CHAPTER III Non-Steroidal Anti-inflammatory Drugs:...

CHAPTER III Non-Steroidal Anti-inflammatory Drugs:

An Overview

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NON STEROIDAL ANTI INFLAMMATORY DRUGS

Non-steroidal anti-inflammatory drugs, usually abbreviated to NSAIDs, are

drugs, with analgesic, antipyretic, and anti-inflammatory effects. They reduce pain,

fever and inflammation. The term ‘non-steroidal’ is used to distinguish these drugs from

steroids. NSAIDs are sometimes also referred to as non-steroidal anti-inflammatory

agents/analgesics (NSAIAS) or non-steroidal anti-inflammatorymedicines

(NSAIMS).Part of the popularity of NSAIDS is that unlike opioids, they do not produce

sedation or respiratory depression and have a very low addiction rate.

Mode of Action

Most of NSAIDS, act as non-selective inhibitors of enzyme

cyclooxygenase, inhibiting both the cyclooxygenase-1 (COX-1) and cyclooxygenase-

2(COX-2) isoenzymes. Cyclooxygenase catalyses the formation of prostaglandins and

thromboxane from arachidonic acid. Prostaglandins act as messenger molecules in the

process of inflammation.

NSAIDs are classified based on their structure. NSAIDs within a group

will tend to have similar characteristics and tolerability.

Salicylates: Aspirin, Amoxipirin, Benorilate, Diflunisal, Methyl salicylate

Arlalkanoic acids: Diclofenac, Aceclofenac, Acemetacin, Bromfenac, Etodolac,

Sulindac, Indomethacin.

2-Aryl propionic acids: Ibuprofen, Carprofen, Fenbufen, Fenoprofen, Ketoprofen,

Naproxen, Suprofen.

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N-Aryl anthranilic acids : Mefanamic acid, Meclofemic acid

Pyrazolidinederivaticves: Phenyl butazone, Azapropazone, Oxyphenbutazone,

Sulfinprazone

Oxicams:Piroxicam, Meloxicam, Lornoxicam, Tenoxicam.

COX-2 Inhibitors : Celecoxib, Etoricoxib, Parecoxib, Rofecoxib, Valdecoxib

Sulphonilides:Nimesulide

Uses

NSAIDS are usually indicated for the treatment of acute or chronic conditions where

pain and inflammation are present. NSAIDs are generally indicated for the symptomatic

relief of the following conditions:

Rheumatoid arthritis, Osteoarthritis, Inflammatory arthropathies (eg.,Ankylosing

spondylitis, Psoriatic arthritis), Acute gout, Dysmenorrhoea, Metastatic bone pain,

Headache and migraine, Post-operative pain, Pyrexia, Renal colic.

Pharmacokinetics

Most NSAIDS are weak acids, with a pKa of 3-5. They are absorbed well from stomach

and intestinal mucosa. They are highly protein bound in plasma (>95%) usually to

albumin, so that their volume of distribution typically approximates to plasma volume.

Most NSAIDS are typically approximates to plasma volume. Most NSAIDS are

metabolized in liver by oxidation and conjugation to inactive metabolites which are

excreted in urine. Some drugs arepartially excreted in bile. Some NSAIDs (typically

oxicams) have very long lives (eg. 20-60 hrs). Ibuprofen and diclofenac have short half-

life (2-3 hrs).

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Adverse Effects

The wide spread use of NSAIDs has meant that the adverse effects of these relatively

safe drugfs have become increasingly prevalent. The two main adverse drug reactions

(ADRs), associated with NSAIDs are gastrointestinal (GI) effects and renal effects of the

agents. The effects are dose dependent and in many cases severe enough to pose the risk

of ulcer perforation, upper GI bleeding. Dyspepsia, Diarrhea, Gastric

ulceration/bleeding.

Newer NSAIDS: Selective COX-2 Inhibitors

The discovery of COX-2 lead to developing an effective NSAID without

gastric problems. It was thought that selective inhibition of COX-2 would result in anti-

inflammatory action without disrupting gastro protective prostaglandins.

COX-1 is constitutively expressed enzyme in regulating many normal

physiological processes. One of these is in the stomach lining, where prostaglandins

serve a protective role, preventing the stomach from being eroded by its own acid.

When non-selective COX-1/COX-2 inhibitors lower stomach prostaglandin levels, these

protective effects are lost and ulcers of the stomach or duodenum and potentially internal

bleeding can result. COX-2 is an enzyme expressed in inflammation, and its inhibition

of COX-2 that produces the desirable effects of NSAIDs. The relatively selective COX-

2 inhibiting oxicam, meloxicam was the first step towards developing a true COX-2

selective inhibitor. Coxibs, the newest class of NSAIDs, can be considered a true

COX-2 seletive inhibitor and include celecoxib, rofecoxib, valdecoxib, parecoxib and

etoricoxib.

LORNOXICAM

Lornoxicam ( L) is a non-steroidal anti

with analgesic ,anti-inflammatory

oral and parenteral formulations

5’-Hydroxylornoxicam, the main

Dosage

Oral: Pain relief; Adult: 8-16 mg daily. Max: 24 mg

Oral: Osteoarthritis; Adult: 12 mg daily in 2

needed.

Oral: Rheumatoid arthritis; Adult: 12 mg daily in 2

needed.

Parenteral: Pain relief; Adult: 8 mg once or twice daily by IM/IV inj. Max: 24 mg daily.

Indications

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LORNOXICAM – A PROFILE

steroidal anti-inflammatory drug (NSAID) of the

inflammatory and antipyretic properties. It is available in

formulations

Hydroxylornoxicam, the mainmetabolite. The additional hydroxyl group is shown in green.

16 mg daily. Max: 24 mg daily.

: 12 mg daily in 2-3 divided doses, up to 16 mg daily if

Rheumatoid arthritis; Adult: 12 mg daily in 2-3 divided doses, up to 16 mg daily if

Adult: 8 mg once or twice daily by IM/IV inj. Max: 24 mg daily.

(NSAID) of the oxicam class

properties. It is available in

group is shown in green.

3 divided doses, up to 16 mg daily if

3 divided doses, up to 16 mg daily if

Adult: 8 mg once or twice daily by IM/IV inj. Max: 24 mg daily.

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Lornoxicam is used for the treatment of various types of pain, especially resulting from

inflammatory diseases of the joints, osteoarthritis, surgery, sciatica, and other

inflammations.

Contraindications

The drug is contraindicated in patients that must not take other NSAIDs, possible reasons

including salicylate sensitivity, gastrointestinal bleeding and bleeding disorders, and

severe impairment of heart, liver or kidney function. Lornoxicam is not recommended

during pregnancy and breastfeeding and is contraindicated during the last third of

pregnancy

Adverse effects

Lornoxicam has side effects similar to other NSAIDs, most commonly mild ones like

gastrointestinal disorders (nausea and diarrhea) and headache. Severe but seldom side

effects include bleeding, bronchospasms and the extremely rare Stevens–Johnson

syndrome.

Interactions

Interactions with other drugs are typical of NSAIDs. Combination with vitamin K

antagonists like warfarin increases the risk of bleeding. Combination with ciclosporin can

lead to reduced kidney function, and to acute renal failure in rare cases. Lornoxicam can

also increase the adverse effects of lithium, methotrexate and digoxin and its derivatives.

The effect of diuretics, ACE inhibitorsand angiotensin II receptor antagonists can be

reduced, but this is only relevant in patients with special risks like heart failure. As

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with piroxicam, cimetidine can increase plasma levels but is unlikely to cause relevant

interactions.

Special Precautions

Active infections; asthma; allergic disorders; hemorrhagic disorders; hypertension;

impaired renal, hepatic, cardiac function.

Other Drug Interactions

Increased lornoxicam blood conc when given concomitantly with cimetidine.Enhanced

effects of anticoagulants, sulfonylureas, methotrexate, ciclosporin, digoxin. Decreased

effects of diuretics, ACE inhibitors.

Pharmacokinetics

Absorption

Lornoxicam is absorbed rapidly and almost completely from the gastro-intestinal tract.

Maximum plasma concentrations are achieved after approximately 1 to 2 hours. Food

protracts the average time to maximum concentration from 1.5 to about 2.3 hours and can

reduce the area under the curve (AUC) by up to 20%.

Distribution

The absolute bioavailability of Lornoxicam is 90–100%. No first-pass effect was

observed

Metabolism

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Lornoxicam is found in the plasma in unchanged form and as its hydroxylated metabolite.

The hydroxylated metabolite exhibits no pharmacological activity. CYP2C9 has been

shown to be the primary enzyme responsible for the biotransformation of the lornoxicam

to its major metabolite, 5’-hydroxylornoxicam.[1] Lornoxicam5’-hydroxylation by the

variant CYP2C9*3 and CYP2C9*13 is markedly reduced compared with wild type, both

in vitro and in vivo.

Elimination

Approximately 1/2 to 2/3 is eliminated via the liver and 1/3 to 42% (data are inconsistent)

via the kidneys as 5’-hydroxylornoxicam.[1]

Mechanism of action

Like other NSAIDs, lornoxicam inhibits prostaglandin biosynthesis by blocking the

enzyme cyclooxygenase. Lornoxicam inhibits both isoforms in the same concentration

range, that is, the ratio of COX-1 inhibition to COX-2 inhibition is 1:1. It readily

penetrates into the synovial fluid. The AUC ratio of synovial fluid to blood plasma is 0.5

after administration of 4 mg twice daily.

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PAST WORK ON LORNOXICAM

Zhang J, Tan X, Gao J, et.al1.,have prepared and characterized two

polymorphs of lornoxicam. Form I and Form II of lornoxicam were prepared by

recrystallization and characterized by X-ray powder Diffractometry (XRPD),

Thermal Analysis, Fourier transform infrared spectroscopy and scanning electron

microscopy. Form I was demonstrated to be triclinic with two kinds intramolecular

hydrogen of intermolecular hydrogen bonds, while Form II was orthorhombic with

two kinds of bonds. Form II had the significantly higher solubility and dissolution

and would be the suitable polymorph for the preparation of oral and injectable

dosage forms of lornoxicam.

Sathiyaraj S, Devi RD, Hari VB.et.al2., have designed and evaluated

Lornoxicam gastro retentive floating matrix tablets to prolong the gastric

residence time of Lornoxicam by fabricating it into a floating sustained release

matrix tablets. In this, hydroxyl propyl methyl cellulose K15M, a high viscous

grade polymer with apparent viscosity of 15,000 cps, was kept as a variable (10-

50%) and calcium carbonate (13%) was used as a gas generator. It was observed

that the buoyancy lasted for up to 24 hrs. Fourier transforms infra-red

spectroscopy peaks assured the compatibility of the drug with excipients and

confirmed the presence of pure drug in the formulation

Yener G, Yildirim S, et.al3., have Designed, characterised and invitro,

invivo studies were carried out on lornoxicam transdermal patches. The study was

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aimedtopreparelornoxicam transdermal patches in order to overcome their side

effects offered by oral application. Hydroxypropyl methylcellulose (HPMC) was

concluded to be suitable polymer for formulation of lornoxicam transdermal films

indicating pharmaceutical quality required. Lornoxicam transdermal patches gave

satisfactory results regarding to the edema inhibition in the assessment of anti-

inflammatory effect. Indicative parameters like log P, molecular weight and

solubility constraint on penetration rate of drugs also indicated good skin

penetration.

HamzaYel-S, Aburahma MHet.al4 ., have conducted studies onDesign

and in vitro evaluation of novel sustained-release double-layer tablets

of lornoxicam: utility of cyclodextrin and xanthan gum combination. Study was

aimed to develop new directly compressed, double-layer tablets (DLTs)

of lornoxicam. An amorphous, freeze-dried inclusion complex of lornoxicam with

hydroxypropyl-beta-cyclodextrin, present in 1:2 (drug/cyclodextrin) molar ratio,

was employed in the fast-release layer to enhance the dissolution of lornoxicam in

the stomac. The drug contained in the fast-release layer showed an initial burst

drug release of more than 30% of its drug content during the first 30 min of the

release study followed by gradual release of the drug for a period of 8 h.

HamzaYel-S, Aburahma MH. et.al5.,have studied the design and in vitro

evaluation of novel sustained- release matrix tablets for lornoxicam based on the

combination of hydrophilic matrix formers and basic pH-modifiers . All the

prepared matrix tablets containing basic pH-modifiers showed acceptable physical

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properties before and after storage. Release studies, performed in simulated gastric

and intestinal fluids used in sequence to mimic the GI transit, demonstrate the

possibility sustaining lornoxicam release by combining hydrophilic matrix formers

and basic pH-Modifiers to prepare tablets that meet the reported sustained-release

specifications.

HamzaYel-S, Aburahma MH. .et.al6.,have formulated and investigated in-

vitro release studies of novel sustained release compression-coated tablets

for lornoxicam. study was aimed to modify the release characteristics

of lornoxicamby preparing compression-coated tablets (CCTs) the prepared CCTs

was composed of a sustained release tablet core and an immediate release coat

layer. Amorphous, well-characterized, freeze-dried solid dispersion

of lornoxicam with polyvinylpyrrolidone K-30 was employed in the coat layer to

attain an initial rapid dissolution of lornoxicam . The in vitro drug release studies,

performed in gastrointestinal transit, CCTs were able to show the desired release

profile.

Kohl C, Steinkellner M. . et.al.,7studied pharmacokinetic drug/drug

interactions from lornoxicam with oral anticoagulants. The increases in steady-

state plasma concentrations or areas under the plasma concentration-time curve of

the oral anticoagulants by concomitant lornoxicam medication were predicted.

(S)-warfarin, 1.58-fold (1.32-fold for racemate); racemic-acenocoumarol, 1.28-

fold (1.09-fold); (R)-acenocoumarol, 1.10-fold (1.0-fold); racemic-

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phenprocoumon, 1.11-fold (1.18-fold); and (S)-phenprocoumon, 1.13-fold (1.24-

fold). Lornoxicam 5'-hydroxylation was competitively inhibited in vitro by both

phenprocoumon (K(i) = 1.2 +/- 0.4 microM) and acenocoumarol (K(i) = 5.5 +/-

3.5 microM). The degree of pharmacokinetic interactions exhibited by oral

anticoagulants and lornoxicam is dependent on the respective contribution of

CYP2C9 to their total clearance.

Masche UP, Rentsch KM, von Felten A. et.al.,8havestudiedopposite effects

of lornoxicam co-administration on phenprocoumon pharmacokinetics and

pharmacodynamics. Aim of the study was to investigate the effect of co-

administration of lornoxicam on the pharmacokinetics of (R)- and (S)-

phenprocoumon and their effect on factor II and VII activities. . Plasma

concentrations of (R)- and (S)-phenprocoumon and activities of coagulation

factors II and VII were measured after a single oral dose of 9 mg

phenprocoumonracemate. Co-administration of lornoxicam at the upper limit of

recommended doses mainly altered the pharmacokinetics of the more potent (S)-

isomer and to a lesser degree those of (R)-phenprocoumon. Despite these changes

in pharmacokinetics, a decrease of the effect on factor II and VII activity was

observed. These results suggest that in the case of lornoxicam co-administration in

a patient treated with phenprocoumon the prothrombin time should be monitored

closely.

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Olkkola KT, Brunetto AV, Mattila MJ. et.al.,9havestudiedPharmacokinetics

of oxicamnonsteroidal anti-inflammatory agents. Oxicamnonsteroidal anti-

inflammatory drugs (NSAIDs) are a group of structurally closely related

substances with anti-inflammatory, analgesic and antipyretic activities. They have

a weakly acidic character and are extensively bound to plasma

proteins.Lornoxicam differs from other oxicam NSAIDs because it has a short

elimination half-life of 3 to 4 hours. On the basis of limited data, some individuals

seem to eliminate lornoxicam very slowly, suggesting the presence of

polymorphic metabolism. The pharmacokinetics of cinnoxicam and sudoxicam

have not been studied thoroughly

Ravic M, Salas-Herrera I, Johnston A, . et.al.,10studied pharmacokinetic

interaction between cimetidine or ranitidine and lornoxicam.” Cimetidine 400 mg

twice daily significantly increased serum concentrations and reduced apparent oral

clearance of lornoxicam 8 mg twice daily in 12 healthy volunteers. Ranitidine 150

mg twice daily produced no significant changes in lornoxicam pharmacokinetics.

ETODOLAC – A PROFIL

Etodolac (E) is a nonsteroidal anti

inflammatory, analgesic, and antipyretic activities in animal models. The mechanism of

action of etodolac, like that of other NSAIDs, is not completely understood, but may be

related to prostaglandin synthetase inhibition.

Etodolac (E) is a member of the pyranocarboxylic acid group of nonsteroidal anti

inflammatory drugs (NSAIDs). Each tablet and capsule contains 400 mg or 500 mg of

etodolac for oral administration. Etodolac is a racemic m

enantiomers. Etodolac is a white crystalline compound, insoluble in water but soluble in

alcohols, chloroform, dimethyl sulfoxide, and aqueous polyethylene glycol. The chemical

name is (±) 1,8-diethyl

molecular weight of the base is 287.37. It has a pKa of 4.65 and an n

partition coefficient of 11.4 at pH 7.4.

and it has the following structural formula:

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A PROFIL E

is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits anti



ostaglandin synthetase inhibition.

is a member of the pyranocarboxylic acid group of nonsteroidal anti


etodolac for oral administration. Etodolac is a racemic mixture of [+]S and [



diethyl-1,3,4,9-tetrahydropyrano-[3,4-b]indole-1

molecular weight of the base is 287.37. It has a pKa of 4.65 and an n

partition coefficient of 11.4 at pH 7.4. The molecular formula for etodolac is C

and it has the following structural formula:

inflammatory drug (NSAID) that exhibits anti-



is a member of the pyranocarboxylic acid group of nonsteroidal anti-


ixture of [+]S and [-]R-



1-acetic acid. The

molecular weight of the base is 287.37. It has a pKa of 4.65 and an n-octanol:water

The molecular formula for etodolac is C17H21NO3,

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Dosage

Oral Increased effect of warfarin, lithium, methotrexate, digoxin, cyclosporin, aspirin.

Effect may be reduced with aspirin. Reduced effect of some diuretics and β-blockers.

Alcohol enhances gastric mucosal irritation.

Other Interactions

Osteoarthritis

Adult: 200-400 mg every 6-8 hr. Max: 1 g/day.

Adult: 600-1000 mg/day in divided doses adjusted according to response.

Max Dosage: 1200 mg daily.

Oral

Rheumatoid arthritis

Adult: 600-1000 mg/day in divided doses adjusted according to response.

Max Dosage: 1200 mg daily.

Oral

Acute pain

Contraindications

Peptic ulcer, hypersensitivity to etodolac/NSAIDs.Childn; pregnancy (3rd trimester) and

lactation.

Side effects: Constipation,diarrhea, gas or bloating, vomiting, headache, dizziness, ringing in the ears,

runny nose, sore throat, blurred vision. Symptoms of overdose may include: lack of

energy, drowsiness, nausea, vomiting, stomach pain, bloody, black or tarry stool, vomit

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that is bloody or looks like coffee grounds, coma (loss of consciousness for a period of

time)

Pharmacokinetics

Absorption

The systemic bioavailability of etodolac from etodolac is 100% as compared to solution

and at least 80% as determined from mass balance studies. Etodolac is well absorbed and

had a relative bioavailability of 100% when 200 mg capsules were compared with a

solution of etodolac. Based on mass balance studies, the systemic availability of etodolac

from either the tablet or capsule formulation is at least 80%. Etodolac does not undergo

significant first-pass metabolism following oral administration. Mean (± 1 SD) peak

plasma concentrations (Cmax) range from approximately 14 ± 4 to 37 ± 9 µg/mL after 200

to 600 mg single doses and are reached in 80 ± 30 minutes. The dose-proportionality

based on the area under the plasma concentration-time curve (AUC) is linear following

doses up to 600 mg every 12 hours. Peak concentrations are dose proportional for both

total and free etodolac following doses up to 400 mg every 12 hours, but following a 600

mg dose, the peak is about 20% higher than predicted on the basis of lower doses. The

extent of absorption of etodolac is not affected when etodolac is administered after a

meal. Food intake, however, reduces the peak concentration reached by approximately

one-half and increases the time to peak concentration by 1.4 to 3.8 hours.

Distribution

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The mean apparent volume of distribution (Vd/F) of etodolac is approximately 390

mL/kg. Etodolac is more than 99% bound to plasma proteins, primarily to albumin. The

free fraction is less than 1% and is independent of etodolac total concentration over the

dose range studied. It is not known whether etodolac is excreted in human milk; however,

based on its physical-chemical properties, excretion into breast milk is expected.

Metabolism

Etodolac is extensively metabolized in the liver. The role, if any, of a specific

cytochrome P450 system in the metabolism of etodolac is unknown. Several etodolac

metabolites have been identified in human plasma and urine. Other metabolites remain to

be identified. The metabolites include 6-, 7-, and 8-hydroxylated-etodolac and

etodolacglucuronide. After a single dose of 14C-etodolac, hydroxylated metabolites

accounted for less than 10% of total drug in serum. On chronic dosing, hydroxylated-

etodolac metabolite does not accumulate in the plasma of patients with normal renal

function. The extent of accumulation of hydroxylated-etodolac metabolites in patients

with renal dysfunction has not been studied. The hydroxylated-etodolac metabolites

undergo further glucuronidation followed by renal excretion and partial elimination in the

feces.

Excretion

The mean oral clearance of etodolac following oral dosing is 49 (± 16) mL/h/kg.

Approximately 1% of aetodolac dose is excreted unchanged in the urine with 72% of the

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dose excreted into urine as parent drug plus metabolite: Although renal elimination is a

significant pathway of excretion for etodolac metabolites, no dosing adjustment in

patients with mild to moderate renal dysfunction is generally necessary. The terminal

half-life (t1/2) of etodolac is 6.4 hours (22% CV). In patients with severe renal dysfunction

or undergoing hemodialysis, dosing adjustment is not generally necessary. Fecal

excretion accounted for 16% of the dose.

Indications

Used for osteoarthritis, rheumatoid arthritis and in acute pain Adverse Reactions

GI disturbances; CNS effects; hypersensitivity reactions.Rash, pruritus; neuromuscular

and skeletal weaknesses; blurred vision.

Potentially Fatal

Acute renal failure; blood disorder; nephrotoxicity; angioedema, arrhythmia, bone

marrow suppression, CHF, dyspnoea, erythema multiforme, exfoliative dermatitis,

hepatitis, hypertension, peripheral neuropathy, Stevens-Johnson syndrome, syncope,

tachycardia, toxic amblyopia, toxic epidermal necrolysis, urticaria.

Precautions

CHF, dehydration, impaired renal, hepatic function, history of GI disease. Elderly,

patients receiving anticoagulant.

Other Drug Interactions

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Peak serum levels and GI distress decreased when taken with food. Cat's claw, dong quai,

evening primrose, feverfew, ginkgo, red clover, horse chestnut, green tea and ginseng

enhance the antiplatelet effect.

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RECENT WORKS ON ETODOLAC

Abd-Elbary A, Tadros MI, Alaa-Eldin AA, et.al.,11Development and in vitro/in

vivo evaluation of etodolac controlled porosity osmotic pump tablets.” work was the

design and evaluation of etodolac controlled porosity osmotic pump (CPOP) tablets

exhibiting zero-order release kinetics. the design of (1) core tablets viz., (a) osmogent

type (sodium chloride, potassium chloride, mannitol, and fructose) and (b)

drug/osmogent ratio (1:0.25, 1:0.50, and 1:0.75), and (2) CPOP tablets viz., (a)

coating solution composition, (b) weight gain percentage (1-5%, w/w), and (c) pore

former concentration (5%, 10%, and 20%, v/v), were investigated. Statistical analysis

and kinetic modeling of drug release data were estimated. Scanning electron

microscopy micrographs of coating membrane confirmed pore formation upon

contact with dissolution medium.

Ibrahim MM, El-NabarawiM,et. al12Polymeric surfactant

based etodolac chewable tablets: formulation and in vivo evaluation”work was

carried out to improve the dissolution rate of etodolac using three carriers through

coevaporation technique. The polymeric surfactant inutec, 2-hydroxypropyl-β-

cyclodextrin, and tromethamine were used at three different drug/carrier ratios. The

results showed significantly higher mean C (max) and shorter mean T (max) (about 2

h earlier) and about 1.32-fold higher mean AUC(0-24) values for the F3 chewable

tablets compared to ET-filled capsules.

BarakatNS.et.a l13Enhanced oral bioavailability of etodolac by self-emulsifying

systems: in-vitro and in-vivo evaluation.” The SEDDS formulations were optimized

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by evaluating their ability to self-emulsify when introduced to an aqueous medium

under gentle agitation, and by determination of the particle size of the resulting

emulsion. SEDDS formulation was 2.3 times that of the pure drug and 1.4 times that

of the suspension form. SEDDS formulation exhibits a 21% increase in paw thickness

compared with a 39% increase on oral administration of etodolac suspension after 4 h

at the same dose of the drug (20 mg/kg).The result indicates the utility of SEDDS for

the oral delivery of etodolac and potentially other lipophilic drugs.

Barakat NS.et.al14In vitro and in vivo characteristics of a thermogelling rectal

delivery system of etodolac.” Rectal etodolac-Poloxamer gel systems composed of

Poloxamer and bioadhesive polymers were developed and evaluated.

Hydroxypropylmethyl cellulose, poly)vinyl) pyrrolidone, methyl cellulose, results

suggested that in situ gelling liquid suppository with etodolac and mucoadhesive

polymer was a physically safe, convenient, and effective rectal dosage form

for etodolac.

Tas C, Ozkan Y, Okyar A, SavaserA,et.a l15In vitro and ex vivo permeation

studies of etodolac from hydrophilic gels and effect of terpenes as enhancers”.

Hydrophilic gel formulations of etodolac were prepared with carboxymethylcellulose

sodium. The effect of different terpenes (anethole, carvacrol, and menthol) as an

enhancer on the percutaneous absorption ofetodolac was also investigated. The

lipophilicity of the enhancers seems an important factor in promoting penetration

of etodolac through the skin. Since etodolac creates gastrointestinal disturbances,

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topical formulations of etodolac in gel form including 1% anethole could be an

alternative.

Barakat NS.et.al16Etodolac-liquid-filled dispersion into hard gelatin capsules: an

approach to improve dissolution and stability ofetodolac formulation.” The carrier

fusion method was used to prepare different dispersion of etodolac using Gelucire

44/14 and D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS). The

physical characteristics of the binary systems were determined by differential

scanning calorimetry (DSC), infrared spectroscopy (IR). It is predicted that acceptable

shelf-lives should result when moisture-resistant packaging is used for pharmaceutical

formulations of this type.

Ozkan Y, Doganay N, Dikmen N, IşimerAet.a l17 Enhanced release of solid

dispersions of etodolac in polyethylene glycol.” Solid dispersions of etodolac were

prepared in different molar ratios of drug/carrier by using solvent and melting

methods. The solid dispersion compound prepared in the molar ratio of 1:5 by the

solvent method was found to have the fastest dissolution profile. The physical

properties did not change after 9 months storage in normal conditions.

Hersh EV, Levin LM, Cooper SA, Reynolds D, et.a l18Conventional and extended-

release etodolac for postsurgical dental pain.” This double-masked, parallel-group,

randomized study compared the analgesic efficacy and tolerability of a single

investigational 1200-mg dose of extended-release etodolac with those of a single 400-

mg dose of extended-release etodolac and twice-daily doses of

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conventional etodolac 200 and 400 mg and placebo. Extended-releaseetodolac 1200

mg has a prolonged analgesic duration and an acceptable side-effect profile in the oral

surgery pain model.

Dey M, Enever R, Kraml M, PrueDG,et.a l19The dissolution and bioavailability

of etodolac from capsules exposed to conditions of high relative humidity and

temperatures. The dissolution of etodolac from capsules exposed to stressed

conditions was also evaluated with enzymes (pancreatin, 1%, w/v) added to the

dissolution medium. Capsules, 200 and 300 mg, exposed to stressed conditions failed

the dissolution (without enzymes) specification [not less than 85% released (80% Q)

in 30 min]. Thus, an in vitro dissolution test with enzymes provides a better indication

of stressed capsule performance in vivo.

Molina-Martinez IT, Herrero R, et.al20Bioavailability and bioequivalence of two

formulations of etodolac (tablets and suppositories).” The study was done in a

crossover design with healthy volunteers of both sexes, of average build, and younger

than 35 years of age. From the concentration in plasma-time data, the maximum

concentration in plasma (Cmax), time to Cmax, and area under the curve up to the last

measurable concentration (AUC0t) or infinity (AUC 0 infinity) were calculated and

compared by analysis of variance. The results indicate that the two routes of

administration are bioequivalent and that the rectal route is an alternative

administration route for etodolac.

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FLURBIPROFEN – A PROFILE

Flurbiprofen, which is a member of the phenylalkanoic acid derivative group of

nonsteroidal anti-inflammatory drugs(NSAIDs) used to treat the inflammation and pain

of arthritis. Flurbiprofen is a racemic mixture of (+)S- and (-)R- enantiomers.

Flurbiprofen is a white or slightly yellow crystalline powder. It is slightly soluble in

water at pH 7.0 and readily soluble in most polar solvents.

The chemical name is [1,1'-biphenyl]-4-acetic acid, 2-fluoro-alphamethyl-, (±)-. The

molecular weight is 244.26. Its molecular formula is C15H13FO2 .

Dosage

Oral

Pain and inflammation associated with musculoskeletal and joint disorders

Adult: 150-200 mg daily in divided doses, increased to 300 mg daily in acute or severe

conditions if necessary.

Oral

Dysmenorrhoea

Adult: Initially, 100 mg followed by 50-100 mg every 4-6 hours. Max: 300 mg/day.

Sore throat - Adult: 1 lozenge (8.75 mg) every 3-6 hours. Max: 5 lozenges/day. Max

83

treatment duration: 3 days.

Child: <12 yr: Not recommended.

Contraindications

Peptic ulcer, GI haemorrhage, asthma, bronchospasm, rhinitis, angioedema,

hypersensitivity; aspirin intolerance; pregnancy (3rd trimester); lactation.

Storage:

Ophthalmic: Store at 15-25°C.

Oral: Store at 15-25°C.

Pharmacokinetics

Flurbiprofen inhibits prostaglandin synthesis by decreasing the activity of

cyclooxygenase resulting in reduced prostaglandin levels. It is also a potent inhibitor of

plateletaggregation.

Absorption

Readily absorbed from the GIT (oral),peak plasma concentrations after 1-2 hours.

Distribution

Small amounts enter breast milk. Protein-binding: 99%

Metabolism

Hepatic via hydroxylation and conjugation.

Excretion

Urine (as metabolites); 3-6 hours (elimination half-life).

Side effects

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Nervousness or anxiety, Depression, Memory problems , Shaking of a part of the body

that you cannot control , Difficulty falling asleep or staying asleep, Vomiting, Gas,

Constipation, Diarrhea, Runny nose.

Flurbiprofen Adverse Reactions / Flurbiprofen Side Effects

Fluid retention, oedema; allergic nephritis, allergic reactions; GI upsets; dizziness,

tinnitus, blurring of vision; local irritation, transient burning and stinging (ophthalmic).

Potentially Fatal: Peptic ulceration, haemorrhage and perforation.

85

RECENT WORKS ON FLURBIPROFEN

Oh DH, Din FU, Kim DW, Kim JO,et.al21 have prepared Flurbiprofen-loaded

nanoparticles prepared with polyvinylpyrrolidone using Shirasu porous glass

membranes and a spray-drying technique: nano-sized formation and improved

bioavailability. Study of flurbiprofen-loaded nanoemulsion was developed further

into a solid form using polyvinylpyrrolidone (PVP) as a carrier by a spray-drying

technique. The flurbiprofen-loaded nanoparticles with a weight ratio

offlurbiprofen/PVP/surfactant mixture of 1/8/2 were connected with about 130 000-

fold enhanced drug solubility and had a mean size of about 70 nm.

These flurbiprofen-loaded nanoparticles can be convenient for distributing a poorly

water-soluble flurbiprofen with improved bioavailability using uniform nano-sized

particles.

Sareen R, Jain N, Dhar KL.et.al22 have developed colon specific microspheres

of flurbiprofen for inflammatory bowel disease. Flurbiprofen was entrapped in

chitosan microspheres, coating with Eudragit S-100 utilizing the benefits of pH

dependent solubility of Eudragit S-100, so as to prevent the premature release of

flurbiprofen in upper GIT. In vitro release studies of uncoated FLB- chitosan

microspheres showed burst release in initial 4 h, while Eudragit S-100 coated

microspheres prevented the premature release of FLB and showed controlled release

for 12 h following Higuchi model, thus suitable for colon specific drug delivery.

Kawadkar J, Jain R, Kishore R,et.al23have formulated and evaluated flurbiprofen-

loaded genipin cross-linked gelatin microspheres for intra-articular delivery. The

86

microspheres were prepared using emulsification-homogenization-cross-linking

method by changing the experimental variables such as concentration of cross-linker,

cross-linking time and cross-linking temperature. significant higher amount (42.56%)

of administered drug in cross-linked microspheres was recovered than uncross-linked

microspheres (8.27%) confirming better drug retention efficiency (p < 0.01).

Baviskar DT, Amritkar AS,et.al24have Modulatied release of drug from

nanocarriers loaded with a poorly water soluble drug (flurbiprofen) comprising

natural waxes.”In this study, flurbiprofen (FLB) Solid Lipid Nanoparticles (SLN)

composed from a mixture of beeswax and carnauba wax, Tween 80 and egg lecithin

as emulsifiers have been prepared. . Nanoparticles with higher beeswax content in

their core exhibited faster drug release than those containing more carnauba wax.

Alexander S, Cosgrove T, Castle TC, et.al25have studied the effect of temperature,

cosolvent, and added drug on Pluronic-flurbiprofen micellization. Structural changes

in the micellization of Pluronics P103 and P123, as a function of temperature,

cosolvent (ethanol, 10 v/v %), and the addition of the hydrophobic drug flurbiprofen,

were investigated by SANS and tensiometry. The addition of flurbiprofen to Pluronic

P103 was also found to reduce the critical micellization temperature from between 15

and 20 °C to below 10 °C and at higher drug concentrations leads to an attractive

interaction between micelles and eventually phase separation.

Veerareddy PR, Vemula SK.et.al26have formulated, evaluated and studied

pharmacokinetics of colon targeted pulsatile system of flurbiprofen. The study was

aimed to develop colon targeted compression coated flurbiprofen pulsatile release

87

tablets that retard the drug release in the upper gastro intestinal system but

progressively release in the colon. coated with hydroxypropyl methylcellulose and

Eudragit S100. Development of pulsatile release compression coated tablets using

combination of time dependent and pH sensitive approaches was suitable to target

the flurbiprofen to colon.

Kai S, Kondo E, Kawaguchi Y,et.al27 have studied Flurbiprofen concentration in

soft tissues is higher after topical application than after oral administration. Study was

aimed to compare tissue concentrations of flurbiprofen resulting from topical

application and oral administration according to the regulatory approved dosing

guidelines. Topical application is an effective method to deliver flurbiprofen to the

human body, particularly to soft tissues near the body surface.

Kawadkar J, Pathak A, Kishore R, .et.al28 have formulated, characterized and

carried in vitro-in vivo evaluation of flurbiprofen-loaded nanostructured lipid carriers

for transdermal delivery. work aims to develop nanostructured lipid carriers (NLCs)

of flurbiprofen and evaluate their potential for transdermal delivery. The NLCs were

prepared by the optimized o/w emulsification-homogenization-sonication technique

using coconut oil (liquid lipid). The stability data revealed that the NLCs were more

stable when stored at 5°C. In NLCs have potential for skin targeting and sustained

drug release.

Kulhari H, Pooja D, Narayan H, ,et.al29 have designed and evaluated the

ocusert for controlled delivery of flurbiprofen sodium. This study is to develop

the flurbiprofen sodium soluble ocusert to increase patient compliance by

88

improving local delivery of the drug. Three different polymers were used in

combination to prepare the rate controlling membrane. An appropriate

combination of hydrophilic and hydrophobic polymers provides better control of

drug delivery.

Idrees M, Rahman N, Ahmad S,et.al30“ Enhance transdermal delivery

of flurbiprofen via microemulsions: Effects of different types of surfactants and

cosurfactants.” Various surfactant-cosurfactant mixtures in ratio of 2:1 (Smix)

along with oleic acid (oil) were selected and phase diagrams were constructed. Six

microemulsions each containing 5% drug, 5% oil, 56% Smix and 34% water, were

prepared and compared for their permeation and phase behaviors to determine the

effects of the type of Smix. and results of this study showed that they are

promising vehicles for improved transdermal delivery and sustained action

of flurbiprofen.

Oh DH, Park YJ, Kang JH, et.al31“ Physicochemical characterization and in

vivo evaluation of flurbiprofen-loaded solid dispersion without crystalline

change.”solid dispersions were prepared with water, sodium carboxylmethyl

cellulose (Na-CMC), and Tween 80. Thus, the flurbiprofen-loaded solid

dispersion would be useful to deliver poorly water-soluble flurbiprofen with

enhanced bioavailability without crystalline change.

Anraku M, Arahira M, Mady FM, Khaled KA, et.al32“ Enhancement of

dissolution and bioavailability of flurbiprofen by low molecular weight

89

chitosans”oral administration from:three types of chitosans (LM chitosans), with

different molecular weights and degree of acetylation, have been studied in

comparison with those of the drug alone. These results suggest that FP from LM

chitosan kneaded mixture increases the dissolution rate and improves the

bioavailability of the drug by the formation of a water-soluble complex.

González-Mira E, Nikolić S, García ML, Egea MA, et.al33“ Potential use of

nanostructured lipid carriers for topical delivery of flurbiprofen. The potential use

of nanostructured lipid carriers (NLC) composed of a fatty acid as solid lipids, and

a mixture of medium chain triglycerides and castor oil as liquid lipids, for skin

administration of flurbiprofen The in vitro and in vivo irritancy and local

tolerability were assessed by running, respectively, the Skintex and Draize test.

Both FB-C888NLC and FB-SANLC were classified as nonirritant.

Shah SN, Asghar S, Choudhry MA,et.al34have carried out studies

onFormulation and evaluation of natural gum-based sustained release matrix

tablets of flurbiprofen using response surface methodology. Aim of the work was

to design oral sustained release matrix tablets of water-insoluble

drug, flurbiprofen, using natural gums as the matrix polymers and to evaluate the

drug release characteristics using response surface methodology. The formulated

matrix tablets followed zero-order kinetics, which was the objective of this study

to produce a formulation avoiding the gastric effects of flurbiprofen.

Darwish MK, Elmeshad AN.et.al35 have carried out studies on

Buccalmucoadhesive tablets of flurbiprofen: Characterization and optimization.

90

Work was to develop and optimize sustained-release mucoadhesive tablets

of flurbiprofen. Mucoadhesive polymers used were chitosan as primary polymer

and hydroxypropylmethylcelluose, hydroxypropyl cellulose, or sodium

carboxymethyl cellulose as secondary polymer. the primary and secondary

polymers were found to have synergistic effects on tablet swelling, bioadhesion,

and in vitro drug release.

Naproxen is a Proprionic acid derivative related to the Arylacetic acid group of

NonSteroidal Anti-Inflammatory drugs.The chemical names For Naproxen and Naproxen

Sodium are (S)-6-Methoxy

Methyl-2-Naphthaleneacetic Acid, Sodium salt, respectively. Naproxen and Naproxen

Sodium have the following structures, respectively

Naproxen (R=-COOH) C14H14O3 MolWt 230.26

Naproxen Sodium (R=-COONa) C14H13NaO3 MolWt 252.23

Naproxen has a Molecular Weight of

Naproxen sodium has a Molecular Weight of 252.23 and a Molecular Formula of

C14H13NaO3 .Naproxen is an odorless, white to off

soluble, practically insoluble in water at lo

The octanol/water Partition coefficient of Naproxen at pH 7.4 is 1.6 to 1.8. Naproxen

sodium is a white to creamy white, crystalline solid, freely soluble in water at neutral pH.

91

NAPROXEN – A PROFILE


Inflammatory drugs.The chemical names For Naproxen and Naproxen

Methoxy-A-Methyl-2-Naphthaleneacetic Acid and (S)

thaleneacetic Acid, Sodium salt, respectively. Naproxen and Naproxen

Sodium have the following structures, respectively

COOH) C14H14O3 MolWt 230.26

COONa) C14H13NaO3 MolWt 252.23

Naproxen has a Molecular Weight of 230.26 and a Molecular Formula of C


Naproxen is an odorless, white to off-white crystalline substance. It is lipid

soluble, practically insoluble in water at low pH and freely soluble in water at high pH.




Inflammatory drugs.The chemical names For Naproxen and Naproxen

Naphthaleneacetic Acid and (S)-6-Methoxy-a-

thaleneacetic Acid, Sodium salt, respectively. Naproxen and Naproxen

230.26 and a Molecular Formula of C14H14O3


white crystalline substance. It is lipid-

w pH and freely soluble in water at high pH.



92

Indications and Usage

Management of mild to moderate Pain, Symptoms of Rheumatoid Or Osteoarthritis,

Bursitis, Tendonitis, Ankylosing Spondylitis, Primary Dysmenorrhea, Acute Gout.

Delayed-release Naproxen is not recommended for initial treatment of acute pain because

absorption is delayed compared to other Naproxen formulations.

Contraindications

Allergy to aspirin, iodides or any NSAID; patients in whom aspirin or other NSAIDs

induce symptoms of asthma, rhinitis or nasal polyps.

Dosage and Administration

Naproxen

Rheumatoid Arthritis, Osteoarthritis, Ankylosing Spondylitis

Delayed-release

PO 375 to 500 mg twice daily.

Controlled release

PO 750 to 1,000 mg every daily. Individualize dosage. Do not exceed 1,500 mg/day.

SuspensionPO 250 mg (10 ml)

Storage/StabilityStore at 59° to 86°F.

93

Side Effects of Naproxen

Chest Pain, Weakness, Shortness Of Breath, Slurred Speech, Problems With Vision Or

Balance , Black, Bloody Or Tarry Stools, Coughing Up Blood Or Vomit That Looks

Like Coffee Grounds , Swelling Or Rapid Weight Gain, Urinating Less Than Usual Or

Not At All , Nausea

Pharmacology

Decreases Inflammation, Pain, and Fever, probably through Inhibition Of

Cyclooxygenase Activity and Prostaglandin Synthesis.

Pharmacokinetics

Absorption

Naproxen is completely absorbed from the GI tract. Tablet T max is 2 to 4 h (immediate-

release); suspension T max is 1 to 4 h; fasted patients' T max is 4 to 6 h (delayed-release);

bioavailability is 95%; steady state is reached in 4 to 5 days.

Distribution

Vd is 0.16 L/kg and protein binding is 99% albumin-bound.

94

Elimination

Naproxen is eliminated in urine (95%), primarily as naproxen less than 1%, 6-0-

desmethylnaproxen less than 1%, or their conjugates (66% to 92%). Naproxen t ½ is 12 to

17 h, Cl is 0.13 mL/min/kg, t ½ of metabolites and conjugates is less than 12 h.

Drug Interactions

Anticoagulants

May increase effect of anticoagulants because of decreased plasma protein binding.May

increase risk of gastric erosion and bleeding.

Lithium May decrease lithium Cl.

MethotrexateMay increase methotrexate levels.

Adverse Reactions

Cardiovascular

Edema; weight gain; CHF; alterations in BP; vasodilation; palpitations; tachycardia; chest

pain; bradycardia.

CNS

95

Headache; dizziness; drowsiness; vertigo; lightheadedness; mental depression;

nervousness; irritability; fatigue; malaise; insomnia; sleep disorders; dream

abnormalities; aseptic meningitis.

Dermatologic

Rash; urticaria; purpura; skin eruptions.

GI

Constipation; heartburn; abdominal pain; peptic ulceration and bleeding; nausea;

dyspepsia; diarrhea; vomiting; anorexia; colitis; flatulence.

Genitourinary

Glomerulonephritis; interstitial nephritis; nephrotic syndrome; acute renal insufficiency

and renal failure; dysuria; hyperkalemia; hyponatremia; renal papillary necrosis.

Hepatic

Increased LFT results.

Hematologic

Increased bleeding time; leukopenia; thrombocytopenia; granulocytopenia; eosinophilia;

ecchymosis.

96

Respiratory

Bronchospasm; laryngeal edema; dyspnea; shortness of breath.

Precautions

Warnings

NSAIDs may cause an increased risk of serious CV thrombotic events, MI, and stroke,

which can be fatal. This risk may increase with length of therapy. Patients with CV

disease or risk factors for CV disease may be at greater risk. NSAIDs cause an increased

risk of serious GI adverse reactions, including bleeding, inflammation, perforation of the

stomach or intestines, and ulceration, which can be fatal. These events can occur any time

during use and without warning symptoms. Elderly patients are at greater risk of serious

GI events.

97

RECENT WORKS ON NAPROXEN

Paudel A, Loyson Y, Van den Mooter G,et.al36An investigation into the

effect of spray drying temperature and atomizing conditions on miscibility,

physical stability, and performance of naproxen-PVP K 25 solid dispersions.”The

study investigates the effect of changing spray drying temperature (40°C-120°C)

and/or atomizing airflow rate (AR; 5-15 L/min) on the phase structure, physical

stability, and performance of spray-dried naproxen-polyvinylpyrrolidone (PVP) K

25 amorphous solid dispersions. The rate and extent of the drug dissolution was

the highest for dispersions prepared at the highest atomizing AR and the lowest for

that prepared with the slowest atomizing condition

Chawla A, Sharma P, Pawar P.et.al37Eudragit S-100 coated sodium alginate

microspheres of naproxen sodium: Formulation, optimization and in vitro

evaluation / AlginatnemikrosferenaproksennatrijaobloženeEudragitom S-100:

Priprava, optimizacija i in vitro vrednovanje.” the study was to prepare site

specific of naproxen sodium using sodium alginate and Eudragit S-100 as a

mucoadhesive and pH-sensitive polymer. Moreover, drug release from Eudragit S-

100 coated microspheres followed the Korsmeyer-Peppas equation with a Fickian

kinetics mechanism. Stability study suggested that the degradation rate constant of

microspheres was minimal, indicating 2 years shelf life of the formulation.

Zhu Q, Toth SJ, Simpson GJ, Hsu HY. et.al38Crystallization and dissolution

behavior of naproxen/polyethylene glycol solid dispersions.” The crystallization

kinetics of naproxen (NAP) in NAP/polyethylene glycol (NAP/PEG) solid

98

dispersions prepared at different crystallization temperatures was studied by in situ

small-angle X-ray scattering/wide-angle X-ray scattering (SAXS/WAXS). The

microstructure of the NAP/PEG solid dispersions and the dissolution behavior also

showed a dependence on the chemical composition of the solid dispersions.

Hsu HY, Toth SJ, Simpson GJ et.al39 Effect of substrates on naproxen-

polyvinylpyrrolidone solid dispersions formed via the drop printing technique.” To

allow for highly controllable products, the drop printing (DP) technique can

provide precise dosages and predictable compositional uniformity of active

pharmaceutical ingredients in two-/three-dimensional structures when integrated

with edible substrates. The surface energy approach was combined with classical

nucleation theory to evaluate the affinity between the nucleus of NAP and

substrates. Finally, the collective results of the drug were correlated to the release

profile of NAP within each sample.

Guo Z, Liu XM, Ma L, Li J, Zhang H, Gao YP. et.al40 “Effects of particle

morphology, pore size and surface coating of mesoporous silica

on Naproxen dissolution rate enhancement.” In this work, the dissolution behavior

of Nap after loading in mesoporous silica materials was investigated in a simulated

intestinal fluid (pH=6.8). The effect of the morphology of mesoporoussilicas on

the dissolution of Nap can be ascribed to the length of pore channels, that the

longer channel showed a longer diffusion pathway of Nap. Moreover, the release

rate of Nap from functionalized mesoporous materials was effectively controlled

compared with that of unmodified materials.

99

Paudel A, Nies E, Van den Mooter G.et.al41 Relating hydrogen-bonding

interactions with the phase behavior of naproxen/PVP K 25 solid dispersions:

evaluation of solution-cast and quench-cooled films.” In this work, investigated

the relationship between various intermolecular hydrogen-bonding (H-bonding)

interactions and the miscibility of the model hydrophobic drug naproxen with the

hydrophilic polymer polyvinylpyrrolidone (PVP) across an entire composition

range of solid dispersions. Two types of H-bonded populations were evidenced

from 25% w/w and 35% w/w naproxen in solution-cast films and quench-cooled

films, respectively, with the higher fraction of strongly H-bonded population in the

drug rich domains of phase separated amorphous film compositions and highly

drug loaded amorphous quench-cooled dispersions.

Raijada D, Bond AD, Larsen FH, .et.al42Exploring the solid-form landscape

of pharmaceutical hydrates: transformation pathways of the

sodium naproxenanhydrate-hydrate system.” Multi-temperature dynamic vapour

sorption (DVS) analysis combined with variable-humidity X-ray powder

diffraction (XRPD) to establish the transformation pathways as a function of

temperature and humidity At 25 °C, anhydrous sodium naproxen (AH) transforms

directly to one dihydrate polymorph (DH-II). At 50 °C, AH transforms stepwise to

a monohydrate (MH) then to the other dihydrate polymorph (DH-I). DH-II

transforms to a tetrahydrate (TH) more readily than DH-I transforms to TH. Both

dihydrate polymorphs transform to the same MH.The properties of the

polymorphic dihydrate control the transformation pathways of sodium naproxen.

100

Kayaert P, Van den Mooter G.et.al43An investigation of the adsorption of

hydroxypropylmethyl cellulose 2910 5 mPa s and polyvinylpyrrolidone K90

around Naproxen nanocrystals.”the study was to investigate the association of two

common pharmaceutical stabilizers [hydroxypropylmethyl cellulose (HPMC)

2910 5 mPa s and polyvinylpyrrolidone (PVP) K90] with the surface

of Naproxen crystals. The conclusion is that the behavior in suspension determines

the behavior of the stabilizer after drying and it is governed by the

physicochemical properties of the polymers.

Ameli A, Alizadeh N. .et.al44Nanostructured conducting molecularly

imprinted polymer for selective uptake/release of naproxen by the

electrochemically controlled sorbent.” A conducting molecularly imprinted

polymer (CMIP) film, based on polypyrrole, was electrosynthesized for selective

uptake/release and determination of naproxen. The CMIP films, as the

electrochemically controlled solid-phase sorbent, were applied for the selective

cleanup and quantification of trace amounts of naproxenfrom physiological

samples. Scanning electron microscopy confirmed the nanostructure morphology

of the films.

Kayaert P, Van den Mooter Get.al45Is the amorphous fraction of a dried

nanosuspension caused by milling or by drying? A case study

with Naproxen.”One of the benefits of nanocrystals is their positive effect on the

solubility and dissolution rate without alterations to the solid state amorphization

of nanocrystals after milling or drying has only rarely been described. results

101

prove that in depth testing and characterization of the solid state of a dried

nanocrystal formulation remains very important.

Ando S, Kikuchi J, Fujimura Y, et.al46Physicochemical characterization

and structural evaluation of a specific 2:1 cocrystal of naproxen-nicotinamide.”

Physicochemical characterization and structural evaluation of a 2:1 naproxen-

nicotinamidecocrystal were performed. . Single-crystal X-ray analysis, which

supported the solid-state NMR results, clarified the geometry and intermolecular

interactions in more detail. The structure is unique among pharmaceutical

cocrystals because each carboxyl group

Dyakonov T, Yang CH, Bush D, et.al47“Design and characterization of a

silk-fibroin-based drug delivery platform using naproxen as a model drug.” The

objective of this proof-of-concept study was to develop a platform for controlled

drug delivery based on silk fibroin (SF) and to explore the feasibility of using SF

in oral drug delivery. The controlled release characteristics of the SF-containing

compositions were evaluated as a function of SF concentration, temperature, and

exposure to dehydrating solvents. The results suggest that SF may be an attractive

polymer for use in controlled drug delivery systems.

Mati SS, Mondal TK, Dhar S, et.al48“Differential contribution of Igepal and

CnTAB micelles on the photophysics of nonsteroidal drug Naproxen.”

Spectroscopic studies of Naproxen (NP), a nonsteroidal drug have been carried out

in well characterized, micellar media of cationic surfactants of a homologous

series having general formula C(n)TAB (alkyl trimethyl ammonium bromide) and

102

of nonionic surfactants of Igepal (Ig) series (poly(oxyethylene) nonyl phenol).

Based on the experimental and theoretical studies, an attempt has been made to

explain the different behavior of the probe in different media.

Čalija B, Milić J, Cekić N, et.al 49“Chitosan oligosaccharide as prospective

cross-linking agent for naproxen-loaded Ca-alginate microparticles with improved

pH sensitivity.”the work was to develop Ca-alginate microparticles for oral

administration of naproxen reinforced with chitosan oligosaccharide (COS) with a

special interest to examine the potential of COS for improvement of microparticles

stability in simulated intestinal fluid (SIF). The obtained findings proved that COS

could be used as an effective cross-linking agent for improvement of Ca-alginate

microparticles stability in SIF, allowing prolonged release of the encapsulated

drug after oral administration.

Ayenew Z, Paudel A, Van den Mooter G, , et.al50 “Can compression induce

demixing in amorphous solid dispersions? A case study of naproxen-PVP K25.”

work is to investigate the effect of compression on miscibility of naproxen (NAP)-

PVP K25 solid dispersions. Solid dispersions with diverse drug/polymer

compositions were compressed at various forces for uniform dwell time. This can

have influence on miscibility resulting from weakening and/or disruption of

intermolecular hydrogen bonding between drug and polymer upon compression.

Tian Q, Ren F, Xu Z, et.al51“Preparation of high

solubilizablemicroemulsion of naproxen and its solubilization mechanism.” the

skin permeation of naproxen with larger dosage, microemulsion with high content

103

of naproxen was investigated for transdermal delivery and its solubilization

mechanism was studied. The powerful permeation enhancing ability of

microemulsion induced by the solubilization of PIT method makes it a promising

vehicle for the transdermal delivery of naproxen.

104

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