications of ketorolac - ocular administration of ketorolac reduces prostaglandin E2 levels

in aqueous humour, secondary to inhibition of prostaglandin biosynthesis.


912


Dose and Administration

Oral: 10 mg orally 4 times a day as needed. The maximum daily dose should not exceed 40

mg.

Patients less than 50 kg: The maximum daily dose should not exceed 40 mg.

Parenteral: IM: Patients less than 65 years of age: one dose of 60 mg. Patients who are

renally impaired, and/or less than 50 kg (110 pounds): one dose of 30 mg. IV: Patients less

than 65 years of age: one dose of 30 mg. Patients who are renally impaired, and/or less than

50 kg (110 pounds): One dose of 15 mg.

Absorption: Rapidly and completely absorbed after oral administration.

Protein binding: 99%.

Metabolism: Primarily hepatic. Less than 50% of a dose is metabolized. The major

metabolites are a glucuronide conjugate, which may also be formed in the kidney,

p-hydroxy ketorolac. Neither metabolite has significant analgesic activity.

Route of elimination: The principal route of elimination of ketorolac and its metabolites is

renal. Approximately 6% of a dose is excreted in the feces.

Half life: 2.5 hours for the S-enantiomer compared with 5 hours for the R-enantiomer.

METHODOLOGY

The bilayer tablets of Ketorolac and Domperidone maleate were developed in two stages.

Blends of immediate release layer of Ketorolac and sustained release layer of Domperidone

maleate were prepared separately by direct compression technique. The individual layers

were optimized based on the in vitro drug release data and bilayer tablets were prepared by

using the optimized formulae.

Analytical Method Development

Determination of Absorption Maxima

A solution of Ketorolac and Domperidone maleate containing the concentration 10 µg/ml

was prepared in 6.8 pH phosphate buffer, U.V Spectrum was taken using (Lab India UV-

3000, Japan). The solution was scanned in the range of 200-400 nm, the results were shown

in.


913


Calibration Curve for Ketorolac

Ketorolac equivalent to 10 mg was weighed accurately and added to 10 ml volumetric flask.

It was dissolved in little amount of water and diluted with phosphate buffer pH 6.8 to get a

stock solution A. From the stock solution A, 1 ml was pipetted out and transferred to another

10 ml volumetric flask and the volume was made up with phosphate buffer pH 6.8 to get a

stock solution B. From the stock solution B, 0.2, 0.4, 0.6, 0.8, 1, 1.2ml was pipetted out and

diluted to 10 ml with phosphate buffer to get 2, 4, 6, 8, 10 and 12 µg/ml solutions.

Absorbance of each of these solutions is recorded spectrophotometrically at 322 nm (Lab

India UV-3000, Japan). The data was presented in (Table 15) and calibration curve was

shown in (Fig 10).

Calibration Curve for Domperidone maleate

Domperidone equivalent to 10 mg was weighed accurately and added to 10 ml volumetric

flask. It was diluted with phosphate buffer pH 6.8 to get a stock solution A. From the stock

solution A, 1 ml was pipetted out and transferred to another 10 ml volumetric flask and the

volume was made up with phosphate buffer pH 6.8 to get a stock solution B. From the stock

solution B, 0.2, 0.4, 0.6, 0.8, 1,1.2 ml was pipetted out and diluted to 10 ml with phosphate

buffer to get 2, 4, 6, 8,10 and 12 µg/ml solutions. Absorbance of each of these solutions is

recorded spectrophotometrically at 283 nm (Lab India UV-3000, Japan). The data was

presented in (Table 16) and calibration curve was shown in (Fig 11).

PRE FORMULATION STUDIES

Organoleptic Properties

a) Colour: A small quantity of Ketorolac and Domperidone maleate powders were taken in

butter paper and viewed in well- illuminated place.

b) Taste and odour: Very less quantity of Ketorolac and Domperidone maleate was used to

get taste with the help of tongue as well as smelled to get odour.

Solution Properties

a) Solubility: The solubility’s of substances is determined by shake flask method, according

to this method the drug is added in surplus to the solvents and shaken at a predetermined

time, the saturation is confirmed by observing the presence of undissolved drug, Solvents

such as methanol, alcohol, water, isopropyl alcohol are used for solubility studies.


914


Flow Properties[125]

: These studies were conducted for the two drugs separately. The data

was presented in the table 21,22.

a) ANGLE OF REPOSE

The angle of repose of was determined by the funnel-method. The accurately weighed

powder was taken in a funnel. The height of the funnel was adjusted in such a manner that the

tip of the funnel just touched the apex of the heap of the granules. The powder was allowed to

flow through the funnel freely onto the surface. The diameter of the powder cone measured

and angle of repose was calculated using the following equation.

Angle of Repose (θ) = tan-1

(h/r)

Where h and r are the height and radius of the powder cone, θ is the angle of repose.

b) Determination of Bulk Density and Tapped Density

An accurately weighed quantity of the powder (W) was carefully poured into the graduated

cylinder and volume (V0) was measured. Then the graduated cylinder was closed with lid and

set into the tap density tester (USP). The density apparatus was set for 100 tabs and after that

the volume (Vf) was measured and continued operation till the two consecutive readings were

equal.

The bulk density and the tapped density were calculated using the following formulae.

Bulk density = W/V0, Tapped density =W/Vf

Where, W = Weight of the powder, V0 = Initial volume, Vf = final volume.

Measurement of Powder Compressibility

a) Compressibility Index (Carr’s Index)

Carr’s index (CI) is an important measure that can be obtained from the bulk and tapped

densities. In theory, the less compressible a material the more flowable it is.

Carr’s Index = Tapped density – Bulk density / Tapped Density

Where, TD is the tapped density and BD is the bulk density.

b) Hausner’s Ratio

It is the ratio of tapped density and bulk density. Hausner found that this ratio was related to

inter particle friction and, as such, could be used to predict powder flow properties. Generally

a value less than 1.25 indicates good flow properties, which is equivalent to 20% of Carr’s

index.


915


Hausner’s ratio = Tapped density / Bulk density

DRUG - POLYMER COMPATIBILITY STUDIES

Fourier Transform Infrared Radiation (FTIR)

The Fourier Transform Infrared Radiation measurement (FTIR) spectral measurements were

taken at ambient temperature using IR spectrophotometer (Shimadzu, model 840, Japan).

Spectra of drug and polymer were taken and analyzed for any major interaction. The pure

drug, physical mixtures and optimized formulations were subjected for FTIR analysis. The

samples were prepared in 1:1 ratio for drug and excipients on KBr-press. The samples were

scanned over a range of 4000-400 cm-1 using Fourier transformer infrared

spectrophotometer. Spectra were analysed for drug polymer interactions. These were done

qualitatively in order to assess the pattern of peaks and for comparison purpose. The graphs

were shown in the(Fig 12,13,14).

FORMULATION OF KETOROLAC IMMEDIATE RELEASE LAYER TABLETS

Ketorolac immediate release layer tablets were prepared by Direct Compression method.

Ketorolac and other excipients like microcrystalline cellulose, sodium starch glycolate, CCS

and CP were sifted through sieve no 40 #. The sifted powders were thoroughly mixed for

approximately 5 min and again passed through sieve no 40 # for maintaining uniformity in

particle size. Vanillin and Citric acid were added. Above mixture was lubricated for 2 min

with magnesium stearate which was already passed through sieve 60 then the tablets were

compressed by using CADMACH multistation compression machine by using 8mm punch.

In batches F1 to F3 CCS was used, F4 to F6 CP was used and in F7 to F9 SSG was used. The

formulation was shown in.

Table 3: Composition of Ketorolac immediate release layer by direct compression.

Ingredients K1 K2 K3 K4 K5 K6 K7 K8 K9

Ketorolac 10 10 10 10 10 10 10 10 10

MCC 156 151.5 147 156 151.5 147 156 151.5 147

CCS 9 13.5 18 - - - - - -

CP - - - 9 13.5 18 - - -

SSG - - - - - - 9 13.5 18

Vanillin 2 2 2 2 2 2 2 2 2

Citric acid 1 1 1 1 1 1 1 1 1

Magnesium

stearate 2 2 2 2 2 2 2 2 2

Total Weight – 180mg


916


FORMULATION OF DOMPERIDONE MALEATE SUSTAINED RELEASE LAYER

The dose of Domperidone for sustained release was taken as 20mg. Tablets were prepared by

direct compression method. Appropriate quantities of Domperidone, and excipeints like

Mannitol, Micro crystalline cellulose, Carbopol, CMC, Vanillin were measured accurately as

per formula and all the measured powders were sifted through Sieve no # 40. The sifted

powders were thoroughly mixed for approximately 5 min and again passed through sieve no

40 # for maintaining uniformity in particle size. Above mixture was lubricated for 2 min with

magnesium stearate which was already passed through sieve 60.

The above powder was compressed into tablets by CADMACH multi station tablet

compression machine by using 8 mm punch. In Batch F1 to F4, Carbopol was used as the

sustained release polymer and in Batch F5 to F8 CMC was used and in F9 to F11 both

Carbopol and CMC were used.

Table 4: Composition of Domperidone maleate sustained release layer.

s.no Ingredients D1 D2 D3 D4 D5 D6 D7 D8 D9 D10 D11

1 Domperidone maleate 20 20 20 20 20 20 20 20 20 20 20

2 Mannitol 40 40 40 40 40 40 40 40 40 40 40

3 MCC 96 76 56 36 96 76 56 36 56 56 56

4 Carbopol 40 60 80 100 - - - - 40 26.6 20

5 CMC - - - - 40 60 80 100 40 53.4 60

6 Vanillin 2 2 2 2 2 2 2 2 2 2 2

7 Magnesium stearate 2 2 2 2 2 2 2 2 2 2 2

Total weight -200mg

PRE-COMPRESSION PARAMETERS OF BLENDS

The Domperidone maleate sustained release layer and Ketorolac directly compressible blends

were evaluated for various pre compression parameters like Angle of repose, Bulk density,

Tapped density, Carr’s index, Hausner’s ratio etc, by following the standard methods

described earlier, The data was presented in.(Table22,23).

EVALUATION OF THE COMPRESSED TABLETS[125]

Both Ketorolac and Domperidone maleate tablets were evaluated for post compression

parameters like hardness, weight variation, friability, drug content uniformity etc. The

Domperidone maleate SR tablets were evaluated for muco adhesive strength and in vitro

dissolution study. Ketorolac IR tablets were evaluated for in vitro disintegration study and in

vitro dissolution study. From the in vitro dissolution study best formulations were selected.


917


Determination of Drug Content for Ketorolac

The drug content was carried out by weighing 10 tablets from each batch and calculated the

average weight. Then the tablets were triturated to get a fine powder. From the resulting

triturate, powder was weighed accurately which was equivalent to 10 mg of Ketorolac and

dissolved in a 100 ml volumetric flask containing 50 ml of phosphate buffer 6.8 pH and

volume was made up to 100 ml with same solvent. The volumetric flask shaken using

sonicator for 1hr and after suitable dilution with phosphate buffer 6.8 pH, the drug content is

determined using UV-Visible Spectrophotometer at 322 nm.

Determination of Drug Content for Domperidone[126]

The drug content was carried out by weighing 10 tablets from each batch and calculated the

average weight. Then the tablets were triturated to get a fine powder. From the resulting

triturate, powder was weighed accurately which was equivalent to 20 mg of Ketorolac and

dissolved in a 100 ml volumetric flask containing 50 ml of phosphate buffer 6.8 pH and

volume was made up to 100 ml with same solvent. The volumetric flask shaken using

sonicator for 1hr and after suitable dilution with phosphate buffer 6.8 pH, the drug content is

determined using UV-Visible Spectrophotometer at 283 nm.

Invitro Disintegration time

The disintegration time for all immediate release formulations was carried out using tablet

disintegration test apparatus. Six tablets were placed individually in each tube of

disintegration test apparatus and discs were placed. The medium, water was maintained at a

temperature of 37°±2°C and time taken for the entire tablet to disintegrate completely was

noted. Average of three determinations was taken. The data was presented in the table.

In-Vitro Bioadhesive strength measurement Test[126]

(Methods Based on Measurement of Adhesion Strength)

For In-vitro study, an apparatus designed for determination of mucoadhesive bond strength

was used. Bioadhesive strength expressed in Newton, required for detachment of the tablet

from the mucosa was determined using the fresh sheep buccal mucosa as mucosal

substrate.

In Vitro DRUG RELEASE STUDIES[126]

In vitro dissolution studies of buccal tablets of Modeldrug were carried out in USP

typeII (paddle) Dissolution Testing Apparatus (Electrolab), employing a paddle stirrer at 50


918


rpm using 900ml of pH 6.8 Phosphate buffer at 37±0.5oC as dissolution medium. One tablet

was used in each test. The tablets were supposed to release drug from one side only; therefore

an impermeable backing membrane side of tablet was fixed to a 2×2 cm glass slide with a

solution of ethyl cellulose coating. Then it was placed in dissolution apparatus.

At predetermined time intervals 5ml of the samples were withdrawn by means of a

syringe fitted with a pre filter. The volume withdrawn at each interval was replaced with

same quantity of fresh dissolution medium maintained at 37±0.5°C. The samples were

analyzed for drug release by measuring the absorbance at 265 nm using UV-Visible

spectrophotometer after suitable dilutions.

FORMULATION OF BI LAYER BUCCAL TABLETS

Bilayer tablets were prepared by taking best formulations from both the individual layers.

Domperidone maleate blend was first introduced into the die cavity, a slight compression was

made and then Ketorolac blend was introduced into the die cavity followed by final

compression with optimum hardness to form the bi layer tablets. Here compression was made

by using tablet compression machine (Cadmach, India) with 12mm punches. Bilayer tablets

were prepared and evaluated for various post compression parameters and in vitro

dissolution. The composition of bilayer buccal tablets were shown in table.

Table 5: Composition of Bilayer Buccal Tablets.

Ingredients K6+D6(mg) K6+D7(mg) K9+D6(mg) K9+D7(mg)

Immediate release layer

Ketorolac 10 10 10 10

MCC 147 147 147 147

CCS - - - -

CP 18 18 - -

SSG - - 18 18

Vanillin 2 2 2 2

Citric acid 1 1 1 1

Magnesium stearate 2 2 2 2

Sustained release layer

Domperidone 20 20 20 20

Mannitol 40 40 40 40

MCC 76 56 76 56

Carbopol - - - -

CMC 60 80 60 80

Vanillin 2 2 2 2

Citric acid 2 2 2 2

Total weight 380 380 380 380


919


EVALUATION OF BILAYER BUCCAL TABLETS

All the post compression parameters like thickness, hardness, weight variation, friability,

content uniformity of both the drugs were measured. The data was presented in the (table 28).

RESULTS AND DISCUSSIONS

Absorption maxima of Ketorolac and Domperidone

Absorption Maximum of Ketorolac was found to be 322nm and for Domperidone maleate the

absorption maximum was found to be 283nm.

Development of Calibration curve

Calibration curve of Ketorolac in 6.8 pH buffer

The wavelength of Ketorolac in 322nm was scanned from the concentration range of

2,4,6,8,10,12 µg/ml.Standard calibration graph of Ketorolac in water at pH6.8 was plotted by

taking concentration vs absorbance and good correlation was obtained with R2

value of 0.998

which obey Beer – Lambert’s law.

Table 16: Data for Calibration Curve of Ketorolac.

S. no Concentration(µg/ml) Absorbance at 322nm

1 0 0

2 2 0.090

3 4 0.185

4 6 0.249

5 8 0.332

6 10 0.406

7 12 0.482

8 14 0.565

Figure 10: Calibration Curve of Ketorolac in pH6.8 Phosphate buffer.


920


Calibration Curve of Domperidone maleate: The wavelength of Domperidone maleate in

283nm was scanned from the concentration range of 0, 2, 4,6,8,10,12, 14 µg/ml. standard

calibration graph of Domperidone maleate in water was plotted by taking concentration vs.

absorbance and a good correlation was obtained with R2 value of 0.998 which obey Beer –

Lambert’s law.

Table 17: Data for Calibration Curve of Domperidone maleate.

S.no Concentration (µg/ml) Absorbance at 283nm

1 2 0.075

2 4 0.118

3 6 0.184

4 8 0.230

5 10 0.298

6 12 0.358

7 14 0.408

Figure 11: Calibration Curve of Domperidone maleate in pH6.8 Phosphate buffer

PREFORMULATION STUDIES

Organoleptic Properties

Table 18: Organoleptic Properties of Ketorolac.

Test Specification/ Limits Observations

Colour White to off white White Powder

Taste Abnormal taste Abnormal taste

Odour Slight characteristic odour Characteristic odour


921


Table 19: Organoleptic Properties of Domperidone maleate

Test Specification/ Limits Observations

Colour White to slightly beige

coloured powder White powder

Taste Sour/bitter taste Bitter taste

Odour Odourless Odourless

Solution Properties

a) Solubility: The following (Table 20,21) illustrates the results

Table 20: Solubility of Ketorolac.

Quantity of Ketorolac Quantity of Solvents Inference

100mg 100ml of water Freely soluble

100mg 100ml of 95% ethanol Slightly soluble

100mg 100ml methanol Freely soluble

Table 21: Solubility of Domperidone maleate.

Quantity of

Domperidone maleate Quantity of Solvents Inference

100 mg 100 ml of water Very slightly soluble in

water

100 mg 100 ml of 95%ethanol Very Slightly soluble

100 mg 100 ml of methanol slightly soluble

Table 22: Precompression Parameters Of Ketorolac.

Formulati

on Code

Bulk density

(g/cc)

±SD

Tapped

density

(g/cc)±SD

Carrs

index(%)

±S.D

Hausners

ratio

±S.D

Angle of

Repose(θ)

±S.D

Powder

flow

properties

K1 0.46±0.006 0.55±0.022 16.36±0.12 1.19±0.09 16.36±0.12 Excellent

K2 0.45±0.006 0.54±0.009 16.6±0.10 1.2±0.08 16.66±0.25 Excellent

K3 0.46±0.005 0.55±0.034 16.36±0.11 1.19±0.08 16.52±0.23 Excellent

K4 0.32±0.006 0.38±0.019 15.7±0.25 1.18±0.72 14.73±0.19 Excellent

K5 0.45±0.004 0.52±0.011 13.46±0.15 1.15±0.06 18.75±0.18 Excellent

K6 0.48±0.004 0.57±0.013 15.78±0.17 1.18±0.065 15.32±0.16 Excellent

K7 0.47±0.005 0.56±0.015 16.07±0.10 1.19±0.072 17.42±0.16 Excellent

K8 0.47±0.002 0.54±0.020 12.9±0.12 1.14±0.058 16.14±0.13 Excellent

K9 0.45±0.003 0.56±0.027 19.6±0.22 1.24±0.075 19.08±0.13 Excellent

K1-K9(Ketorolac Formulations)(n=3,±S.D) (S.D= Standard deviation)


922


Table 23: Precompression Parameters Of Domperidone Maleate.

Formulat

ion code

Bulk

density(g/cc)

±S.D

Tapped

density(g/cc)±S

D

Carrs

index

(%)±S.D

Hausners

ratio±S.D

Angle of repose

Degrees±S.D

Powder flow

properties

D1 0.214±0.02 0.251±0.026 14.74±0.18 1.17±0.23 25.49±0.18 Good

D2 0.308±0.01 0.364±0.025 15±0.12 1.18±0.24 26.24±0.12 Good

D3 0.276±0.03 0.322±0.022 14±0.14 1.16±0.19 29.05±0.14 Good

D4 0.521±0.03 0.629±0.026 17±0.12 1.2±0.16 33.65±0.12 Fair

D5 0.324±0.01 0.376±0.0212 13±0.13 1.16±0.19 29.25±0.13 Good

D6 0.320±0.01 0.397±0.02 19±0.13 1.24±0.18 32.27±0.13 Fair

D7 0.341±0.02 0.388±0.02 12±0.16 1.13±0.18 26.97±0.16 Free flowing

D8 0.518±0.012 0.627±0.023 17±0.15 1.21±0.18 33.21±0.15 Fair

D9 0.422±0.011 0.506±0.025 19±0.13 1.19±0.23 26.56±0.13 Fair

D10 0.481±0.011 0.572±0.026 15±0.14 1.18±0.24 28.75±0.13 Good

D11 0.475±0.013 0.566±0.027 16±0.17 1.19±0.19 27.33±0.17 Fair

D1 – D11 (Domperidonemaleate formulations) n=3,±S.D) (S.D= Standard deviation)

DRUG - POLYMER COMPATIBILITY STUDY

Fourier Transform Infrared Radiation (FTIR)

All the above bands associated with the Ketorolac and Domperidone maleate are present in

the FTIR spectra of drug(fig12,fig13). This shows there is no chemical interaction between

drug and excipients(fig 14).

Figure 12: FTIR spectra of Pure Ketorolac.


923


S.no Functional

Group

Characteristic Peak

cm-1

Observed Peaks

cm-1

1 0-H 3200-3600 3422.48

2 C=0 1670-1820 1628.09

3 C-N 1080-1360 1277.28

4 C=C 1400-1600 1474.69

Figure 13: Ftir Spectra of Pure Domperidone.

S.no Functional

Group

Characteristic Peak

cm-1

Observed Peaks

cm-1

1 C-N 1080-1360 1285.62

2 N-H 3300-3500 3350.97

3 C-H 2850-3000 2938.30

4 C=C 1400-1600 1600.95


924


Figure 14: FTIR Spectra of Bilayered Buccal tablets (ketorolac IR layer+Domperidone

maleate SR layer).

S.no Functional

Group

Characteristic Peak

cm-1

Observed Peaks

cm-1

1 0-H 3500-3700 3505.03

2 C-H 2850-3000 2918.67

3 C=0 1670-1820 1728.04

4 N-H 3300-3500 3400.28

EVALUATION OF COMPRESSED TABLETS

Table 24 Results of post compression parameters of Ketorolac trimethamine.

Formulation

code

Average

Weight (mg)

(n=20)

Thickness

(mm)

(n=3)

Hardness

(Kg/cm2 )

(n=3)

Friability

(n=20)

Disintegration

time(sec)

Drug

content%

K1 178.67±0.42 2.22±0.01 2.40 0.56 1min 10sec 99.03±0.53

K2 180.48±0.53 2.30±0.02 2.35 0.47 43 sec 99.86±0.51

K3 178.72±0.85 2.34±0.04 2.30 0.51 32 sec 99.27±0.42

K4 180.81±0.63 2.42±0.02 2.30 0.64 57sec 100.61±0.47

K5 179.76±1.30 2.35±0.03 2.25 0.45 36sec 98.83±0.23

K6 180.60±0.76 2.40±0.02 2.22 0.40 20sec 100.83±0.21

K7 179.26±0.72 2.32±0.01 2.45 0.51 47sec 97.56±0.13

K8 178.35±1.30 2.25±0.02 2.35 0.44 30sec 99.63±0.22

K9 181.02±0.03 2.22±0.02 2.25 0.39 18sec 99.27±0.12

*(±S.D)(S.D= Standard deviation)


925


Data of Ketorolac

The prepared tablets containing CP,CCS, sodium starch glycolate ( as super disintegrant

were evaluated for parameters such as Weight variation, Hardness, Friability, Thickness,

drug content, in vitro disintegration time and in vitro dissolution profile was shown in

(Table 24,26).

From the results reported in (Table 24) weight variation was found to be less than±7.5%,

which is the pharmacopoeial limits.

Hardness of formulation was in the range of 2.25 to 2.45 kg/cm2.

The friability value of the formulation was 0.40% to 0.64% the results of friability

indicate that the tablets were mechanically stable, complies with pharmacopoeial limit of

F less than 1%.

Thickness of the formulation was between 2.22±0.01 to 2.42±0.02 mm showing fairly

uniform tablets. Drug content was uniform ranging from 97.56±0.13 to 100.83±0.21, the

in vitro disintegration time was found to be in the range of 18 sec to 1min 10sec.

Table 25 Results of Post compression parameters of Domperidone maleate

Formulation

code

Average

Weight (gms)

(n=20)

Thickness

(mm)

(n=3)

Hardness(k

g/cm2)

(n=3)

Friability

(n=20)

Muco adhesive

strength

(gms)

Drug

content%

D1 199.51±0.87 2.41±0.06 5.7±0.2 0.56 19 99.83±0.2

D2 199.24±0.82 2.45±0.06 5.8±0.3 0.49 23 98.94±0.3

D3 200.09±1.04 2.49±0.02 6.1±0.2 0.63 30 98.12±0.42

D4 199.95±0.94 2.49±0.02 6.2±0.2 0.54 36 99.63±0.25

D5 199.61±0.86 2.42±0.02 5.7±0.3 0.56 13 99.52±0.23

D6 199.40±0.73 2.51±0.04 5.6±0.3 0.38 18 100.83±0.2

D7 199.86±0.57 2.60±0.04 5.5±0.4 0.54 23 99.12±0.26

D8 199.27±0.83 2.62±0.02 6.0±0.2 0.69 26 100.02±0.1

D9 198.58±0.51 2.56±0.02 5.8±0.3 0.54 25 98.7±0.35

D10 199.90±0.93 2.54±0.02 6.0±0.2 0.46 27 99.6±0.29

D11 200.09±1.04 2.52±0.02 5.8±0.3 0.41 28 99.21±0.19


Data of Domperidone maleate: It was observed from (Table. 24) that the prepared tablets

were evaluated for Weight variation, Hardness, Friability, Thickness, muco adhesive

strength, drug content.

Thickness was found to be in the range of 2.42 to 2.62 mm.

Hardness of the tablets was in the range of 5.5±0.2 to 6.2±0.2 kg/cm2 which was

sufficient for the handling of tablets throughout the shelf life.


926


Percentage % friability was between 0.38 – 0.69 % and complies with pharmacopoeial

limit of less than 1%.

Weight variation was found to be than±7.5% which is a pharmacopoeial limit.

Drug content of Domperidone maleate was found to be in the range of 98.12±0.42 to

100.83±0.78%, was within the limits as per I.P and ICH guidelines.

Muco adhesive strength was found to be in the range of 13 -36 gms.

Invitro drug release of ketorolac tablets

Table 26: Cumulative % Drug Release of ketorolac tablets*(n=3,±S.D)( S.D = Standard

deviation).

Time

(min) K1 K2 K3 K4 K5 K6 K7 K8 K9

2 14.23

±1.3

16.2

±1.2

25.3

±1.22

18.32

±1.14

23.11

±1.3

39.02

±1.2

12.04

±1.2

18.04

±1.22

23.04

±1.20

4 25.02

±1.2

30.12

±1.22

38.04

±1.23

33.33

±1.12

40.21

±1.2

56.17

±1.3

28.17

±1.21

32.05

±1.3

39.04

±1.21

6 37.05

±1.2

45.42

±1.1

56.12

±1.32

46.19

±1.21

59.31

±1.24

72.19

±1.21

39.23

±1.27

44.12

±1.26

50.13

±1.14

8 58.13

±1.1

60.21

±1.20

68.14

±1.34

58.42

±1.26

67.52

±1.1

86.25

±1.25

50.22

±1.24

59.16

±1.23

68.14

±1.18

10 69.24

±1.2

72.02

±1.32

79.25

±1.21

71.45

±1.22

80.12

±1.4

95.24

±1.27

63.17

±1.3

74.27

±1.16

77.24

±1.28

12 80.22

±1.3

85.14

±1.25

90.26

±1.20

89.52

±1.18

95.12

±1.32

99.32

±1.31

78.16

±1.32

83.28

±1.12

96.28

±1.17

14 91.17

±1.4

93.17

±1.3

96.28

±1.25

95.23

±1.3

97.04

±1.22

100.0

5±1.2

90.23

±1.1

97.32

±1.22

99.51

±1.21

*(n=3,±S.D)(S.D = Standard deviation)

From the table it can be noted that the drug release of formulations K1,K2,K3 at the end of

14sec was found to be 91.17±1.4, 93.17±1.3 and 96.28±1.25.

The drug release of K4,K5, K6 was found to be 95.23±1.3, 97.04±1.22, 100.05±1.2 at the end

of 14 min.

The drug release of K7, K8, K9 was found to be 90.23±1.1, 97.32±1.22 and 99.51±1.21 at the

end of 14 min.

In formulations K1, K2, K3, CCS was used as super disintegrant with increasing

concentrations of 9mg in K1,13.5 mg in K2 and 18mg in K3.


927


In formulations from K4 to K6,CP was used as super disintegrant with increasing

concentrations of 9mg in K4, 13.5mg in K5 and 18mg in K6. In formulations from K7 to

K9,SSG was used as super disintegrant with increasing concentrations of 9mg in K7,13.5mg

in K8 and 18 mg in K9.

Invitro drug release of Domperidone maleate tablets

Table 27: Cumulative % drug release of Domperidone maleate tablets.

Time

(hrs) D1 D2 D3 D4 D5 D6 D7 D8 D9 D10 D11

1 27.02

±1.1

13.12

±1.2

9.12

±1.22

3.12

±1.12

22.12

±1.24

12.04

±1.23

8.03

±1.21

3.12

±1.1

10.23

±1.16

8.12

±1.1

16.02

±1.36

2 38.12

±1.21

20.20

±1.3

17.12

±1.2

7.13

±1.21

35.16

±1.3

25.21

±1.12

16.04

±1.3

12.23

±1.2

18.11

±1.2

14.02

±1.12

24.13

±1.34

3

43.14

±1.23

31.31

±1.32

26.02

±1.20

14.03

±1.14

46.25

±1.29

32.04

±1.21

24.12

±1.26

18.16

±1.34

27.12

±1.17

20.13

±1.31

32.12

±1.27

4 56.24

±1.16

43.32

±1.24

30.32

±1.23

26.04

±1.23

59.27

±1.26

44.17

±1.21

36.13

±1.11

24.09

±1.22

39.05

±1.14

26.12

±1.26

40.14

±1.26

5 73.26

±1.24

52.21

±1.21

39.12

±1.14

32.52

±1.23

76.21

±1.31

51.31

±1.31

48.21

±1.24

35.91

±1.26

46.54

±1.22

37.34

±1.16

47.02

±1.21

6 82.32

±1.31

67.23

±1.23

45.47

±1.16

39.53

±1.28

80.31

±1.13

66.29

±1.32

63.14

±1.31

39.54

±1.14

57.36

±1.22

41.37

±1.23

53.21

±1.12

7 87.51

±1.29

70.06

±1.26

56.81

±1.11

43.24

±1.29

83.32

±1.20

79.10

±1.21

79.12

±1.22

47.23

±1.22

60.12

±1.28

52.12±

1.42

67.21

±1.23

8 89.53

±1.30

79.12

±1.18

58.23

±1.2

46.36

±1.10

87.13

±1.12

90.12

±1.26

92.05

±1.11

68.12

±1.32

72.23

±1.30

69.44

±1.16

78.22

±1.21


The drug release of Domperidone formulations D1, D2, D3 was found to be 89.53±1.30,

79.12±1.18, 58.23±1.2 at the end of 8hrs.The drug release of D4, D5, D6 was found to be

46.36±1.10, 87.13±1.12 and 90.12±1.26 at the end of 8th

hr. The drug release of D7, D8, D9

at the end of 8 hrs was found to be 92.05±1.11, 68.12±1.32 and 72.23±1.30. The drug release

of D10 and D11 was found to be 69.44±1.16 and 78.22±1.21 at the end of 8th

hr. Carbopol

was used in the formulations from D1 to D4 in increasing concentrations from 40 to 100mg.

CMC was used in the formulations from D5 to D8 in increasing concentrations from 40 to

100mg.

In formulations from D9 to D11 both Carbopol and CMC were used, with equal

concentrations of Carbopol and CMC in D9(40mg of Carbopol and 40mg of CMC)and

uneual quantities of Carbopol and CMC in D10 and (26.6mg of Carbopol and 53.4 mg of

CMC) and 20mg of Carbopol and 60mg of CMC in D11.


928


Table 28: Evaluation of Bilayer Buccal Tablets.

Formulation

Code

Average

weight±S.D(n=20)

Hardness (kg/cm2)

(±S.D)(n=3)

Thickness

(mm)(±S.D)(n=3)

Friability

(%) (n=20)

Drug Content (%)

Ketorolac Domperidone

K6+D6 379.23±0.87 5.7±0.2 4.41±0.06 0.45 100.12±0.2 99.12±0.13

K6+D7 380.12±0.42 5.7±0.3 4.5±0.05 0.51 100.83±0.3 99.95±0.17

K9+D6 378.21±0.12 5.6±0.2 4.23±0.03 0.52 99.42±0.2 99.82±0.21

K9+D7 378.12±0.23 5.5±0.2 4.32±0.04 0.58 99.27±0.4 98.12±0.32


In Vitro DRUG RELEASE OF BILAYER BUCCAL TABLETS

Table 29 Cumulative % Drug Release of Bilayer Buccal Tablets.

Time

Intervals K6+D6 (%) K6+D7(%) K9+D6(%) K9+D7(%)

Ketorolac Domperidone Ketorolac Domperidone Ketorolac Domperidone Ketorolac Domperidone

0min 0 0 0 0 0 0 0 0

2min 38.12±1.24 - 38.16±1.3 - 24.09±1.14 - 25.12±1.12 -

4 min 56.21±1.2 - 55.15±1.13 - 38.91±1.21 - 39.12±1.2 -

6min 71.39±1.3 - 72.13±1.22 - 50.86±1.12 - 50.12±1.4 -

8 min 86.18±1.12 - 86.23±1.21 - 67.87±1.23 - 68.21±1.3 -

10 min 94.25±1.33 - 93.12±1.24 - 75.78±1.24 - 77.12±1.23 -

12 min 99.09±1.24 - 98.12±1.12 - 96.96±1.13 - 95.03±1.27 -

14 min 99.51±1.21 - 100.12±1.16 - 99.5±1.12 - 99.73±1.1 -

1 hrs - 12.09±1.21 - 8.13±1.2 - 13.43±1.13 - 9.12±1.23

2 hrs - 27.63±1.22 - 16.23±1.3 - 26.86±1.22 - 17.12±1.23

3 hrs - 32.89±1.3 - 25.43±1.2 - 31.86±1.23 - 25.09±1.13

4 hrs - 45.36±1.33 - 37.31±1.11 - 44.96±1.24 - 34.12±1. 24

5 hrs - 52.63±1.34 - 49.23±1.23 - 50.47±1.12 - 49.13±1.25

6 hrs - 66.23±1.24 - 64.56±1.21 - 66.37±1.11 - 65.23±1.31

7hrs - 79.02±1.3 - 78.12±1.23 - 80.12±1.21 - 80.02±1.25

8hrs - 90.02±1.14 - 92.57±1.23 - 89.12±1.21 - 91.25±1.13



929


The bilayer tablets prepared by combining K6,K9 of Ketorolac immediate release layer and

D6, D7 of Domperidone sustained release layer were evaluated for weight variation,

hardness, friability, thickness, drug content, in vitro drug release etc. The properties were

shown in the (table 27,28).

Data of Bilayer buccal tablets

The thickness of the tablets was found to be 4.41±0.06, 4.5±0.05, 4.23±0.03, 4.32±0.04

mm.

The hardness of the tablets was found to be 5.7±0.2, 5.7±0.3, 5.6±0.2, 5.5±0.2 kg/cm2 and

was sufficient for the handling throughout the shelf life.

Percentage weight loss (or) % Friability was measured and found to be in the range of

0.45, 0.51, 0.52, 0.58 % and was within the pharmacopoeial limit that is less than 1%.

The tablets passed the weight variation test as per USP limits as they have shown less

than 5% of deviation from their weight.

Drug contents of Ketorolac and Domperidone maleate in the bilayered tablet were found

to 100.12±0.2 and 99.12±0.13, 100.83±0.3 and 99.95±0.17, 99.42±0.2 and 99.82±0.21,

99.27±0.4 and 98.12±0.32 respectively.

For both drugs their drug contents were within the limit as per I.P and ICH guidelines and

have shown good content uniformity.

In vitro dissolution studies

Dissolution profile of bilayer buccal tablets was reported in (Table 28). Dissolution was

performed in pH 6.8 Phosphate buffer for 12 hrs and % drug release was calculated by UV–

spectroscopic method, Ketorolac release occurred initially for 14 min by giving %

99.51±1.21, 100.12±1.16, 99.5±1.12, 99.73±1.1 drug release.

Here, drug release was calculated by measuring absorbance by keeping Domperidone maleate

formulation as blank. Domperidone maleate drug release was measured up to 8 hrs from first

hour by keeping Ketorolac formulation as a blank. Domperidone maleate gave 90.02±1.14,

92.57±1.23, 89.12±1.21, 91.251.13 drug release at the end of 8 hrs.

Out of the four optimised formulations K6+D6,K6+D7,K9+D6,K9+D7, the drug release was

more in case of K6+D7,hence it is considered as the best formulation.


930


Figure 15: Comparison of in vitro dissolution characteristics of Ketorolac K1,K2,K3(×)

(n = 3).


(n = 3).


(n = 3).


931


Figure 18: Comparison of in vitro dissolution characteristics of Domperidone maleate

D1,D2,D3(×) (n = 3).

Figure 19: Comparison of in vitro dissolution characteristics of Domperidone maleate

D4,D5,D6(×) (n = 3).

Figure 20 Comparison of in vitro dissolution characteristics of Domperidone maleate

D7,D8,D9(×) (n = 3).


932


Figure 21: Comparison of in vitro dissolution characteristics of Domperidone

D10,D11(×) (n = 3).

Table 30 In vitro Kinetic Release Characteristics of Formulation (K6+D6).

Time(hours) SQRT

Time Log Time

%

Cumulative

Drug release

%

Cumulative

Drug

remained

Log %

Cumulative

Drug release

Log %

Cumulative

Drug

remained

0 0 0 0 0 0 0

1 1 0 12.09 87.91 1.082 1.944

2 1.414 0.301 27.63 72.37 1.44 1.859

3 1.732 0.477 32.89 67.11 1.517 1.826

4 2 0.602 45.36 54.64 1.656 1.737

5 2.236 0.699 52.63 47.37 1.721 1.675

6 2.44 0.778 66.23 33.77 1.821 1.528

7 2.64 0.845 79.02 20.98 1.897 1.321

8 2.82 0.903 90.02 9.98 1.954 0.999

Figure 22: Zero Order Graph of Optimized Formulation K6+D6.


933


Figure 23: First Order Graph of Optimized Formulation K6+D6.

Figure 24: Higuchi Graph of Optimized Formulation K6+D6.

Figure 25: Korsmeyer - Peppas Graph of Optimized Formulation K6+D6.


934


Table 31: In vitro Kinetic Release Characteristics of Formulation (K6+D7).

Time(hours) SQRT

Time

Log

Time

%

Cumulative

Drug

release

%

Cumulative

Drug

remained

Log %

Cumulative

Drug release

Log %

Cumulative

Drug

remained

0 0 0 0 0 0 0

1 1 0 8.13 91.87 0.91 1.963

2 1.414 0.301 16.23 83.77 1.21 1.923

3 1.732 0.477 25.43 74.57 1.405 1.872

4 2 0.602 37.31 62.69 1.571 1.797

5 2.236 0.699 49.23 50.77 1.692 1.705

6 2.44 0.778 64.56 35.44 1.809 1.549

7 2.64 0.85 78.12 21.88 1.892 1.340

8 2.82 0.903 92.57 7.43 1.966 0.87




935


Figure 28: Higuchi Plot of Optimized Formulation K6+D7.


Table 32: In vitro Kinetic Release Characteristics of Formulation (K9+D6).

Time(hours) SQRT Time Log Time

%

Cumulative

Drug release

%

Cumulative

Drug

remained

Log %

Cumulative

Drug release

Log %

Cumulative

Drug

remained

0 0 0 0 0 0 0

1 1 0 13.43 86.57 1.128 1.937

2 1.414 0.3010 26.86 73.14 1.429 1.864

3 1.732 0.4771 31.86 68.14 1.503 1.833

4 2 0.602 44.96 55.04 1.652 1.74

5 2.236 0.6990 50.47 49.53 1.703 1.694

6 2.44 0.778 66.37 33.63 1.821 1.526

7 2.64 0.85 80.12 19.88 1.903 1.298

8 2.82 0.903 89.12 10.88 1.949 1.036


936




Figure 32: Higuchi plot of Optimized Formulation K9+D6.


937



Table 33: In vitro Kinetic Release Characteristics of Formulation (K9+D7)

Time(hours) SQRT Time Log Time

%

Cumulative

Drug release

%

Cumulative

Drug

remained

Log %

Cumulative

Drug release

Log %

Cumulative

Drug

remained

0 0 0 0 0 0 0

1 1 0 9.12 90.88 0.959 1.958

2 1.414 0.301 17.12 82.88 1.233 1.918

3 1.732 0.477 25.09 74.91 1.399 1.874

4 2 0.602 34.12 65.88 1.533 1.818

5 2.236 0.699 49.13 50.87 1.691 1.706

6 2.44 0.778 65.23 34.77 1.814 1.541

7 2.64 0.85 80.02 19.98 1.903 1.300

8 2.82 0.903 91.25 8.75 1.960 0.942

Figure 34: Zero order graph of optimised formulation K9+D7.


938


Figure 35: First order graph of optimised formulation K9+D7.

Figure 36: Higuchi graph of optimised formulation K9+D7.

`

Figure 37: Korsmeyer - Peppas graph of optimised formulation K9+D7


939


Table 34: Results of Kinetic Studies for Optimized Bilayer Buccal Tablets

S.no Formulation Zero

Order R2

First

Order R2

Higuchi

R2

Koresmeye

r Peppas R2

N Mechanism of Drug

Release

1 K6+D6 0.994 0.712 0.914 0.694 0.865 Zero order release,

Non fickian diffusion


Erosion

3 K9+D6 0.992 0.707 0.908 0.696 0.848 Zero order release,non

fickian diffusion


erosion *

R2 = Correlation coefficient; n= Diffusional exponent

KINETIC STUDY FOR DOMPERIDONE BUCCAL SR LAYER OF BILAYER

TABLET

The release rate kinetic data for K6+D6, K6+D7, K9+D6, K9+D7 is shown in (Table

29,30,31,32). As shown in (Figures 22-37), drug release data was best explained by zero

order equation, as the plots showed the highest linearity (R2 = 0.994), (R

2 = 0.987), (R

2 =

0.992), (R2 = 0.981) followed by and Higuchi’s equation (R

2 = 0.914), (R

2 = 0.847), (R

2 =

0.908), (R2 = 0.841). As the drug release was best fitted in zero order kinetics, indicating that

the rate of drug release is concentration independent. Higuchi’s kinetics explains why the

drug diffuses at a comparatively slower rate as the distance for diffusion increases.

Mechanism of drug release

In order to understand the complex mechanism of drug release from the K6+D6,

K6+D7,K9+D6, K9+D7, the % in vitro drug release was fitted into Korsmeyer - peppas

model and the diffusional exponent value (n) was interpreted for mechanism of drug release.

The release exponent value (n) thus obtained was 0.865, 0.955, 0.848, 0.932 therefore, we

can conclude that K6+D6,K9+D6 follows non- Fickian Transport, with Zero order, Higuchi

mechanism and K6+D7,K9+D7 follows Zero order, Higuchi mechanism with erosion release.

STABILITY STUDIES

The formulations (K6+D6), (K6+ D7), (K9+D6),(K9+D7) were evaluated for stability by

conducting accelerated stability studies. The formulation were stored at 40o C at 75% RH for

2 months and analyzed for their physical parameters and drug content and in vitro drug

release studies at every one month interval. The data was shown in the (Table 34,35).


940


Table 35: Characteristics of Bilayer Buccal Tablets during Stability Studies.

Time

Drug content(%) Hardness (kg/cm

2)

Ketorolac Domperidone

K6+

D6 K6+D7 K9+D6 K9+D7 K6+D6 K6+D7 K9+D6

K9+

D7 K6+D6

K6+

D7 K9+D6

K9+

D7

Zeromonth 100.9±0.12 100.77±0.65 99.39±0.56 99.24±0.12 99.07±0.31 99.91±0.46 99.76±0.42 98.1±0.31 5.7±0.1 5.7±0.2 5.6±0.2 5.5±0.2

First month 99.77±0.53 99.81±0.38 98.25±0.24 98.16±0.35 98.42±0.27 98.91±0.28 98.57±0.35 97.42±0.28 5.65±0.1 5.67±0.2 5.55±0.2 5±0.1

Twomonth 99.29±0.26 99.46±0.19 98.16±0.32 98.05±0.15 98.12±0.13 98.57±0.17 98.12±0.13 97.11±0.17 5.6±0.3 5.61±0.1 5.5±0.3 4.9±0.3


Table 36: Characteristics of Bilayer buccal Tablets during Stability Studies.

Time Friability (%) In Vitro Drug Release at the end of 8 hrs

K6+D6 K6+D7 K9+D6 K9+D7 K6+D6 K6+D7 K9+D6 K9+D7

Zero month 0.41 0.48 0.51 0.56 90±0.58 92.35±0.34 89.1±0.54 91.12±0.12

First month 0.35 0.46 0.48 0.51 89.56± 0.61 92.15±0.32 88.89±0.52 90.99±0.21

Two month 0.31 0.41 0.45 0.48 89.12±0.45 92.07±0.12 88.65±0.65 90.85±0.35



941


CONCLUSION

In the present study an attempt was made to design a biphasic Bilayer buccal Tablet

containing Ketorolac immediate release layer and Domperidone maleate sustained release

layer. FT-IR studies reveal that there were no significant interactions between both the drugs

and between the drugs and their respective excipeints. For achieving sustained release of

Domperidone maleate, bucco adhesive polymers Carbopol and CMC were used Formulations

D6 and D7 gave drug release 90.12±1.26 and 92.15±1.11 after 8hrs. Therefore D6 and D7

were considered as best formulations among D1 –D 11 for formulation of bilayer buccal

tablets.

For achieving immediate result of Ketorolac, from the results it was concluded that

disintegration activity is good with Crosspovidone and SSG, K6 releasing 100. 05±1.2 and

K9 releasing 99.51±1.21 % after 14min. The bilayered tablets prepared by taking D6 and D7

of Domperidone maleate and K6 and K9 formulations of Ketorolac as 2layers

(K6+D6,K6+D7,K9+D6,K9+D7) have shown good post compression parameters like

hardness, friability weight variation, drug content etc which were within the limits. Hence

they are considered as optimized formulations.

Out of the four optimized formulations, K6+D7 showed good % drug release, hence it is

considered as the best formulation. The stability study indicates that the formulations were

stable. From this study by preparing bilayer buccal tablets by direct compression technique, it

was concluded that we could reduce the total dose, dosage frequency, dose related side

effects, and improve the bioavailability of Domperidone maleate which in turn improves the

patient compliance. Future scope for this study is the scaling up for industrial applications.

REFERENCES

1. Joseph A. DiMasi et al., The price of innovation: new estimates of drug development

costs, Journal of Health Economics, 2003; 22: 151-185.

2. Shojaei AH. Buccal mucosa as a route for systemic drug delivery: a review. J Pharm

Pharmaceut Sci, 1998; 1: 15-30.

3. Rossi Silvia et al. Buccal drug delivery: A challenge already won?. Drug Discov Today

Technol, 2005; 2(1): 59-65.

4. Andrews Gavin P. et al. Mucoadhesive polymeric platforms for controlled drug delivery

Eur J Pharm Biopharm, 2009; 71: 505-518.


942


5. Yajaman S et al. Buccal bioadhesive drug delivery: A promising option for orally less

efficient drugs. J Control Release, 2006; 114: 15-40.

6. Dixit RP, Puthli SP. Oral strip technology: Overview and future potential. J Control

Release, 2009; 139: 94-107.

7. Lee Jin W et al. Bioadhesive-based dosage forms: the next generation. J. Pharm. Sci,

2000; 89: 850-866.

8. Colonna Claudia. Innovative drug delivery system for challenging molecules. Scientifica

Acta, 2007; 1(1): 70-7.

9. Khairnar GA, Sayyad FJ. Development of buccal drug delivery system based on

mucoadhesive polymer. International Journal of Pharm Tech Research, 2010; 2(1):

719- 735.

10. Madhav NV, Satheesh et al., Orotransmucosal drug delivery systems: A review. J Control

Release, 2009; 140: 2-11.

11. Vyas SP and Khar RK. Controlled drug delivery concepts and advances. 1st Ed., New

Delhi; Vallabh Prakashan, 2002.

12. Bhalodia Ravi et al., Buccoadhesive drug delivery Systems: A review. International

Journal of Pharma and Bio Sciences, 2010; 1(2): 1-32.

13. Obradovic T, Hidalgo Ismael J. Drug Absorption Studies Biotechnology. Pharmaceutical

Aspects, AAPS Press, 2008; 7(2): 167-181.

14. Junginger HE et al. Recent advances in buccal drug delivery and absorption- in vitro and

in vivo studies. J Control Release, 1999; 149: 149-159.

15. Edith Matiowitz, The Encyclopedia of drug delivery. 1st Ed., In: Mucosal drug delivery,

Buccal, New York; John Wiley & Sons Inc, 1999; 2: 553.

16. Yie Chien W. Novel Drug Delivery Systems. New York; Marcel Dekker Inc, 2009;

183-185.

17. Shojaei, Amir H, Chang, Richard K, Guo, Xiaodi, Burnside, Beth A, Couch, Richard A.

Systemic drug delivery via the buccal mucosal route. Pharmaceutical technology 2001,

www.pharmaportal.com, 70-81.

18. Rossi Silvia et al. Buccal drug delivery: A challenge already won?. Drug Discov Today

Technol, 2005; 2(1): 59-65.

19. Haris D, Robinson JR. Drug delivery via the mucous membrane of the oral cavity.

J.Pharm. Sci, 1992; 81: 1-10.

20. Gandhi, R.E. and Robinson, J.R., Bioadhesion in drug delivery, Ind J Pharm. Sci, 1988;

50: 145-152.


943


21. Harris, D. and Robinson, J R drug delivery via the mucous membrane of the oral cavity,

J.Pharm, Sci., 1992; 81: 1-10. Reproduced with permission of the American

Pharmaceutical Association

22. Wertz, P. W and Squier, C.A., Cellular and molecular basis of barrier function in oral

epithelium, Crit. Rev. Ther. Drug Carr. Sys, 1991; 8: 237-269.

23. Squier, C.A., Cox, P., and Wertz, P W., Lipid content and water permeability of skin and

oral mucosa, The J.Invest Dermat, 1991; 96: 123-126.

24. Squier, C.A. and Wertz, P. W. Structure and function of oral mucosa and implications for

drug delivery, in eds. M. J. Rathbone, Oral mucosal drug delivery, Marcel Dekker, Inc.,

Newyork, Newyork, 1-26, 1996.

25. Jain NK. Controlled and Novel drug delivery. 1st Ed., New Delhi; CBS publishers, 1997;

52-53.

26. Sangeetha S, Nagasamy Venkatesh D, Krishnan PN, Saraswathi R. Mucosa as a route for

systemic drug delivery. RJPBCS, 2010; 13: 178-83.

27. Prasanth VV, Sirisha Mudiyala, Sam T Mathew, Rinku Mathapan. Buccal tablet-As

mucoadhesive drug delivery: An overview. Journal of Pharmacy Research, 2011; 4(3):

706-709.

28. Bruschi ML, Osvaldo F. Oral bioadhesive drug delivery systems. Drug development and

Industrial Pharmacy, 2005; 31(3): 293-310.

29. Wani Manish S. Current status in buccal drug delivery system, Pharmainfo.net, 2007;

5(2).

30. Galey, W.R., Lonsdale, H.K., and Nacht, S., The in vitro permeability of skin and buccal

mucosa to selected drugs and tritiated water, J. Invest. Dermat, 1976; 67: 713-717.

31. Harris, D. and Robinson, J.R., Drug delivery via the mucous membranes of the oral

cavity, J. Pharm. Sci, 1992; 81: 1-10. Reproduced with permission of the American

Pharmaceutical Association.

32. Gandhi, R.B. and Robinson, J.R., Oral cavity as a site for bioadhesive drug delivery, Adv.

Drug Del. Rev, 1994; 13: 43-74.

33. Wertz, P.W. and Squier, C.A., Cellular and molecular basis of barrier function in oral

epithelium, Crit. Rev. Ther. Drug Carr. Sys, 1991; 8: 237-269.

34. Peppas, N.A. and Buri, P.A., Surface, interfacial and molecular aspects of polymer

bioadhesion on soft tissues, J. Control. Rel, 1985; 2: 257-275.

35. Rathbone, M., Drummond, B., and Tucker, I., Oral cavity as a site for systemic drug

delivery, Adv. Drug Del. Rev, 1994; 13: 1-22.


944


36. Fiebrig I. et al. Transmission electron microscopy studies on pig gastric mucin and its

interactions with chitosan. Carbohydr. Polym, 1995; 28: 239-244.

37. Flavia CC, Marcos LB, Raul CE, Maria Palmira Daflon Gremião. Mucoadhesive drug

delivery systems. Brazilian J. Pharm. Sci, 2010; 46(1): l-17.

38. Bhatt JH. Designing and evaluation of mucoadhesive microspheres of metronidazole for

oral controlled drug delivery. Pharmainfo.net, 2009; 2: 1-13.

39. Sheila A. Bioadhesive Polymers, Power Point Presentation, Slide No.1-50.

userweb.port.ac.uk/~roldom/Mucoadhesives/Bioadhesives.ppt.

40. Sharma HK, Sarangi B, Pradhan, Prasad S. Preparation and in-vitro evaluation of

mucoadhesive microbeads containing Timolol Maleate using mucoadhesive substances of

Dillenia indica L. Arch. Pharm. Sci. Res, 2009; 1: 181-188.

41. Smart, JD. The basics and underlying mechanisms of mucoadhesion. Sci. Dir, 2005;

57(11): 1556-1568.

42. Ugwoke MI, Agu RU, Verbeke N, Kinget R. Nasal mucoadhesive drug delivery:

background, applications, trends and future perspectives. Adv. Drug Del. Rev, 2005; 57:

1640–1665.

43. Lee JW, Park JH, Robinson JR. Bioadhesive-based dosage forms: The next generation. J

Pharm. Sci, 2000; 89(17): 850-866.

44. Shojaei A, Li X. Mechanisms of buccal mucoadhesion of novel copolymers of acrylic

acid and polyethylene glycol monomethylether monomethacrylate. J. Control Rel, 1997;

47: 151–161.

45. Dodou D, Breedveld P, Wieringa P. Mucoadhesives in the gastrointestinal tract: revisiting

the literature for novel application. Eur. J. Pharm. Biopharm, 2005; 60: 1–16.

46. Kinloch AJ. The science of adhesion. J. Mater. Sci, 1980; 1: 2141–2166.

47. Smart, JD. The basics and underlying mechanisms of mucoadhesion. Sci. Dir, 2005;

57(11): 1556-1568.

48. Jabbari E, Peppas NA. A model for inter diffusion at interfaces of polymers with

dissimilar physical properties. Polymer, 1995; 36(3): 575–586.

49. Ludwig A. The use of mucoadhesive polymers in ocular drug delivery. Adv. Drug Del.

Rev, 2005; 57: 1595–1639.

50. Chickering-III DE, Mathiowitz E. Fundamentals of bioadhesion. In Bioadhesive drug

delivery systems-Fundamentals, Novel Approaches and Development. Mathiowitz E,

Chickering-III DE, Lehr CM (eds.), Dekker M, 1999; 1-85.


945


51. Bredenberg S, Nystrom C. In vitro evaluation of bioadhesion in particulate systems and

possible improvement using interactive.

52. Bredenberg S, Nystrom C. In vitro evaluation of bioadhesion in particulate systems and

possible improvement using interactive mixtures. J. Pharm. Pharmacol, 2003; 55:

169-177.

53. R. Khanna, S. P. Agrawal and Alka Ahuja. “Mucoadhesive Buccal drug delivery A

potential alternative to conventional thereapy.” Indian Journal of pharmaceutical scienes,

1998; 60(1): 1-11.

54. Marcos Luciano Bruschi, Osvaldo de Freitals “oral bioadhesive drug delivery systems”,

Drug Development and Industrial Pharmacy, 2005; 31: P 293-310.

55. Smart JD. An in vitro assessment of some mucosaadhesive dosage forms. Int J Pharm,

1991; 73: 69-74.

56. Patil SB, Murthy RSR, Mahajan HS, Wagh RD, Gattani SG. Mucoadhesive polymers:

Means of improving drug delivery. Pharma Times, 2006; 38(4): 25-28.

57. Andrews GP, Laverty TP, Jones DS. Mucoadhesive polymeric platforms for controlled

drug delivery. Eur. J. Pharm. Biopharm, 2009; 71: 505–518.

58. Sakkinen M, Marvola J, Kanerva H, Lindevall K, Ahonen A, Marvola M. Are chitosan

formulations mucoadhesive in the human small intestine? An evaluation based on gamma

scintigraphy. Int. J. Pharm, 2006; 307: 285–291.

59. Lehr CM. Bouwstra JA., Kok W, De Boer AG., Tukker JJ., Verboet JC., Breimer DD.,

Junginger HE. J. Pharm. Pharmacol, 1992; 44: 402.

60. Matharu RS, Sanghavi NM. Novel drug delivery system for captopril. Drug Dev. Ind.

Pharm, 1992; 18: 1567-74.

61. Krauland A, Guggi D, Bernkop SA. Oral insulin delivery: the potential of thiolated

chitosan–insulin tablets on non-diabetic rats. J. Control Rel, 2004; 95: 547–555.

62. Patel VM, Prajapati BG, Patel MM. Formulation, evaluation, and comparison of bilayered

and multilayered mucoadhesive buccal devices of propranolol hydrochloride. AAPS

Pharm. Sci. Tech, 2007; 8(1): 147-154.

63. Hoogstraate JJ, Wertz P, Wertz P. Drug delivery via the buccal mucosa. Pharm. Sci.

Tech, 1998; 1: 309–316.

64. Saettone M, Salminen L. Ocular inserts for topical delivery. Adv. Drug Deliv. Rev, 1995;

95: 95–106.


946


65. Nakamura K, Maitani Y, Lowman A, Takayama K, Peppas N, Nagai T. Uptake and

release of budesonide from mucoadhesive, pH-sensitive copolymers and their application

to nasal delivery. J. Control Rel, 1999; 61: 329–335.

66. Soane RJ, Frier M, Perkins AC, Jones NS, Davis SS, Illum L. Evaluation of the clearance

characteristics of bioadhesive systems in humans. Int. J. Pharm, 1999; 178: 55–65.

67. Krauland A, Guggi D, Bernkop SA. Thiolated chitosan microparticles: A vehicle for

nasal peptide drug delivery. Int. J. Pharm, 2006; 307: 270–277.

68. Alpar HO, Somavarapu S, Atuah KN, Bramwell VW Biodegradable mucoadhesive

particulates for nasal and pulmonary antigen and DNA delivery. Adv. Drug Deliv. Rev,

2005; 57: 411–430.

69. Carlfors J, Edsman K, Petersson R, Jornving K. Rheological evaluation of Gelrite in situ

gels for ophthalmic use. Eur. J. Pharm. Sci, 1998; 6: 113–119.

70. Wei G, Xu H, Ding P, Li S, Zheng J. Thermosetting gels with modulated gelation

temperature for ophthalmic use: the rheological and gamma scintigraphic studies. J.

Control Rel, 2002; 83: 65–74.

71. Valenta C, Kast C, Harich I, Bernkop-Schnürch A. Development and in vitro evaluation

of a mucoadhesive vaginal delivery system for progesterone. J. Control Rel, 2001; 77:

323–332.

72. Robinson J, Mlynek G. Bioadhesive and phase-change polymers for ocular drug delivery.

Adv. Drug Deliv. Rev, 1995; 16: 45–50.

73. Patil SB, Murthy RSR, Mahajan HS, Wagh RD, Gattani SG. Mucoadhesive polymers:

Means of improving drug delivery. Pharma Times, 2006; 38(4): 25-28.

74. Leede LGJ, Boer AG, Portzgen E, Feijen J, Bremier DD. J. Control. Rel, 1986; 4: 17.

75. Wikipedia, The free encyclopedia, http://en.wikipedia.org/wiki.

76. Batchelor H novel bio adhesive formulations in drug delivery, The drug delivery

companies Report Autumn/Winter, Pharma ventures ltd, 2004.

77. Haris D, Robinson JR. Drug delivery via the mucous membrane of the oral cavity. J.

Pharm. Sci., 1992; 81: 1-10.

78. Giunchedi et al. Formulation and in vivo evaluation of Chlorhexidine buccal tablets

prepared using drug-loaded chitosan microspheres. Eur. J. Pharm. Biopharm, 2002; 53:

233-239.

79. Wong et al. Formulation and evaluation of controlled release Eudragit buccal patches. Int.

J. Pharm, 1999; 178: 11-22.


947


80. Arakawa Y et al. Effect of low-molecular-weight β-cyclodextrin polymer on release of

drugs from mucoadhesive buccal film dosage form. Biol Pharm Bull, 2005; 28:

1679-1683.

81. Arakawa Y et al. Effect of low-molecular-weight β-cyclodextrin polymer on release of

drugs from mucoadhesive buccal film dosage form. Biol Pharm Bull, 2005; 28:

1679- 1683.

82. http://emc.medicines.org.uk/medicine/18302/XPIL/Buccastem(accessedon10th

Nov 2009).

83. http://www.forestlabs.com/products/prescription/suscard buccal tablets/spc(accessed on

10th

Nov 2009).

84. http://www.actiq.com(accessed on 10th

Nov 2009).

85. http://www.drugs.com/nda/loramyc-090819.html(accessed on 10Nov 2009).

86. http://www.access data.fda.gov/scripts/cder/drugsatfda/index.cfm fuseaction=Search.

Drug Details.

87. Smart J.D.Buccal drug delivery.Expert opinion Drug Del, 2005; 2(3): 507-517.

88. http://www.net doctor.co.uk/medicines/100000608.html(accessed on 10th

Nov 2009).

89. http://home.intekom.com/pharm/bm-squib/orabase.html(accessed on 10th

Nov 2009).

90. http://www.net doctor.co.uk/medicines/100000611.html(accessed on 10th

Nov 2009).

91. http://www.bonjela.co.uk(accessed on 10th

Nov 2009).

92. Leon Lachman, Herbert A.lieberman, Joseph L.kanic, The theory and practice of

industrial pharmacy, Varghese publishing house, third edition, 293-345.

93. en.wikipedia.org/wiki/migraine.

94. en.wikipedia.org/wiki/migraine.

95. Vishnu M. Patel,1 Bhupendra G. Prajapati,2 Harsha V. Patel,3 and Karshanbhi M. Patel 4

Mucoadhesive Bilayer Tablets of Propranolol Hydrochloride AAPS Pharm Sci Tech,

2007; 8(3): Article 77

96. Luana Perioli,1 Valeria Ambrogi,1 Stefano Giovagnoli,1 Maurizio Ricci,1 Paolo Blasi,1

and Carlo Rossi1 Mucoadhesive Bilayered Tablets for Buccal Sustained Release of

Flurbiprofen AAPS Pharm Sci Tech, 2007; 8(3): Article 54.

97. Balamurugan M1, Saravanan VS1, Ganesh P*1, Senthil SP1, Hemalatha PV1 and Sudhir

Pandya2 Development and In-vitro Evaluation of Mucoadhesive Buccal Tablets of

Domperidone Research J. Pharm. and Tech, Oct.-Dec. 2008; 1(4).

98. Ashwini Madgulkar, Shivajirao Kadam, Varsha Pokharkar Development of trilayered

mucoadhesive tablet of itraconazole with zero-order release research article year, 2008;

2(1): 57-60.

http://www.asiapharmaceutics.info/searchresult.asp?search=&author=Ashwini+Madgulkar&journal=Y&but_search=Search&entries=10&pg=1&s=0

http://www.asiapharmaceutics.info/searchresult.asp?search=&author=Shivajirao+Kadam&journal=Y&but_search=Search&entries=10&pg=1&s=0

http://www.asiapharmaceutics.info/searchresult.asp?search=&author=Varsha+Pokharkar&journal=Y&but_search=Search&entries=10&pg=1&s=0


948


99. JG Hiremathi*, MD Sarfarazi, D Hiremathi, SA Sarudkar Preparation and

Physicochemical Characterization of Simvastatin Loaded Mucoadhesive Bilayered Tablet

research article Indian Journal of Novel Drug Delivery, Oct-Dec, 2009; 1(1): 18-24.

100. GV. Wadageri1*, SA. Raju2, SB. Shirsand2 and P. Vijay Prakash Reddy Development

and Evaluation of Mucoadhesive Bilayer Buccal Tablets of Carvedilol research article

International Journal of Research in Pharmaceutical and Biomedical Sciences ISSN:

2229-3701.

101. K.Shivanand1*, S.A.Raju2, B.Jaykar3 Mucoadhessive Bilayered Buccal Tablets of

Tizanidine Hydrochloride International Journal of Pharm Tech Research CODEN

(USA): IJPRIF ISSN: 0974-4304 Vol.2, No.3, pp 1861-1869, July-Sept 2010.

102. Bhanja Satyabrata*1, P Ellaiah1, Rohit Choudhury1, KVR Murthy2,Panigrahi

Bibhutibhusan3, Martha Sujit Kumar1 Design and evaluation of methotrexate buccal

mucoadhesive patches Research article Int J Pharm Biomed Sci, 2010; 1(2): 31-36.

ISSN No: 0976-5263

103. Narasimha Reddy D*1, Srinath MS2, Hindustan Abdul Ahad*3, Sravanthi M3 and

Kavitha K3 Formulation and in vitro Evaluation Glimepiride and Parecoxib

Mucoadhesive Tablets for diabetics associated with pain and inflammation Pelagia

Research Library Der Pharmacia Sinica, 2011; 2(2): 101-109.

104. Swamy P.V.*, Kinagi M. B., Biradar S. S., Gada S. N. and Shilpa H Formulation

Design and Evaluation of Bilayer Buccal Tablets of Granisetron Hydrochloride Ind J

Pharm Edu Res, Jul-Sept, 2011; 45(3).

105. T Banerjee*1, V. Muruganantham1, B. S. Venkateswarlu1 and B Jayker1 Formulation

and Evaluatiion of Mucoadhesive Tablets of NSAID combination with Proton pump

inhibitor IJPRD, November 2011; 3(8): 160- 169.

106. Preeti Karwa*1, P. V. Kasture2 Formulation and in vitro evaluation of Bilayer Tablets

of Zolpidem tartrate for Biphasic Drug Release International Journal of Pharm Tech

Research, Oct-Dec 2011; 3(4): 1919-1929.

107. Pranjal Kumar Singh*1, V. K. Shukla 2, T.S. Easwari 3, Sanjoo Kumar 4, Ramkumar

Chaudary 5, Alok Nath Sharma 6, Saurabh Saraswath 7 Formulation Development and

Evaluation of Mucoadhesive oral dosage form containing Clarithromycin using

different Mucoadhesive Polymers International Journal of Pharmaceutical Science and

health care, April 2012; 2(2).

108. EL-Nabarawai M.A1, Makky A.M1, EL-Setouhy D. A1, ABD Elmonem R. A2 and

Jasti B.A3 Development and Characterisation of Ketorolac Tromethamine (KT)


949


Orobuccal films International Journal of Pharmacy and Pharmaceutical Sciences ISSN-

0975-1491 Vol 4, Issue 4, 2012 research article.

109. Songa Ambedkar Sunil; Meka Venkata Srikanth; Nali Sreenivasa Rao; Sakamuri Balaji;

Kolapalli Venkata Ramana Murthy Design and evaluation of lornoxicam bilayered

tablets for biphasic release Braz. J. Pharm. Sci, Oct./Dec. 2012; 48(4): São Paulo.

110. Uday Kumar N, Harish G, Duraivel S, Debijet Bhowmik; Ketorolac trimethamine fast

dissolving tablets – Formulation and Evaluation Journal of Chemical and

Pharmaceutical sciences ISSN: 0974-2115.

111. Yuwaraj Dilipsingh Dixit*, Pravin Babarao Suruse, Umesh Dhaniram Shivhare

Formulation and Evaluation of Muco adhesive tablet of Domperidone Maleate research

article Indonesian J. Pharm, 24(1): 47–55 ISSN-p: 0126-1037.

112. http://en.wikipedia.org/wiki/Domperidone.

113. http://www.drugs.com/cons/domperidone.html.

114. http://www.drugs.com/pro/ketorolac.html.

115. http://en.wikipedia.org/wiki/Ketorolac.

116. http://en.wikipedia.org/wiki/Microcrystalline_cellulose.

117. Raymond CR, Paul JS, Sian CO. Handbook of Pharmaceutical excipients. 5th

ed.London: Pharmaceutical Press; 2006.

118. http://www.nbent.com/crosscarmellose.htm.

119. http://www.ordonearresearchlibrary.org/Data/pdfs/IJDFR216.pdf.

120. http://en.wikipedia.org/wiki/Vanillin.

121. http://en.wikipedia.org/wiki/Citric_acid.

122. http://en.wikipedia.org/wiki/Magnesium_stearate.

123. http://en.wikipedia.org/wiki/Mannitol.

124. http://www.carbomer.info/.

125. http://en.wikipedia.org/wiki/Carboxymethyl_cellulose.

126. http://en.wikipedia.org/wiki/ sodium starch glycolate.

127. Leon Lachman, Herbert A.lieberman, Joseph L.kanic, The theory and practice of

industrial pharmacy, Varghese publishing house, third edition, 293-345.

128. Yuwaraj Dilipsingh Dixit*, Pravin Babarao Suruse, Umesh Dhaniram Shivha

Formulation and Evaluation of Mucoadhesive buccal tablet of Domperidone maleate

Indonesian J. Pharm. 24(1): 47–55. 0126-1037.

http://en.wikipedia.org/wiki/Ketorolac

Documents

World Journal of Pharmaceutical Research et al. World ... · Venkataswamy et al. World Journal of Pharmaceutical Research PREPARATION AND EVALUATION OF BIPHASIC BILAYERED ... Transmucosal