chapter-3 plan of work literature review - shodhganga : a...

CChhaapptteerr--33

PPllaann ooff WWoorrkk&&

LLiitteerraattuurree RReevviieeww

Plan of Work

Suresh Gyan Vihar University, Jaipur Page 79

3. PLAN OF WORK

1. Review of literature

2. Selection of dosage form

3. Procurement of drug(s)

4. Procurement of polymers

5. Procurement of chemicals

6. Preformulation study:

a) Identification of drug(s)

b) Organoleptic properties

c) Solubility determination

d) Partition Co-efficient (Shaking Flask Method)

e) Particle size (Microscopic Method)

f) Melting point (Capillary Method)

g) Standard curve Of Drug(s) (Uv Spectroscopy)

7 .Optimization and formulation of transdermal gel

8. Evaluation of formulations:

Static release study.

Viscosity

Measurement of pH

Spreadability

Drug content

Stability studies

10. Results and Conclusion

Literature Review


4. LITERATURE REVIEW

1) Gajanan Darwhekar et al., (2011) Transdermal drug delivery is an alternative

route for systemic drug delivery which minimizes the absorption and increases the

bioavailability. Orally Clopidogrel bisulfate has a short elimination half-life (7-8

hrs.), low oral bioavailability (50%) undergoes extensive first pass metabolism

(85%) and frequent high doses (75 mg) are required to maintain the therapeutic

level as a result, dose development toxic effect. The purpose of this research work

was to Formulation and evaluation of transdermal drug delivery system of

Clopidogrel bisulfate using various polymers such as HPMC, PVP and Ethyl

cellulose by solvent evaporation technique for improvement of bioavailability of

drug and reducing toxic effects. The prepared formulations were evaluated for

different physicochemical characteristics like thickness, folding endurance, drug

content, percentage moisture absorption, percentage moisture loss and weight

uniformity. The diffusion studies were performed by using modified Franz

diffusion cells. The result of diffusion study shows that formulation, F2 (Hydroxy

propyl methylcellulose and PVP) showed maximum release of 90.06 % in 24 h,

whereas F5 (HPMC and Ethyl cellulose) showed minimum release of 78.24% in

24 h. Based on the drug release and physicochemical values obtained the

formulation F2 is considered as an optimized formulation which shows higher

percentage of drug release of 90.06 % in 24 h. The developed transdermal patches

increase the therapeutic efficacy and reduced toxic effect of Clopidogrel

bisulfate.132

2) Mutalik.s et al., (2011) In this study the significant effect of chitosan on

improving the dissolution rate and bioavailability of Aceclofenac has been

demonstrated by simple solvent change method. Chitosan was precipitated on

Aceclofenac crystals using sodium citrate as the salting out agent. The pure

Aceclofenacnd the prepared co-crystals with different concentrations of chitosan

(0.05-0.6%) were characterized in terms of solubility, drug content, particle size,

thermal behaviour (differential scanning calorimetry, DSC), X-ray diffraction

(XRD), morphology (scanning electron microscopy, SEM), in vitro drug release

and stability studies. The in vivo performance was assessed by preclinical

pharmacodynamic (analgesic and anti-inflammatory activity) and pharmacokinetic

Literature Review


studies. The particle size of the prepared co-crystals was drastically reduced

during the formulation process. The DSC showed a decrease in the melting

enthalpy indicating disorder in the crystalline content. The XRD also revealed a

characteristic decrease in crystallinity. The dissolution studies demonstrated a

marked increase in the dissolution rate in comparison with pure drug. The

considerable improvement in the dissolution rate of Aceclofenac from optimized

crystal formulation was attributed to the wetting effect of chitosan, decreased drug

crystallinity, altered surface morphology and micronization. The optimized co-

crystals exhibited excellent stability on storage at accelerated conditions. The in

vivo studies revealed that the optimized crystal formulation provided a rapid

pharmacological response in mice and rats besides exhibiting improved

pharmacokinetic parameters in rats.133

3) Polli je et al., (2011) The objective of this work was to gain insight into the

biopharmaceutical performance of four different but bioequivalent ranitidine

hydrochloride tablet formulations. This analysis employed a recently described

method1 to relate in vitro and in vivo data and aimed to facilitate an understanding

of oral drug product performance. For each ranitidine formulation, dissolution was

performed using the USP procedure. A four-way, single dose bioequivalence

study (n = 14) was performed. The fraction of the total amount of dose absorbed

at each plasma sample time was determined by the Wagner-Nelson method.

Equation 1 (see below) was fitted to the in vitro vs. in vivo data. For all four

formulations, this analysis suggests absorption was permeation-rate limited, where

ranitidine exhibited a low permeation rate constant of 0.01/min.134

4) Updesh B. Lade et al., (2011) Budesonide is a highly potent synthetic,

nonhalogenated corticosteroid. The mechanism of action of corticosteroids in

allergic rhinitis remains unknown, but may involve reductions in number of

various mediator cells such as basophils, eosinophils, T-helper cells, mast cells,

and neutrophils. In the nasal mucosa, nasal reactivity to allergens, and release of

inflammatory mediators and proteolytic enzymes. Budesonide is very effective

and quikly acting as it is rapidly and almost completely absorbed after oral

administration, but has poor systemic availability (about 10%) due to extensive

first-pass metabolism in the liver, mainly by the cytochrome P450 isoenzyme

Literature Review


CYP3A4. The major metabolites, 6-β- hydroxybudesonide and 16-α-

hydroxyprednisolone have less than 1% of the glucocorticoid activity of

unchanged drug with a terminal half-life of about 2 - 4 hours. Polymeric films

containing Eudragit RL 100: Eudragit RS: drug (7:3:1, 7: 2:1) and Ethyl cellulose:

PVP: drug (7:3:1, 7:2:1) were selected for transdermal administration based on

evaluation studies. These polymeric films were prepared by mercury substrate

method employing PEG-400 as plasticizer. Two different penetration enhancers

Urea and Dimethyl sulphoxide (DMSO) were employed in the study. The patches

in each group were uniform in drug content, thickness. In Vitro drug permeation,

moisture absorption and WVTR studies were carried out on these test patches. It

was found that at all humidity condition the absorption increases which were

linear to the moisture absorbed. In PVA and EUDRAGIT RL 100 patches the

water vapor transmission rate was found to be higher at 75% RH, RT conditions.

Therefore at both % RH, RT condition the PVA and EUDRAGIT RL 100 patches

provide the best resistance to water vapor. Therefore, when applied to animals (in

further studies) these patches may provide more occlusion to water vapor loss

from skin thus making atmosphere beneath the skin more hu-mid that aid in drug

permeation.135

5) Arpad Pardutz et al., (2010) Migraine is a common disabling neurological

disorder with a serious socio-economical burden. By blocking cyclooxygenase

nonsteroidal anti-inflammatory drugs (NSAIDs) decrease the synthesis of

prostaglandins, which are involved in the pathophysiology of migraine headaches.

Despite the introduction more than a decade ago of a new class of migraine-

specific drugs with superior efficacy, the triptans, NSAIDs remain the most

commonly used therapies for the migraine attack. This is in part due to their wide

availability as over-the-counter drugs and their pharmaco-economic advantages,

but also to a favorable efficacy/side effect profile at least in attacks of mild and

moderate intensity. We summarize here both the experimental data showing that

NSAIDs are able to influence several pathophysiological facets of the migraine

headache and the clinical studies providing evidence for the therapeutic efficacy

of various subclasses of NSAIDs in migraine therapy. Taken together these data

indicate that there are several targets for NSAIDs in migraine pathophysiology

and that on the spectrum of clinical potency acetaminophen is at the lower end

Literature Review


while ibuprofen is among the most effective drugs. Acetaminophen and aspirin

excluded, comparative trials between the other NSAIDs are missing. Since

evidence-based criteria are scarce, the selection of an NSAID should take into

account proof and degree of efficacy, rapid GI absorption, gastric ulcer risk and

previous experience of each individual patient. If selected and prescribed wisely,

NSAIDs are precious, safe and cost-efficient drugs for the treatment of migraine

attacks.136

6) Eseldin Keleb et al., (2010) The human skin is a readily accessible surface for

drug delivery. Skin of an average adult body covers a surface of approximately 2

m 2 and receives about one-third of the blood circulating through the body. Over

the past three decades, developing controlled drug delivery has become

increasingly important in the pharmaceutical industry. The human skin surface is

known to contain, on an average, 10-70 hair follicles and 200-250 sweat ducts on

every square centimeters of the skin area. It is one of the most readily accessible

organs of the human body. The potential of using the intact skin as the port of

drug administration to the human body has been recognized for several decades,

but skin is a very difficult barrier to the ingress of materials allowing only small

quantities of a drug to penetrate over a period of time. During the past decade, the

number of drugs formulated in the patches has hardly increased, and there has

been little change in the composition of the patch systems. Modifications have

been mostly limited to refinements of the materials used. The present article

reviews the selection of drug candidates suitable to be formulated as Transdermal

system and the methods of evaluation.137

7) Raju.R.Thenge et al., (2010) Lercanidipine HCl is poorly absorbed after oral

administration with peak plasma concentrations in 1 to 3 hours after a dose.

Bioavailability is about 44% and extensively metabolized in liver. The half life is

about 4.6 hours. Lercanidipine HCl due to its low therapeutic dose (2.5-20mg) and

substantial biotransformation in liver becomes it ideal candidate for design and

development of transdermal therapeutic system. Lercanidipine hydrochloride

patches were prepared by using different concentration of Eudragit RS100,

Hydroxypropyl methyl cellulose and ethyl cellulose using solvent casting

techniques on a mercury substrate and the effect of polymer on the various

Literature Review


physicochemical characteristics and in vitro drug release studies, ex vivo skin

permeation studies. Formulations were prepared by taking 20 mg (Lercanidipine

HCl), 10% w/w of propylene glycol and 10% w/w of dibutyl phthalate in ethanol.

The formulations exhibited uniform thickness, weight and good uniformity in

drug content. The maximum drug releases in 24 hrs for formulations were

depending on the hydrophobicity of the polymer. On the basis of in vitro drug

release and ex vivo skin permeation studies, Formulation containing (Eudragit

RS100 andHydroxypropyl methyl cellulose) was showed sustained and extended

drug release over a period of 24 hrs. In Vitro and Ex vivo permeation of

Lercanidipine HCl shows that patches of ERS 100: HPMC are suitable compared

to ERS 100: EC patches. The results of the study show that Lercanidipine HCl

could be administered transdermally over a period of 24 h. through the matrix type

TDDS for effective control of hypertension.138

8) Vargas F et al., (2010) Aceclofenac (Airtal) (1) is a photoallergic and phototoxic

anti-inflammatory and analgesic agent. This drug is photolabile under aerobic and

anaerobic conditions. Irradiation of an ethanol-solution of Aceclofenac under

oxygen or argon at 290-320 nm affords via decarboxlation compound 2 as the

main isolated and spectroscopically identified photoproduct, besides

hydroxylamine derivates 3 and 4. A radical intermediate was evidenced

spectrophotometrically with GSH and DTNB, as well as by the dimerization of

cysteine. Red blood cell lysis photosensitized by 1-4 was investigated.

Furthermore, in a lipid-photoperoxidation test with linoleic acid the in vitro

phototoxicity of Aceclofenac was also verified. The photoinduced generation of

peroxide by compound 1 was determined during the irradiation in presence of

NADPH by chemiluminescence. In relation to the photoallergic activity of this

drug, the interaction of Aceclofenac with human serum albumin (HSA) has been

studied through fluorescence spectroscopy. No photoinduced binding was

observed after irradiation of compounds 1 in the presence of human serum

albumin.139

9) Belgamwar et al., (2009) studied and evaluated the suitability of pluronic lecithin

organogels containing flurbiprofen for topical application. Four formulations were

developed using flurbiprofen, lecithin, pluronic F127, isopropyl palmitate, water,

Literature Review

Suresh Gyan Vihar University, Jaipur 6

sorbic acid and potassium sorbate. All the formulations carried 30% w/w of

lecithin phase and 70% w/w of pluronic phase. The formulated organogels were

evaluated for appearance and feel psychorheologically, in vitro diffusion study,

drug content, viscosity and pH.140

10) Byrav et al., (2009) clinical studies have demonstrated that lornoxicam has

advantageous profile in moderate to severe pain in combination with an anti

inflammatory efficacy comparable to other NSAIDs. In addition, it may be an

alternative to other NSAIDs for the treatment of painful arthritic and

inflammatory diseases. Furthermore, it possesses superior gastrointestinal safety

profile as compared to other NSAIDs.141

11) Chandra et al., (2009) studied that microemulsions increased the permeation rate

of dexamethasone compared with the control. The optimum formulation

consisting of 0.1% dexamethasone, 10% olive oil, 70% egg lecithin:IPA (2:1), and

water showed a permeation rate of 54.9 µg/cm 2 /h. The significantly (P < 0.05)

higher anti-inflammatory potential. The nutmeg oil-based transtudied

microemulsion-based hydrogel was stable toward centrifugation test and was

nonirritating to the skin. The pharmacodynamic studies indicated that

microemulsion based on nutmeg oil demonstrated a sdermal microemulsion gel

system demonstrated 73.6% inhibition in rat paw edema. Thus, microemulsion-

based transdermal systems are a promising formulation for dermal delivery of

dexamethasone.142

12) Dhamankar et al., (2009) concluded that the two novel O/W microemulsions

containing ketoprofen were designed for improving transdermal absorption. The

components and their concentration range for the formation of microemulsion

were decided constructing pseudo-ternary phase diagrams. Their concentrations

were optimized after the evaluation of their effect on skin permeation of the drug.

Both the developed formulations were free flowing, translucent and spontaneously

formed. When microemulsions were gelled, they found to have uniform viscosity,

spreadability, elegant appearance and did not produce skin irritation. Drug content

at top, middle and bottom of the formulations revealed the percentage of drug

Literature Review


close to 100%. The results of physicochemical characteristics are satisfactorily.

Both the formulations are superior to marketed formulation in the respect of drug

permeation across the membrane.143

13) Hinz B et al., (2009) The mechanism of action of Aceclofenac is currently

unclear. This study investigated whether biotransformation to metabolites (4'-

hydroxy-Aceclofenac, diclofenac, 4'-hydroxy-diclofenac) contributes to inhibitory

effects on the cyclooxygenase (COX) isozymes in vitro and ex vivo. METHODS:

In vitro investigations were performed with human whole blood and human blood

monocytes. A randomized crossover study was performed in volunteers receiving

100 mg Aceclofenac or a sustained-release resinate formulation of 75 mg

diclofenac to assess the pharmacokinetics and the ex vivo inhibition of COX-1.

RESULTS: In short-term in vitro assays, neither Aceclofenac nor 4'-hydroxy-

Aceclofenac affected COX-1 or COX-2, whereas diclofenac and 4'-hydroxy-

diclofenac inhibited both isoforms. In long-term in vitro assays, Aceclofenac and

4'-hydroxy-Aceclofenac suppressed both COX isoforms. However, this inhibition

was paralleled by a conversion to diclofenac and 4'-hydroxy-diclofenac,

respectively. Maximal plasma concentrations of diclofenac after oral

administration of Aceclofenac (0.39 micromol/L) or diclofenac (1.28 micromol/L)

were sufficient for a greater than 97% inhibition of COX-2 (50% inhibitory

concentration, 0.024 micromol/L) and a 46% (Aceclofenac treatment) or 82%

inhibition (diclofenac treatment) of COX-1 (50% inhibitory concentration, 0.43

micromol/L). Moreover, ex vivo COX-1-dependent thromboxane B(2) synthesis

was inhibited significantly less by Aceclofenac than by diclofenac.

CONCLUSIONS: Inhibition of COX isozymes by Aceclofenac requires

conversion into diclofenac. Although 100 mg Aceclofenac yielded diclofenac

concentrations substantially lower than 75 mg diclofenac, these were sufficient for

a sustained block of COX-2 but caused a minor and shorter inhibition of COX-1

than 75 mg diclofenac. In conclusion, both COX-1-sparing and COX-2-inhibitory

actions of Aceclofenac may rest in its limited but sustained biotransformation to

diclofenac.144

14) . Hasan NY et al., (2009) Five new selective, precise and accurate methods for

the determination of Aceclofenac in the presence of its degradation product;

Literature Review


diclofenac are described. Method A utilizes third derivative spectrophotometry at

242 nm. Method B is RSD(1) spectrophotometric method based on the

simultaneous use of the first derivative of ratio spectra and measurement at 245

nm. Method C is a pH-induced difference (deltaA) spectrophotometry using UV

measurement at 273 nm. Method D is a spectrodensitometric one, which depends

on the quantitative densitometric evaluation of thin layer chromatogram of

Aceclofenac at 275 nm. Method E is RP-HPLC that depends on using methanol:

water (60:40 v/v) as mobile phase at a flow rate of 1 ml/min and UV detection at

275 nm. Regression analysis of a beer's plot showed good correlation in the

concentration ranges 5-40, 10-40, 15-50, 50-200, 1-50 microg/ml for methods A,

B, C, D and E, respectively. These methods are suitable as stability indicating

methods for the determination of Aceclofenac in presence of its main degradation

product, diclofenac. The proposed methods were applied for the analysis of the

drug in its pharmaceutical formulation and the results obtained were compared

with those obtained with the official B.P. method.145

15) Kisan et al., (2009) studied and investigated the suitability of microemulsion

based lecithin organogel formulations for topical delivery of fluconazole in order

to bypass its gastrointestinal adverse effects. Solubility of fluconazole in EO-

lecithin reverse micellar system was almost 3 folds higher than that in EO. Hence,

the present lecithin based organogel appears beneficial for topical delivery of

fluconazole in terms of easy preparation, safety, stability and low cost.146

16) Kannaiyan et al., (2009) studied the formulated liopsomal gel having CP of 1.5%

concentration would be stable and keeps the medicament for a longer time period

from the leaching process of the lipid bilayer. Thus, highly degradable, potent

drug can be formulated in this CP gel liposomal drug delivery thus enhancing the

potency of the Aceclofenacnd protecting the drug's therapeutic efficacy till the

desired period.147

17) Patel et al., (2009) concluded that the release pattern follows zero order kinetics,

which fits, into Peppa’s model, indicating that mechanism of drug release by

Literature Review


swelling. The optimized formulation containing Carbopol 934: Eudragit L100

(3:7), with enhancer hyaluronidase showed 84% drug release after 24 hours.148

18) Reginster JY et al., (2009) The aim of this article is to critically review the

potential role of Aceclofenac in the treatment of inflammatory pain and chronic

osteoarticular disorder, based on its activity on the mediators of inflammation, its

effect on cartilage remodeling and on the results of clinical studies comparing

Aceclofenac with other NSAIDs in these disorders. Aceclofenac has an

outstanding anti-inflammatory profile, involving besides a classical inhibition of

prostaglandins E2, a decrease in the expression of several cytokines including

interleukin 1 and tumor necrosis factor alpha. It also inhibits activated oxygen

species production and influences cells adhesion. Aceclofenac and its main

metabolite, 4-hydroxyAceclofenac, has positive effects on cartilage anabolism

combined with modulating effect of matrix catabolism. Clinically, Aceclofenac

has been consistently shown to have a similar efficacy than that of widely

marketed NSAIDs and a tolerance profile at least as good, if not better than the

profile observed for other NSAIDs in the treatment of osteoarthritis, rheumatoid

arthritis and ankylosing spondylitis. As of today, no head to head comparison

between Aceclofenac and coxibs have been performed, nor for efficacy neither for

tolerance. The specific profile of Aceclofenac makes this NSAID an interesting

candidate for long-term treatment of chronic rheumatic disorders as well as for

treatment of acute inflammatory episodes.149

19) Shashikant D. Barhate et al., (2009) Carvedilol, a nonselective b-adrenergic

blocker frequently used in hypertension, congestive cardiac failure and angina.

Transdermal drug delivery can be efficiently used for the active agents which

undergoes first pass metabolism, with this objectives, the transdermal patches of

carvedilol were prepared by using combination of polyvinyl alcohol (PVP) and

polyvinyl pyrrolidone (PVP K30) along with glycerin, polyethylene glycol 400

and propylene glycol as a plasticizers. The prepared formulations were evaluated

for thickness, drug content uniformity, folding endurance, percent elongation at

break, tensile strength, in-vitro permeation studies. It was observed that the system

with PVA:PVP in the ratio 8:6 along with used plasticizers was a promising

Literature Review


controlled release transdermal drug delivery system for carvedilol. Formulated

transdermal patches of carvedilol, exhibits zero-order release kinetics.150

20) Singh et al., (2009) concluded that the incorporating ketoprofen into bioadhesive

gels containing a penetration enhancer in various concentrations enhanced the

drug permeation through rat skin and in vivo performance. Bioadhesive gels of

ketoprofen containing oleic acid may offer promise as an anti-inflammatory

dosage form, ensuring more effective therapy, but additional experiments should

be performed before the formulation is used in humans.151

21) Belgamwar et al., (2008) studied and gave detail insight of pluronic lecithin

organogels (PLOs) as a topical and transdermal drug delivery system. Pluronic

lecithin organogel is a microemulsion-based gel. It is thermodynamically stable,

viscoelastic, and biocompatible gel composed of phospholipids (lecithin), organic

solvent, and polar solvent. Various types of therapeutic agents have been easily

incorporated in PLO to improve their topical drug delivery. Pluronic lecithin

organogel improves the topical administration of drug mainly because of desired

drug partitioning, biphasic drug solubility, and the modification of skin barrier

system by organogel components. Thus, in future, it has wide range of

applications and opportunities to experiment with various drugs in this type of

drug delivery system.152

22) Murthy et al., (2008) concluded that all gels were found to exhibit plastic flow.

The gel formulations showed good extrudability, spreadability and viscosity.

Formulation G6 was found to have better permeation and hence may be considered

as candidate for development of topical dosage forms.153

23) Maneiro E et al., (2008) Interleukin 1 receptor antagonist (IL-1Ra) may play an

important role in cartilage degradation by inhibiting IL-1 activity and therefore

blocking IL-1 stimulation of prostaglandin E2 (PGE2) synthesis. Nitric oxide

(NO) formation is increased during inflammation. High concentrations of NO

exert negative effects on chondrocyte functions. We investigated the possible

effects of 3 different nonsteroidal antiinflammatory drugs (NSAID; Aceclofenac,

piroxicam, aspirin) on IL-1Ra and NO production in human articular

Literature Review


chondrocytes. METHODS: Normal and osteoarthritic (OA) cartilage samples

were obtained from autopsy and prosthetic joint surgery, respectively.

Chondrocytes were isolated and stimulated with 4 different stimuli: IL-1, tumor

necrosis factor-alpha (TNF-alpha), lipopolysaccharide (LPS), and insulin-like

growth factor (IGF). The 3 NSAID were added simultaneously to each different

concentration of stimulus. IL-1Ra was measured in supernatant by ELISA; nitrites

were quantified by the Griess reaction; PGE2 level was measured by enzyme

immunoassay. RESULTS: OA samples spontaneously produced higher levels of

IL-1Ra than normal samples (130+/-2.3 vs 30+/-3.1 pg/mI). IL-1, TNF-alpha, and

LPS produced dose dependent increases in synthesis of IL-1Ra. In their presence,

IL-1Ra was detected in supernatant at 48 h, but its highest level was measured at

144 h. The most potent stimulus was IL-1, followed by TNF-alpha. Fetal bovine

serum and IGF in turn did not modify the basal levels of IL-1Ra. In contrast to

piroxicam and aspirin, Aceclofenac 10 microg/ml and TNF-alpha 10 ng/ml

increased almost 46 times the basal amount of IL-1Ra produced by OA

chondrocytes. Additionally, Aceclofenac and aspirin inhibited NO synthesis.

Finally, the 3 NSAID reduced the levels of PGE2 detected after stimulation with

IL-1. CONCLUSION: Proinflammatory stimuli induce IL-IRa synthesis in human

articular chondrocytes. Aceclofenac may modulate PGE2 production by

increasing IL-IRa production and decreasing NO synthesis. Some NSAID exert

diverse prostaglandin independent effects.154

24) Vintiloiu et al., (2008) studied and gave a global view of organogels, with special

emphasis on the interplay between the gelator's structural characteristics and the

ensuing intermolecular interactions. A subsequent focus is placed on the

application of organogels as drug delivery platforms for active agent

administration via diverse routes such as transdermal, oral, and parenterals.155

25) Dooley M et al(2007) Aceclofenac is an orally administered phenylacetic acid

derivative with effects on a variety of inflammatory mediators. Through its

analgesic and anti-inflammatory properties, Aceclofenac provides symptomatic

relief in a variety of painful conditions. In patients with osteoarthritis of the knee,

the drug decreases pain, reduces disease severity and improves the functional

capacity of the knee to a similar extent to diclofenac, piroxicam and naproxen.

Literature Review


Aceclofenac reduces joint inflammation, pain intensity and the duration of

morning stiffness in patients with rheumatoid arthritis, and is similar in efficacy to

ketoprofen, diclofenac, indomethacin and tenoxicam in these patients. The

duration of morning stiffness and pain intensity are reduced, and spinal mobility

improved, by Aceclofenac in patients with ankylosing spondylitis, with

improvements being similar to those observed with indomethacin, naproxen or

tenoxicam. Aceclofenac is also effective in other painful conditions (e.g. dental

and gynaecological). In contrast to some other NSAIDs, Aceclofenac has shown

stimulatory effects on cartilage matrix synthesis. Aceclofenac is well tolerated,

with most adverse events being minor and reversible, and affecting mainly the GI

system. Although the incidence of GI adverse events with Aceclofenac was

similar to those of comparator NSAIDs in individual clinical trials, withdrawal

rates due to these events were significantly lower with Aceclofenac than with

ketoprofen and tenoxicam. Superior overall and/or GI tolerability of the drug

relative to other NSAIDs has been indicated by a nonrandomised comparison with

sustained release diclofenac in 10,142 patients, a meta-analysis of 13 comparisons

with diclofenac, naproxen, piroxicam, indomethacin, tenoxicam or ketoprofen in

3574 patients, and preliminary details of a comparison with 10 other NSAIDs in

142,776 patients. Further analysis of the above meta-analytical data has indicated

that costs incurred as a result of adverse event management are lower with

Aceclofenac than with a range of comparator NSAIDs. CONCLUSIONS: Trials

of 2 to 6 months' duration have shown Aceclofenac to be an effective agent in the

management of pain and rheumatic disease. Data from in vitro studies indicate

properties of particular interest with respect to cartilage matrix effects and

selectivity for cyclo-oxygenase-2. Aceclofenac is well tolerated, with encouraging

reports of improved general and GI tolerability relative to other NSAIDs from a

meta-analysis of double-blind trials and from large nonblind studies.156

26) Jain et al., (2007) studied that the application of clindamycin phosphate gel after

the pretreatment of skin with adapalene gel for 5 min may contribute significantly

to the increased efficacy of therapy.157

27) Lakshmi et al., (2007) studied that the Human repeated insult patch test did not

produce any significant irritation or sensitization on healthy human volunteers.

Literature Review


The placebo and marketed gels were compared with niosomal methotrexate gel.

At Week 12, with niosomal methotrexate gel, there was reduction in total score

from 6.2378±1.4857 to 2.0023±0.1371. These results suggest that niosomal

methotrexate gel is more efficacious than placebo and marketed methotrexate

gel.158

28) Ruiz et al., (2007) concluded that formulations containing Pluronic gel as a

vehicle and permeabilizing agent for transdermal preparations has increased in

recent years. Two transdermal formulations for Aceclofenacdministration as an

alternative to oral or parenteral administration were prepared and compared. The

characteristics of these excipients may facilitate the application and may avoid the

gastrointestinal tract and the first-pass effect.159

29) Dooley et al., (2006) Aceclofenac is an orally administered phenylacetic acid

derivative with effects on a variety of inflammatory mediators. Through its

analgesic and anti-inflammatory properties, Aceclofenac provides symptomatic

relief in a variety of painful conditions. In patients with osteoarthritis of the knee,

the drug decreases pain, reduces disease severity and improves the functional

capacity of the knee to a similar extent to diclofenac, piroxicam and naproxen.

Aceclofenac reduces joint inflammation, pain intensity and the duration of

morning stiffness in patients with rheumatoid arthritis, and is similar in efficacy to

ketoprofen, diclofenac, indomethacin and tenoxicam in these patients. The

duration of morning stiffness and pain intensity are reduced, and spinal mobility

improved, by Aceclofenac in patients with ankylosing spondylitis, with

improvements being similar to those observed with indomethacin, naproxen or

tenoxicam. Aceclofenac is also effective in other painful conditions (e.g. dental

and gynaecological). In contrast to some other NSAIDs, Aceclofenac has shown

stimulatory effects on cartilage matrix synthesis. Aceclofenac is well tolerated,

with most adverse events being minor and reversible, and affecting mainly the GI

system. Although the incidence of GI adverse events with Aceclofenac was

similar to those of comparator NSAIDs in individual clinical trials, withdrawal

rates due to these events were significantly lower with Aceclofenac than with

ketoprofen and tenoxicam. Superior overall and/or GI tolerability of the drug

relative to other NSAIDs has been indicated by a nonrandomised comparison with

Literature Review


sustained release diclofenac in 10 142 patients, a meta-analysis of 13 comparisons

with diclofenac, naproxen, piroxicam, indomethacin, tenoxicam or ketoprofen in

3574 patients, and preliminary details of a comparison with 10 other NSAIDs in

142 776 patients. Further analysis of the above meta-analytical data has indicated

that costs incurred as a result of adverse event management are lower with

Aceclofenac than with a range of comparator NSAIDs. Conclusions: Trials of 2 to

6 months' duration have shown Aceclofenac to be an effective agent in the

management of pain and rheumatic disease. Data from in vitro studies indicate

properties of particular interest with respect to cartilage matrix effects and

selectivity for cyclo-oxygenase-2. Aceclofenac is well tolerated, with encouraging

reports of improved general and GI tolerability relative to other NSAIDs from a

meta-analysis of double-blind trials and from large nonblind studies.160

30) Gattani et al., (2006) concluded that the polymeric matrix-type transdermal films

of ondansetron hydrochloride prepared with different grades and ratios of

polymers holds potential for transdermal delivery. A slow and controlled release

of drug versus time is linear and this constitutes the basis for transdermal delivery

of ondansetron hydrochloride.161

31) Kumar et al., (2006) concluded that to overcome all these drawbacks, liposomes

of methotrexate for transdermal drug delivery were formulated and evaluated for

drug entrapment, particle size and microscopically.162

32) Kim YG et al., (2006) A bioequivalence study of Aceclofenac tablets (test

formulation: Dong-A, reference formulation: Airtal) was conducted in 16 healthy

male Korean volunteers who received each medicine at a dose of 100 mg in a 2 x

2 crossover study. There was a one-week washout period between the doses.

Plasma concentrations of Aceclofenac were monitored by high-performance liquid

chromatography over a period of 24 hours after the administration. AUCinf (the

area under the plasma concentration-time curve from time zero to time infinity)

was calculated by the linear-log trapezoidal method. Cmax (maximum plasma

drug concentration) and tmax (time to reach Cmax) were compiled from the

plasma concentration-time data. Analysis of variance was carried out using

logarithmically transformed AUCinf and Cmax, and non-transformed tmax. There

Literature Review


were no significant differences between the medications in AUCinf and Cmax.

The point estimates and 90% confidence intervals for AUCinf (parametric) and

Cmax (parametric) were 1.04 (0.93 to approximately 1.17) and 0.99 (0.91 to

approximately 1.08), respectively, satisfying the bioequivalence criteria of the

European Committee for Proprietary Medicinal Products and the US Food and

Aceclofenacdministration Guidelines. The corresponding value for tmax was 0.75

(0.00 to approximately 1.00). Moreover, the modified Pitman-Morgan's adjusted

F-test indicated that the bioavailabilities of Aceclofenac in the 2 medications were

comparable regarding intra- and interindividual variability. Therefore, these

results indicate that the 2 medications of Aceclofenac are bioequivalent and, thus,

may be prescribed interchangeably.163

33) Ponsoda X et al., (2006) Cultured human hepatocytes are considered a close

model to human liver. However, the fact that hepatocytes are placed in a

microenvironment that differs from that of the cell in the liver raises the question:

to what extent does drug metabolism in vitro reflect that of the liver in vivo? This

issue was examined by investigating the in vitro and in vivo metabolism of

Aceclofenac, an analgesic/anti-inflammatory drug. METHODS: Hepatocytes

isolated from programmed liver biopsies were incubated with Aceclofenac, and

the metabolites formed were investigated by HPLC. During the course of clinical

recovery, patients were given the drug, and the metabolites, largely present in the

urine, were analyzed. In vitro and in vivo data of the same individual were

compared. RESULTS: The relative abundance of oxidized metabolites in vitro

(i.e. 4'OH-Aceclofenac + 4'OH-diclofenac vs. total hydroxylated metabolites;

Spearman's p = 0.855), as well the hydrolysis of Aceclofenac (4'OH-diclofenac vs.

4'OH-Aceclofenac + 4'OH-diclofenac; p = 0.691) correlated well with in vivo

data. The conjugation of the drug in vitro (24.6 +/- 7.6%) was lower than that in

vivo (44.9 +/- 5.3%). The rate of 4'OH-Aceclofenac formation in vitro correlated

with the amount of metabolites excreted in urine after 16 h (p = 0.95).

CONCLUSIONS: The in vitro/in vivo metabolism of the drug was surprisingly

similar in each patient. The variability observed in vitro reflected an existing

phenotypic variability among donors.164

Literature Review


34) Richards et al., (2006) explored the use of pluronic lecithin organogel (PLO) as

a base for the delivery of bioactive polyunsaturated fatty acids from fish oil,

eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and ketoprofen.

Oruvail gel (2.5% ketoprofen) was included for comparison. Unlike EPA and

DHA, substantial amounts of ketoprofen permeated when applied as infinite

doses. Oruvail, a Carbopol 940-based hydrogel containing 2.5% ketoprofen and

ethanol, delivered the greatest amount, although similar to the PLO gel containing

5% ketoprofen.165

35) Kumar et al., (2005) reviewed and gave an insight into the considerable potential

of lecithin organogels (LOs) in the applications meant for topical drug delivery.

Several therapeutic agents have been formulated as LOs for their facilitated

transport through topical route (for dermal or transdermal effect), with some very

encouraging results. The utility of this novel matrix as a topical vehicle has further

increased owing to its very low skin irritancy potential. The review also includes a

detailed account on the mechanistics of organogelling.166

36) Lim et al., (2005) formulated a transdermal gel containing an appropriate

enhancer for a controlled drug release. Terpenes, namely limonene, linalool and

cineole, in propylene glycol (PG) were first investigated in vitro for their capacity

to enhance the percutaneous release of an anti-psychotic drug, haloperidol (HP).

Relative to oxygenated linalool and cineole, hydrocarbon limonene was more

effective as a skin enhancer; it increased human skin permeability and decreased

lag time. Limonene was thus incorporated in an organogel comprised of gelator

GP1 and PG.167

37) Murdan S., (2005) gave an overview of organogels is presented, followed by a

more in-depth review of the gels that have been investigated for Aceclofenacnd/or

vaccine delivery. These include microemulsion-based gels and lecithin gels

(studied for transdermal delivery), sorbitan monostearate organogels and

amphiphilogels (studied as vaccine adjuvants and for oral and transdermal drug

delivery, respectively), gels composed of alanine derivatives (investigated as in

situ forming gels) and Eudragit organogels (studied as a matrix for suppositories).

Finally, pluronic lecithin organogels, descendents of lecithin gels but which are

Literature Review


not really organogels, are briefly discussed for their interesting history, their root

and the wide interest in these systems.168

38) Nemutlu et al., (2005) developed the Zero and first order derivative UV

spectrophotometric method for the analysis of lornoxicam (LOR). It was

concluded that the methods developed were accurate, sensitive, precise, robust,

rugged and useful for the quality control of LOR in pharmaceutical

preparations.169

39) Sen et al., (2005) studied that Transdermal nitroglycerine can improve analgesic

effects when used with other analgesics (Lornoxicam). The aim of the study was

to investigate the additive effects of nitroglycerine combined with lornoxicam for

acute pain in rats.170

40) Blot L et al., (2004) Since nonsteroidal anti-inflammatory drugs (NSAIDs) may

impair the ability of the chondrocyte to repair its damaged extracellular matrix, we

explored the changes in the metabolism of newly synthesized proteoglycan and

hyaluronan (HA) molecules produced by Aceclofenac, diclofenac and meloxicam

in human osteoarthritic (OA) cartilage. 2. Explants were sampled from the medial

femoral condyle and were classified by use of the Mankin's histological-

histochemical grading system. Cartilage specimens exhibited moderate (M) OA in

20 subjects and had severe (S) OA in 20. 3. Cartilage explants were pulsed with

[-3H]-glucosamine and chased in the absence or in the presence of 0.3 - 3 microg

ml(-1) of either Aceclofenac, diclofenac or meloxicam. After papain digestion, the

labelled chondroitin sulphate ([-3H]-proteoglycans) and [-3H]-HA molecules

present in the tissue and media were purified by anion-exchange

chromatography. 4. In cartilage with MOA and SOA, the metabolic balance of

proteoglycan and HA was unaffected by diclofenac. In contrast, and in a

dose-dependent manner, Aceclofenac and meloxicam both increased the synthesis

of proteoglycans and HA in explants with MOA and SOA; these two NSAIDs

also reduced significantly the net loss of [-3H]-proteoglycans and [-3H]-HA

molecules from cartilage explants. 5. The data obtained in short-term in vitro

cultures indicate that, at the concentrations found in synovial fluid, Aceclofenac

Literature Review


and meloxicam may exert a favourable effect on the overall metabolism of

proteoglycans and HA in cartilage with MOA and SOA.171

41) Kyle et al., (2004) studied that the Fungi often infect the skin surface and

subsequently invade the stratum corneum to avoid being shed from the skin

surface by desquamation. Pharmacologic agents applied to the surface of the skin

in the form of creams, lotions, or sprays, readily penetrate into the stratum

corneum to kill the fungi (fungicidal agents), or at least render them unable to

grow or divide (fungistatic agents). Thus, topical therapies work well to rid the

skin of topical fungi and yeasts. The azole drugs are often preferred for these

types of infections. This article reviews various treatments of cutaneous fungal

infections, with special emphasis on cure rates and rationales for choosing

particular products.172

42) Muatlik S et al., (2000) The objective of present study was to improve the

solubility, dissolution rate, micromeritic properties and bioavailability of

Aceclofenac (NSAID) by formulating its spherical agglomerates. They were

prepared with different water soluble polymers (polyvinylpyrrolidone-K30,

polyvinylpyrrolidone-K90 and sodium alginate) by using acetone-

water-dichloromethane solvent system. The agglomerates were subjected to

various physicochemical properties, DSC, IR spectroscopy, scanning electron

microscopy (SEM), micromeritic properties and dissolution studies. The in vivo

studies (anti-inflammatory, analgesic and pharmacokinetic studies) were

conducted in Wistar rats and Swiss albino mice. SEM studies showed that

agglomerates were spherical in structure and formed by cluster of small crystals.

The agglomerates prepared with polyvinylpyrrolidone-K90 exhibited improved

solubility, dissolution rate and micromeritic properties compared to those prepared

with other polymers and pure drug. These optimized agglomerates showed rapid

analgesic and anti-inflammatory activity besides exhibiting improved

bioavailability of drug when compared to pure drug.173

43) Hoffman et al., (2000) studied that custom veterinary pharmacies have offered

methimazole in a transdermal gel containing pluronic and lecithin (PLO), with

Literature Review


anecdotal evidence of efficacy. The purpose of this study was to determine the

bioavailability, relative to i.v. and oral routes of administration, of transdermal

methimazole in a PLO gel in cats.174

44) Rosenow et al., (1998) concluded that the analgesic efficacy and tolerability of

lornoxicam, a new nonsteroidal anti-inflammatory drug, was compared with that

of morphine. These results suggest that lornoxicam is an alternative to morphine

for the treatment of moderate to severe postoperative pain. Implications: After

surgery for lumbar disk disease, patients obtained statistically equivalent pain

relief with lornoxicam and morphine when administered by patient-controlled

analgesia. However, lornoxicam was associated with a lower incidence of adverse

events. This study suggests that lornoxicam provides an alternative to morphine

for the treatment of postoperative pain.175

45) Dreher et al., (1996) studied that the soybean lecithin microemulsion gel can be

used as a possible matrix for transdermal drug delivery. In vitro percutaneous

penetration studies of two anti-inflammatory drugs, indomethacin and diclofenac,

dissolved in the gel-system resulted in steady state fluxes of about 1 Ixg h -~ cm -

2. These studies indicated that the lecithin gel, in particular isopropyl palmitate,

affects the stratum corneum lipid organization even after 1-day incubation (FFIR,

DSC), whereas recent in vivo human skin irritation tests showed no significant

irritancy.176

46) Grahame. et al., (1995) studied transdermal non-steroidal anti-inflammatory

agents and concluded that topical NSAIDs as an effective alternative to local

steroid injection in cases of soft-tissue rheumatism, either where the injection is

not acceptable to the patient or where the doctor has not acquired the necessary

techniques. The safety profile of topical NSAIDs is good. Skin reactions are rare,

and this apparently applies to all topical NSAIDs currently available. It is logical

to treat a local pathological lesion with a local therapy, provided the agent is

delivered effectively and sagely to the target organ or tissue. Where this can

obviate the risk of life-threatening complications such as gastric hemorrhage, the

case for substituting local for systemic medication is overwhelming.177

Literature Review


47) Willimann et al., (1992) studied a composition useful in the delivery of

pharmaceutically active agents through the skin. In one embodiment of the

invention, the composition is formulated with a nonsteroidal anti-inflammatory

agent, such as ibuprofen or ketoprofen; a muscle relaxant, such as

cyclobenzaprine; or other active ingredient .In another embodiment of the

invention, the composition is formulated with an antineoplastic or other

pharmaceutically-active agent. Such formulation is rapidly absorbed through the

skin to provide local delivery.178

chapter-3 plan of work literature review - shodhganga : a...

Documents