3. Review of Literature

3.1. DRUG PROFILE OF KETOROLAC TROMETHAMINE

Chemical Structure:

Chemical name:5-(benzoyl)-2,3-dihydro-1H-pyrrolizine-1-carboxylicacid

Molecular formula: C15H13NO3

Molecular weight: 255.268

Description:

Melting point: 165-1670C

State: Solid

Category: Anti-Inflammatory Agent, Non-Steroidal, Cyclooxygenase inhibitors

Solubility in Water: 200 g/l

Dose: 10 mg given three to four times a day orally

Storage: Store in a cool and dry place

Pharmacology: Ketorolactromethamine (KT), an anti-inflammatory agent with analgesic

and anti-pyretic properties, is used to treat osteoarthritis and control acute pain. It is a

peripherally acting analgesic. The biological activity of ketorolac tromethamine is

associated with the S-form. Ketorolac tromethamine possesses no sedative or anxiolytic

properties.

Indications: For the short-term management of moderately severe acute pain that

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

Contraindications: Ketorolac (KT) is contraindicated in patients with a

previously demonstrated hypersensitivity to ketorolac and in patients with the complete

or partial syndrome of nasal polyps, angioedema, bronchospastic reactivity or other

allergic manifestations to aspirin or other non-steroidal anti-inflammatory drugs (due to

possibility of severe anaphylaxis). Ketorolac should be avoided with all NSAID’s in

patients with renal dysfunction. Further it use in patients at highest risk was detrained

especially in elderly and those with fluid imbalances or with compromised renal function

(e.g., heart failure, diuretic use, cirrhosis, dehydration, and renal insufficiency).

Mechanism of action: The anti-inflammatory effects of KT was due to inhibition

of both cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) pathways. It leads

to inhibition of prostaglandin synthesis with 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 and therapeutic, effects. Analgesia is probably produced peripherally due to

blockade of pain impulse generation results from decreased prostaglandinactivity.

Table 3.1.1. Pharmacokinetic properties of ketorolac tromethamine

PARAMETER DATA

Absorption Rapidly and completely absorbed after oral

administration

Bioavailability 100% (All routes)

Site of absorption Throughout the GIT

Plasma protein binding 99%

Biotransformation Primarily hepatic. Less than 50% of a dose is

metabolized. The major metabolites are a

glucuronate conjugate, which may also be

formed in the kidney, and p-hydroxy

ketorolac. Neither metabolite has significant

analgesic activity.

Route of excretion Renal: 91.4% (mean)

Biliary: 6.1% (mean)

Biological half life 2.5-5 hours

BCS class Class I

Table 3.1.2. Toxic effects of ketorolac tromethamine

BODY SYSTEMS EFFECTS

General Edema Less frequentlyhypersensitivity reactions (such as

anaphylaxis, bronchospasm, laryngeal edema, tongue edema,

hypotension), flushing, weight gain, or fever. Very infrequently,

asthenia

Cardiovascular Hypertension. Less frequently, palpitation, pallor, or fainting

(syncope

Dermatalogic Rash or pruritus. Less frequently, Lyell's syndrome, Stevens-

Johnson syndrome, musculo-papularrash, exfoliative dermatitis.

Gastrointestinal Less frequently, peptic ulceration, gastrointestinal hemorrhage,

gastrointestinal perforation, melena, rectal bleeding, gastritis.

Table 3.1.3. Drug interactions of ketorolac tromethamine

DRUG INTERACTION

Acenocoumarol The NSAID increases the anticoagulant effect

Alendronate Increased risk of gasrtic toxicity

Anisindione The NSAID increases the anticoagulant effect

Aspirin Increases toxicity of ketorolac

Dicumarol The NSAID increases the anticoagulant effect

Lithium The NSAID increases serum levels of lithium

Methotrexate The NSAID increases the effect and toxicity of

methotrexate

Probenecid Probenecid increases toxicity of ketorolac

Warfarin The NSAID increases the anticoagulant effect

3.2. DRUG PROFILE OF ACECLOFENAC[48]

Drug Aceclofenac

IUPAC name 2-[[2-[2-[(2, 6-dichlorophenyl) amino] phenyl] acetyl]

oxy] acetic acid

CAS name 2-[(2,6-Dichlorophenyl)amino]benzeneacetic acid

carboxymethyl ester

CAS number 89796-99-6.

Chemical structure

Molecular formula C16H13Cl2NO4

Molecular weight 354.18472 g/mol

Description A white or almost white crystalline powder

Melting point 149 - 153˚C

Solubility Insoluble in water, freely soluble in acetone, soluble

in 96% ethanol.

Dose The usual dose is 100 mg given twice daily by

mouth, one tablet in the morning and one in the

evening.

Specifications

Loss on drying : ≤0.5%

Heavy metals : ≤10ppm

Sulphated ash : ≤0.1%

Assay : 99.0%-101.0%

Pharmacokinetics

Aceclofenac is rapidly and completely absorbed after

oral administration, peak plasma concentrations are

reached 1 to 3 hours after an oral dose. Aceclofenac is

metabolized to a major metabolite, 4'-

hydroxyaceclofenac and to a number of other

metabolites including 5-hydroxyaceclofenac, 4'-

hydroxydiclofenac, diclofenac and 5-

hydroxydiclofenac.

Oral bioavailability : nearly 100%

Effect of food : Rate of absorption will

be reduced

Protein binding : 99 %

Volume of distribution : approximately 25 litres.

Peak plasma concentration : 1-3 hours.

Plasma elimination half-life: 2-4 hours.

Metabolism : 20% primary

Steady state concentration : 3 days.

Urinary clearance : 20 %

Fecal clearance : 20 %

PHARMACODYNAMICS

Anti – inflammatory

activity

Aceclofenac relieves pain and inflammation through a

variety of mechanisms and in addition exerts

stimulatory effects on cartilage matrix synthesis.

The anti-inflammatory effects of aceclofenac have

been shown in both acute and chronic inflammation.

It inhibits various mediators of pain and inflammation

including:

PGE2 via cyclooxygenase inhibition after

intracellular metabolism to 4’ hydroxy-

aceclofenac and diclofenac in human

rheumatoid synovial cells and other

inflammatory cells.

IL-1β, IL-6 and tumor necrosis factor in

human osteoarthritic synovial cells and

human articular chondrocytes.

Reactive oxygen species has also been

observed in patients with osteoarthritis of

knee.

Expression of cell adhesion molecules has

also been shown in human neutrophils.

Drug interactions

It may increase plasma concentrations of lithium,

digoxin and methotrexate, increase the activity of

anticoagulant, inhibits the activity of diuretics,

enhance cyclosporin nephrotoxicity and precipitate

convulsions when co-administered with quinolone

antibiotics.

Adverse drug reactions

Most common events include dyspepsia, abdominal

pain, nausea, diarrhoea, flatulence, gastritis,

constipation, vomiting, ulcerative stomatitis,

pancreatitis. Other adverse effects, which are not

common, are dizziness, vertigo, and tremor.

Clinical efficacy

In osteoarthritis

In large trials of 2 to 6 months duration, aceclofenac

significantly reduced pain and improves functional

capacity and mobility relative to baseline in patients

with osteoarthritis, rheumatoid arthritis or ankylosing

spondylitis and reduces inflammation in patients with

rheumatoid arthritis.

In patients with osteoarthritis of the knee, aceclofenac

decreases pain, reduces disease severity and improves

the functional capacity of the knee to a similar extent

to diclofenac, piroxicam, and naproxen.

In rheumatoid arthritis

In ankylosing spondylitis

In dental pain

In postoperative pain

The anti-inflammatory and analgesic efficacy of

aceclofenac is similar to that of ketoprofen,

indomethacin, tenoxicam and diclofenac in patients

with rheumatoid arthritis.

The duration of morning stiffness and pain intensity

are reduced and spinal mobility improved, by

aceclofenac in patients with ankylosing spondylitis

The analgesic efficacy as single doses of aceclofenac

has been assessed in patients with moderate to severe

tooth pain and in extraction of impacted third molars.

Aceclofenac 100 mg was superior to paracetamol 650

mg in providing relief from postepisiotomy pain,

particularly 3 to 5 hours after ingestion.

3.3. PROFILE OF HYDROXY PROPYL METHYL CELLULOSE

Nonproprietarynames

BP : Hypromellose

JP : Hydroxypropylmethylcellulose

PhEur : Hypromellosum

USP : Hypromellose

Synonyms

Benecel MHPC, hydroxypropyl methylcellulose, HPMC,

methocel, methylcellulose propylene glycol ether, metolose.

Chemical name

Cellulose hydroxypropyl methyl ether

CAS registry number

[9004-65-3]

Structural formula

Description

Hypromellose is an odorless and tasteless, white or creamy

white fibrous or granular powder.

Functionalcategory

Coating agent, film-former, rate-controlling polymer for

sustained release, stabilizing agent, suspending agent, tablet

binder, viscosity-increasing agent.

Typicalproperties

Acidity/alkalinity: pH = 5.5–8.0 for a 1% w/w aqueous solution.

Ash: 1.5–3.0%, depending upon the grade and viscosity.

Auto ignition temperature: 360oC

Density (bulk): 0.341 g/cm3

Density (tapped): 0.557 g/cm3

Density (true): 1.326 g/cm3

Melting point: browns at 190–200oC; chars at 225–230

oC.

Glass transition temperature: 170–180oC.

Solubility

Soluble in cold water, forming a viscous colloidal solution,

practically insoluble in chloroform, ethanol (95%), and ether,

but soluble in mixtures of ethanol and dichloromethane,

mixtures of methanol and dichloromethane, and mixtures of

water and alcohol.

Specific gravity: 1.26 g/cm3

Viscosity (dynamic)

A wide range of viscosity types are commercially available.

Aqueous solutions are most commonly prepared. Solutions

prepared using organic solvents tend to be more viscous,

increasing concentrations also produces more viscous solutions.

Applications

Hypromellose is widely used in oral, ophthalmic, topical and

pharmaceutical formulations. In oral products, it is primarily

used as a tablet binder, in film-coating, and as a matrix former

for use in extended-release tablet formulations, as a suspending

and thickening agent in topical formulations, emulsifier, and

stabilizing agent in topical gels and ointments.

Stabilityandstorage

Hypromellose powder is a stable material, although it is

hygroscopic after drying. Solutions are stable at pH 3–11.

Increasing temperature reduces the viscosity of solutions.

Aqueous solutions are comparatively enzyme-resistant,

providing good viscosity, stability during long-term storage.

Hypromellose powder should be stored in a well-closed

container, in a cool, dry place.

Incompatibilities

Hypromellose is incompatible with some oxidizing agents.

Since it is non-ionic, hypromellose will not complex with

metallic salts or ionic organics to form insoluble precipitates.

Safety

Hypromellose is widely used as an excipient in oral and topical

pharmaceutical formulations and in cosmetics and food

products. It is generally regarded as a nontoxic and

non-irritant material, although excessive oral consumption may

have a laxative effect.

3.4 PROFILE OF ETHYL CELLULOSE

Nonproprietarynames BP : Ethylcellulose

PhEur : Ethylcellulosum

USPNF : Ethylcellulose

Synonyms Aquacoat ECD, aqualon, E462, ethocel, surelease.

Chemical name Cellulose ethyl ether

CAS registry number

[9004-57-3]

Structural formula

Description Ethylcellulose is a tasteless, free-flowing, white to light tan

colored powder.

Solubility Ethylcellulose is practically insoluble in glycerin,

propylene glycol, and water.

Functionalcategory Coating agent, flavoring fixative, tablet binder, tablet filler,

viscosity-increasing agent.

Typicalproperties Density (bulk): 0.4 g/cm3

Glass transition temperature: 129–1330C

Specific gravity 1.12–1.15 g/cm3

Viscosity The viscosity of ethylcellulose is measured typically at

250C using 5% w/v ethylcellulose dissolved in a solvent blend

of 80% toluene : 20% ethanol (w/w).

Uses Use Concentration (%)

Microencapsulation 10.0–20.0

Sustained release tablet coating 3.0–20.0

Tablet coating 1.0–3.0

Tablet granulation 1.0–3.0

Applications

It is widely used in oral and topical pharmaceutical

formulations, hydrophobic coating agent for tablets and

granules, to modify the release of a drug, to mask an unpleasant

taste, or to improve the stability of a formulation. Higher

viscosity grades tend to produce stronger and more durable

films.

Safety Ethylcellulose is not metabolized following oral consumption

and is therefore a non-calorific substance. Parenteral use may be

harmful to the kidneys.

Incompatibilities

Incompatible with paraffin wax and microcrystalline wax.

Stabilityandstorage Ethylcellulose is a stable, slightly hygroscopic material. It is

chemically resistant to alkalis, both dilute and concentrated, and

to salt solutions, although it is more sensitive to acidic materials

than are cellulose esters.

It should be stored at a temperature not exceeding 320C in a dry

area away from all sources of heat. It should not be stored next

to peroxides or other oxidizing agents.

3.5 PROFILE OF POLY VINYL PYRROLIDONE

Nonproprietarynames BP : Pyrrolidone

PhEur : Pyrrolidone

Synonyms γ-Aminobutyric acid lactam, 4-aminobutyric acid lactam,

gaminobutyric lactam, γ -aminobutyrolactam, γ -butyrolactam.

Butyrolactam, 2-ketopyrrolidine, 2-oxopyrrolidine, 2-Pyrol.

Chemical name 2-Pyrrolidinone

CAS registry number

[616-45-5]

Empiricalformula C4H7NO

Molecular weight 85.11 g/mol

Structural formula

Description N-Methylpyrrolidone occurs as a clear, hygroscopic

liquid with a mild amine odor.

Solubility Miscible with ethanol (95%), propan-2-ol, and water.

Also miscible with other organic solvents like benzene, carbon

disulfide, chloroform, ether, and ethyl acetate.

Specific gravity 1.11 at 25oC

Viscosity (dynamic) 13.3 mPa s at 25oC

Functionalcategory Penetration agent, plasticizer, solvent, solubilizing agent.

Typicalproperties Acidity/alkalinity pH = 8.2 – 10.8 for a 10% v/v aqueous

solution.

Boiling point : 245oC

Dipole moment : 2.3 Debye at 25oC

Flash point : 129oC

Applications

Pyrrolidone and N-methylpyrrolidone are mainly used as

solvents in veterinary injections, a better solubilizer than

glycerin, propylene glycol, or ethanol, as effective penetration

enhancers in topical applications.

Stability and storage Pyrrolidone is chemically stable and, if it is kept in unopened

original containers, the shelf-life is approximately one year. It

should be stored in a well-closed container protected from light

and oxidation, at temperatures below 20oC.

Incompatibilities

Incompatible with oxidizing agents and strong acids.

Safety Mainly used in veterinary injections and have also been

suggested for use in human oral, topical, and parenteral

pharmaceutical formulations.

3.6 PROFILE OF DIBUTYL PHTHALLATE

Nonproprietarynames BP : Dibutyl Phthalate

PhEur : Dibutyl Phthalate

USP-NF : Dibutyl Phthalate

Synonyms Araldite 502, benzenedicarboxylic acid, butyl phthalate,

celluflex DBP, dibutyl benzene 1,2-dicarboxylate, dibutyl

ester of 1,2-benzenedicarboxylic acid, dibutylisphthalas,

dibutyl-o-phthalate, Polycizer DBP, PX 104, RC Plasticizer

DBP.

Chemical name Dibutyl benzene-1,2-dicarboxylate

CAS registry number

[84-74-2]

Empiricalformula C16H22O4

Molecular weight 278.34 g/mol

Structural Formula

Description Dibutyl phthalate occurs as an odorless, oily, colorless, or

very slightly yellow-colored, viscous liquid.

Solubility Very soluble in acetone, benzene, ethanol (95%), and ether;

soluble 1 in 2500 of water at 20oC.

Functionalcategory Film-forming agent, plasticizer, solvent.

Typicalproperties Boiling point : 34oC

Flash point : 171oC

Melting point : 35oC

Incompatibilities

Dibutylphthallate reacts violently with chlorine. It also

reacts with oxidizing agents, acids, bases, and nitrates.

Applications

Dibutyl phthalate is used in pharmaceutical formulations as a

plasticizer in film-coatings, evaluated as a pore-forming

agent in novel delivery systems, extensively as a solvent,

particularly in cosmetic formulations such as antiperspirants,

hair shampoos, and hair sprays, as an insect repellent,

although it is not as effective as dimethyl phthalate.

Stabilityandstorage Should be stored in a well-closed container in a cool, dry,

location. Containers may be hazardous when empty since

they can contain product residues such as vapors and liquids.

Safety Dibutyl phthalate is generally regarded as a relatively

nontoxic material, although it has occasionally been reported

to cause hypersensitivity reactions. It is widely used in

topical cosmetic and some oral pharmaceutical formulations.

3.7. PROFILE OF TRIETHYL CITRATE

Nonproprietarynames BP : Triethyl citrate

PhEur : Triethyl citrate

USP-NF : Triethyl citrate

Synonyms Citric acid ethyl ester, citroflex 2, citrofol AI, E1505, ethyl

citrate, hydagen CAT, 1,2,3-propanetricarboxylic acid, 2

hydroxy-, triethyl ester , TEC, triethyliscitras.ester of

1,2-benzenedicarboxylic acid, dibutylisphthalas,

dibutyl-o-phthalate, di-n-butyl phthalate.

Chemical name 2-Hydroxy-1,2,3-propanetricarboxylic acid triethyl ester

CAS registry number

[77-93-0]

Empiricalformula C12H20O7

Molecular weight 276.29 g/mol

Structural Formula

Description Triethyl citrate is a clear, viscous, odorless, and practically

colorless, hygroscopic liquid.

Solubility Soluble 1 in 125 of peanut oil, 1 in 15 of water.

Miscible with ethanol (95%), acetone, and propan-2-ol.

Viscosity (dynamic) 35.2 mPa s at 250C

Functionalcategory Plasticizer, solvent.

Typicalproperties Acid value : 0.02

Boiling point : 294oC

Flash point : 155oC

Pour point : 45oC

Applications

Citrate, and acetyltributyl citrate are used to plasticize

polymers in formulated pharmaceutical coatings. The coating

applications include capsules, tablets, beads, and granules for

taste masking, immediate release, sustained-release, and

enteric formulations. It is also used as a direct food additive

for flavoring, for solvency, and as a surface active agent.

Stabilityandstorage Triethyl citrate should be stored in a closed container in a

cool, dry location. When stored in accordance with these

conditions, triethyl citrate is a stable product.

Incompatibilities

Incompatible with strong alkalis and oxidizing materials.

Safety Triethyl citrate is used in oral pharmaceutical formulations

and as a direct food additive. It is generally regarded as a

nontoxic and nonirritant material. However, ingestion of large

quantities may be harmful.

3.8 PROFILE OF TALC

Nonproprietarynames BP : Purified Talc

JP : Talc

PhEur : Talc

USP : Talc

Synonyms Altalc, E553b, hydrous magnesium calcium silicate, hydrous

magnesium silicate, magnesium hydrogen meta silicate,

magsilosmanthus, powdered talc, purified French chalk,

purtalc,soapstone, steatite, superiore, talcum.

Chemical name Talc

CAS registry number

[14807-96-6]

Description Talc is a very fine, white to grayish-white, odorless,

impalpable, unctuous, crystalline powder. It adheres readily to

the skin and is soft to the touch and free from grittiness.

Solubility Practically insoluble in dilute acids and alkalis, organic

solvents, and water.

Specific gravity 2.7–2.8 g/cm3

Functionalcategory Anti-caking agent, glidant, tablet and capsule diluents, tablet

and capsule lubricant.

Typicalproperties Acidity/alkalinity pH = 7–10 for a 20% w/v aqueous

dispersion.

Hardness (Mohs) 1.0–1.5

Moisture content : Talc absorbs insignificant amounts of water

at 250C and relative humidity’s up to about 90%.

Applications

Talc was once widely used in oral solid dosage formulations

as a lubricant and diluent, as a dissolution retardant in the

development of controlled-release products, as an adsorbant.

In topical preparations, talc is used as a dusting powder. Talc

is additionally used to clarify liquids and is also used in

cosmetics and food products, mainly for its lubricant

properties.

Stabilityandstorage Talc is a stable material and may be sterilized by heating at

1600C for not less than 1 hour. It may also be sterilized by

exposure to ethylene oxide or gamma irradiation. Talc should

be stored in a well-closed container in a cool, dry place.

Incompatibilities

Incompatible with quaternary ammonium compounds

Safety Talc is used mainly in tablet and capsule formulations. Talc is

not absorbed systemically following oral ingestion and is

therefore regarded as an essentially nontoxic material.

3.9.1. PAST WORK CARRIED OUT ON KETOROLAC

TROMETHAMINE

Bytul Rahman et al., prepared and compared ketorolac tromethamine tablets.

Formulated KT tablets gave higher dissolution rates than marketed product. Direct

compression method was adopted for preparation of tablet using different excipients

namely; microcrystalline cellulose, spray dried lactose and starch 1500. The effect of

excipients on the drug release from prepared tablets was also studied. All the tablet

quality control tests were studied. All formulations showed good mechanical properties

and complied with the USP 28 pharmacopoeial standard requirements for content

uniformity of dosage units and friability [49]

.

Rukmani et al., prepared matrix type formulations with dicalcium phosphate

dihydrate (DCPD) using a polymeric binder (Eudragit RSPO) to obtain controlled release

of Ketorolac tromethamine (KT).The drug, DCPD and Eudragit RSPO were granulated

by using isopropyl alcohol with and without a plasticizer (Diethyl phthalate, DEP).

Addition of Eudragit appear to affect the release profile. However, addition of a

plasticizer had a significant effect on the rate of release. The release appeared to follow

first order kinetics and the rate constant decreased linearly with increasing DEP

concentration. A directly compressible mixture was also formulated by coating DCPD

particles with DEP with and without Eudragit RSPO[50]

.

Sakshikanth et al., formulated gastro retentive multiparticulate drug delivery

systems to improve the absorption and bioavailability of ketorolac trometamol by

retaining the system in the stomach for prolonged period of time. The floating drug

delivery system of ketorolac trometamol was prepared by emulsion solvent diffusion

method by using ethyl cellulose, HPMC K4M, Eudragit R 100, Eudragit S 100 polymers

in varying concentration. Formulations were evaluated for percent yield, particle size,

entrapment efficiency, in vitro buoyancy and in vitro release studies. The percentage

yield of all the formulated batches of microspheres was more than 70 %. The optimized

formulations showed good buoyancy and invitro controlled release of ketorolac

trometamol. In vitro dissolution studies in 0.1N HC1 and in phosphate buffer pH 7.4

showed pH independent release of ketorolac trometamol[51]

.

Samir Roy et al., worked on transdermal delivery of ketorolac tromethamine, a

potent non-narcotic analgesic, through human skin in vitro and in vivo. In order to

enhance and sustain the flux of ketorolac through human skin, various compositions of

isopropyl alcohol (IPA), water, and isopropyl myristate (IPM) were evaluated. The

solubility of ketorolac acid in an IPA/water binary vehicle mixture increased as the

volume fraction of IPA increased from 0 to 90%. The solubility of ketorolac acid in an

IPA/water/IPM (saturated) ternary vehicle mixture was practically the same as in the

IPA/water binary vehicle mixture. The permeation of ketorolac acid through cadaver skin

was evaluated using modified franz diffusion cells. The skin flux increased as the IPA

volume fraction was increased from 0 to 50% and then leveled off beyond 80% IPA

loading. When IPM was added to the IPA/water binary vehicle mixture, a significant

increase in the skin flux of ketorolac was observed. The skin flux decreased exponentially

as the donor solution pH was raised from 3.5 to 7.0. The permeability of ketorolac

through various membranes such as a micro porous membrane and pressure-sensitive

adhesive was evaluated. While a micro porous membrane offered practically no diffusion

resistance, the in vitro flux of ketorolac through cadaver skin decreased substantially

upon lamination of pressure-sensitive adhesive onto a micro porous membrane [52]

.

Ibrahim et al., investigated permeation of ketorolac across excised rabbit skin

from various proniosome gel formulations using franz diffusion cells. Each of the

prepared proniosomes significantly improved drug permeation and reduced the lag time.

Proniosomes prepared with span 60 provided a higher ketorolac flux across the skin

thanthose prepared with Tween 20. A change in the cholesterol content did not affected

the efficiency of the proniosomes, and the reduction in the lecithin content did not

significantly decrease the flux. The encapsulation efficiency and size of niosomal vesicles

formed by proniosome hydration were also characterized by specific high performance

liquid chromatography method and scanning electron microscopy. Each of the prepared

niosomes achieved about 99% drug encapsulation. Vesicle size was markedly dependent

on the composition of the proniosomal formulations [53]

.

Aysegul et al., prepared occular inserts of water-soluble Ketorolac tromethamine

and water- insoluble indomethacin using hydrogels such as poly (butyl methacrylate),

poly (2-hydroxyethyl methacrylate), and poly (2-hydroxypropyl methacrylate), and a

plasticizer such as polyethylene glycol 300 by film casting method. Swelling properties

of these inserts was determined and they were irradiated with an absorbed dose of 1.2 M

rad by means of a Co- 60 source. The effects of these parameters on the drug release were

examined. The mechanism of drug release was identified by means of the semi-empirical

equation developed by korsmeyer and peppas. Water–soluble ketorolac showed higher

release than water–insoluble indomethacin. The release of ketorolac mainly fitted to the

fickian diffusion mechanism whereas the drug release of indomethacin fitted to non-

fickian release mechanism as per the ‘n’ exponent values [54]

.

Sanatkumar et al., formulated microspheres of ketorolac tromethamine for oral

delivery by complex coacervation and simple coacervation methods without the use of

chemical cross–linking agent (glutaraldehyde) to avoid the toxic reactions and other

undesirable effects of the chemical cross-linking agents. Alternatively, ionotropic

gelation was employed by using sodium-tripolyphosphate as a cross linking agent.

Chitosan and gelatin B were used as polymer and copolymer respectively. The release

study was carried out in pH 1.2 buffer for 2 hours andpH 7.4 phosphate buffer medium

for 8hours. It was observed that the rate of release decreased as the concentration of the

carrier was increased. This may be due to low permeability of polymer to the drug [56]

.

Lutfi gen et al., prepared enteric-coated film tablets of Ketorolac by the spray

technique. Different members of the Eudragit series may be employed for taste-masking

or as enteric-coating agents or dissolution rate-controlling membranes in sustained-

release dosage forms.Eudragit S-100 and L-100 were selected as coating materials.

Polyethylene glycol (PEG) 4000 was used as a plasticizer agent. Core tablets of ketorolac

were prepared by the direct compression technique. Tablet specifications were

determined and evaluated statistically [57]

.

Somanikumar et al., fabricated controlled release microcapsules of ketorolac by

coacervation phase separation and solvent evaporation technique. Microcapsules were

formulated using Eudragit RL100, Eudragit RS100 and Ethyl cellulose, bearing core:

polymer ratio of (1:1) and (1:2). The effects of various formulation and process variables

on the internal and external particle morphology, micromeritic properties, physical state

of the incorporated drug, drug loading and in vitro drug release were studied [58]

.

Sam Mathew et al., prepared albumin microspheres of ketorolac tromethamine by

emulsion cross-linking method. Selected formulations were characterized for their

entrapment efficiency, particle size, surface morphology, and release behavior. The

release pattern was biphasic, characterized by an initial burst effect followed by a slow

release. All selected microspheres, except those having less polymer proportion exhibited

a prolonged release for almost 24 hours. The release mechanism was regulated by drug:

polymer ratio and amount of cross-linking agent. From the experimental data obtained

with respect to particle size and extent of drug release, it was concluded that the prepared

microspheres are useful for once-a-day intramuscular administration of ketorolac

tromethamine[55]

.

Mohammad Etman et al., prepared ketorolac pellets using nonpareil seeds as an

inert carrier. Nonpareil seeds were first pan coated successively with EudragitRS 100

solution in isopropyl alcohol (12.5%) until they became visually insoluble in water. KT

was then applied onto nonpareil coated pellets in a conventional stainless steel pan.

Subsequently, the prepared KT pellets were sieved (2 mm) and coated by four coating

formulations using various proportions of Eudragit RL100 and Eudragit RS100 and the

drug release studies of the prepared pellets were studied [55]

.

Esmail Mohammed et al., prepared Ketorolac tromethamine loaded mucoadhesive

liquid suppository as a site-specific mucoadhesive rectal dosage form. Poloxamer mixture

formed of 21% P407 and 9% P188 were used as liquid suppository base. Invitro release

rate of KT from liquid suppository was studied and compared to that from conventional

suppository. The safety of the prepared suppository on GIT was conducted,

hepatotoxicity of KT after 5 days of administration of liquid suppository was evaluated

histologically and biochemically [60]

.

3.9.2. PAST WORK DONE ON ACECLOFENAC

Raghavendra Rao et al. ,developedaceclofenacloaded chitosan microparticles by

ionotropic gelation method using binary polymer mixture and by surface coating method.

Drug loadingefficiency (DLE) of microparticles was found to be between 62.20 to 92.93

% and depended up on the formulation variables. An increase in the

tripolyphosphateconcentration and cross-linking time decreased the drug release. The

particle size decreased with increase in cross-linking time and found between therange of

1194.1 to 1568.9 µm. Microparticles swelled and showed burst effect when shifted from

acid buffer pH 1.2 to phosphate buffer pH 7.4 andwere having poor mechanical strength.

Surface coating with alginate, alginate-pectin, chemical cross-linking with glutaraldehyde

and addition ofnon-ionizing polymer HPMC, were proved to be effective in controlling

the burst effect, prolonging the drug release with improved particle strength in both the

media. The research finally concluded that tripolyphosphate-chitosan microparticles

developed with binary polymer mixture and by surface coating method may

becomepotential delivery system to prolong the release of drug aceclofenac[61]

.

Jignesh Modi et al., investigated the potential of a nanoemulsion formulation for

topical delivery of aceclofenac. Various oil-in-water nanoemulsions were prepared by the

spontaneous emulsification method. The nanoemulsion area was identified by

constructing pseudoternary phase diagrams. Topical permeation of aceclofenac through

rat abdominal skin was determined. The in vitro skin permeation profile of optimized

formulations was compared with that of aceclofenac conventional gel and Nanoemulsion

gel. The anti-inflammatory effects of formulation showed a significant increase percent

inhibition value after 24 hours when compared with aceclofenac conventional gel and

nanoemulsion gel on carrageenan-induced paw edema in rats. These results suggested

that nanoemulsions are potential vehicles for improved transdermal delivery of

aceclofenac[62]

.

Pavan Kumar et al., investigated the use of biodegradable polymers for

microencapsulation of aceclofenac using solvent evaporation technique. Poly lactic acid

was selected as a retardant polymer because of its advantage over otherbiodegradable

polymers. Four different batches of microspheres were prepared by varying the

concentration of polymer from50% to 80% w/w. It was observed that the increase in

concentration of the polymer had increased the meanparticle size of the microspheres.It

can be seen that by increasing the polymer concentration, the rate of drug releasefrom the

microspheres dramatically decreased. The kinetics of drug release from F1 and F2

microspheres predominantly followsHiguchi pattern followed by zero order and then first

order. The release kinetics of F3 and F4 predominantly follows zeroorder followed by

Higuchi and then first order[63]

.

Hindustan Abdul Ahad et al., developed matrix tablets of aceclofenac with

Prosophisjulifloragum and studied its functionality as a matrix forming agent for once

daily sustained release tablet formulations. Various formulations of

aceclofenacProsophisjulifloragum were prepared and the formulated tablets found to

have better uniformity of weight and drug content with low standard deviation values.

The swelling behavior and release rate characteristics were studied. The dissolution study

proved that the driedProsophisjulifloragum can be used as a matrix forming material for

making once daily sustained release matrix tablets.This result has shown thatas the

proportion of Prosophisjulifloragum increased, theoverall time of release of the drug

from the matrix tabletwas also increased[64]

.

Tank Chintankumar et al., prepared aceclofenac loaded maltodextrin based

proniosomes by slurry method with different surfactantto cholesterol ratio. The niosomal

suspensions were evaluated for entrapment efficiency, invitro release study, release

kinetic dataanalysis, stability study, and invivo anti-inflammatory study. The result from

SEM analysis has showed smooth surface ofproniosome. The optimized formulation

showed higher entrapment efficiency of 83.24 ± 1.34 and in-vitro releases of 97.122%at

the end of 24hrs was found to be best among the other formulations. Release was best

explained by zero order kinetics.Kinetic analysis shows that the drug release follows

super case II transport diffusion. Proniosome formulation has showedappropriate stability

for 90 days by storing the formulation at refrigerator condition[65]

.

Yadav et al., designed the work to investigate the effect of size enlargement

methods like melt granulation and liquisolid technique on the physicochemical properties

such as solubility and dissolution rate of a poorly water-soluble drugaceclofenac.

Initially, the granules were prepared by melt granulation technique using melt binders,

diluent and super-disintegrants. The liquisolid systems were also prepared by using non-

volatile organic solvent, coating polymer, diluents and super disintegrants. The size

enlarged granules were prepared by both techniques and they exhibited improvement in

solubility, dissolution rate, wettability and flowability compared to aceclofenac. The melt

granules containing poloxamer with sodium starch glycolate and liquisolid systems,

containing micro crystalline cellulose with croscaramellose sodium showed higher

solubility and dissolution rate compared to other melt-granules andliquisolid systems.

The XRD and FTIR studies revealed acharacteristic decrease in thecrystallinity of the

granules[66]

.

Gopal Venkatesh Shavi et al., developed an enteric coated multi-unit dosage form

containing aceclofenac, a non-steroidal anti-inflammatory drug. The pellets were

prepared by using extrusion/spheronization method, and the core pellets were coated with

a pH sensitive poly methacrylate copolymer to achieve site specific drug release. The

formulated pellets were characterized for percentage yield, size distribution, surface

morphology studies, drug content and flow properties. In vitro dissolution test was used

for comparison of drug release profiles of various coated pellets and the practical yield

was found to be 90-95%[67]

.

PAST WORK CARRIED OUT ON ETHYL CELLULOSE

Ravikumaran et al,. prepared surfactant-coated, nimesulide-free, and nimesulide-

loaded ethylcellulose or methylcellulose nanoparticles by varying drug concentration,

polymer concentration, and surfactant concentration. Ethyl cellulose and methyl cellulose

nanoparticles prepared by desolvation method produced discrete particles and they were

characterized by SEM, AFM, and FTIR studies. The encapsulation efficiency decreased

with the increase of nimesulide concentration with respect to polymer concentration [68]

.

Satit Prasertmanakit et al., developed ethyl cellulose microcapsules for use as a

drug-delivery device for protecting folic acid from release and degradation in the

undesirable environmental conditions of the stomach, whilst allowing its release in the

intestinal tract to make it available for absorption. The controlled release folic acid-

loaded ethyl cellulose microcapsules were prepared by oil-in-oil emulsion solvent

evaporation using a mixed solvent system, consisting of a 9:1 (v/v) ratio of acetone:

methanol and light liquid paraffin as the dispersed and continuous phase.

Samuelov et al., prepared cast films composed of different ratios of polyethylene

glycol and ethyl cellulose containing salicylic acid, caffeine, and tripelennamine as model

dispersed drugs were for sustained release. The drug content of the film declined at an

apparent first-order rate initially, whereas the drug quantity released was proportional to

the square root of time. The release rates were independent of film thickness and

proportional to drug concentration in pure ethyl cellulose films; in polyethylene glycol-

ethyl cellulose films, a positive deviation from linearity was observed [69]

.

Parthasarathy et al., reported the development of a sustained-release system of

sparfloxacin for use in the treatment of periodontal disease. A sustained-release

sparfloxacin device was formulated, based on ethyl cellulose (EC) 10 cps, polyethylene

glycol (PEG) 4000, and diethyl phthalate (DEP). It will hereafter be called the

sparfloxacin chip. The chip has dimensions of 10 mm length, 2 mm width, and 0.5 mm

thickness. The in vitro drug release pattern and clinical evaluation of the formulations

were studied [70]

.

Emeje et al., investigated the effect of some commonly used release enhancers on

the compaction characteristics of EC. The wet granulation method of massing and

screening was used, and compacts were produced by compressing granules for 60

seconds at various compression pressures.He also studied the effects of four commonly

used hydrophilic additives such as polyethylene glycol (PEG) 4000, PEG 10, 000,

sorbitol, and mannitolon the compaction characteristics of ethyl cellulose using density

measurements and the Heckel equation. It can be concluded that additives such as PEG

4000, PEG 10 000, sorbitol, and mannitol, which are often used as channeling agents in

sustained-release formulations containing hydrophobic matrix formers, affect the

deformation characteristics of EC, with the extent and nature of the effect dependent on

the nature of the additive[71]

.

Baria et al., prepared sustained release (SR) suppositories containing aceclofenac

microspheres. In the first part of the study, aceclofenac microspheres were prepared by

solvent evaporation method employing ethyl cellulose as a microsphere forming polymer.

The effect of drug: polymer ratio and stirring rate on microspheres formation, average

particle size, incorporation efficiency, micromeritic properties and in vitroaceclofenac

release were investigated [72]

.

Muhammad Khan Sarfraz et al., developed sustained released matrix tablets of

naproxen with ethyl cellulose, a hydrophobic polymer. Matrix tablets were prepared by

incorporating various proportions of ethyl cellulose in the matrix system using wet

granulation technique [73]

.

Golomb et al., prepared cast films of ethyl cellulose with or without polyethylene

glycol, containing metronidazole, and they exhibited sustained release. The

microbiological results proved that embedding metronidazole in ethyl cellulose film does

not inhibit the biological activity. The release kinetics of in vivowere correlated with in

vitro results, exhibiting a sustained release of metronidazole over a period of three days

[74].

Hemangi Patil et al., prepared floating microspheres of acyclovir using different

viscosities of ethyl cellulose to achieve an extended retention in upper GIT which may be

resulted in enhanced absorption and thereby improves bioavailability. The floating

microspheres were prepared by emulsion solvent diffusion technique and triethyl citrate

was used as a plasticizer [75]

.

Bhupendra .Prajapati et al., formulated matrix tablets of nicorandil by the polymer

blend to get desirable release profile. In the present study, HPMC K200M, which was

used in hydrophilic matrix drug delivery systems have been employed to formulate

sustained-release tablets of nicorandil but alone it did not give good results. So it was

used in combination with hydrophobic polymer like Eudragit RSPO and Ethyl cellulose

[76].

Hosseinali Tabandeh et al., fabricated matrix aspirin tablets with ethylcellulose

(EC), Eudragit RS100, and Eudragit S100 were prepared by direct compression. EC with

an amount as little as 10 percent in formulation could make sustained-release aspirin

tablets in which the release profile is not sensitive to moderate changes in hardness.

Anjali et al., studied the applicability of fine particle ethyl cellulose to produce

matrix tablets by wet granulation technique. Tablets were prepared by wet granulation of

drug and fine particle ethyl cellulose in an appropriate mass ratio. As its content and the

hardness of the tablets were increased, the release rate of the drug was decreased [77]

.

Phutaneet et al., developed microspheres by emulsion solvent diffusion-

evaporation technique by using the modified ethanol,-dichloromethane co-solvent

system. The polymer mixture of ethyl cellulose and Eudragit® S100 was used in different

ratios (1:0, 1:1, 2:3, 1:4 and 0:1) to formulate batches. The formulated microspheres were

discrete, spherical with relatively smooth surface, and with good flow properties. Among

different formulations, the fabricated microspheres of batch F3 had shown the optimum

percent drug encapsulation of microspheres and the sustained release of the Glipizide for

about 12 h.The data obtained thus suggest that a microparticulate system can be

successfully designed for sustained delivery of Glipizide and to improve dosage form

characteristics for easy formulation.[78]

.

Sandip Tiwari et al., studied the effect of concentration of hydrophilic

(hydroxypropyl methylcellulose [HPMC]) and hydrophobic polymers (hydrogenated

castor oil [HCO], ethylcellulose) on the release rate of tramadol. Hydrophilic matrix

tablets were prepared by wet granulation technique, while hydrophobic (wax) matrix

tablets were prepared by melt granulation technique and in vitro dissolution studies were

performed. Hydrophobic matrix tablets resulted in sustained in vitro drug release (>20

hours) as compared with hydrophilic matrix tablets (<14 hours) [79]

.

Akhil Sharma et al., formulated and evaluated salbutamol sulphate sustained

release tablets using different polymers as release retarding agents. Preformulation study

was done initially and the results were directed for further course of formulation. Based

on preformulation studies, different batches of salbutamol sulphate were prepared using

xanthan gum, carbopol and ethyl cellulose due to their different hydrophilic properties to

calculate the sustained release properties [80]

.

Vatsaraj et al., formulated a sustained-release tablet of Ketorolac tromethamine,

which is a nonsteroidal anti-inflammatory agent. A 23 full factorial design (8 runs) was

selected. The variables studied were the amount of drug (30 and 40 mg), ratio of

hydroxypropyl methylcellulose (HPMC)/sodium carboxymethylcellulose (NaCMC)

(240/40 and 140/140 mg), and amount of ethylcellulose (140 and 180 mg). Swelling-

controlled matrix tablets were manufactured by direct compression of formulation

ingredients using a Stokes single punch tablet press [81]

.

Giunchedi et al., studied on Ketoprofen which was a non-steroidal anti-

inflammatory drug. It has been incorporated into polymeric micro matrices

(microspheres) made of cellulose acetate trimellitate (CAT)/ethylcellulose (EC) blends

by spray drying process. Drug loaded microspheres were obtained by spray-drying

organic solutions of the two polymers and the drug. Characterization of the

microparticles (morphology, particle size distribution, drug content, yield of production,

surface properties, and solvent residues) was carried out and invitro release behavior was

measured. The release rate of the drug was diminished as the proportion of EC was

raised[82]

.

Hitesh Gevariya et al., formulated ocular inserts of levofloxacin and evaluated

their potential for sustained ocular delivery. Matrix-type of ocular inserts were prepared

by the film casting technique in Teflon-coated Petri dishes and in vitrocharacterization

was done by drug release studies using a flow-through apparatus that simulated the eye

conditions. Total 9 formulations were developed, which differed in the ratio of polymers

such as polyethylene oxide (PEO), hydroxypropyl cellulose (HPC) and ethyl cellulose

(EC). It was also observed that increasing the proportion of PEO and HPC to EC

increases the rate of release of Levofloxacin [83]

.

Abu HenaMostafa Kamal et al., prepared Indomethacin microcapsules using ethyl

cellulose (EC) and hydroxy propyl methyl cellulose phthalate (HPMCP) by o/w

emulsification-solvent evaporation technique. The rate was increased exponentially with

the addition of HPMCP in EC. IM rate was observed highest with the highest

concentration of HPMCP (3:7 ratio of EC: HPMCP), used in the present studies. On the

other hand, IM rate was lowest when EC and HPMCP combination was used at the ratio

of 10:0 [84]

.

Verhoeven et al., developedmini-matrices (multiple-unit dosage form) with

release-sustaining properties by means of hot-melt extrusion using ibuprofen as the

model drug and ethylcellulose as sustained-release agent. Xanthan gum, a hydrophilic

polymer, was added to the formulation to increase the drug release since ibuprofen

release from the ibuprofen/ethylcellulose matrices (60/40, w/w) was too slow (20% in

24 h). Drug release from the mini-matrices was mainly diffusion controlled, but swelling

played an important role to obtain complete drug release within 24 hours[85]

.

PAST WORK CARRIED OUT ON PELLETS

Eskandari has developed an extended release pellet formulation of indomethacin

by the centrifugation (rotary fluid bed granulation) or powder layering method. Layered,

nonpareil pellets composed of sugar, Avicel PH 101 and lactose were prepared using

FREUND CFgranulator and were treated by a binder solution (HPC-L) applied by spray

gun. A conical designed powder-feeding unit applies the drug powder. Drug content of

pellets was determined by HPLC method. Eudragit NE 30 D was used for coating the

prepared pellets. The results showed that increasing the amount of Eudragit NE 30 D,

Opadray and SDS in coating solution adjusts the release rate of the pellets [86]

.

Cronlein et al., investigated the enteric performance of aqueous enteric-coated

multiparticulate formulations containing lansoprazole in bio-relevant media which better

simulates the gastric environment of a patient on a multiple dose regimen of PPI’s. A

secondary objective of this study was to characterize the stability of the finished dosage

form under room temperature and accelerated storage conditions [87]

.

Sonali Naikwade et al., developed enteric-coated pellets of piroxicam in order to

avoid local gastrointestinal irritation which is one of the major side effects of non-

steroidal anti-inflammatory drugs after oral ingestion. Three polymers namely Eudragit

L100, cellulose acetate phthalate and hydroxyl propyl methyl cellulose phthalate were

used. Pellets were made by an extrusion–spheronization process. Two approaches were

used viz. enteric matrix and enteric polymer coating. Matrix and coated pellets were

evaluated for physicochemical properties. Influence of excipients on in vitro release of

drug was evaluated. Piroxicam release from uncoated pellets was measured in phosphate

buffer (pH 6.8) using paddle dissolution method(USP XXIII). Enteric-coated pellets were

tested in 0.1 N HCl and phosphate buffer, pH 6.8. Optimum formulations were subjected

to stability studies under accelerated conditions. Enteric pellets prepared using eudragit

L100 gave promising results for matrix pellets [88]

.

Cara Young et al., worked on Lansoprazoledelayed-release pellets which have

been shown to have better absorption properties than a delayed-release tablet. However,

binder solutions for drug layering and extrusion-spheronization excipients were

incompatible with lansoprazole. In contrast, dry powder layering technology has been

reported to provide a more stable manufacturing method for acid-labile drugs. The

objective of this study was to evaluate the performance of lansoprazole powder layered

pellets coated with a fully formulated aqueous enteric system (Acryl-EZE®

93F19255) in

various media [89]

.

Radke et al., cinnarizine pellets were prepared by powder-layering technique,

using cinnarizine as active ingredient and Eudragit RS-100, Eudragit RL-100, Ethyl

cellulose as coating agents, propylene glycol as plasticizer and PVPK-30 as binder. Drug

content was estimated spectrophotometrically at 254 nm. The prepared pellets were

further evaluated for surface texture by scanning electron microscopy, uniformity of

diameter, thickness and weight,in vitro drug release pattern and short-term stability.

Pellets coated with 10% Eudragit RS-100 showed promising results releasing more than

95% of drug up to 12 hours. This study concluded that the powder layering technique can

be used for designing sustained release drug delivery systems providing drug release over

a period of 12 hours [90]

.

Mustafa Sinan Kaynak has prepared the pellet formulations by pan coating

method. They have prepared formulations in order to decrease the dosage regimen which

is twice daily for conventional tablet. Formulation of Glipizide pellets were aimed to

maintain the necessary blood Glipizide concentration for the treatment. The in

vitrocharacterization as well as microscopic investigation of the pellet formulations was

evaluated[91]

.

Alireza Ghaffari et al., prepared pellets containing theophylline as a model drug

and microcrystalline cellulose, in a ratio of 6:4, by the extrusion-spheronization method.

The pellets were coated with Eudragit RS aqueous dispersions, containing various

amounts of pectin-chitosan complex and different coating mass gains, using a fluidized-

bed apparatus. Twelve formulations were developed, which differed in two factors:

coating mass gain (10, 15 and 20%, w/w) and the amount of pectin-chitosan complex (5,

10, 15 and 20%, w/w). Drug release studies were conducted using the USP apparatus I

(basket) in dissolution media, mimicking the conditions prevailing in the stomach, small

intestine or colon. Studies have shown that the drug release rate and pattern were

dependent on both of the two mentioned factors. Some formulations showed bimodal and

burst drug release, being triggered in the colonic medium bythe action of

pectinolyticenzymes [92]

.

Gopal Venktesh Shavi et al., developed an enteric-coated multi-unit dosage form

containing aceclofenac, a nonsteroidal anti-inflammatory drug (NSAID). The pellets

were prepared by using extrusion/spheronization method, and the core pellets were

coated with a pH-sensitive poly (meth acrylate) copolymer (Eudragit L100-55) to achieve

site-specific drug release. The formulated pellets were characterized for percentage yield,

size distribution, surface morphology studies, drug content, and flow properties. In vitro

dissolution test was used for the comparison of drug release profiles of various coated

pellets. The practical yield was found to be 90–95% [93]

.

Halle Bechgaard et al., conducted a clinical trial investigating the safety and

efficacy of two multiple unit controlled release esomeprazole capsule formulations

containing enteric coated pellets bioequivalent to a standard capsule in respect of extent

of bioavailability in a cross over study with normal human subjects. However, drug

absorption from the enteric coated pellet formulations was slower when compared to that

from the reference capsule, the standard reference capsule releases 85% of its drug

content in vitroduring 10min at pH 6.5 and 98% during 1hr at pH 7.5. The data indicated

that multiple units of controlled release formulations represent a reliable and reproducible

source of esomeprazole, which by avoiding extremes of local or systemic drug

concentration[94]

.

Akelesh et al., developeda pharmaceutically equivalent, stable, cost effective and

quality improved formulation of venlafaxine HCl pellets in the form of sustained release

capsule. Pellets containing different polymers have been investigated with the intention

of gaining a deeper understanding the formulation factors. The optimized formulation

gave satisfactory dissolution profile and releases more than 98.29% of drug within 24 hrs.

Drug release rate was more when compared with the innovator sample and its dissolution

profile matches with the innovatordissolution profile and follows first order kinetics[95]

.

Audity Ganguly Rupesh, et al,. designed an oral controlled onset of dosage form

intended to approximate the chronobiology ofrheumatoid arthritis which was proposed

for colonic targeting. The multiparticulate systemcomprising of non-pareil seeds coated

with eudragit S100 was designed for chronotherapeuticdelivery of valdecoxib. The drug

was coated onto non-pareil seeds by powder layeringtechnique using the conventional

coating pan. The in vitro dissolution tests showed that the release of valdecoxib from the

coatedpellets depended on the pH of the dissolution fluid and the coat weights applied.

All theformulations exhibited no release of drug in the pH 1.2 and pH 4 buffers, drug

release has taken place in phosphate buffer of pH 7.4. Further intactness of the drug in the

formulation and theuniformity of the polymer coating were checked by the infrared study

and scanning electronmicroscopy. All the above results showed thatthe formulation could

be highlyadvantageous in the chronotherapy of rheumatoid arthritis withappreciable drug

release and physiochemical properties[96]

.

Lian-Dong Hu et al., prepared metformin hydrochloride sustained-release pellets

by centrifugal granulation. Experimental results indicated that talc modification made a

decisive contribution to control the drugrelease by avoiding dose dumping.The relative

bioavailability of the sustainedreleasepellets was studied in 12 healthy volunteers after

oral administration in a fast state using a commercially available immediate release

tablet. Restricted delivery of metformin hydrochloride to the small intestine from

differently coated pellets resulted in increased relativebioavailability and a sustained

release effect. So the adoption of several different pH dissolution media established a

better relationshipbetween the in vitro release and in vivo absorption of the sustained-

release pellets[97]

.

Heinämäki evaluated the tackiness of aqueous chitosan film coatings and effects

of anti-sticking agents on sticking tendency. High molecularweight chitosan plasticized

with glycerol was used as a film-forming agent.Film coatings were performed in

aminiaturized top-spray coater. The incorporation of anti-sticking agents led to a clear

decrease in tackiness of the chitosan films. Film-coated pellets containing magnesium

stearate as an anti-sticking agent were very easily fluidized and were thusclassified as

the best flowing and the least sticking samples.Thus the research gave an idea on the

determination of the experimental minimum fluidization velocity in a fluidized bed,

which is a usefuland sensitive method of measuring the tackiness tendency of film-coated

pellets[98]

.

Rajesh et al., prepared pellets loaded withaceclofenac sodium (ACS) as model

drug through pelletization technique by using theblend of sodium alginate (SA) and

glycerylpalmito stearate (GPS) as hydrophilic andhydrophobic carriers, along with

methyl crystalline cellulose (MCC) as spheronizerenhancer in various concentrations and

examined the influence of various processparameters on drug containing pellets. The

research showed that oral controlled release aceclofenac sodium pellets were able to

prolong the drug release,minimizing the drug related adverse effects and improve

bioavailability in different GItractconditions. Formulated drug loaded pellets were

investigated for physicochemicalproperties and drug release potential. The release of

drug was controlled for more than 24 h. The rate of drug releasefollowed first order

kinetics and the mechanism of drug release followed fickiandiffusion. Thus they finally

concluded that the drug release performance was greatly affected by the materials used

inpellets preparations, which allows absorption in the intestinal tract by a

controlledmanner[99]

.

Fatemeh Sadeghi et al., investigated the release of metoclopramide hydrochloride

(a water-soluble cationic drug) and diclofenac sodium (a sparingly soluble anionic drug)

from pellets coated with ethylcellulose from an aqueous ethylcellulose dispersion

(Surelease®) at different coating loads. The release rates of each drug decreased as the

coating load of Surelease® increased. [100]