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Review ArticleRecent Advances in Delivery Systems and Therapeutics ofCinnarizine A Poorly Water Soluble Drug with AbsorptionWindow in Stomach

Smita Raghuvanshi and Kamla Pathak

Department of Pharmaceutics Rajiv Academy for Pharmacy NH No 2 PO Chattikara Mathura Uttar Pradesh 281001 India

Correspondence should be addressed to Kamla Pathak kamlapathak5gmailcom

Received 23 July 2014 Accepted 15 October 2014 Published 13 November 2014

Academic Editor Juan M Irache

Copyright copy 2014 S Raghuvanshi and K Pathak This is an open access article distributed under the Creative CommonsAttribution License which permits unrestricted use distribution and reproduction in any medium provided the original work isproperly cited

Low solubility causing low dissolution in gastrointestinal tract is the major problem for drugs meant for systemic action afteroral administration like cinnarizine Pharmaceutical products of cinnarizine are commercialized globally as immediate releasepreparations presenting low absorption with low and erratic bioavailability Approaches to enhance bioavailability are widely citedin the literature An attempt has been made to review the bioavailability complications and clinical therapeutics of poorly watersoluble drug cinnarizine The interest of writing this paper is to summarize the pharmacokinetic limitations of drug with specialfocus on strategies to improvise bioavailability along with effectiveness of novel dosage forms to circumvent the obstacleThe paperprovides insight to the approaches to overcome low and erratic bioavailability of cinnarizine by cyclodextrin complexes and noveldosage forms self-nanoemulsifying systems and buoyant microparticulates Nanoformulations need to systematically explored infuture for their new clinical role in prophylaxis ofmigraine attacks in children Clinical reports have affirmed the role of cinnarizinein migraine prophylaxis Research needs to be dedicated to develop dosage forms for efficacious bioavailability and drug directlyto brain

1 Introduction

Low aqueous solubility of drug has always presented majorobstacle towards the development of drug delivery systemswhich often compromises patient compliance Oral route isthought to be common and easy for drug administration Onoral administration of drug in its dosage form it is expectedto dissolve and release the drug into the gastrointestinalfluid before the absorption [1] Poor solubility may limitthe dissolution of drug in gastrointestinal tract resultingto low bioavailability that can pharmacologically affect thetherapeutic efficacy of drug [2] The drugs belonging toBCS class II and IV particularly fall in this category andhave been extensively researchedmolecular optimization anddevelopment of novel efficacious dosage forms

Cinnarizine (E)-1-(diphenylmethyl)-4-(3-phenylprop-2-enyl) piperazine (Figure 1) molecular formula C

26H28N2

and molecular weight 36851 gmol is white or almost whitepowder Originally obtained from woodreed roots (Cinna)

cinnarizinewas first synthesized by Janssen Pharmaceutica in1955 and marketed in 1958 under the brand name StugeronIt is a weak base with poor aqueous solubility According to apaper the solubility of cinnarizine is highly pH dependentthat is 029mgmL at pH 2 0017mgmL at pH 5 and0002mgmL at high pH of 65 (all the results were at 37∘C)[3] It is highly lipophilic molecule with log 119875 value 571[4] Pharmaceutically it belongs to BCS class II as displayspreferential absorption in stomach (Table 1)

11 Pharmacokinetics After oral administration cinnarizineis rapidly absorbed (119879max = 2ndash4 h) fromgastrointestinal tractwith an absorption window in upper gastrointestinal tract[5] On repetitive dosing in healthy human accumulationof cinnarizine occurs due to its pharmacokinetic properties[6] The drug can cross the blood-brain barrier by simplediffusion due to weakly basic and lipophilic [7] It ismetabolized preferably in liver by glucuronidation andoxidation Cinnarizine is oxidized by cytochrome P450 into

Hindawi Publishing CorporationJournal of Drug DeliveryVolume 2014 Article ID 479246 15 pageshttpdxdoiorg1011552014479246

2 Journal of Drug Delivery

Table 1 A summary of physicochemical pharmacokinetic and pharmacodynamic features of cinnarizine

Properties Pharmacokinetics Pharmacodynamics

Piperazine derivative Multiple dosing results in accumulation of drugAntihistaminic calcium channel blockerantidopaminergic anticholinergic and antiserotinergic

Weak base Rapid absorption through upper part of GIT(119879max = 2ndash4 h)

Selectively binds to calcium channels in openconfiguration specifically active in arteries

Poor aqueous solubility(BCS class II) Cross blood brain barrier by simple diffusion Blocking effect on L-type calcium channels actively

helpful for smooth muscle cells

pH dependent solubility Preferably metabolized in liver Melanogenesis inhibition regarded as skinwhitening agents

Highly lipophilic(log P = 571) Metabolism by oxidation via cytochrome P450 Reduction in membrane permeability to

extracellular calcium

Melting point 118ndash122∘CCYP2D6 and CYP2B6 selectively catalyzep-hydroxylation of cinnamyl phenyl ring anddiphenyl methyl group respectively

Exhibits inhibitory effect on potassium currentsfacilitating effect against vestibular vertigo

UV (120582max = 253 nm) Highly protein bound (91) Inhibitory action on 5HT serotonin uptake byplatelets

Excretion is preferably via urine or in feaces tosome extent Promote cerebral blood flow

Aggravates parkinsonism upon chronicmedication

References to the above mentioned points are cited in the text

N

N

Figure 1 Structure of cinnarizine

metabolites such as 1-(diphenylmethyl)piperazine(C1) 1(di-phenylmethyl)-4-[3-(41015840-hydroxyphenyl)-2-propenyl] pipera-zine (C2) and benzophenone(c3) 1-[(41015840-hydroxyphenyl)-phenylmethyl]4-(3-phenyl-2-propenyl)piperazine(C4) [8]Among the various CYP enzymes only CYP2D6 can cata-lyze p-hydroxylation of the cinnamyl phenyl ring of cin-narizine (C-2 formation) and only CYP2B6 can catalyze p-hydroxylation of the diphenylmethyl group (C-4 formation)of cinnarizine On the other hand CYP2C9 with CYP1A1-1A2 andor -2A6 have affinity for N-desalkylation at the 1-and 4-positions of the piperazine ring that results in C-1 andC-3 formation These promoted microsomal metabolismof cinnarizine [9 10] It has high protein binding capacityof 91 [11] The drug is predominantly excreted in urineas metabolites and in feces mainly as unchanged drug withelimination half-life of 3ndash6 h The pharmacokinetic aspectsare also compiled in Table 1

12 Pharmacodynamics Pharmacodynamically cinnarizineis classified as an antihistamine and calcium channel blocker

Additionally it also shows anticholinergic antiserotonergicand antidopaminergic activity [12] Cinnarizine ismoderatelysedative antihistaminic agent that acts by inhibition of H1receptor It is selective calcium ion entry blocker whichselectively acts on arteries These agents do not show actionon slow calcium channels in myocardium but have selec-tive action on arteries The drug binds to target calciumchannels when they are in an open conformation [13] Theinhibitory effects of cinnarizine on the noradrenaline andCa-induced contraction of the rabbit thoracic aorta andmesenteric arteries were compared to papaverine [14] Cin-narizine was found to block the Ca-evoked contractionof the depolarized vessels but was less effective againstthe noradrenaline-induced contraction of the mesentericarteries and even failed to antagonize the response of thethoracic aorta to noradrenaline Cinnarizine was effectivein mesenteric arteries exposed to noradrenaline by blockingthe Ca

0dependent response while papaverine was less

effective towards the Ca0dependent response but efficiently

inhibited the initial fast response more Cinnarizine was lesseffective or even failed to inhibit the response producedby thoracic aorta to nonadrenaline These results suggestedreduction of membrane permeability to extracellular cal-cium was the mechanism by which cinnarizine acted Thereport also suggested that papaverine inhibits the contrac-tion to less extent than that of cinnarizine It attenuatesvasoconstriction action of many endogenous substances bymodulation of calcium fluxes Cinnarizine is known topromote the cerebral blood flow So have wide applicationin treatment of cerebral apoplexy cerebral arteriosclerosisand posttraumatic cerebral symptoms [15] According to arecent paper the effect against vestibular vertigo was due toinhibiting potassium (K+) currents activated by heightened

Journal of Drug Delivery 3

hydrostatic pressure on the hair cells instead of blockingcalcium channels [16] It inhibits contraction of smoothmuscle cells by blocking L-type calcium channels [5] Reportson inhibitory action on 5H serotonin uptake by platelets arealso available [17] The drug inhibits 5-HT more efficientlythan K+-induced contractions [18] Its moderate antagonisticproperties at dopamine D2 receptors are known to resem-ble the mechanism of action of most antipsychotic drugsThe active metabolite of cinnarizine [1-(diphenylmethyl)-4-[3-(41015840-hydroxyphenyl)-2-propenyl] piperazine has higheraffinity for D2-receptors than the parent drug that indicatessignificant role in inducing parkinsonism as adverse effecton chronic medication [19] Recently cinnarizine has beenreported as melanogenesis inhibitors Additionally the drugwas suggested to be used in cosmeceuticals as skin whiteningagents for treatment of skin hyperpigmentation [20] Thepharmacodynamic features are tabulated in Table 1

2 Clinical Therapeutics and Trials

Clinically cinnarizine is used for treatment of vertigo andprevention of motion sickness due to its calcium channelblocking activity Vertigo indicates a sensation of false move-ment (generally described like rotation) and vestibular ver-tigo may be induced by increase in the endolymphatic pres-sure that activates pressure-dependent K+ currents (119868K119901) investibular hair cells this modulates transmitter release Cin-narizine acts by enhancing the transmitter release in vestibu-lar type II hair cells by inhibition of (119868K119901) thus enhancingdepolarization and increasing the voltage-dependent activa-tion of Ca2+ currents [16] The therapeutics of cinnarizinehas been proved employing clinical trials and the reportsare compiled in Table 2 Briefing the reports the early trialswere conducted for vertigo chronic asthma Additionallycinnarizine has evoked clinical interest for other disordersConsequently recently summarized reports suggest clinicalapplication of drug for migraine prophylaxis On the otherhand cinnarizine is known to aggravate Parkinsonrsquos disease[21] When used in average dose of 150mg daily it canaggravatemotor function in patientswith Parkinsonrsquos diseasehowever the effect was reversible and disappeared uponwithdrawal of drug Its use with caution is recommended

3 Commercial Products

Commercial cinnarizine is available as tablets and capsulesusually administered 2-3 times a day Drowsiness to deepsleep and dizziness are some common adverse effects Highdose should be used with caution in patients with hypoten-sion owing to the possibility of further decrease in bloodpressure and is contraindicated in pregnancy due to terato-genic and embryocidal effects on the foetus The drug canonly be prescribed if the potential benefit justifies the poten-tial risk to the foetus Cinnarizine is widely marketed as com-binationmedicationwith other drugs In the Indian domesticpharmaceuticalmarket its combinationwith domperidone ispredominant whereas combination with other drugs such asdimenhydrinate dihydroergocristine chlorcyclizine phenyl-propanolamine and piracetam are available with overseas

0

10

20

30

40

50

60

70

80

Bran

ds

Indi

aBa

ngla

desh

Italy

Mal

aysia

Chin

aTh

aila

ndTa

iwan

Peru

Phili

ppin

esVe

nezu

ela

Bulg

aria

Rom

ania

The N

ethe

rland

sSl

oven

iaSl

ovak

iaAu

stria

Lith

uani

aCh

ileBr

azil

Figure 2 Global distribution of cinnarizine commercial brands

pharmaceutical companies Some of the combination brandsare enlisted in Table 3 Cinnarizine pharmaceutical productsare commercialized all over the world (Figure 2) Indialeads in terms of commercialization of different brands ofcinnarizine comprising approximately more than 50 brandsincluding both drug in alone as well as in combination withother drugs Among all brands Stugeron has the highestdistribution in around 39 countries [22 23]

4 Bioavailability Enhancement

It has been accounted in research that bioavailability ofcinnarizine is remarkably influenced by gastric acidity [24]displaying its pH dependent solubility and in turn dissolu-tion The marketed dosage forms account for low and erraticbioavailability [25] mainly due to the above-mentionedpharmacokinetic reasons Also high dosing frequency isneeded because of its short elimination half-life [5] Its poorsolubility at high pH results in incomplete absorption Beinga weak base it is very soluble in acidic solutions and clinicalabsorption of cinnarizine was found to depend on the gastricacidity of patients Cinnarizine showed rapid dissolutionin individuals having high gastric acid content (pH = 12)providing good absorption characteristics whereas in caseof low-gastric acid content (pH = 6) reduction was observedin 119862max and AUC approximately 75 to 85 [26]

Literature retrieval on enhancement in solubility andbioavailability of cinnarizine highlighted various effectiveapproaches since 1984 till date In 1984 Tokumura et al[27] in his report claimed 30 times improved dissolutionfor inclusion complex of cinnarizine with 120573-cyclodextrinthan the drug alone whereas no difference in bioavailabilitywas observed Further working with the cinnarizine 120573-cyclodextrin complex Tokumurawith other research devisedamethod for improvement of bioavailability on simultaneousadministration of proposed 120573-cyclodextrin with compet-ing agent It was found that the penetration rate constantof cinnarizine in complex decreased which was restoredon addition of competing agents These agents compete


Table 2 Clinical therapeutics and trial reports on cinnarizine

Title Comments Reference

Cinnarizine for the prophylaxis of migraineassociated vertigo a retrospective study

After three months of cinnarizine therapy the meanfrequency of vertigo and migraine along with the durationand intensity of migraine headaches per month weresignificantly reduced (119875 lt 0001) The results were suggestivefor the safe and effective use of cinnarizine againstco-morbidity of migraine and vertigo among patients whosuffer from vestibular migraine or migraine with brain stemaura associated with vertigo

Togha et al [69]

Comparison of therapeutic effects ofalprazolam and cinnarizine in patients withidiopathic tinnitus a clinical trial study

Both the drugs were effective for treatment of idiopathictinnitus The side effect of drowsiness was less in case ofcinnarizine (316) with high rate of partial remission(684)

Salari et al [70]

Efficacy and safety of cinnarizine in theprophylaxis of migraine headaches in childrenan open randomized comparative trial withpropranolol

No significant difference was seen in 50 reduction of thebaseline headache frequency between treatment fromcinnarizine and propanolol separately (119875 = 0358) along withinsignificant adverse effects This trial proved cinnarizine tobe as effective and safe as propranolol for prophylaxis ofmigraine in children but recommended to be confirmed by adouble-blind placebo-controlled trial

Togha et al [71]

A reassessment of diagnostic criteria andtreatment of idiopathic urticarial vasculitis aretrospective study of 47 patients

Most patients did not show clinical and laboratory features ofurticarial vasculitis after treatment with cinnarizine Thus setforth the use of cinnarizine as effective treatment andsuggested as a valuable medication for utricarial vasculatis

Tosoni et al [72]

Cinnarizine in refractory migraineprophylaxis efficacy and tolerability Acomparison with sodium valproate

Cinnarizine and sodium valproate group showed 612 and638 subjects as responders towards treatment respectivelywith no statistically significant differences suggesting theefficacy of cinnarizine in severe migraine

Mansoureh et al[73]

Open-label trial of cinnarizine in migraineprophylaxis

Significant reduction in attack duration and severity(119875 lt 0001) with no serious adverse events was reportedconcluded the efficacy of cinnarizine as well-toleratedprophylactic antimigraine medication with early onset ofeffectiveness

Togha et al [74]

Cinnarizine has an atypical antipsychoticprofile in animal models of psychosis

The drug at a dose of 20mgkg significantly counter actedMK-801 (025mgkg) and amphetamine (5mgkg)locomotors effects and remain same on increasing dose to 60or 180mgkg with appearance of mild catalepsy The reportsuggested that cinnarizine has a potential antipsychotic effect

DallrsquoIgna et al [75]

Cinnarizine is a useful and well-tolerated drugin the treatment of acquired cold urticaria(ACU)

The report supported the effective and well-toleratedtreatment for acquired cold utricaria by administering highdose of drug

Tosoni et al [76]

New approaches to the management ofperipheral vertigo Efficacy and safety of twocalcium antagonists in a 12-weekmultinational double-blind study

Treatment with cinnarizine reduced the incidence ofmoderate vertigo episodes by 658 and extreme vertigo by898 The report suggested efficacious use of cinnarizine fortreatment of peripheral vertigo

Pianese et al [77]

Cinnarizine in the prophylaxis of seasicknesslaboratory vestibular evaluation and sea study

Effectiveness of cinnarizine on vestibule-ocular reflexsupported the potency of cinnarizine for the prevention ofseasickness in lab study and during voyage in rough sea Adose of 50mg was resulted in effective medication forprevention of sea sickness

Shupak et al [78]

The vestibulo-ocular reflex (VOR) under theinfluence of cinnarizine

A dose of 25mg and 50mg of drug showed decrease ingained VOR Reduction was also observed for patientstreated with cinnarizine 25mg in combination with 10mgdomperidone or 1 transdermal scopolamine patch Nonotable side effects were observed suggesting safe use ofcinnarizine alone or in combination against VOR

Doweck et al [79]


Table 2 Continued


Effect of cinnarizine on various types ofvertigo Clinical and electronystagmographicresults of a double-blind study

The study provided favorable results against suddenperipheral vestibular deficit from vertigo of circulatory originand from post traumatic vertigo Thus concluded to be welltolerated with minor side effects for treatment against vertigo

Hausler et al [80]

Antihypoxidotic and nootropic drugs Proof oftheir encephalographic and pharmacodynamicproperties by quantitative EEG investigations

The result suggested cinnarizine induced desired EEGchanges only in V-EEG showing effectiveness in case ofgeriatric population

Saletu andGrunberger [81]

Cinnarizine in the treatment of chronic asthma

The drug is also shown to exert anti-asthmatic effect inpatients with chronic asthma by antagonizing calcium iontransport across the mast cell membrane The report provedcinnarizine as first drug of a new family of anti-asthmaticdrugs offering a protective effect when taken systemically

Emanuel et al [82]

Table 3 Few brands of Cinnarizine in combination with other drugs

Brand name Combination ManufacturerArlevert Dimenhydrinate Hampton Pharmaceuticals UKArlevertan Dimenhydrinate Hennig Arzneimittel Gmbh amp Co ItalyAzinorm-C Domperidone Azine healthcare IndiaCinacris forte Dihydroergocrocristine Ivax ArgentinaCinnasia-D Domperidone Willow pharmaceuticals IndiaClinadil Dihydroergocristine STADA SpainCombitropil Piracetam Sintez Russian FederationDomstal-CZ Domperidone Torrent pharmaceuticals Ltd IndiaExit Piracetam Farmasa BrazilNeurozine Paracetamol Psycardia neurosciencesultramark healthcare Pvt Ltd IndiaOmaron Piracetam Nizhpharm GeorgiaPhezam Piracetam Balkanpharma BulgariaPrimatour Chlorcyclizine Meda pharma NeitherlandRinomar Phenylpropanolamine Recip SwedenStugil Domperidone J amp J (Janssen) IndiaVernavo Domperidone Neiss labs Pvt Ltd India

with 120573-cyclodextrin in complex formation thus keepingmore available free drug to penetrate the lipid barrier Inthe same content two papers were projected One wasbased on the investigation of the competing ability of DL-phenylalanine to improve the bioavailability of cinnarizine[28] On simultaneous administration of DL-phenylalaninewith cinnarizine 120573-cyclodextrin complex bioavailability wasremarkably enhanced This enhancement depends on thedose of competing agent administered It was concludedthat a minimum effective dose of 1 g of DL-phenylalaninemight be required for every 50mg of cinnarizine in 120573-cyclodextrin complex On the similar lines the ability of L-Leucine and L-Isoleucine was also investigated for competingeffect in gastrointestinal tract [29] As a result the 119862max wasincreased to 27 and 19 times as compared to that of drugalone and its 120573-cyclodextrin respectively Conclusively L-isoleucine showed stronger competing effect than L-leucinecoupled with significantly improved bioavailability of thedrug In the next year in 1987 enhancement of bioavailabilityof cinnarizine as its oleic acid solution in hard capsulefor oral administration was reported [30] Use of lipid

vehicle for oral administration of drug was ascertained toimprove the bioavailability when compared to cinnarizinetablet When investigated in beagle dogs the 119862max andAUC for oleic acid solution of cinnarizine were remarkablyimproved by 29 and 4 times than that of tablet respec-tively The results were encouraging and somewhat similarto those obtained with simultaneous administration of 120573-cyclodextrin and competing agent discussed above In yetanother report the120573-cyclodextrin derivatives SBE4-beta-CDand 2-hydroxypropyl-120573-cyclodextrin (HP-beta-CD) wereused to form complex with cinnarizine to enhance the oralbioavailability [31] The absolute bioavailability of solutionor capsule containing drug alone was compared to 120573-cyclodextrin derivatives complex of drug as a solution andin capsule To assess the bioavailability cinnarizine wasadministered to beagle dogs in the dose of (and an amountequivalent in case of 120573-cyclodextrin derivatives complex)25mg orally and 125mgmL intravenously The bioavailabil-ity of cinnarizine was 8 plusmn 4 for solution of drug and 08 plusmn04 for capsule filled with drug alone This was observed tobe significantly increased to 55ndash60 and 38 plusmn 12 in case


of 120573-cyclodextrin derivative complex of drug formulated assuspension and that filled in capsules respectivelyThehigherbioavailability achieved in case of cinnarizine 120573-cyclodextrinderivative complex formulated as suspension than that filledin capsules was attributed to rapid dissociation of drug fromits inclusion complex thus causing improved absorption

The enhancement in bioavailability was also attributed toenhancement in dissolution As mentioned earlier the drugexhibits dissolution rate limited absorption Based on thisconcept a simple technique of preparing solid dispersion ofdrug by fusion method was exploredThe study was aimed atachieving increased dissolution and sustained release effectseparately The purpose was served by the use of two lipidcarriers separately Gelucire 4414 (gastric acid soluble) andother Compritol 888ATO (gastric acid insoluble) In case ofGelucire 4414 the results suggested initial rapid release ofdrug which then sustained for over 5 h giving a release ofapproximately 90 whereas Compritol 888ATO at a maxi-mum ratio of 1 1 (drug compritol888ATO) more prolongedthe release when compared to pure drug and commercialtablet supported the efficiency of solid dispersion to enhancethe bioavailability [32]

The drug being a weak base exhibits higher solubilityin acidic environment of stomach and hence dissolutionOn the other hand it displays poor dissolution in basicenvironment of small intestine The inhibited drug release ofdrug in basic environment can be raised by incorporationof acidifiers in the formulation that create acidic environ-ment Incorporation of acidifiers like citric acid or fumaricacid in matrix tablet to raise the solubility and hence pHindependent drug release was also suggested [33] The drugrelease under the influence of acidifiers was examined bypreparing three combinations formulation containing onlycitric acid (70mg) or fumaric acid (70mg) separately andin combination with citric acid and fumaric acid (35 35mg)too Drug dissolution study was carried out using modifiedflow through cell The acidifiers are able to reduce the pHof the intestinal and maintaining it for extended period oftime thus providing sustained drug release The drug releasewas 573 and 535 after 8 h which increases to 752 and662 after 12 h for citric acid and fumaric acid respectivelywhereas it was only 265 after 12 h This shows betterefficiency of citric acid for maintaining low pH environmentThe lack point is depletion of acidifier from the tablet matrixthe rate of which is dependent on type of acidifier Citricacid was quickly depleted in comparison to fumaric acidAcidifiers are also known to resist precipitation of drug athigher pH Hence the result suggested that proper selectionof acidifiers may give pH independent release profiles that inturn would lead to higher bioavailability

Conclusively the problematic issue of low and erraticbioavailability of poorly aqueous soluble drug cinnarizinewas a topic of interest to researchers The efforts were dedi-cated from the use of well known 120573-cyclodextrin complex tosome recent use of liquid cubic phases and acidifiers like citricacid and fumaric acid Additional use of competing agents(such as DL-phenylalanine and L-isoleucine) in combinationwith 120573-cyclodextrin complex and lipid vehicles like oleicacid was proved to be advantageous and further increased

the bioavailability of drug On establishment of comparisonbetween these mentioned techniques to that of cinnarizinein alone or its marketed preparations the results wereencouraging with remarkable enhancement in bioavailabilityof cinnarizine

5 Drug Delivery Systems

Various dosage formsdelivery systems have been approachedto solve the solubility and bioavailability issue These includefast dissolving tablets nanoemulsions microparticles andas gastroretentive systems To the best of our knowledgehere is the compilation of research reports till date ondelivery related approaches to overcome the pharmacokineticconstraints of cinnarizine These systems have their ownadvantages and limitations as listed in Table 4 Critical analy-sis based on in vitro results revealed improved bioavailabilityof cinnarizine formulated as various dosage forms whencompared to marketed preparation In contrast to in vitroresults the in vivo data for improvement in bioavailabilityis limited and efforts are needed to be made to assess thebioavailability and performance of cinnarizine in vivo

51 Fast Dissolving Tablets Cinnarizine could serve as suit-able candidate for fast dissolving tablet that may improve thebioavailability and patient compliance Fast release tablet ofcinnarizine was prepared [34] The in vitro dissolution rateof granules was increased (80ndash90 60min) on comparisonwith drug alone (less than 50 80min) because of the higherhydrophilic character imparted by hydrophilic carriers andreduction in drug crystallinity in case of granulesThe reportsuggested the use of fluidized hot melt granulationmethod asan advantageous means of producing granules of cinnarizinewith PEG 6000 as amelt binder which does not need solventsor water Chitosan based orodispersible tablet of cinnarizinewas reported with the aim of improving absorption of drugwhich steps towards improved oral bioavailability [35] Thestudy guided the use of chitosan based orodispersible tabletto be a valuable alternative in respect to use of expensivesuperdisintegrant The prepared tablets have advantage ofdisintegrating within few seconds without need of waterwhich lead to enhanced absorption of drug The disintegra-tion time of optimized formulation was 11 sec giving 90of drug release in a time period of 5min According tothis report the researchers assumed that if 90 of drug isreleased in the dissolution media in vitro then it will exertfull effect in vivo So based on the results the sufficientdissolution was assumed to enhance the absorption of drugthat leads to improvise the bioavailability when assessed invivo providing effective therapyThis ultimately aims towardsimproving patient compliance with main focus on childrenand elderly patients Basu et al [36] developed fast dissolvingtablet of cinnarizine using combination of superdisintegrantssodium starch glycolate (SSG) and croscarmellose sodium(CCS) and camphor as a subliming material Camphor wasadded to aid the porosity of the tablet The optimizedformulation (SSG = 12mg CCS = 12mg and camphor =10mg) when compared to widely used commercial tablet


Table 4 Comments on advantages and limitations of cinnarizine delivery systems as included in the text

Delivery system Advantages Limitations

Fast dissolving tablets

Rapid absorption and quick onset of action Have insufficient mechanical strengthRapid drug therapy intervention Require handling precautionsEase of administration especially to pediatric andgeriatric population

Generally hygroscopic in nature so requirespecialized product packaging

Disintegrate within seconds without the need ofwater May lead to unpleasant gritty mouth feeling

Improve dissolution of poorly soluble drugAllow high drug loadingPregastric absorption avoids hepatic metabolism andreduce side effects

Lipid based systems

Enhance solubilization of poorly soluble drugs Lack of sound in vitro predictive modelsOvercome dissolution step Chemical instability of drugsSubmicron droplets size increases surface area forabsorption resulted in increased rate and extent ofabsorption

Need high surfactant concentration (30ndash60)

Selectively target to specific site in GIT May permit less drug loadingMore consistent drug absorption Lack of appropriate in vitro-in vivo correlationResist precipitation of drug in upper part of GIT andon shifting the pH compatible for cinnarizine

May exhibit limited lymphatic uptake from emulsionbased systems

Unsaturated fatty acids (an essential excipient)enhance solubility

Oxidation of unsaturated fatty acids in theformulation

Prevent drug degradation in GITDiminishes fasted and fed state variation inabsorption and also food effectLiquid crystalline nanostructured particles providedbetter scope for sustained deliveryCubosomes improvise stability bioadhesivity andbiocompatibilityHexasomes accentuate stability of encapsulated drug

Gastroretentive systems

Residence in stomach for longer duration providessustained effect Floating tablets and films undergo all or none effects

Suitable system for drugs that have absorptionwindow in upper GIT

May be swept away due to Migrating MyoelectricComplex motility pattern

Diminishes precipitation of basic drug at alkalinepH May cause gastric irritation

Appreciable therapeutic activity Bioadhesive systems have high turnover rate ofmucus

Account for once a day therapy Require presence of food to delay gastric emptyingAdvantageous for drugs with narrow therapeuticindex

Microspheres microballoons have low drug loadingcapacity

Lesser risk of dose dumping for multiparticulatesystemsLess inter and intra subject variabilityMicrospheres microballoons provide high degree ofdispersion in digestive tract


(Stugeron)was reported to bemore effectivewith drug releaseof 99 in 16min In another report fast dissolving tabletsof cinnarizine were prepared by sublimation technique andregarded as effective alternative approach compared to useof expensive excipients [37] The tablets were evaluated for

various precompressional and postcompressional parame-ters The precompressional evaluation revealed good freeflowing properties within the prescribed limit Consideringthe pharmacopoeial test the drug was uniformly distributedthroughout the tablet with high drug content (ge1015)


The average percent deviation was less than plusmn75 thatprovided gooduniformity Apart from these the friabilitywaslt 1 in all formulations The subliming agents have directlyproportional effect on the disintegration of tablets whichfurther affect the drug release The optimized formulationwas reported to have 119905

50 of 625min and 11990590 of 1974min

It was stated that upon storage the disintegration of tabletwas significantly decreased (119875 lt 005) The report concludedthe effectiveness of sublimation method as an alternativeapproach for fast dissolving tablet of cinnarizine to reachthe optimum point in shortest time with minimum effortsIn yet another report oral dispersible tablets were preparedby three different methods effervescent superdisintegrantaddition and sublimation method [38] The tablets showedtotal release of drug in a period of 6 hwith total disintegrationin 253 sec The report concluded that the superdisintegrantaddition method with L-hydroxypropyl cellulose (10wv)was best to fulfill the aim Recently Heer et al [39] developedfast dissolving orodispersible film and fast dissolving tabletof cinnarizine and assessed the effect of superdisintegrantsFor this purpose three different superdisintegrants sodiumstarch glycolate crospovidone and croscarmellose sodiumwere used The tablet was prepared by direct compressionmethod and solvent casting method was employed for prepa-ration of orodispersible filmThe two preparations were eval-uated for weight variation thickness drug content foldingendurance and tensile strength (for orodispersible film)As a result among three superdisintegrants crospovidoneat 4ww was proved to have promising superdisintegrantproperty required to prepare fast dissolving formulationsFast dissolving orodispersible filmwas concluded to be betterover fast dissolving tablet in terms of faster drug release withbetter flexibility suggestive to patient compliant dosage form

52 Lipid Based Drug Delivery Systems Lipid based drugdelivery systems were topic of interest to scientist as noveldrug delivery platform [40] and well known to improve theoral bioavailability of poorly water soluble drug that belongsto BCS class II and IV The most interesting mechanism ofenhanced bioavailability was regarded as improved absorp-tion due to enhancement of gastrointestinal solubilisation[38] The factors that relate to bioavailability from lipidformulations include digestion of lipid the mean emulsiondroplet diameter the lipophilicity of drugs and types oflipids The lipids are preferred for oral administration as theycan be formulated in solution suspension emulsions self-emulsifying andmicroemulsions [41] Lee et al [42] reportedlipid based formulation of drug and studied the effect of lipidon drug absorption The in vivo absorption study revealedhigher bioavailability with long chain triglyceride thanmedium chained triglyceride giving a value of 321 plusmn 23and 166plusmn23 respectively but was independent of quantityof lipid administered However the report concluded that thebioavailability was observed to increase with lipid dose of125ndash250mg but reached static point at 500mg Improvementin solubility of drug in self-nanoemulsified drug deliverysystem was reported [43 44] Lipids have the capability tokeep drug in solution upon dispersion in aqueous mediumSNEDDS containing combination of Brij 97 (176ww) and

PEG 400 (88ww) revealed good bioavailability in vivowith an area under curve (AUC

0ndash48 h) of 773plusmn148ngmLminus1 hminus1A double peak phenomenon was observed for plasma profileThe reason for high bioavailability was due to presence ofhigh content of surfactantThis helped in keeping cinnarizinesolubilized even at lower part of gastrointestinal tract thus itis available for absorption for longer duration It was observedthat the biorelevant media greatly affected the type and sizeof droplets formed Upon dispersion in media containinglow bile acid content vesicles were formed whereas it wasmicelle formation in presence of higher bile acid contentTheresulted nanostructured composition influenced the solubi-lization capacity of composition which potentially affectedthe absorption of drug from resultant media This researchreport on SNEDDS suggested the approach to be suitable forbetter absorption of drug Again working with SNEDDS theresearcher published another paper this time to assess theeffect of increasing loading level of cinnarizineThree formu-lations were developed SNEDDSHigh SNEDDSMedium andSNEDDSLow with 50 25 and 125mg of drug respectivelyThe in vitro lipolysis at pH 65 showed that SNEDDS withhigh concentration of cinnarizine leads to precipitation ofdrug whereas it decreased in drug loading There was nosignificant difference in AUC 119879max and 119862max for the threeformulations The 119879max was 18 plusmn 014 h 23 plusmn 064 h and3 plusmn 071 h after 1 g SNEDDSHigh 2 g SNEDDSMedium and 4 gSNEDDSLow respectively The AUC obtained was 355 plusmn 74485 plusmn 68 and 392 plusmn 52 ngmLlowasthminus1 for the three formulationsin order of their increased drug loading respectively Thereport presented that on oral administration the drugloading level in SNEDDS and amount of Snedds vehicledid not affect the bioavailability [45] A lipid based liquidcrystalline matrix of cinnarizine was prepared for sustainedrelease delivery of drug which ultimately enhances thebioavailability [46]The lipids used were glyceryl monooleateand oleyl glycerate In vitro lipolysis study suggested lesssusceptibility of oleyl glycerate to hydrolysis by pancreaticlipase than that of glycerylmonooleate In order to investigatethe improvement in bioavailability cinnarizine was orallyadministered in the formof suspension or solution in glycerylmonooleate or olely glycerate The bioavailability was moreenhanced by administering cinnarizine with oleyl glycerateand appeared to be 344 (aqueous suspension formulationassigned a reference bioavailability of 100) The reportconcluded the efficiency of lipids that have an ability toform liquid crystalline structures in excess water to be setforth as an application for oral sustained delivery of drugto enhance bioavailability Vithlani et al [47] developedSEDDS with the aim of improving aqueous solubility anddissolution profile The SEDDS with 30ww of CapmulPG-12 when evaluated in phosphate buffer pH 72 providedremarkable enhancement in drug solubility in phosphatebuffer(s) with rapid drug release The SEDDS showed leastsolubility of drug to be 1500 120583M in phosphate buffer pH 72It was concluded that the SEDDS prepared by combinationof Capmul PG-12 Tween 20 and Cremophor RH 40 canbe a suitable alternative dosage form to fulfill the aim ofthe research that is to improve solubility and dissolution of


drug SNEDDS of the drug was also reported with the aimof exploring the effect of type of lipid on solubility and drugrelease [25] Proper balance between rapid and efficient self-emulsifying ability higher solubility of drug maintaininghigh amount of drug in solution after aqueous dispersion (atleast 85) and lower droplet size upon aqueous dilutionwerethe selection criteria for optimal formulations The lengthof lipid chain significantly influenced the solubility of drugand long chain lipids showed higher solubility than mediumchained In terms of glyceride composition the mediumchain monoglycerides had better solubility than mediumchain triglycerides Furthermore the unsaturated fatty acidswith long chain lipids resulted in higher solubility thanthe above two SNEDDS showed significantly better releasein vitro in simulated gastric fluid (SGF) (to mimic the invivo condition more accurately) than marketed preparationStugeron The SNEDDS showed a release of 84ndash95 after15min which was only 66 in case of Stugeron in simulatedgastric fluid After 15min of shifting into simulated intestinalfluid the marketed preparation showed comparatively muchhigher drug precipitation (83) than the SNEDDS whichcauses only 7ndash23 of drug precipitation This suggestedsuperiority of SNEDDS to resist drug precipitation on shiftingto basic pH A paper was also reported to enhance the oralbioavailability of cinnarizine from its medium chain lipidsolution formulation Lipid based formulation of cinnarizinewas administered intraduodenally and perorally to rats inorder to assess the contribution of dispersion and digestionin the stomach towards bioavailability The bioavailabilitywas observed to be decreased after intraduodenal adminis-tration The difference in bioavailability was also observedfor medium chain and long chain triacylglycerides owingto difference in the dispersion and digestion in the gastricand intestinal compartments The difference between thebioavailability was large in case of medium chain lipidwhen compared to long chain lipid in case of both peroraland intraduodenal administration The result suggested thatthe passage of medium chain lipid formulation throughstomach led to critical gastric digestion than long chainlipid formulations The report concluded that rapid transferof medium chain formulation to intestinal mixed micellespossibly was achieved by efficient dispersion and partialdigestion in stomach Also absorption in the upper intestineprior to drug precipitation was preferred [48]

In yet another report the high solubility and stability ofcinnarizine loaded emulsion (CLE) had been proved [15]Egg lecithin was used with the aim of minimizing drugdegradation from both water and oil The drug was localizedin the interfacial lecithin layer of emulsion so as not tocontact with oil or water medium On further workingwith the CLE in next year the researchers provided reportsfor pharmacokinetics and tissue distribution of drug [49]When assessed in vivo in rats the novel formulation (CLE)revealed significantly higher AUC and lower clearance anddistribution volume On iv administration of 2mgkg ofcinnarizine loaded emulsion the AUC was observed to be1879556120583gLhminus1 whereas it was 865725 120583gLhminus1 for aqueouscinnarizine solution prepared using Tween 80 (1 g) and 12propylene glycol (10 g) The result revealed lower clearance

(0947 Lhkg) for drug loaded emulsion Consequentlycirculation in blood stream achieved for longer durationresulted in better therapeutic effects The tissue distributionexhibited lower side effects due to drug precipitation in vivoThe system provided better bioavailability improving thepharmacokinetics of drug Contributing to bioavailabilityof drug researchers explored self-microemulsifying system(SMEDDS) [50] SMEDDS is known to spread readily inthe gastrointestinal tract and the agitation provided bydigestive motility of stomach and the intestine results in self-emulsification SMEDDS containing oleic acid (1666ww)Tween 80 (5555ww) and Transcutol P (2777ww)improved the solubility and drug release when comparedto marketed formulation of cinnarizine In the report theauthors have explained formation of small sized particlesleading to rapid drug release of 8196 in 5min whichslightly increases to 8767 in 60min This suggested thepotential use of SMEDDS to improve oral bioavailability byovercoming the solubility issue In addition to this SMEDDSof cinnarizine was prepared to characterize a better under-standing of the mechanisms behind the precipitation of cin-narizine during in vitro lipolysis of a self-microemulsifyingdrug delivery system [51] In the period of in vitro lipolysisof the SMEDDS with or without cinnarizine samples werewithdrawn at different time points and ultracentrifugedInitially cinnarizine content in pellet was 4which increasedto 59 during lipolysis There was good correlation betweenprecipitation of cinnarizine and degree of lipid digestionDissolution was performed in biorelevant media and initiallythe dissolution rate of cinnarizine from pellets containingprecipitated cinnarizine was 10-fold higher than dissolutionfrom blank pellet spiked with crystalline cinnarizine whichincreased to more than 50 drug dissolved in the firstminute Pellets were further characterized by X-ray powderdiffraction (XRPD) and polarized light microscopy (PLM)Results indicated that either amorphous form or a moleculardispersion of cinnarizine resulted in precipitation duringin vitro lipolysis of SMEDDS thus improving dissolutionprofile Recently SNEDDS was also investigated [52] toeliminate the effect of food on cinnarizine absorption Anutritional drink Fresubin energy (200mL) was used tosimulate the fed state conditions to induce food effectThe SNEDDS capsules or tablets in fed state were assessedfor bioavailability by administering SNEDDS equivalent to50mg of drug orally to male beagle dog (10ndash135 kg) withone week wash-out period between dosing The dogs werefasted overnight for about 20ndash24 hThe nutritional drink wasadministered 30min prior to dosing Pentagastrin (6 120583gkg)was administered to dogs in order to control the gastric pHThe result also established the effect of food to extend the119879maxto 25 times than fasted state and increased bioavailability forconventional tablets (119865fasted = 209 plusmn 57 and 119865fed = 538 plusmn301) In contrast to this the food condition did not affectthe absorption of drug from SNEDDS capsules and tabletswhile 119879max was observed to extend the absorption and thusenhanced the bioavailability The fed state showed 25 and33 times longer 119879max than fasted state for SNEDDS tabletsand SNEDDS capsules respectively The bioavailability ofSNEDDS capsules was higher at both fed (793 plusmn 147) and


fasted state (581 plusmn 167) than that of SNEDDS tablet (119865fed =437plusmn67 and 119865fasted = 327plusmn115) SNEDDS formulation wasobserved to diminish the variation in absorption at fasted andfed conditions leading to overall increase in bioavailabilitycompared to conventional tablets At the end the conclusivepoints were drawn that food affects the absorption of BCSclass II drug causing increased bioavailability in fed statewhich can be significantly reduced by the use of SNEDDScapsules and tablets In the same context another report waspublished in the same year to predict the performance of twoabove discussed lipid formulations (SNEDDS capsules andSNEDDS tablets)The two formulations were compared withconventional tablets on the basis of gastrointestinal in vitrolipolysis model in both fasted (pH = 2) and fed conditions(pH = 6) The in vitro lipolysis model was supposed tosimulate the digestion in the stomach and intestine Tomimicthe lipolysis events in fed state conditions fat milk (35)was administered with 04mgmL of pepsin At gastricstep during fasted state a high concentration of drug wasfound in aqueous phase whereas it was lower for SNEDDStablet which can be explained on the basis of presenceof alkaline excipients that lead to increase of the pH to364 and cause lower solubility The solubilization of drugremained constant for SNEDDS formulations upon initiationof duodenal step suggested the role of lipid to enhance thesolubilization of cinnarizineThe total amount of cinnarizinerecovered from fasted state lipolysis was almost similar forall formulation with an average of 84 plusmn 12 On examiningfed state condition approximately 1 of cinnarizine fromSNEDDSwas shown in aqueous phase in gastric stepwhereasit was only 01 for conventional tablet On passing intoduodenal step SNEDDS formulations showed an aqueouscinnarizine content of 40 after 83min and maintained itthroughout the lipolysis while the conventional tablet lostsolubilization capability decreasing to 254 plusmn 17 at the endWhen compared to in vivo data provided by paper discussedabove these in vitro results were in accordance with in vivoThe order was similar as SNEDDS capsules gt SNEDDS tabletgt conventional tablet for performance in vitro and in vivoMore conclusively the in vitro fasted state model was ableto predict the correlation with in vivo study whereas the fedstate model cannot exactly establish a correlation but wasable to predict the best formulation similar to that predictedby in vivo study [53] In the path of lipid based nanosizeddelivery of cinnarizine a report was published to stabilizethe nanosuspensions by the utilization of bead layering Thenanosuspension of drug was coated on sugar beads by theuse of fluidized bed pellet coater with Wurster insert Thesenanosuspensions showed complete dissolution in 15minwhereas it was only 11 in 1 h for unmilled powder Thecoated nanocrystals resulted in slower release of cinnarizinethan that of original nanosuspensions due to formation ofreagglomeration upon release from coating The conclusivepoint suggested influence of drug physicochemical propertieson in vitro dissolution after bead layering [54]

Utilization of lipids for pharmaceutical and biomedicalapplications was known to overcome the issues relatedto biocompatibility and biodegradability In this respectthe unique mesophasic structure of lipids such as cubic

hexagonal and sponge phase structures provides advantageof stability and production feasibility The cubic structurehas advantage of improved stability bioadhesivity and bio-compatibility whereas the hexagonal arrangement exhibitedhexasomes accounts for encapsulation of different drugswith high stability [55] The similar reports on cinnarizineare discussed further The contribution towards improvedabsorption of cinnarizine was made by novel approach ofcubic liquid crystalline phase [56]The cubic phase improvedthe solubility of cinnarizine and provided sustained releaseof drug In addition to this another highlight of cubicphase is its temperature sensitivity in the range of 20ndash37∘Csuggesting it to be a putative material for the purpose of insitu gelation The in vivo absorption study was performed onanaesthetized male Sprague-Dawley rats (280ndash320 g) Cubicphase equivalent to 5mg of cinnarizine was administeredintraduodenally The result illustrated large difference inthe rate of cinnarizine absorption from cubic phase andsuspension The absorption profile was more sustained andcontinued beyond 8 h after dose period for cubic phasethus supporting its application to improve bioavailabilityThe119862max obtained for cubic phase was 262 ngmL after 47 hwhereas it was 999 ngmL after 22 h for suspension provingsustained absorption for former case Another remarkablecontribution towards improved bioavailability was maderecently [57] The report was the first to reveal the abilityof liquid crystalline nanostructured particles (cubosomes)to attain sustained absorption of cinnarizine These cubo-somes were developed using phytantriol (an alcohol) andglyceryl monooleate (a lipid) Phytantriol cubosomes showedimproved results with sustained absorption beyond 48 hThe oral bioavailability was improved to 21 compared tosuspension (119865 = 9) and oleic acid emulsion (119865 = 12)In such cases of nondigestible phytantriol cubosomes theslow release can be facilitated by stomach that acts as anonsink reservoir Thus the report suggested the potentialuse of nondigestible liquid crystalline nanostructured par-ticles as a novel approach for sustained oral drug deliverysystems leading to improvise the bioavailability of poorlywater soluble drugs In the same year the researchers madeanother contribution towards nanosized lipid formulation[58] Hexagonal liquid crystals (hexosomes) of cinnarizinewere prepared with the aim of sustaining the absorptionfor increment in bioavailability The pharmacokinetics wasevaluated on oral administration of bolus lipid solution ofdrug in selachyl alcohol to rats The results revealed thatafter oral administration sustained plasma profile with 20ndash40 ngmLof drugmaintained over the first 24 hwas observedWhen compared to suspension the 119905max was longer forhexosomes (1 h and 235 plusmn 59 h resp) The absolute oralbioavailability was improved for hexasomes (17) comparedto that of suspension (9) Selachyl alcohol is not susceptibleto digestion which attributed to prolong the absorption assimilar to nondigestible phytantriol cubic system discussedabove The nanostructure of hexasomes remained unaffectedby simulated intestinal fluid and drug The report concludedthe potential use of nondigestible liquid crystalline systemswith additional advantages of nanostructured particles asnovel system for sustained drug delivery


53 Gastroretentive Systems The gastroretentive preparationof cinnarizine was first reported in 1989 [59] The researchreported two preparations one was a buoyant tablet con-taining powdered soyabean drug and sodium bicarbonateand the other was laminated floating film comprising of adrug film an effervescing film of sodium bicarbonate andan outer drug release regulating film The in vitro studiesassured the suitable floating ability and sustained releaseproperty of the two formulations Linear dissolution wasobserved after 2 h in case of laminated film not similar totablet due to structural difference The absorption study wasdone by oral administration of buoyant tablet and film inbeagle dogs As a result cinnarizine was observed in bloodeven 24 h after oral administration concluding the efficiencyof the two preparations as sustained delivery systems so asto upgrade the absorption and bioavailability of cinnarizineFloating microballoons were prepared by diffusion solventevaporation technique using 23 factorial design to improvebioavailability [60]The preparation was supposed to providesustained delivery of cinnarizine In vitro drug release wasperformed in pH 12 for 8 h and then in pH 74 for 2 hMicroballoon released approximately whole drug during 10 hperiod with sufficient buoyancyThemicroballoons preparedwith combination of Eudragit S100 and Eudragit RL in aratio of 1 3 proved most effective results suggesting theefficient use of microballoons for oral sustained delivery ofcinnarizine Nagarwal et al [61] developed single unit matrixtablet dosage form for gastroretentive purpose These tabletswere prepared using four viscosity grades of HPMC withgas forming agent The sustained drug release was achieveddue to rapid hydration of polymer on the surface of floatingtablet thus forming a gel layer surrounding the matrix Thiscontrols penetration of water to the center of matrix tabletand retards the release It was reported that with increase inviscosity of polymer drug release rate was increased Whilestudying the release rate with different polymers it was alsorevealed that the drug release rate depends on the surfacearea as well as hydration capacity of polymer Based onthese results the optimized formulation containing HPMCK100LV (90mg) was compared (in vivo) to oral suspensionand bioavailability was studied The absorption phase wasslow and prolonged in case of matrix tablet thus indicatingprolonged plasma concentration The overall bioavailabilityof floating matrix tablet was 285 times greater than thatof oral suspension In 2012 floating tablet of cinnarizinein combination of domperidone maleate was developedfor gastroretentive delivery The pH independent polymerMethocel polymer of different viscosity grades was used atconcentration of 20ndash50ww to prepare floating tablets Theformulation was reported to remain buoyant for 12 h with lagtime of 10ndash15 sec in 01 N HCl Sodium bicarbonate (15mg)and sodium alginate (18mg) were used as gas generatingagent necessary to impart sufficient buoyancy So the reportsuggested improved retention of tablet of combination of twoantiemetic drugs at gastric pH that was supposed to haveimproved therapeutic effects [62]

Multiparticulate systems reported as gastroretentivefloating microspheres were developed to assess the effect

of formulation variables on microsphere formation [63]Microspheres were developed using Acrycoat S100 EudragitRS100 and ethyl cellulose as gastroretentive polymers Whenassessed in vitro in 01 N HCl the microspheres remainedbuoyant for 12 h Among these microspheres containingAcrycoat S100 (100mg) showed best results for sustaineddrug release (9814) floatability (72) in 12 h and stabilityAnother effort to sustain the release of cinnarizine wasattained by preparation of drug loaded chitosan methyl-cellulose interpenetrating polymer network (CSMC IPN)microspheres intended for mucoadhesive gastroretentiveapplication The study explores the interpenetrating networkof two biopolymers chitosan andmethylcellulose to prolongthe residence of microspheres in the stomach The micro-sphereswere prepared using central composite design at threedifferent levels of polymeric ratio and glutaraldehyde Theformulations were evaluated for degree of mucoadhesivenesswhich was correlated to amount of polymer and interpene-trating network of polymers For optimized formulation thepercent of mucoadhesion was 7385 plusmn 278 at 4 h with 119905

50of

43221 plusmn 2615min The other observed results were for meandiameter (6132 plusmn 138 120583m) swelling index (238 plusmn 006) andentrapment efficiency (8413 plusmn 132) The report suggestedthe utilization of chitosan methylcellulose interpenetratingpolymer network (CSMC IPN) as potential approach toimpart mucoadhesive property for gastroretentive delivery ofweakly basic drugs [64] Recently in the past year Patel et al[65] prepared mucoadhesive microparticles by supercriticalfluid method using chitosan as mucoadhesive polymer Theefficiency of this physical coating process for producingmicroparticles was established by X-ray powder diffractom-etry and differential scanning calorimetry The preparedmicroparticles were proposed for better bioavailability thanthe suspension in test animal due to gastroretention Thecomparison was done in vivo by administering both sus-pension and mucoadhesive microparticles to rabbit in fastedstate The mucoadhesive microparticles showed sustaineddrug release for more than 20 h Goodmucoadhesive proper-ties and strong adherence of microparticles to gastric mucuslayer were established both in vitro and in vivo resultingin gastroretention for an extended period of time Theseformulations accounts for sustained effect of drug reducingthe dosing frequencies In the same year mucoadhesivetablets of cinnarizine were developed using Eudragit RLPOas polymer with the aim of investigating the effect of ironoxide in the formulation [66] The mucoadhesive tabletswere prepared at different concentrations of Eudragit RLPOiron oxide and PVP K 30 and evaluated for mucoadhesivestrength 119905

50 11990590 and mean dissolution time effect ofiron oxide was investigated Ex vivo mucoadhesion test wasperformed employing texture analysis The result clarifiesthe synergistic effect of combination of Eudragit RLPO ironoxide and PVP K 30 to enhance the mucoadhesive strengthwhen compared to their individual effect As per the resultsthe mucoadhesive tablets containing 858ww EudragitRLPO 668ww iron oxide and 786ww PVP K 30 wereselected to be optimized and fulfilledmaximumrequirementswith better mean dissolution time (26644 plusmn 382min) 119905

50(12494plusmn540min) 119905

90 (75553plusmn429min) and desirability


of 0727 The Incorporation of iron oxide was found toenhance the mucoadhesive strength due to induction ofionic interaction Retardation of drug release with meandissolution time of 22956plusmn330min at higher concentrationof iron oxide was achieved due to reduction in polymericchain disentanglement and polymer erosion caused by theentrapment of iron oxide in the polymeric chain network

A novel approach of gastroretention with controlledrelease was recently negotiated by preparing an unfoldingtype film of cinnarizine [67] The polymeric film was pro-cured by solvent casting method using ethyl cellulose andhydroxyl propyl methyl cellulose K15 and folded in hardgelatin capsuleThe presence of stearic acid in polymeric filmhas crucial role As obtained by in vitro drug release studythe film describes fast release of drug in the first hour dueto initial leaching out of drug which was followed by slowrelease by diffusion through hydroxyl propyl methyl celluloseand ethyl cellulose providing more steady controlled releasegiving total release of 8193 in 13 hThe result also suggestedmore appropriate use of unfolding film in simulated gastricfluid when compared to roll folded pattern The researchstrongly indicated the gastroretentive potential of prepareddosage formwhich can be explored further for in vivo studies

Apart from these preparations enteric microparticleswere developed [68] Cinnarizine is known to precipitateat high pH on gastric emptying and show slow and erraticbioavailability The microparticles with enteric coating wereprepared to circumvent this obstacle Microparticles pre-pared using pH responsive polymer Eudragit L by emulsionsolvent evaporation method showed improved bioavailabil-ity The microparticles inhibited the in vitro release of drugunder gastric conditions due to high threshold pH 6 Atfavorable intestinal conditions thesemicroparticles dissolvedrapidly and the drug released This diminishes the impactof drug precipitation and improved the absorption In vivocomparison with drug powder suspension was done by oraldosing in rats and Eudragit L (3 g) loaded microparticlesshowed twofold increase in bioavailability although 119862

(max)and 119879

(max) were not significantly different

6 Conclusion

Despite wide therapeutic applications and worldwide com-mercialization of cinnarizine the marketed formulationaccounts for low and erratic bioavailability due to gastricacidity dependent absorption Progressively the approachto overcome these limitations had been worked on Earliercomplexation techniques were practiced but now recentlydeveloped dosage forms such as SNEDDS gastroretentivesystems are in interest Lipid based systems emerged withimproved solubility and dissolution in vitro (80ndash95) and invivo bioavailability (AUC approximately 4 times higher thantablets) The purpose to circumvent the obstacles associatedwith drug was also achieved by the preparations aimed tolonger retention at gastric environment These provided newachievements for sustained release of cinnarizine so as toreduce dosing frequencies and attain patient compliance Useof nanosized liquid crystalline particles (cubosomes) can be

proved as new field of interest for sustained absorption ofcinnarizine

7 Future Perspective

Patient compliance is the ultimate aim for any pharmaceuticaldosage form For the control of drug release or sustained ben-efits for patients the control of gastrointestinal transit profilecould be the focus of next upcoming time The microsizedparticles microballoons microspheres and microspongesalone or in combination with other approaches like useof bioadhesive polymers or coating materials to facilitateintimate adherence to gastric mucosa and incorporation ofacidifiers in order to improve pH dependent solubility ofcinnarizine might result in the availability of new productwith improved potential for the therapeutics of cinnarizineCinnarizine solubility is highly dependent on gastric acidityso pHcontrolled systems can be proposed to provide constantrate release irrespective of location of dosage form in theGITRelease of cinnarizine from its dosage form independent ofenvironmental conditions can also be achieved by designingosmotically controlled gastroretentive drug delivery systemswhich can further be modified by coating external surfacewith some erodible polymer to provide alternate chances ofimprovement and must be assessed further

Use of lipid based systems as gastroretentive systemscan set forth for the new era of overcoming the pharma-cokinetic constraints of cinnarizine Tablets and capsulesformulated using self-emulsifying drug delivery system con-taining droplets size extending from few nanometers tomicrons can be developed while sustaining good flowabilitycohesive property and high content uniformity Methodsby which a transiently supersaturated state can be gen-erated and maintained in situin the GI tract can be setforth for development In this context novel formulationapproach of use of polymeric precipitation inhibitors orretarders like hydroxyl propyl methyl cellulose incorporatedinto self-nanoemulsifying delivery systems to produce asupersaturated drug concentration and prolong such a drugconcentration for an extended period of time for an optimalabsorption thereby improving oral bioavailability can beset forth for assessment for future development of cinnar-izine The various techniques discussed herein can be betteroption for companies to focus on commercializing themTheapproach may present a system to potentially improve thepharmacokinetics of the drug

Conflict of Interests

The work is not under financial or personal relationshipswith other person or organization So the authors report nodeclaration of interest

References

[1] P Kumar and C Singh ldquoA study on solubility enhancementmethods for poorly water soluble drugsrdquoThe American Journalof Pharmacological Sciences vol 1 no 4 pp 67ndash73 2013


[2] H Chen C Khemtong X Yang X Chang and J GaoldquoNanonization strategies for poorly water-soluble drugsrdquo DrugDiscovery Today vol 16 no 7-8 pp 354ndash360 2011

[3] C-H Gu D Rao R B Gandhi J Hilden and K RaghavanldquoUsing a novel multicompartment dissolution system to predictthe effect of gastric pHon the oral absorption ofweak baseswithpoor intrinsic solubilityrdquo Journal of Pharmaceutical Sciencesvol 94 no 1 pp 199ndash208 2005

[4] J H Fagerberg O TsinmanN Sun K Tsinman A Avdeef andC A S Bergstrom ldquoDissolution rate and apparent solubilityof poorly soluble drugs in biorelevant dissolution mediardquoMolecular Pharmaceutics vol 7 no 5 pp 1419ndash1430 2010

[5] B Patel P Jayvadan T Rashmin et al ldquoImprovement ofsolubility of cinnarizine by using solid dispersion techniquerdquoInternational Research Journal of Pharmacy vol 1 pp 127ndash1312010

[6] B-Q Li G-Q Yang S-H Fang et al ldquoEffect of route ofadministration on the pharmacokinetics and toxicokineticsof cinnarizine in dogsrdquo European Journal of PharmaceuticalSciences vol 40 no 3 pp 197ndash201 2010

[7] J Kornhuber A W Henkel T W Groemer et al ldquoLipophiliccationic drugs increase the permeability of lysosomal mem-branes in a cell culture systemrdquo Journal of Cellular Physiologyvol 224 no 1 pp 152ndash164 2010

[8] S Kariya S Isozaki S Narimatsu and T Suzuki ldquoOxidativemetabolism of cinnarizine in rat livermicrosomesrdquoBiochemicalPharmacology vol 44 no 7 pp 1471ndash1474 1992

[9] S Kariya S Isozaki K Uchino T Suzuki and S NarimatsuldquoOxidativemetabolism of flunarizine and cinnarizine bymicro-somes from B-lymphoblastoid cell lines expressing humancytochrome P450 enzymesrdquo Biological and PharmaceuticalBulletin vol 19 no 11 pp 1511ndash1514 1996

[10] S Narimatsu S Kariya S Isozaki et al ldquoInvolvement ofCYP2D6 in oxidative metabolism of cinnarizine and flunar-izine in human liver microsomesrdquo Biochemical and BiophysicalResearch Communications vol 193 no 3 pp 1262ndash1268 1993

[11] S C Sweetman Martindle The Complete Drug Reference ThePharmaceutical Press London UK 33rd edition 2002

[12] D Turner Y Lurie Y Finkelstein et al ldquoPediatric cinnarizineoverdose and toxicokineticsrdquo Pediatrics vol 117 no 5 ppe1067ndashe1069 2006

[13] M G Lopez M A Moro C F Castillo C R Artalejo andA G Garcia ldquoVariable voltage-dependent blocking effects ofnitrendipine verapamil diltiazem cinnarizine and cadmiumon adrenomedullary secretionrdquo British Journal of Pharmacol-ogy vol 96 no 3 pp 725ndash731 1989

[14] A Broekaert and T Godfraind ldquoA comparison of the inhibitoryeffect of cinnarizine and papaverine on the noradrenaline-and calcium-evoked contraction of isolated rabbit aorta andmesenteric arteriesrdquo European Journal of Pharmacology vol 53no 3 pp 281ndash288 1979

[15] S Shi H Chen Y Cui and X Tang ldquoFormulation stability anddegradation kinetics of intravenous cinnarizine lipid emulsionrdquoInternational Journal of Pharmaceutics vol 373 no 1-2 pp 147ndash155 2009

[16] T Haasler G Homann T A Duong Dinh E Jungling MWesthofen and A Luckhoff ldquoPharmacological modulation oftransmitter release by inhibition of pressure-dependent potas-sium currents in vestibular hair cellsrdquo Naunyn-SchmiedebergrsquosArchives of Pharmacology vol 380 no 6 pp 531ndash538 2009

[17] T G Pukhalrsquoskaya O A Kolosova M Y Menrsquoshikov and A MVein ldquoEffects of calcium antagonists on serotonin-dependent

aggregation and serotonin transport in platelets of patients withmigrainerdquo Bulletin of Experimental Biology and Medicine vol130 no 7 pp 633ndash635 2000

[18] Y S Medeiros and J B Calixto ldquoInfluence of calcium entryblockers and calmodulin inhibitors on 5-hydroxytryptamine-potassium- and calcium-induced contractions in humanumbil-ical artery in-vitrordquo Journal of Pharmacy and Pharmacology vol43 no 6 pp 411ndash416 1991

[19] S Kariya S Isozaki Y Masubuchi T Suzuki and S Nari-matsu ldquoPossible pharmacokinetic and pharmacodynamic fac-tors affecting parkinsonism inducement by cinnarizine andflunarizinerdquo Biochemical Pharmacology vol 50 no 10 pp1645ndash1650 1995

[20] T-S Chang andVC-H Lin ldquoMelanogenesis inhibitory activityof two generic drugs cinnarizine and trazodone in mouse B16melanoma cellsrdquo International Journal of Molecular Sciencesvol 12 no 12 pp 8787ndash8796 2011

[21] J F Marti Masso J A Obeso N Carrera and J M Martinez-Lage ldquoAggravation of Parkinsonrsquos disease by cinnarizinerdquo Jour-nal of Neurology Neurosurgery and Psychiatry vol 50 no 6 pp804ndash805 1987

[22] CinnarizineDrugscommdashDrug Information 2013 httpwwwdrugscominternationalcinnarizinehtml

[23] Cinnarizine Brand name Drugs updatecom 2013 httpwwwdrugsupdatecombrandshowavailablebrands467

[24] H Ogata N Aoyagi N Kaniwa et al ldquoGastric acidity depen-dent bioavailability of cinnarizine from two commercial cap-sules in healthy volunteersrdquo International Journal of Pharmaceu-tics vol 29 no 2-3 pp 113ndash120 1986

[25] A A-W Shahba K Mohsin and F K Alanazi ldquoNovel self-nanoemulsifying drug delivery systems (SNEDDS) for oraldelivery of cinnarizine design optimization and in-vitroassessmentrdquo AAPS PharmSciTech vol 13 no 3 pp 967ndash9772012

[26] P S Burton J T Goodwin T J Vidmar and B M AmoreldquoPredicting drug absorption how nature made it a difficultproblemrdquo Journal of Pharmacology and ExperimentalTherapeu-tics vol 303 no 3 pp 889ndash895 2002

[27] T Tokumura H Ueda Y Tsushima et al ldquoInclusion complexof cinnarizine with 120573-cyclodextrin in aqueous solution and insolid staterdquo Journal of Inclusion Phenomena vol 2 no 3-4 pp511ndash521 1984

[28] T Tokumura M Nanba Y Tsushima et al ldquoEnhancement ofbioavailability of cinnarizine from its 120573-cyclodextrin complexon oral administration with DL-phenylalanine as a competingagentrdquo Journal of Pharmaceutical Sciences vol 75 no 4 pp 391ndash394 1986

[29] T Tokumura Y Tsushima K TatsuishiM Kayano YMachidaandTNagai ldquoEnhancement of the bioavailability of cinnarizinefrom its 120573-cyclodextrin complex on oral administration with L-isoleucine as a competing agentrdquo Chemical and PharmaceuticalBulletin vol 34 no 3 pp 1275ndash1279 1986

[30] T Tokumura Y Tsushima K TatsuishiM Kayano YMachidaand T Nagai ldquoEnhancement of the oral bioavailability of cin-narizine in oleic acid in beagle dogsrdquo Journal of PharmaceuticalSciences vol 76 no 4 pp 286ndash288 1987

[31] T Jarvinen K Jarvinen N Schwarting and V J Stella ldquo120573-Cyclodextrin derivatives SBE4-120573-CD and HP-120573-CD increasethe oral bioavailability of cinnarizine in beagle dogsrdquo Journal ofPharmaceutical Sciences vol 84 no 3 pp 295ndash299 1995

[32] B S Kalava M Demirel and Y Yazan ldquoPhysicochemicalcharacterization and dissolution properties of cinnarizine solid


dispersionrdquo Turkish Journal of Pharmaceutical Sciences vol 2no 2 pp 51ndash62 2005

[33] D M Mehta P B Parejiya B S Barot and P K ShelatldquoInvestigation of the drug release modulating effect of acidifiersin modified release oral formulation of cinnarizinerdquo AsianJournal of Pharmaceutical Sciences vol 7 no 3 pp 193ndash2012012

[34] R P Patel and A Suthar ldquoFormulation and process opti-mization of cinnarizine fast-release tabletsrdquo PharmaceuticalTechnology vol 33 no 8 pp 53ndash59 2009

[35] M Nagar and A V Yadav ldquoCinnarizine orodispersible tablets achitosan based fast mouth dissolving technologyrdquo InternationalJournal of PharmTech Research vol 1 no 4 pp 1079ndash1091 2009

[36] B Basu A Bagadiya S Makwana V Vipul D Batt andA Dharamsi ldquoFormulation and evaluation of fast dissolvingtablets of cinnarizine using superdisintegrant blends and sub-liming materialrdquo Journal of Advanced Pharmaceutical Technol-ogy and Research vol 2 no 4 pp 266ndash273 2011

[37] N G Raghavendra Rao U Kulkarni and B S Patil ldquoDesignand development of fast dissolving Cinnarizine tablets bysublimation techniquerdquo Research Journal of Pharmacy andTechnology vol 4 no 4 pp 585ndash588 2011

[38] B P Patel J K Patel G C Rajput and R S Thakor ldquoFormula-tion and evaluation of mouth dissolving tablets of cinnarizinerdquoIndian Journal of Pharmaceutical Sciences vol 72 no 4 pp 522ndash525 2010

[39] D Heer G Aggarwal and S L H Kumar ldquoDevelopmentof fast dissolving oral films and tablets of cinnarizine effectof superdisintegrantsrdquo International Journal of Pharmacy andPharmaceutical Sciences vol 6 no 2 pp 186ndash191 2014

[40] NThomas RHolm T Rades andAMullertz ldquoCharacterisinglipid lipolysis and its implication in lipid-based formulationdevelopmentrdquo The AAPS Journal vol 14 no 4 pp 860ndash8712012

[41] B K Nanjwade D J Patel R A Udhani and F V ManvildquoFunctions of lipids for enhancement of oral bioavailability ofpoorly water-soluble drugsrdquo Scientia Pharmaceutica vol 79 no4 pp 705ndash727 2011

[42] KW Lee C J Porter andB J Boyd ldquoThe effect of administereddose of lipid-based formulations on the In Vitro and In Vivoperformance of cinnarizine as a model poorly water-solubledrugrdquo Journal of Pharmaceutical Sciences vol 102 no 2 pp565ndash578 2013

[43] A T Larsen A Ogbonna R Abu-Rmaileh B Abrahamsson JOslashstergaard andAMullertz ldquoSNEDDS containing poorlywatersoluble cinnarizine development and In vitro characterizationof dispersion digestion and solubilizationrdquo Pharmaceutics vol4 no 4 pp 641ndash665 2012

[44] A T Larsen A G Ohlsson B Polentarutti et al ldquoOralbioavailability of cinnarizine in dogs relation to SNEDDSdroplet size drug solubility and in vitro precipitationrdquoEuropeanJournal of Pharmaceutical Sciences vol 48 no 1-2 pp 339ndash3502013

[45] A T Larsen P Akesson A Jureus et al ldquoBioavailability ofcinnarizine in dogs effect of SNEDDS loading level and corre-lation with cinnarizine solubilization during in vitro lipolysisrdquoPharmaceutical Research vol 30 no 12 pp 3101ndash3113 2013

[46] B J Boyd S-M Khoo D V Whittaker G Davey and C JH Porter ldquoA lipid-based liquid crystalline matrix that providessustained release and enhanced oral bioavailability for a modelpoorly water soluble drug in ratsrdquo International Journal ofPharmaceutics vol 340 no 1-2 pp 52ndash60 2007

[47] S Vithlani S Sarraf and C S Chaw ldquoFormulation and in vitroevaluation of self-emulsifying formulations of CinnarizinerdquoDrug Development and Industrial Pharmacy vol 38 no 10 pp1188ndash1194 2012

[48] K W Y Lee C J H Porter and B J Boyd ldquoGastric pre-proc-essing is an important determinant of the ability of medium-chain lipid solution formulations to enhance oral bioavailabilityin ratsrdquo Journal of Pharmaceutical Sciences vol 102 no 11 pp3957ndash3965 2013

[49] S Shi H Chen X Lin and X Tang ldquoPharmacokineticstissue distribution and safety of cinnarizine delivered in lipidemulsionrdquo International Journal of Pharmaceutics vol 383 no1-2 pp 264ndash270 2010

[50] M Yasir and S Rai ldquoCinnarizine loaded lipid based systempreparation optimization and in-vitro evaluationrdquo IOSR Jour-nal of Pharmacy vol 2 no 5 pp 47ndash56 2012

[51] P J Sassene MM Knopp J Z Hesselkilde et al ldquoPrecipitationof a poorly soluble model drug during in vitro lipolysischaracterization and dissolution of the precipitaterdquo Journal ofPharmaceutical Sciences vol 99 no 12 pp 4982ndash4991 2010

[52] M L Christiansen R Holm J Kristensen et al ldquoCinnarizinefood-effects in beagle dogs can be avoided by administrationin a Self Nano Emulsifying Drug Delivery System (SNEDDS)rdquoEuropean Journal of Pharmaceutical Sciences vol 57 no 1 pp164ndash172 2014

[53] P C Christophersen M L Christiansen R Holm et alldquoFed and fasted state gastro-intestinal in vitro lipolysis invitro in vivo relations of a conventional tablet a SNEDDSand a solidified SNEDDSrdquo European Journal of PharmaceuticalSciences vol 57 no 1 pp 232ndash239 2014

[54] P Kayaert M Anne and G van den Mooter ldquoBead layeringas a process to stabilize nanosuspensions influence of drughydrophobicity on nanocrystal reagglomeration following in-vitro release from sugar beadsrdquo Journal of Pharmacy andPharmacology vol 63 no 11 pp 1446ndash1453 2011

[55] T Shanmugam and R Banerjee ldquoNanostructured self assem-bled lipid materials for drug delivery and tissue engineeringrdquoTherapeutic Delivery vol 2 no 11 pp 1485ndash1516 2011

[56] G A KossenaWN Charman B J Boyd andC J H Porter ldquoAnovel cubic phase of medium chain lipid origin for the deliveryof poorly water soluble drugsrdquo Journal of Controlled Release vol99 no 2 pp 217ndash229 2004

[57] T-H Nguyen T Hanley C J H Porter and B J BoydldquoNanostructured liquid crystalline particles provide long dura-tion sustained-release effect for a poorlywater soluble drug afteroral administrationrdquo Journal of Controlled Release vol 153 no2 pp 180ndash186 2011

[58] T-H Nguyen T Hanley C J H Porter and B J Boyd ldquoNanos-tructured reverse hexagonal liquid crystals sustain plasmaconcentrations for a poorlywater-soluble drug after oral admin-istrationrdquo Drug Delivery and Translational Research vol 1 no6 pp 429ndash438 2011

[59] Y Machida K Inouye T Tokumura M Iwata and T NagaildquoPreparation and evaluation of intragastric buoyant prepara-tionsrdquo Drug Design and Delivery vol 4 no 2 pp 155ndash161 1989

[60] J Varshosaz M Tabbakhian and M Zahrooni ldquoDevelopmentand characterization of floating microballoons for oral deliveryof cinnarizine by a factorial designrdquo Journal of Microencapsula-tion vol 24 no 3 pp 253ndash262 2007


[61] R C Nagarwal D N Ridhurkar and J K Pandit ldquoIn vitrorelease kinetics and bioavailability of gastroretentive cinnar-izine hydrochloride tabletrdquo AAPS Pharmaceutical Sciences andTechnology vol 11 no 1 pp 294ndash303 2010

[62] K N Tarkase M K Tarkase M D Dokhe and V SWagh ldquoFormulation optimization and comparative evaluationof Gastroretentive drug delivery system of Cinnarizine andDomperidone maleate floating tabletrdquo International Journal ofPharmaceutical Sciences Review and Research vol 17 no 2 pp29ndash35 2012

[63] A Patnaik and S Mantry ldquoFormulation amp evaluation ofgastroretensive floating microsphere of CINNARiZINErdquo AsianJournal of Pharmaceutical and Clinical Research vol 5 no 4 pp100ndash109 2012

[64] P Kumar and M Bhatia ldquoFunctionalization of chitosanmeth-ylcellulose interpenetrating polymer network microspheres forgastroretentive application using central composite designrdquoPDA Journal of Pharmaceutical Science and Technology vol 64no 6 pp 497ndash506 2010

[65] J K Patel P S Patil and V B Sutariya ldquoFormulation andcharacterization of mucoadhesive microparticles of cinnarizinehydrochloride using supercritical fluid techniquerdquoCurrent drugdelivery vol 10 no 3 pp 317ndash325 2013

[66] I Singh and V Rana ldquoIron oxide induced enhancement ofmucoadhesive potential of Eudragit RLPO formulation evalu-ation and optimization of mucoadhesive drug delivery systemrdquoExpert Opinion on Drug Delivery vol 10 no 9 pp 1179ndash11912013

[67] S Verma K Nagpal S K Singh and D N Mishra ldquoUnfoldingtype gastroretentive film of cinnarizine based on ethyl celluloseand hydroxypropylmethyl celluloserdquo International Journal ofBiological Macromolecules vol 64 pp 347ndash352 2014

[68] M A Alhnan S Murdan and A W Basit ldquoEncapsulation ofpoorly soluble basic drugs into enteric microparticles a novelapproach to enhance their oral bioavailabilityrdquo InternationalJournal of Pharmaceutics vol 416 no 1 pp 55ndash60 2011

[69] M Togha F Taghdiri S R Jahromi and F Refaeian ldquoCin-narizine for the prophylaxis of migraine associated vertigo aretrospective studyrdquo SpringerPlus vol 3 article 231 2014

[70] R Salari H Hatefi E Abbasi H-R Soltani-Gerdefaramarziand M-H Mortazavi ldquoComparison of therapeutic effects ofalprazolam and cinnarizine in patients with idiopathic tinnitusa clinical trial studyrdquo Journal of Mazandaran University ofMedical Sciences vol 23 no 106 pp 11ndash18 2013

[71] M Togha R A Malamiri N Rashidi-Ranjbar S Asa FMahvelati andM R Ashrafi ldquoEfficacy and safety of cinnarizinein the prophylaxis of migraine headaches in children anopen randomized comparative trial with propranololrdquo ActaNeurologica Belgica vol 112 no 1 pp 51ndash55 2012

[72] C Tosoni F Lodi-Rizzini M Cinquini et al ldquoA reassessmentof diagnostic criteria and treatment of idiopathic urticarialvasculitis a retrospective study of 47 patientsrdquo Clinical andExperimental Dermatology vol 34 no 2 pp 166ndash170 2009

[73] T Mansoureh M Rahmat Jirde K Nilavari H Ashrafian SRazeghi and L Kohan ldquoCinnarizine in refractory migraineprophylaxis efficacy and tolerability A comparison withsodium valproaterdquo Journal of Headache and Pain vol 9 no 2pp 77ndash82 2008

[74] M Togha H Ashrafian and P Tajik ldquoOpen-label trial of cin-narizine in migraine prophylaxisrdquo Headache vol 46 no 3 pp498ndash502 2006

[75] O P DallrsquoIgna A B L Tort D O Souza and D R LaraldquoCinnarizine has an atypical antipsychotic profile in animalmodels of psychosisrdquo Journal of Psychopharmacology vol 19 no4 pp 342ndash346 2005

[76] C Tosoni F Lodi-Rizzini L Bettoni et al ldquoCinnarizine is auseful and well-tolerated drug in the treatment of acquired coldurticaria (ACU)rdquo European Journal of Dermatology vol 13 no1 pp 54ndash56 2003

[77] C P Pianese L O V Hidalgo R H Gonzalez et al ldquoNewapproaches to the management of peripheral vertigo efficacyand safety of two calcium antagonists in a 12-week multina-tional double-blind studyrdquoOtology andNeurotology vol 23 no3 pp 357ndash363 2002

[78] A Shupak I Doweck C R Gordon and O Spitzer ldquoCinnar-izine in the prophylaxis of seasickness laboratory vestibularevaluation and sea studyrdquo Clinical Pharmacology andTherapeu-tics vol 55 no 6 pp 670ndash680 1994

[79] I Doweck C R Gordon O Spitzer Y Melamed and AShupak ldquoThe vestibulo-ocular reflex (VOR) under the influenceof cinnarizinerdquo Journal of Vestibular Research Equilibrium andOrientation vol 4 no 3 pp 215ndash220 1994

[80] R Hausler E Sabani and M Rohr ldquoEffect of cinnarizine onvarious types of vertigo Clinical and electronystagmographicresults of a double-blind studyrdquo Acta Oto-Rhino-LaryngologicaBelgica vol 43 no 2 pp 177ndash185 1989

[81] B Saletu and J Grunberger ldquoAntihypoxidotic and nootropicdrugs proof of their encephalotropic and pharmacodynamicproperties by quantitative EEG investigationsrdquo Progress inNeuro-Psychopharmacology vol 4 no 4-5 pp 469ndash489 1980

[82] M B Emanuel J A Chamberlain SWhiting B G Rigden andA H Craven ldquoCinnarizine in the treatment of chronic asthmardquoBritish Journal of Clinical Pharmacology vol 7 no 2 pp 189ndash195 1979

Submit your manuscripts athttpwwwhindawicom

PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom

Volume 2014

ToxinsJournal of

VaccinesJournal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AntibioticsInternational Journal of

ToxicologyJournal of


StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Drug DeliveryJournal of



Advances in Pharmacological Sciences

Tropical MedicineJournal of


Medicinal ChemistryInternational Journal of


AddictionJournal of



BioMed Research International

Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014


Autoimmune Diseases


Anesthesiology Research and Practice

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of


Pharmaceutics


MEDIATORSINFLAMMATION

of


Table 1 A summary of physicochemical pharmacokinetic and pharmacodynamic features of cinnarizine

Properties Pharmacokinetics Pharmacodynamics

Piperazine derivative Multiple dosing results in accumulation of drugAntihistaminic calcium channel blockerantidopaminergic anticholinergic and antiserotinergic

Weak base Rapid absorption through upper part of GIT(119879max = 2ndash4 h)

Selectively binds to calcium channels in openconfiguration specifically active in arteries

Poor aqueous solubility(BCS class II) Cross blood brain barrier by simple diffusion Blocking effect on L-type calcium channels actively

helpful for smooth muscle cells

pH dependent solubility Preferably metabolized in liver Melanogenesis inhibition regarded as skinwhitening agents

Highly lipophilic(log P = 571) Metabolism by oxidation via cytochrome P450 Reduction in membrane permeability to

extracellular calcium

Melting point 118ndash122∘CCYP2D6 and CYP2B6 selectively catalyzep-hydroxylation of cinnamyl phenyl ring anddiphenyl methyl group respectively

Exhibits inhibitory effect on potassium currentsfacilitating effect against vestibular vertigo

UV (120582max = 253 nm) Highly protein bound (91) Inhibitory action on 5HT serotonin uptake byplatelets

Excretion is preferably via urine or in feaces tosome extent Promote cerebral blood flow

Aggravates parkinsonism upon chronicmedication


N

N

Figure 1 Structure of cinnarizine

metabolites such as 1-(diphenylmethyl)piperazine(C1) 1(di-phenylmethyl)-4-[3-(41015840-hydroxyphenyl)-2-propenyl] pipera-zine (C2) and benzophenone(c3) 1-[(41015840-hydroxyphenyl)-phenylmethyl]4-(3-phenyl-2-propenyl)piperazine(C4) [8]Among the various CYP enzymes only CYP2D6 can cata-lyze p-hydroxylation of the cinnamyl phenyl ring of cin-narizine (C-2 formation) and only CYP2B6 can catalyze p-hydroxylation of the diphenylmethyl group (C-4 formation)of cinnarizine On the other hand CYP2C9 with CYP1A1-1A2 andor -2A6 have affinity for N-desalkylation at the 1-and 4-positions of the piperazine ring that results in C-1 andC-3 formation These promoted microsomal metabolismof cinnarizine [9 10] It has high protein binding capacityof 91 [11] The drug is predominantly excreted in urineas metabolites and in feces mainly as unchanged drug withelimination half-life of 3ndash6 h The pharmacokinetic aspectsare also compiled in Table 1

12 Pharmacodynamics Pharmacodynamically cinnarizineis classified as an antihistamine and calcium channel blocker

Additionally it also shows anticholinergic antiserotonergicand antidopaminergic activity [12] Cinnarizine ismoderatelysedative antihistaminic agent that acts by inhibition of H1receptor It is selective calcium ion entry blocker whichselectively acts on arteries These agents do not show actionon slow calcium channels in myocardium but have selec-tive action on arteries The drug binds to target calciumchannels when they are in an open conformation [13] Theinhibitory effects of cinnarizine on the noradrenaline andCa-induced contraction of the rabbit thoracic aorta andmesenteric arteries were compared to papaverine [14] Cin-narizine was found to block the Ca-evoked contractionof the depolarized vessels but was less effective againstthe noradrenaline-induced contraction of the mesentericarteries and even failed to antagonize the response of thethoracic aorta to noradrenaline Cinnarizine was effectivein mesenteric arteries exposed to noradrenaline by blockingthe Ca

0dependent response while papaverine was less

effective towards the Ca0dependent response but efficiently

inhibited the initial fast response more Cinnarizine was lesseffective or even failed to inhibit the response producedby thoracic aorta to nonadrenaline These results suggestedreduction of membrane permeability to extracellular cal-cium was the mechanism by which cinnarizine acted Thereport also suggested that papaverine inhibits the contrac-tion to less extent than that of cinnarizine It attenuatesvasoconstriction action of many endogenous substances bymodulation of calcium fluxes Cinnarizine is known topromote the cerebral blood flow So have wide applicationin treatment of cerebral apoplexy cerebral arteriosclerosisand posttraumatic cerebral symptoms [15] According to arecent paper the effect against vestibular vertigo was due toinhibiting potassium (K+) currents activated by heightened







0

10

20

30

40

50

60

70

80

Bran

ds

Indi

aBa

ngla

desh

Italy

Mal

aysia

Chin

aTh

aila

ndTa

iwan

Peru

Phili

ppin

esVe

nezu

ela

Bulg

aria

Rom

ania

The N

ethe

rland

sSl

oven

iaSl

ovak

iaAu

stria

Lith

uani

aCh

ileBr

azil











Togha et al [69]



Salari et al [70]



Togha et al [71]



Tosoni et al [72]



Mansoureh et al[73]



Togha et al [74]






Tosoni et al [76]



Pianese et al [77]



Shupak et al [78]



Doweck et al [79]


Table 2 Continued




Hausler et al [80]






Emanuel et al [82]






















Lipid based systems






















50 of 625min and 11990590 of 1974min

















50of



50(12494plusmn540min) 119905






(max)and 119879


6 Conclusion








References




























































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of







0

10

20

30

40

50

60

70

80

Bran

ds

Indi

aBa

ngla

desh

Italy

Mal

aysia

Chin

aTh

aila

ndTa

iwan

Peru

Phili

ppin

esVe

nezu

ela

Bulg

aria

Rom

ania

The N

ethe

rland

sSl

oven

iaSl

ovak

iaAu

stria

Lith

uani

aCh

ileBr

azil











Togha et al [69]



Salari et al [70]



Togha et al [71]



Tosoni et al [72]



Mansoureh et al[73]



Togha et al [74]






Tosoni et al [76]



Pianese et al [77]



Shupak et al [78]



Doweck et al [79]


Table 2 Continued




Hausler et al [80]






Emanuel et al [82]






















Lipid based systems






















50 of 625min and 11990590 of 1974min

















50of



50(12494plusmn540min) 119905






(max)and 119879


6 Conclusion








References




























































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of






Togha et al [69]



Salari et al [70]



Togha et al [71]



Tosoni et al [72]



Mansoureh et al[73]



Togha et al [74]






Tosoni et al [76]



Pianese et al [77]



Shupak et al [78]



Doweck et al [79]


Table 2 Continued




Hausler et al [80]






Emanuel et al [82]






















Lipid based systems






















50 of 625min and 11990590 of 1974min

















50of



50(12494plusmn540min) 119905






(max)and 119879


6 Conclusion








References




























































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of


Table 2 Continued




Hausler et al [80]






Emanuel et al [82]






















Lipid based systems






















50 of 625min and 11990590 of 1974min

















50of



50(12494plusmn540min) 119905






(max)and 119879


6 Conclusion








References




























































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of


















Lipid based systems






















50 of 625min and 11990590 of 1974min

















50of



50(12494plusmn540min) 119905






(max)and 119879


6 Conclusion








References




























































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of



50 of 625min and 11990590 of 1974min

















50of



50(12494plusmn540min) 119905






(max)and 119879


6 Conclusion








References




























































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of













50of



50(12494plusmn540min) 119905






(max)and 119879


6 Conclusion








References




























































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of





(max)and 119879


6 Conclusion








References




























































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of



























































































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of

review article recent advances in delivery systems and … · 2019. 12. 12. · review article...

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