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CHAPTER III Non-Steroidal Anti-inflammatory Drugs:
An Overview
60
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.
61
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).
62
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
63
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.
64
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
65
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
66
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.
67
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
68
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
69
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-
70
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.
71
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:
72
A PROFIL E
is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits 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
ostaglandin synthetase inhibition.
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 mixture of [+]S and [
enantiomers. Etodolac is a white crystalline compound, insoluble in water but soluble in
alcohols, chloroform, dimethyl sulfoxide, and aqueous polyethylene glycol. The chemical
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-
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
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
ixture of [+]S and [-]R-
enantiomers. Etodolac is a white crystalline compound, insoluble in water but soluble in
alcohols, chloroform, dimethyl sulfoxide, and aqueous polyethylene glycol. The chemical
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,
73
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
74
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
75
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
76
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
77
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.
78
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
79
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,
80
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
81
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
Naproxen is a Proprionic acid derivative related to the Arylacetic acid group of
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 sodium has a Molecular Weight of 252.23 and a Molecular Formula of
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.
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.
Naproxen is a Proprionic acid derivative related to the Arylacetic acid group of
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
Naproxen sodium has a Molecular Weight of 252.23 and a Molecular Formula of
white crystalline substance. It is lipid-
w pH and freely soluble in water at high pH.
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.
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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