Indian Journal of Research in Pharmacy and Biotechnology (IJRPB-1(3) IJRPB

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Volume 1 Issue 3 www.ijrpb.com May-June 2013

Indian Journal of Research in Pharmacy and Biotechnology

ISSN: 2320-3471 (Online)

ISSN: 2321-5674 (Print)

EditorB.Pragati Kumar, M.Pharm, Assistant Professor,

Nimra College of Pharmacy

Consulting editor

Dr. S Duraivel, M.Pharm, Ph.D., Principal,Nimra College of Pharmacy

Associate Editors

Mr. Debjit Bowmick, M.Pharm., (Ph.D)Assistant Professor, Nimra College of Pharmacy

Mr. Harish Gopinath, M.Pharm., (Ph.D)Assistant Professor, Nimra College of Pharmacy

Dr. M. Janardhan, M.Pharm., Ph.D.Professor, Nimra College of Pharmacy

Dr. A. Ravi Kumar, M.Pharm., Ph D.Professor, Bapatla College of Pharmacy

Editorial Advisory Board

Dr.Y.Narasimaha Reddy, M. Pharm., Ph D.Principal, University college of Pharmaceutical

Sciences, Kakatiya University, Warangal.

Dr. Biresh Kumar Sarkar,Asstt.Director (Pharmacy),

Kerala

Dr.V.Gopal, M. Pharm., Ph D.Principal, Mother Theresa Post Graduate & Research

Institute of Health Sciences,Pondicherry-6

Dr. M.Umadevi, M.Sc. (Agri), PhdResearch Associate, Tamil Nadu Agricultural

University, Coimbatore

Dr. J.Balasubramanium, M. Pharm., Ph D.General Manager, FR&D

R A Chem Pharma Ltd., Hyderabad

Dr. V.Prabhakar Reddy, M. Pharm., Ph D.Principal, Chaitanya College of Pharmacy Education &

Research, Warangal

Dr.P.Ram Reddy, M. Pharm., Ph D.General Manager, Formulation,

Dr.Reddy’s Laboratory, Hyderabad

Dr. S.D.Rajendran, M. Pharm., Ph D.Director, Pharmacovigilance, Medical Affairs,

Sristek Consultancy Pvt. Ltd, Hyderabad


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INDIAN JOURNAL OF RESEARCH IN PHARMACY AND BIOTECHNOLOGY

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Indian Journal of Research in Pharmacy and Biotechnology

ISSN: 2320-3471 (Online)

ISSN: 2321-5674 (Print)


17. Transdermal sonophoresis technique- an approach for controlled drug deliveryK.P.Sampath Kumar, Debjit Bhowmik, M.Komala

379-381

18. A comprehensive review of Eladi VatiNavin Dixit, Sheo Dutt Maurya , Bhanu P.S.Sagar

382-384

19. Preparation and characterization of some herbal ointment formulations with evaluation ofantimicrobial propertyPulak Majumder and Susmita Majumder

385-390

20. The effects of air pollution on the environment and human healthShyam Bihari Sharma, Suman Jain, Praveen Khirwadkar, Sunisha Kulkarni

391-396

21. Formulation and evaluation of orodispersible tablets of Cinnarizine by superdisintegrants addition methodPraveen Khirwadkar, Kamlesh Dashora, Shyam Bihari Sharma

397-400

22. Effective hypoglycemic action of metformin combinations against Dexamethasoneinduced diabetes mellitus in ratsMohanraghupathy.S, Jayabharath N, Bhuvana Tejay, Hameera Khanam B, Lavanya Lahari B

401-403

23.

A review on medicinal plants having antioxidant potentialProf.S.K Sharma, Mr. Lalit Singh, Suruchi Singh404-409

24. Invitro anti-inflammatory activity of Strychnos potatorum linn seed by HRBC membranestabilizationV.Vijayakumar, Dr C.K.Hindumathy

410-412

25. Synthesis and characterization of 1, 3, 4-oxadiazole and 1,3,4- thiadiazoleRamanji Naik

413-419

26. Preparation, characterization and evaluation of Olmesartan medoxomil β - cyclodextrincomplexesV. Prudhvi Raj, Subhashis Debnath, Maleswari, M. Niranjan Babu

420-427

27. Wafers technology – a newer approacah to smart drug dilevery systemPapola Vibhooti*, Kothiyal Preeti

428-439

28. Evaluation of anti-ulcer effects of ethanolic extract of Delonix regia flowerSamaresh Pal Roy, Kamlesh Prajapati, Ramji Gupta, Dipanwita Bhadra, Nikunj Patel,

Archana Batiwala, Gautam Sonara, Neerav Gheewala, T. Kannadasan

440-445

29. A study on medication non-adherence in ambulatory diabetic patients and need forpharmacist intervention for improving patient adherence

Dr. Praveen Kumar G

446-447

30. Recent trends in positive and negative aspects of food on bioavalabilty of drugsGowthami B, Sk Nahida Fazilath, Sanaulla Md, K Prudhvi Raj, Dastagiriah G, Tabassum Sk

448-460

31. A review on collagen based drug delivery systemsSahithi B, Ansari Sk, Hameeda Sk, Sahithya G, Durga Prasad M, Yogitha Lakshmi

461-468


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Anusha P et.al I ndian Journal of Research in Pharmacy and Biotechnology

Volume 1(3) May-June 2013 Page 275

DEVELOPMENT AND EVALUATION OF DROTOVERINE TASTE

MASKED TABLETS WITH IMPROVED DISSOLUTION EFFICIENCY USING

SOLID DISPERSION TECHNIQUEAnusha P*

1, Nirajana V.A

2, Syed Mohammed

1, Shaik Jilani

1, Ch. Murali Krishna, Harish.G

1

1. Nimra college of Pharmacy, Jupudi, Vijayawada, Andhra Pradesh, India

2. Faculty of Pharmacy, Sri Ramachandra University, Porur, Chennai.*Corresponding author: E.Mail:[email protected]

ABSTRACT

The purpose of this research is to mask the bitter taste of the drug, Drotoverine using solid dispersiontechnique. The taste-masked drug is formulated in to a conventional tablet by direct compression method for easeof administration. Taste masking was done by solid dispersion using polymer such as urea and mannitol bymelting/fusion method Fourier transform infrared spectroscopy (FTIR) and scanning electron microscopy (SEM)were performed to identify the physicochemical interaction between drug and carrier, hence its effect on

dissolution. Conventional taste masked tablets were evaluated for weight variation, disintegration time, hardnessand friability. In vitro drug release studies were performed for conventional tablets of drotoverine. Bitterness

score was evaluated on volunteers. FTIR spectroscopy and SEM showed no interaction between drug and carriers.Conventional tablets prepared using solid dispersion, showed faster disintegration and complete bitter taste

masking of drotoverine. In addition the prepared tablets exhibited better dissolution profile. Taste evaluation of taste masked tablets in human volunteers rated tasteless with a score of 0. Thus, results conclusively demonstratedsuccessful masking of taste and oral disintegration of the formulated tablets in the oral cavity with improved

dissolution.Key words: Drotoverine, conventional tablet, solid dispersion, taste masking

INTRODUCTION

The oral route is the most convenient, appropriate and acceptable way to administer medications. Severaloral active pharmaceuticals ingredients and bulking agents have Unpleasant bitter taste; hence this often times

results to non compliance to medications by Patients. Taste masking is a means of masking the bitter taste of drugin order to improve the Palatability of the drug, which in turn improves patience compliance. Drotoverine is anovel non-Anticholinergic smooth muscle antispasmodic drug. Its Chemical name is 1- [(3, 4-diethoxy phenyl)

methylene]-6, 7-diethoxy-1, 2, 3, 4-tetrahydroisoquinoline with a molecular formula of C24 H31NO4. HCl. It

decreases the influx of active calcium into smooth muscles due to inhibiting of phosphodiesterase andintracellular increase of cAMP level. Its oral bioavailability is about 100% with a biologic half- life of about 7 to12 h. It adult dose is about 40 to 80mg one to three times a day.

Drotoverine has poor aqueous solubility, and thus resulting in incomplete absorption after oraladministration. This is due to a large fraction of the dose remaining undissolved for absorption. Under suchconditions, the bioavailability can be increased by using, a more water soluble formulation. Solid dispersion is an

efficient means of improving the dissolution rate and hence the bioavailability of a range of poorly soluble drug.

Further drotoverine has an extremely unpleasant bitter taste. The exact mechanism of bitterness is unknown.Masking of bitter taste of the drotoverine is an extremely important factor in the formulation of tablets to ensure

patient compliance. Taster masked tablets were useful in patients, such as pediatric, geriatric, who may facedifficulty in swallowing conventional tablets or capsules and liquid orals or syrup.

Many reported techniques such as polymer coating, microencapsulation, use of lecithins and related

substances, liposomes and various polymeric materials mask the bitterness by controlling drug release at salivary pH. However it is a major challenge to develop taste masked conventional tablets with improved drug release.Thus in the present study an attempt has been made to formulate taste masked conventional tablets of drotoverinewith improved dissolution so as to prepare a “patient-friendly dosage form”. Furthermore, the study undertakes to

investigate solid-state characterization, and attempts to see the possible mechanism of taste masking andimproved dissolution rate.

2. MATERIALS AND METHODS2.1. Materials: Drotoverine was obtained as a gift sample from Apex laboratory ltd, Chennai; sodium starchglycolate, aspartame, magnesium stearate and micro crystalline cellulose was obtained as a gift sample from Intex

chemicals, Chennai.


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2.2. Methods

2.2.1. Preparation of Drotoverine Solid Dispersion Using Mannitol and Urea as Carriers: The soliddispersion of drotoverine with urea and mannitol in 1:1, 1:2 and 1:3 ratios were carried out using melting or fusion method. The preparation of physical mixture of a drug and a water-soluble carrier and heating it directlyuntil it melted. The melted mixture is then solidified orally in an ice-bath under vigorous stirring. The final solidmass is crushed, pulverized and sieved.

2.2.2. Characterization of solid dispersion: The prepared drotoverine and mannitol, drotoverine and urea soliddispersions were characterized for solubility studies, FTIR studies and SEM studies.2.2.3. Tablet Formulation: Oral conventional tablets containing equivalent of 80 mg of drotoverine werecompressed on an eight-station single rotary tabletting press (GMC, using a flat punch with break line by directcompression technique.3. Characterization of Prepared Tablets: The prepared tablets were evaluated for its physical characteristicslike hardness thickness, weight variation, friability, disintegration test.3.1. I n vitro dissolution study: One tablet of F1 or F2 or MKT formulation were placed in a cylindrical basket(aperture size 425μm: diameter 20mm; height 25mm), and immersed in 900ml of leaching fluid (Stimulatedgastric fluid maintained at 37 ± 2oC). The fluid was stirred at 100rpm (Model Disso 2000, Lab India). Samples of the leaching fluid (5ml) were withdrawn at selected time intervals with a syringe fitted with a cotton wool plugand replaced with an equal volume of drug-free dissolution fluid. The samples were suitably diluted with blank

dissolution fluid and were analyzed for content of drotaverine hydrochloride spectrophotometrically at λmax,302.8 nm by using an ElicoSL 210 UV-Visible double beam spectrophotometer (Elico, India). The amountsreleased were expressed as a percentage of the drug content in each dissolution medium. The dissolution test wascarried out in quadruplicate and the mean results reported.3.2. Taste evaluation: Taste evaluation was done on 6 volunteers by using time intensity method. One tablet was

held in mouth for 10 seconds bitterness levels were recorded instantly and after 10 seconds,30seconds, 1 minute and 2 minutes, bitterness levels were recorded.

4. RESULTS

Table.1. Formulation table for solid dispersion Table.2. Formulation Table for Tablets

Formulation code Polymer Ratio

F1 Mannitol 1:1

F2 Mannitol 1:2

F3 Mannitol 1:3F4 Urea 1:1

F5 Urea 1:2

F6 Urea 1:3

*for all the formulations

Name of the ingredient Quantity per single tablet*

Drug polymer SD 80mg

Sodium starch glycolate 6.6mg

Aspartame 1.1mg

Microcrystalline cellulose 16.8mg

Magnesium stearate 5.5mg

Total 110mg

Table.3. Pre-compression parameters for drug polymer solid dispersion

Formulation code F1 F2 F3 F4 F5 F6

Angle of repose 25°71’ 26°42’ 28°93’ 24°32’ 25°43’ 29°47’

Bulk Density(gm/ml) 0.74 0.72 0.69 0.64 0.75 0.78

Tapped Density(gm/ml) 0.86 0.82 0.87 0.85 0.89 0.89

Compressibility Index (%) 13.95 12.19 20.68 24.70 15.73 12.35

Hausners ratio 1.18 1.14 1.25 1.30 1.16 1.14 Table.4. Post compression studies

Formulation

code

Weight

variation (mg)

Thickness

(mm)

Hardness

(Kg/cm2)

Friability

(%)

Assay

(%)

F1 Complies 1.9 4 0.05 99.56

F2 Complies 1.9 4 0.06 98.45

F3 Complies 2.0 5 0.03 99.12

F4 Complies 1.9 4 0.05 98.22

F5 Complies 2.1 5 0.06 97.44

F6 Complies 2.0 4 0.01 99.61


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Table.5. In-vitro dissolution study for Drotoverine solid dispersionTime in

min

Percent drug release formulation code

F1 F2 F3 F4 F5 F6

0 0 0 0 0 0 0

5 14.11 14.75 15.39 16.56 22.25 26.03

10 25.03 26.14 30.01 32.78 39.56 45.35

15 34.22 36.78 40.56 43.06 54.09 69.46

20 41.86 45.67 52.88 55.12 67.03 78.75

25 52.45 55.76 61.75 67.95 73.25 86.95

30 58.56 65.20 67.25 72.15 84.02 92.10

Table.6. In-vitro dissolution study for

marketed drotoverine tablets

Table.7.Comparison of dissolution profile for formulated

and marketed productsTime in min Percent drug release

0 0

5 24.36

10 35.12

15 54.32

20 67.7525 75.55

30 82.36

Time in

min

%Drug Release

Marketed drotoverine

tablets

Formulated

drotoverine tablets

0 0 0

5 24.36 26.03

10 35.12 45.3515 54.32 69.46

20 67.75 78.75

25 75.55 86.95

30 82.36 92.10

Table.8. Bitterness evaluations of prepared drotoverine tablets:volunteers Formulation code and bitterness

F1 F2 F3 F4 F5 F6

1 0 0 0 0 0 0

2 0 0 X 0 0 0

3 0 0 0 X 0 0

4 x 0 0 0 x 0

5 0 0 0 0 0 00=No bitterness; x=Threshold bitterness

Figure.1. IR spectro of the pure drug, Drotaverine Hcl Figure.2.IR spectro of the formulation F1

Figure.3.IR spectro of the formulation F2 Figure.4. IR spectro of the formulation F3


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Figure.5.IR spectro of the formulation F4 Figure.6.IR spectro of the formulation F5

Figure.6. IR spectro of the formulation F6

Figure.7.SEM image of the pure drug,

Drotaverine Hcl

Figure.8.SEM image of the formulation F1

Figure.9.SEM image of the formulation F2 Figure.10.SEM image of the formulation F3

Figure.11. SEM image of the formulation F4 Figure.12.SEM image of the formulation F5

Figure.13. SEM image of the formulation F6


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Figure.14. In-Vitro Dissolution studies of the

formulated batches

Figure.15. In-Vitro Dissolution studies Optimized

and marketed

5. DISCUSSION

Fourier Transform Infrared Spectroscopy: Infrared spectra matching approach was used for thedetection of

any possible chemical reaction between the drug and the polymer. The IR spectrum of the physical mixture wasdone to detect any appearance or disappearance of peaks. The compatibility between the drug and the polymer

were evaluated using FTIR matching method. The IR spectra of pure drug and polymer are shown in (figure 1). Pre-Formulation Studies: The angle of repose of prepared drotaverine tablet mixture was in the range 20°-30°.

Normally if the value falls between 20°-30°, it shows good flow property. The bulk density and tapped density

were found to be in the range of 0.7 to 0.8 g/cm3. A Hausner’s ratio was within the range of 1.13 to 1.32, lesser than 1.25 is considered to be an indication of good flow property. The compressibility index was within the range of 10-25 hence falls within the good range.Post-Compressional studies: The post compressional characteristic for all the formulated batches was found to

be within the limits as per Indian pharmacopeia. The hardness was found to be within 4-5 Kg/cm2 in all theformulations. In all the formulations, the friability value is less than 1% giving an indication that tabletsformulated are mechanically stable. All the tablet formulations compile the weight variation test. The weight of

all the formulations was found to be within the limits. The assay of all the formulations was found to be within the pharmacopoeial (Table 4).

In-vitro dissolution study: All the formulation was subjected to dissolution studies and it was absorbed that the batch F6 showed about 92.10% of release and was found to be maximum when compared to other batches.Formulated batch F1 and F2 showed a slow release pattern with about only 58.56% and 65.20% of drug release at

the end of 30mins. (table 5), and the batches F3, F4, F5 showed a release of about 67.25% to 84.02% of drugrelease. For the formulation f7 the percentage amount of drug release was found to be with the pharmacopeiallimits.the comparission of dissolution profiles for formulated drotaverine and marketed drotaverine tablets wereshown in the table no 8 and it was concluded that percent drug release for formulated drotaverine tablets wasmore when comparared to marketed drotaverine tablets.Taste evaluation of all formulations: The time intensity study for taste in human volunteers of the formulateddrotaverine hydrochloride with the polymer SD revealed considerable masking of the bitter taste of drotaverineHCl with degree of bitterness below the threshold value within 120seconds (See Table 8). Sensory evaluation of the tablets with both polymers proved good palatability.

6. CONCLUSIONThis study has established effective taste masking of drotaverine HCl with the use of the solid dispersion

techniques using urea and mannitol as carriers. Taste masking and rapid dissolution of drotaverine HCl tablets

formulated in this investigation may possibly help in the administration of drotaverine HCl in a more palatableform in the absence of water and more importantly since drotaverine HCl solid dispersion tablet formulations are

not presently in the market. Hence, “patient-friendly dosage form” of bitter drugs, especially for pediatric andgeriatric patients, can be developed using this technique.

7. REFERENCES

A. Rajpoot, Formulation and In-vitro Evaluation of Immediate release tablets of Drotaverine HCl, J. Chem.Pharm. Res, 3(4), 2011, 333-341


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Srikanth MV, Uhumwangho MU, Sunil SA, Design and evaluation of taste masked Drotaverine HCl

orodispersible tablets using polymethacrylate polymers, Der Pharmacia Lettre, 2(6), 2010, 223-231.

Vijayanand P, Formulation, Development and Evaluation of Novel Dosage Form Containing Silk Fibroin for

Elderly Patients, RJPBCS, 3(1), 2010, 524,


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Hari sh G et.al I ndian Journal of Research in Pharmacy and Biotechnology


EFFECT OF DIFFERENT DISINTEGRANTS ON CIPROFLOXACIN

CONVENTIONAL TABLETSHarish.G1*, Ch.Bhargavi1, A.Riyajune1, Md.Yasmeen1, Syed Mohammed1, Ch.Murali Krishna1, Sk.Jilani1,

Nirajana.V.A2

1.Nimra College of Pharmacy, Jupudi, Vijayawada.

2. Faculty of pharmacy, Sri Ramachandra University, Chennai. *Corresponding author: E.Mail: [email protected]

ABSTRACT

The objective of the present study is to design and evaluate the effect of disintegrating agents such asStarch, Cross Caramellose Sodium and Sodium starch glycolate on ciprofloxacin tablet. The nature of the

Ciprofloxacin which is slightly soluble in water which affects the drug disintegration process there by inhibits thedrug release from the Conventional Tablet. Hence in the present study the effect of disintegrating agents at

different concentrations is carried out on the ciprofloxacin hcl to find out the optimized concentration followed bystability studies for a period of 3 months.

INTRODUCTION

Despite increasing interest in controlled-release drug delivery systems, the most common tablets are thoseintended to be swallowed whole and to disintegrate and release their medicaments rapidly in the gastrointestinal

tract (GIT). The proper choice of disintegrant and super-disintegrant to improve its consistency of performance isof critical importance to the formulation development of such tablets. Drug release from a solid dosage form can

be enhanced by addition of suitable disintegrants. In more recent years, increasing attention has been paid to

formulating fast dissolving and/or disintegrating tablets that are swallowed, but also orally disintegrating tabletsthat are intended to dissolve and/or disintegrate rapidly in the mouth. The present study is an attempt to select best

possible combination of drug and disintegrating agent to formulate rapidly disintegrating tablet of ciprofloxacinconventional tablets which disintegrates faster thereby reducing the time of onset of action. Lactose is selected as

diluents, Starch, Sodium starch glycolate, CCS and Crospovidone were selected as disintegrants. PVP K 30M paste was used as a binder in all formulations, Magnesium stearate and Talc as a Lubricant, Aerosil as a Glidant.The percentage Drug content of all tablets was found to be between 95% - 105%, which was within the limit.

From the data obtained, it is observed that the formulation containing crosprovidone disintegrant disintegraterapidly when compared to other disintegrating agents such as Starch, SSG, and CCS with ciprofloxacin.

MATERIALS AND METHODSCiprofloxacin obtained as a gift sample from Intex chemicals Pvt ltd, Chennai. Starch, Cross CaramelloseSodium and Sodium Starch Glycolate was obtained from Fischer Ltd, Chennai. All other excipients which are

used are of high standard analytical grade.

Pre-Formulation Studies:

Drug-excipients compatibility studies: Compatibility of drug with excipients was determined by FTIR usingkBr pellet technique, in the wavelength region of 4000-400cm-1.

Table 1: Formulation Table of Ciprofloxacin Hcl conventional tablet

Formulation FA1 FA2 FA3 FB1 FB2 FB3 FC1 FC2 FC3 FD1 FD2 FE1 FE2

Ciprofloxacin

(mg)

500 500 500 500 500 500 500 500 500 500 500 500 500

Starch (%) 50 10 15 - - - - - - - - - -

SSG (%) - - - 4 5 6 - - - - - - -

CCS (%) - - - - - - 10 20 30 - - - -

BCD (%) - - - - - - - - - 40 80 40 80

Aerosil (%) 200 200 200 200 200 200 200 200 200 200 200 200 200

Lactose 220 260 255 246 265 264 260 250 240 230 90 230 90

PVP (%) 50 50 50 50 50 50 50 50 50 50 50 50 50

Talc (%) 50 50 50 50 50 50 50 50 50 50 50 50 50

Magnesium

Sterate (%)

30 30 30 30 30 30 30 30 30 30 30 30 30

Total Weight

(mg)

1000 1000 1000 1000 1000 1000 1000 1000 1000 1000 1000 1000 1000

mailto:[email protected]:[email protected]


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Quantity sufficient of Ciprofloxacin for a batch of 50 tablets was separately mixed to ensure complete

mixing. A tablet containing 500 mg equivalents of ciprofloxacin was compressed. All ingredients were weighedand passed through 40# sieve, blended in a Poly Bag except Magnesium Stearate for 10 minutes. Mix half the partof the disintegrated with the above mixture after passing through the sieve. The resultant mixture was wet massedusing suitable binder (qs) for granulation. This wet mass was passed through 20# sieve in order to form granules.These granules were dried and the dried granules were passed through 30# sieve. These dried granules were

lubricated with Magnesium stearate, which was previous, passed through 60# Sieve. The lubricated granules were punched to tablets using single punching machine.Drug content: The estimation of drug content for ciprofloxacin tablets was performed by crushing three tabletsand quantity equivalent to 45mg was taken and determined using 0.1M Hcl using UV spectrophotometer at about276nmWeight Variation: The USP weight variation test was run by weighing 20 tablets individually, calculating theaverage weight, and comparing the individual tablet weights to the average. The tablets met the USP tests that

were not more than 2 tablets were outside the percentage limit and no tablets differed by more than 2 times the percentage limit.Hardness: Hardness of the tablets was determined by breaking it between the second and third fingers withthumb being as a fulcrum. There was a sharp snap the tablet was deemed to have acceptable strength. Hardness of the tablets was determined by Stokes Monsanto Hardness Tester and the hardness should be found within the

range of 3.5-5.5 kg/cm². Friability: The friability of tablets was determined by Roche Friablator. 20 tablets were taken and weighed. After weighing the tablets were placed in the Roche Friablator and subjected to the combined effects of abrasion andshock by utilizing a plastic chamber that revolves at 25RPM for minutes dropping the from a distance of sixinches with each revolution. After operation the tablets were de-dusted and reweighed.Content Uniformity: In this test, 30 tablets were randomly selected contained for sample, CiprofloxacinHydrochloride should contain not less than 98.0 per cent and not more than 102.0 percent. Thickness: The thickness of a tablet was the only dimensional variable related to the process. 10 tablets weremeasured for their thickness and diameter with a Caliper, Thickness Gauge. Average thickness and diameter werecalculated.

Disintegration Test: Disintegration time is considered to be one of the important criteria in selecting the bestformulation. For most tablets the first important step toward solution is break down of tablet into smaller particles

or granules, a process known as disintegration. Place one tablet into each tube and suspend the assembly in to the1000ml beaker containing water maintained at 37 ± 2

oC and operate the apparatus for 30 seconds. Remove the

assembly form the liquid. Observe the tablets, if one or two tablets fail to disintegrate completely; repeat the test

on 12 additional tablets. The requirement is met if not less than 16 of the total of 18 tablets tested aredisintegrated.

In-Vitro Drug Release Studies: In our case to study the release kinetics of drug we used USP II apparatus

(Paddle type, 2) with 900 ml, pH 6.8 phosphate buffer as the dissolution medium. The paddle was rotated 50 rpmand 5ml of aliquots were withdrawn at pre-determined time intervals and an equal amount of thee medium was

replaced to maintain sink conditions. The aliquots were diluted suitably and the amount of drug(s) released wasdetermined spectrophotometrically using U.V. at wavelength 271 nm.

Evaluation of Formulated Ciprofloxacin Tablet:Evaluation of blend characteristics: Ciprofloxacin Tablet was prepared by using wet granulation method.

Various formulations were made as shown in table: 6. The Formulated Ciprofloxacin tablet were evaluated for Pre-formulation parameters like angle of repose, bulk density, tapped density, Compressibility index andHausner’s Ratio.

The results of disintegration time of all the tablets prepared by wet granulation found to be varied withchange in concentration of disintegrating agents from few seconds to several minutes. Formulations FD 1 and FE1disintegrated within 3min and found to be more effective. The disintegration time of the tablets using differentdisintegrants decreases in the following order BC > croscarmellose sodium > SSG > Starch. It is observed that,when BC is used as disintegrant, tablets disintegrate rapidly with in less time compared to other tablets prepared

using croscarmellose sodium, starch and sodium starch glycolate disintegrants. Though tablets prepared by intraand extra granulation method found to be more effective in comparison with formulation prepared by only extra


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granulation. When concentration of Starch, SSG, CCS and BC is increased, the disintegration time was reduced

The angle of repose of prepared Ciprofloxacin tablet was in the range of 20°-30°. Normally if the value falls between 20°-30°, it shows good flow property. The bulk density and tapped density were found to be in the rangeof 0.37 to 0.38 g/cm

3and 0.44 to 0.45g/cm

3respectively. A Hausner ratio was within the range of 1.16 to 1.17,

lesser than 1.25 is considered to be an indication of good flow property. The compressibility index was within therange of 5-15 hence falls within the excellent range.

The results were tabulated in table 15. The pre-formulation characteristics results for all theformulation of ciprofloxacin tablets using FB as disintegrating agent found to be within the range, compressibilityindex for FB1 and FB3 was found to be with in good range of 12-16 were as FB2 was in excellent range. Theangle of repose of prepared tablet was in the range of 20°-30°. Normally if the value falls between 20°-30°, itshows good flow property. The bulk density and tapped density were found to be in the range of 0.34 to

0.36g/cm3 and 0.39 to 0.40 g/cm3 respectively. A Hausner ratio was within the range of 1.07 to 1.18, lesser than1.25 is considered to be an indication of good flow property. The compressibility index was within the range of 5-

15 hence falls within the excellent range. The results were tabulated in table 16.The pre-formulation characteristics results for all the formulation of ciprofloxacin tablets using FC as

disintegrating agent found to be within the range, angle of repose and compressibility index was found to bewithin good range. The angle of repose of prepared ciprofloxacin tablet was in the range of 20°-30°. Normally if the value falls between 20°-30°, it shows good flow property. The bulk density and tapped density were found to

be in the range of 0.35 to 0.36 g/cm3 and 0.39 to 0.41 g/cm3 respectively. A Hausner ratio was within the range of 1.08 to 1.18, lesser than 1.25 is considered to be an indication of good flow property. The compressibility indexwas within the range of 5-15 hence falls within the excellent range. The results were tabulated in table 17. Theformulation of ciprofloxacin using 4% B.C disintegrant found to be within the limits for both FD1 and FD2 andfalls in good range. The angle of repose of prepared ciprofloxacin tablet was in the range of 20°-30°. Normally if

the value falls between 20°-30°, it shows good flow property. The bulk density and tapped density were found to be in the range of 0.36 to 0.38g/cm3 and 0.40 to 0.41 g/cm3 respectively. A Hausner ratio was within the range of 1.07 to 1.16, lesser than 1.25 is considered to be an indication of good flow property. The compressibility indexwas within the range of 5-15 hence falls within the excellent range.

The angle of repose of prepared ciprofloxacin using FE as disintegrant was in the range of 20°-30°.

Normally if the value falls between 20°-30°, it shows good flow property. The bulk density and tapped densitywere found to be in the range of 0.36 to 7 g/cm3 and 0.340 to 0.41g/cm3 respectively. A Hausner ratio was within

the range of 1.10 to 1.11, lesser than 1.25 is considered to be an indication of good flow property. Thecompressibility index was within the range of 5-15 hence falls within the excellent range.

The post compressional characteristic for all the formulated batches was found to be within the limits as

per Indian pharmacopeia 2007. The hardness was found to be within the range of 3.5 to 5.5 Kg/cm2 in all theformulations indicating good mechanical strength with an ability indicating physical and mechanical strength withan ability to withstand physical and mechanical stress conditions while handling. In all the formulations, the

friability value is less than 1% giving an indication that tablets formulated are mechanically stable. All the tabletformulations passed the weight variation test. The weight of all the formulations was found to be within the limits.

The assay of all the formulations was found to be with in the 90% to 110% acceptable limits.The disintegration time of the entire Formulated batch varies with change in concentration of

disintegrating agents from few seconds to several minutes. Formulations FD2 and FE2 disintegrated within 3minand found to be more effective. The disintegration time of the tablets using different disintegrants decreases in the

following order Starch > CCS > SSG >CP. It is observed that, when BC is used as disintegrant, tabletsdisintegrate rapidly with in less time compared to other tablets prepared using croscarmellose sodium, starch andsodium starch glycolate disintegrants. Though tablets prepared by intra and extra granulation method found to be

more effective in comparison with formulation prepared by only extra granulation. When concentration of Starch,SSG, CCS and BC is increased, the disintegration time was reduced significantly show in table 2..

In vitro drug release studies were conducted for the formulation using USP dissolution apparatus type-II(paddle), at 50 rpm. The percentage drug release at the end of 30 min was found in the range 48 – 73% using FAas disintegrant and 67-77% using FB as disintegrant. Invitro drug release studies were conducted for the

formulation using USP dissolution apparatus type-II (paddle), at 50 rpm. The percentage of drug release wasdetermined at a time interval of 0, 5, 10, 15, 20, 25, 30 min and at the end of 30 min it was found in the range 80-


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95% using FC as disintegrant. Invitro drug release studies were conducted for the formulation using USP

dissolution apparatus type-II (paddle), at 50 rpm. The percentage of drug release was determined at an timeinterval of 0, 5, 10, 15, 20, 25, 30 min and at the end of 30 min it was found in the range 81-95% using 4% BC asdisintegrant and 78-98% using 8% BC as disintegrant shown in figure 9, 10 and 11.Stability Studies: Drug molecules are of reactive naturally, the additives are considered to be inert substance butthis may not be true for all additives in a formulations. Hence, in developing any formulation, when additive are

selected the same must be super imposed on to drugs and with other additives present in the formulation, to seehow compatible they are with the other formulation ingredients. A lot of literature has got piled up on drug-excipients incompatibilities, which is a handy tool in the hand of a formulation man, to avoid possible drug-excipient interactions. But even with this literature at the back, formulation may be highly individualistic and eachformulation may have problems of its own. There are methods called FTIR, differential scanning calorimetric,

thin layer chromatography for investigating these interactions in short period of time.On many occasions, even with the sum total of knowledge available, it is not possible to envisage, all the

interactions and a formulation while remaining good for a certain period of time, may go bad in the long run.There is not ready made answer for such situation and all that is possible is to “wait and watch”, the methodcalled “Real time study”. As per ICH guide line for stability study, which advice the formulation to store their

products at 30 ° c and 65 % RH to find out actual shelf life period or to assure the product quality free fromunwanted interactions. Real time study of ICH guidelines involves storage of products at 40° C& 65 % RH for the

complete proposed shelf life period, and analyzing the product sample every month in the first 3 months, every 3months from 4th month onwards up to one year, every 6 month in the second year of storage, afterwards once in ayear till shelf life is completed. ICH guidelines also demands for storing samples at 40 ° c and 75 % RH (stresscondition or accelerated stability study) for relatively short period of time (3-6 months) which depends on claimedshelf life period as well as the zone (zone 1/2/3/4 of the world) to which the product is meant to be exported. This

later study (with stress conditions) is to mine the alternating climates condition during the shelf life of the product.The stability parameters for all the formulation were evaluated after 15, 30, 45, 60, and 90 days for 40 °C at 75%RH.

Tab 2: Disintegration Time of the Ciprofloxacin Fast disintegrating tablet

Formulation With Disk Without Disk

I II III I II III

FA1 11min 43 sec 10 min 30 sec 10min 52sec 14min 32 sec 15min 11sec 15min 48 sec

FA2 8min 2sec 9min 33 sec 8min 18 sec 11min 14sec 12min 31 sec 11min 56 sec

FA3 4min 41 sec 5min 8 sec 4min 55sec 9min 23sec 9min 51 sec 8min 50sec

FB1 11min 41 sec 10min 21 sec 10min 54 sec 14min 11sec 14min 56sec 13min 34sec

FB2 8min 43sec 9min 21sec 9min 5sec 12min 37sec 14min 12sec 12min 44sec

FB3 4min 21sec 5min 32 sec 4min 13sec 7min 23sec 7min 47 sec 6min 43sec

FC1 9min 21sec 8min 55 sec 10min 12 sec 11min 15 sec 11min 24 sec 10min 55min

FC2 7min 43sec 8min 11 sec 8 min 5sec 9min 22 sec 9min 17 sec 10 min 31 sec

FC3 5min 22 sec 5min 42sec 6min 31sec 6 min 4 sec 7min 41sec 7min 18sec

FD1 4min 45 sec 4min 52 sec 3min 21sec 7min 19 sec 7min 47 sec 6min 14 sec

FD2 2 min 51 sec 2min 11 sec 1min 33sec 3min 46sec 4min 23 sec 4min 11sec

FE1 4min 31sec 5min 55sec 4min 14sec 9min 50sec 8min 14sec 8min 19sec

FE2 3min 11 sec 2 min 47 sec 3min 17sec 5min 11sec 6min 42sec 5min 4 sec


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Fig 1: IR spectra of the pure drug, Ciprofloxacin

Hcl.

Fig 2: IR spectra of FA

Fig 3: IR spectra of FB Fig 4: IR spectra of FC

Fig 5: IR spectra of the FD&FE Disintegrant Fig 6: IR spectra of the mixture of the

Ciprofloxacin and FA

Fig 7: IR spectra of the mixture of the Ciprofloxacin

and FB Fig 7: IR spectra of the mixture of the

Ciprofloxacin and FC


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0

20

40

60

80

100

0 10 20 30 40

% C u m

u l a t i v e a m o u n t o f d r u g

r e l e a s e

Time in Minutes

FA1

FA2

FA3

FB1

FB2

FB3

0

20

40

60

80

100

0 20 40 % C u m

u l a t i v e a m o u n t o f d r u g

r e l e a s e

Time in minutes

FC1

FC2

FC3

0

20

40

60

80

100

120

0 20 40

% C u m u l a t

i v e a m o u n t o f d r u g

r e l e a s e

Time in minutes

FD1

FD2

FE1

FE2

Fig 8: IR spectra of the mixture of the Ciprofloxacin and FD &FE

Fig 9: Dissolution profile of Ciprofloxacin tablets

Using FA and FB as disintegrant

Fig 10: Dissolution profile of Ciprofloxacin tablets

Using FC disintegrants

Fig 11: Dissolution profile of Ciprofloxacin tablets Using FD disintegrants

CONCLUSION

Selecting appropriate formulation excipients and manufacturing technology can obtain the design

feature of fast disintegrating tablet. The disintegrants have the major function to oppose the efficiency of the tablet binder and the physical forces that act under compression to form the tablet. The stronger the binder, the more

effective must be the disintegrating agents in order for the tablet to release its medication. Ideally, it should causethe tablet to disrupt, not only into the granules from which it was compressed, but also into powder particles fromwhich the granulation was prepared. From this study, it is concluded that the disintegrants such as Starch, SSG,

CCS was compared with combination of disintegrants and in this study optimized combination of disintegrant prepared by intra and extra granulation method was found to be the most effective as they disintegrate rapidly

when compared to other disintegrants, and the percentage drug release also shows a higher dissolution profile.

REFERENCES Budavani S O, Neil N J, Smith A, The Merck Index, An Encyclopedia of Chemicals, Drugs and Biologicals,29th Ed, Published by Merck Research Laboratories, Division of Merck & Co. Inc, 1996, 181

http://www.pharmainfo.net/excipientshttp://www.pharmainfo.net/excipients


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Caramella C, Colombo P, Conte U, La Manna A, Tablet disintegration update: the dynamic approach, Drug.

dev.Ind.Pharm, 13 (12), 1987, 2111-2145.

Chaudhary K P R, Sujata Rao, Formulation and Evaluation of Dispersible tablets of poorly soluble drugs, IndianJ. Pharm. Sci, (2), 1992, 31-32.

Cohen Y, Lach JL, Factors affecting the Effect of Disintegrating Agent, J. Pharm. Sci, 52, 1963, 122.

Cousin, Rapidly Disintegrable multiparticular Tablets, U S Patent, 5, 464, 632 (1995).

E Sallam, Ibrahim H, R Abu Dahab, M Shubair, Enam Khalil, Drug.Dev and Industrial Pharmacy, Vol. 24(6),1998, 501 – 507.

Garnpimol C, Ritthidej, Parichat Chomto, Sunibhond Pummangura, Piamsak Menasveta, Chitin and Chitosan asDisintegrants in Paracetamol Tablets, Drug Dev. Ind. Pharm, 20(13), 1994, 2109-2134.

Grasono Alesandro, US Patent 6,197,336 2001

Gupta G D, Gaud R S, Formulation and Evaluation of Nimesulide Dispersible Tablets Using NaturalDisintegrants, Indian.J. Pharm Sci., 62(5), 2000, 339-342.

H N Bhargava, D Shah, A Anaebonam, B Oza, An Evaluation of Smecta as a Tablet Disintegrant and Dissolution

Aid, Drug. Dev.Ind.Pharm, 17(15), 1991, 2093-2102.

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Papola Vibhooti I ndian Journal of Research in Pharmacy and Biotechnology


CHRONOTHERAPY FOR NOCTURNAL ASTHAMA Papola Vibhooti

*Rajan G, Bisht Seema, Dr.Kothiyal Preeti

Shri Guru Ram Rai Institute of Technology & Sciences Dehradun, Uttarakhand, India

*Corresponding author:[email protected]

ABSTRACT

Chronotherapeutic drug delivery system is useful in the treatment of disease, in which drug availability is timed to match rhythm of disease, in order to optimize therapeutic effect and minimize side

effect. Nocturnal asthma is defined as any sleep related worsening of reversible airway disease. Approximately 80 percent of severe asthmatic attacks occur between midnight and 8 a.m. Nocturnal

asthma is associated with critical symptoms and urgent need for proper medications. The onset of nocturnal asthmatic attacks is rare in the first part of night , 80% of asthmatic attacks occur betweenmidnight and 8 a.m., and deaths from asthma are more common during these hours. In a study of asthma

mortality, 79% of the patients who died had a disturbed sleep before the death. In a survey of almost 8000 patients with varying degrees of asthma found that approximately - 75% of asthmatics attacks happened

once a week with symptoms, 64 % three times a week, and 39 % every night. Nocturnal asthma iscurrently controlled by taking either a long-acting β2 agonists like salmetrol inhalers, sustained releasetheophylline. All the current sustained release formulation has a shortcoming of inability to maintain high

blood levels for that long period. This may lead to leaving the patient unprotected against the worseevents of nocturnal asthma. Thus, a smart drug delivery that is administrated before sleep and maintainshigh blood levels for longer period (from midnight to 8 am in the morning) could be very much beneficial

for proper management of nocturnal asthma.Key words: Chronotherapy, cardian rhythm, nocturnal, morbidity, diurnal

INTRODUCTION

In order to increase the effectiveness of drug there are many approaches which have been applied. The pharmaceutical formulations which are for direct ingestion for oral administration and orally administrated drugsare generally absorbed from the gastrointestinal tract. Many functions of the human body show considerable

change in a day. These variations cause changes both in disease state and in plasma drug concentrations (Lin,

2011). Coordination of biological rhythms with medical treatment is called chronotherapy. Chronotherapyconsiders a person’s biological rhythms in determining the timing and amount of medication to optimize a drug’s

desired effects and minimize the undesired ones. Study of influence of biological rhythm on the effects of medication is known as chronopharmacology while the science of study of biological rhythms is known as

chronobiology. With the understanding of biological time keeping the idea came that these rhythms must affect

how the body responds to drugs administered over the course of the day (Hizli, 2009) (Ohdo, 2006).Appropriate timing of administration can improve efficacy and diminish toxicity. Chronotherapy is

relevant when the risk or intensity of the symptoms of disease vary with time as in the case of allergic rhinitis,arthritis, asthma, myocardial infarction, congestive heart failure, stroke and peptic ulcer disease (Haus, 2007).The human circadian rhythm is based on sleep activity cycle, is influenced by our genetic makeup and hence,

affects the body’s functions day and night (24-hour period) (Devdhawala, 2010).

Coordination of biological rhythms with medical treatment is called Chronotherapy. Chronotherapyconsiders a person’s biological rhythms in determining the timing and amount of medication to optimize a drug’sdesired effects and minimize the undesired ones. Study of influence of biological rhythm on the effects of

medication is known as chronopharmacology while the science of study of biological rhythms is known aschronobiology. To understanding the biological time keeping the idea came that these rhythms must affect howthe body responds to drugs administered over the course of the day (Awasthi, 2010) (Hizli, 2009).

raditionally, drug delivery systems have focused on constant/sustained drug output with the objective of minimizing peaks and valleys of drug concentrations in the body to optimize drug efficacy and to reduce adverseeffects. A reduced dosing frequency and improved patient compliance can also be expected for the

controlled/sustained release drug delivery systems, compared to immediate release preparations (Saigal N, 2009).Some of the rhythms that affect our body are ultradian (cycles shorter than a day like firing of neurons take

milliseconds), circadian (cycles lasting 24 h such as sleeping and waking pattern), infradian (cycles longer than aday like menstrual cycles) and seasonal rhythms (such as seasonal affective disorders causing more depression in


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susceptible individuals in winter). Circadian rhythm governs every process of our body. The term circadian

rhythm was first given by Halberg and Stephens in 1959.

Chronotherapy: The term "chrono" basically refers to the observation that every metabolic event undergoesrhythmic changes in time. Perhaps the best known and studied chronobiology frequency is the circadian rhythmwhich approximates the earth's 24-hour rotation around the sun. Researchers have recently concluded that bothdisease states and drug therapy are affected by a multitude of rhythmic changes that occur within the human body.

Chronotherapeutic refers to a treatment method in which in vivo drug availability is timed to match rhythms of disease in order to optimize therapeutic outcomes and minimize side effects. It is based on the observation thatthere is an interdependent relationship between the peak-thorough rhythmic activity in disease symptoms and risk factors, pharmacologic sensitivity and pharmacokinetics of many drugs. Biological rhythms concern to the controlof biological functions including those of the autonomic nerve system, endocrine system, and immune system, are

fundamental in homeostasis and in protection against various diseases.Chronotherapeutics: The first chronotherapy to be widely applied in clinical practice was introduced in the

1960s the alternate-day morning schedule of conventional tablet corticosteroid medication. Other chronotherapieshave since been widely used in clinical medicine in the U S, Europe, and Asia; These include special eveningtheophylline systems for chronic obstructive pulmonary disease, conventional evening H2 -receptor ant agonistsfor peptic ulcer disease, and conventional evening cholesterol medications for hyperlipidemia.

Chronotherapeutics refers to a treatment method in which in vivo drug availability is timed tomatch

rhythms of disease in order to optimize therapeutic outcomes and minimize side effects. It is based on theobservation that there is an interdependent relationship between the peak-to trough rhythmic activity in diseasesymptoms and risk factors, pharmacologic sensitivity, and pharmacokinetics of many drugs .

Figure.1.Human biological lock

Circadian Time Structure: Circadian rhythms are the rhythm in the chronotherapeutic and the dysfunction of circadian rhythms can affect the brain functioning and it can be improved by the chronotherapeutic approach.Circadian rhythms are self-sustaining, endogenous oscillations that occur with a periodicity of about 24hours.Circadian rhythm regulates several body functions such as metabolism, physiology, behavior, sleep

patterns, hormone production, and so on. The circadian rhythm not only affects most physiological functions butalso influences the absorption, distribution, metabolism, and elimination (ADME) of drugs, leading to changes in

drug availability and target cell responsiveness.


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Figure.2. Human circadian time structure

Circadian rhythms can change the sleep-wake cycles, hormone release, body temperature, and other important bodily functions driving the alteration of various physiological, biochemical, and behavioral processes.Circadian Rhythms of Diseases: The biological rhythm studies help in defining the temporal organization of human beings. One means of illustrating the human circadian time structure is to depict the peak time of 24-h

rhythms on a clock--like diagram. The 24 h clock pattern of diseases showing prominent day-night patterns whensymptoms of disease are most frequent .Variation in the severity of many diseases over a 24-hour period is wellknown diseases such as bronchial asthma, myocardial infarction, angina pectoris, rheumatic disease, ulcers 43,diabetes, and attention deficit syndrome, hypercholesterolemia and hypertension show symptomatic changes dueto circadian rhythm city. Aggravation of asthmatic attacks occur after midnight or in the early morning due tolimited lung function promoted by circadian changes at that time. Many common diseases also display a marked

circadian variation during onset or exacerbation of symptoms,

Figure.3.The circadian pattern of diseases

Asthma: Asthma may be the most common disease with the largest circadian variation. It is considered as a

chronic condition where airways are hyperreactive to certain irritants which can constrict them, and so makingdifficulty in breathing. Such a constriction is often called as bronchospasm and is followed by excess productionof mucus and inflammation in the membranes lining the walls of the airways. “Breathing through a straw” is acommonly description that can explain the situation. Allergens, fumes, smoke, and/or dry and cold air are

common irritants. Laughing or exercise can also cause the constriction of airways. Asthmatics vary considerablyin the impact of illness on their life, response to treatment and severity of symptoms. Because asthma has such astriking circadian variation, several types of chronotherapy have been tried. In one study, use of a timed-releaseformulation of theophylline (Theo- 24) achieved therapeutic drug concentrations during the night and avoidedtoxic levels during the day. Asthma is well suited for chronotherapy, with beta 2- agonists and oral

corticosteroids.


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Nocturnal asthma: Some biological rhythms come about monthly or even annually, asthma changes fairly

predictably on a circadian cycle or 24 hour. Even in normal, lung function differs between day and night. Theactivity of the lung exhibits a circadian rhythm with a maximum around 4 p.m. and a minimum around 4 a.m. Inasthmatic patients, the intensity of variation in lung function is as much as 50% in a day. Bronchial reactivitygenerally follows the same circadian cycle in Asthmatic patients. It can be defined as any sleep-related Worseningof reversible airway disease. Shortness of breath or wheezing at night is symptoms generally shown. Nocturnal

asthma is associated with critical symptoms and urgent need for proper medications. The onset of nocturnalasthmatic attacks is rare in the first part of night 80% of asthmatic attacks occur between midnight and 8 a.m., anddeaths from asthma are more common during these 9 hours. In a study of asthma mortality, 79% of the patientswho died had a disturbed sleep before the death. In a survey of almost 8000 patients with varying degrees of asthma found that approximately 75% of asthmatics attacks happened once a week with symptoms, 64 % three

times a week, and 39 % every night.Causes of Nocturnal Asthma: Nocturnal asthma is probably because of multiple factors than to a single cause.

Asthma attacks are aggravated mainly by irritants. Exposure to allergens daytime can be as important as exposureto allergens in the bedroom during sleep. A series of physiological events from three to eight hours are poorestabout 4 a.m after the initial exposure called late-asthma response (LAR); it may match to the night time for some

people and it can persist over nights. An increase in a susceptible patient's risk of LAR from 40 to 90 % byallergen exposure in the evening. In some people, the inflammation worsens correspondingly with circadian

changes in peak expiratory flow rates in night. Another contributing factor to nocturnal asthma may be airwaysecretions. About 70 % of asthmatics experience postnasal drip and/or chronic sinusitis. Asthma often improveswhen the sinuses are cleared in daytime. Influence of airway temperature on onset of symptoms was studied.Bronchospasm is produced after a brief exposure to cold and dry air. Breathing warm humidified air can reversethis.Diagnosis of Nocturnal Asthma: If asthma symptoms worsen at night it is important to inform clinician.Monitoring lung function using a peak flow meter is necessary. Peak flow meter is a portable device thatmeasures the lung volume and how time by which air can be expelled from the lungs. Low peak flow meter values indicates that there is a tightening of the airways, and can be an early warning of impending respiratorysymptoms, such as shortness of breath and wheezing. Recording peak flow rates at bedtime serves as a document

for nocturnal asthma. During any awakening at night and in the morning also serves as a record .Chronotharapy of asthma:Asthma and Sleep: In asthma, the relative role of circadian and sleep systems has

been a subject of controversy, and this issue remains unresolved.Initially, it was suspected that sleep systems played the major role. In a study of shift-workers, there appeared to be an immediate phase shift in the circadianrhythm of peak expiratory flow (PEF) when subjects rotated shifts, such that the decline in airway function

remained coupled to the sleep period. In asthma, the resistance increases progressively across the night, whether subjects sleep or not, although the increase is much greater during sleep. These results are supported by theobservations that the onset of asthmatic attacks is less common in the first part of the night. These data allow us to

reach certain conclusions. First, it seems likely that both circadian and sleep factors play a role in asthma. Also,the progressive decline in airway function across the night does not suggest a typical change in a neuronal control

process coupled to sleep. Notably, airway function is maximal at the time of increased sleepiness during theafternoon, and declines as sleep pressure dissipates during sleep.

Effect of nocturnal asthma on daytime performance, morbidity, and mortality: With the decreased sleepefficiency in asthma, and reports of daytime tiredness/sleepiness, the possibility exists that performance at work

or school will be affected. A study of nocturnal asthmatic and control subjects demonstrated that the asthmaticsubjects had increased scores for subjective sleepiness. This reflected decreased objective sleep quality.Interestingly, daytime cognitive performance was worse in the nocturnal-asthma group. This area of research

needs further investigation. The morbidity of ventilatory failure, and also the mortality in asthma, are linked to thenocturnal worsening of lung function, which may be related to a blunted arousal mechanism caused byfragmented sleep. Interestingly, in one study of asthma mortality, 79% of the 168 patients who died had a sleepdisturbance reported prior to the terminal event This contrasts with the usually accepted mortality risk factors of a

previous ICU admission (5% in the study cited ), more than two hospitalizations/emergency- room (ER) visits in

the preceding year (28%), or psychologic disturbance (13%).


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Circadian/sleep physiologic and challenge response:

Lung function and thoracic blood volume: It has been shown that sleep enhances the nocturnal increases inairway resistance and also leads to marked reduction in the volume of hyperinflated lungs in patients withnocturnal asthma. Such volume changes do not account directly for all of the nocturnal change in airwayresistance. However, artificially reducing lung volumes in awake asthmatic individuals to their typical levelsduring sleep did trigger worsening of airway obstruction, suggesting that the effects of sleep on lung volume

could contribute to the nocturnal worsening of asthma. The effects of sleep on lung volume could be mediated byseveral different mechanisms including:a sleep associated reduction in inspiratory muscle tone, a decrease in

pulmonary compliance; and an increase in intrapulmonary blood pooling. In particular, the effects of sleep onintrapulmonary blood volume (IPBV) are intriguing, since there is evidence that such pooling of blood can

promote airway narrowing. Using capillary volume (Vc) as a surrogate marker of IPBV, it has been shown that

Vc increased overnight in asthmatic individuals with nocturnal worsening of lung function . Gastrointestinal Function and the Lung: There is significant variation in gastrointestinal (GI) function during

sleep. The circadian rhythm of human basal gastric-acid secretion is characterized by a peak in the early eveningand a nadir between 5:00 and 11:00 in the morning. There are conflicting data as to whether esophageal acidcauses a decrease in airway function. In one study of sleeping individuals with nocturnal asthma, no significantacute or sustained change was observed in airflow resistance relative to periods of increased esophageal acidcontent, suggesting that gastroesophageal reflux (GER) contributed little to the nocturnal worsening of asthma.

Although it appears that asthma is more responsive to the ets of GER during the diurnal cycle than during thenocturnal cycle, the exact role of circadian/sleep effects in esophageal acid-induced bronchoconstriction remainsunclear.Nasal-Sinus – Lung Interaction: There is evidence that upper-airway disease (i.e., allergic rhinitis, sinusitis, andnasal polyps) influences and may contribute to the intensity of lower-airway disease. Allergic rhinitis, for

example, can intensify airway responsiveness and even provoke asthma symptoms. Data indicate that treatment of allergic rhinitis diminishes bronchial responsiveness and asthma. Active sinusitis can also cause an increase in theasthma process as shown in animal models, which appears to involve drainage of nasal mediators into the lower airway. Other processes that link the nasal sinus to the lung have been identified in studies of viral infections of the nose that produce an increase in lower-airway reactivity. Also, there is a day – night cycle in nasal patency and

perhaps in inflammation. All of these data suggest an important interaction between the nasal sinus and lower-airway function.

ChronotherapyGeneral Principles: Bodily functions have been incorrectly assumed to be relatively constant throughout the 24 hof the day and other periods of time. Numerous studies have shown that the kinetics and dynamics of

pharmacotherapies vary significantly according to the biologic time of administration during the 24 h-cycle,menstrual cycle, or annually, owing to the cumulative effect of endogenous rhythms in crucial physiologic and

biochemical functions. Chronotherapeutics is the synchronization of medication levels in time with reference to

need, taking into account biologic rhythms in the pathophysiology of medical conditions, and/or rhythm-dependencies in patient tolerance for given chemical interventions. Chronotherapeutics can sometimes be

achieved by the judicious timing of conventional sustained- release (SR) formulations, although reliance onspecial drug-delivery systems seems to constitute a more dependable means of matching drug level to biologic

need and tolerance.

β2-Agonists, Theophylline, and Anticholinergic Therapy: Certain SR formulations of theophylline can be

administered so that a rising blood level of the drug occurs when airway obstruction is increasing, while adverseeffects are reduced. For this purpose, SR theophylline is administered once daily, in the evening, for themanagement of nocturnal asthma. Various tablet formulations for the sustained-release of b-agonists have been

used in a chronotherapeutic fashion for the management of asthma. As with theophylline, very little informationexists about comparing the effects of or adding a long-acting b2-agonist oral preparation to an inhaledcorticosteroid using chronotherapeutic techniques. Salmeterol has been shown to control symptoms of nocturnalasthma to a substantial degree, and to improve sleep quality and daytime cognitive performance in patients withchronic asthma. Drugs that antagonize the vagal nervous system should be useful in the management of nocturnal

asthma as a means of counteracting the enhanced nocturnal parasympathetic tone that occurs in the disease.


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Corticosteroids and Leukotriene-active Drugs: Corticosteroids have been used in a chronotherapeutic manner,

with the finding that their long-term oral administration at 8:00 A.M. and 3:00 P.M. was more effective incontrolling nocturnal asthma than the same doses given at 3:00 P.M. and 8:00 P.M. Other studies have shown thata single 3:00 P.M. dose of prednisone improved lung function and reduced airway inflammation more effectivelythan the same single dose given at 8:00 A.M. and 8:00 P.M (Beam, 1992). Not only can oral steroids be dosedchronotherapeutically, but inhaled corticosteroids can also be efficacious when used in this manner (Pincus,

1995). Although the leukotriene-active drugs, including zileuton, zafirlukast and montelukast, are new in thetreatment of asthma, they have been shown to alleviate the symptoms and the decrement in lung function seen innocturnal asthma. It has been shown that zileuton in particular decreased nighttime increases in leukotriene B4(LTB4) and (LTE4) while improving lung function (Wenzel, 1995). Zafirlukast has also been shown to decreasenighttime awakenings and improve morning PEF rates . Although these agents have only been studied at set doses

and times regardless of the presence or absence of nocturnalasthma, the improvements observed were significant,and it is likely that these agents will prove very useful in the treatment of nocturnal asthma when used

chronotherapeutically.Ideal Characteristics of Chronotherapeutic Drug Delivery System should:

be non-toxic within approved limits of use, have a real-time and specific triggering biomarker for a given disease state,

have a feed- back control system (e.g. self-regulated and adaptative capability to circadian rhythm and individual patient to differentiate between awake – sleep status), be biocompatible and biodegradable, especially for parenteral administration, be easy to manufacture at economic cost, be easy to administer in to patients in order to enhance compliance to dosage regimen.

Chronotherapeutic drug delivery systems: Controlled release formulations can be divided into subgroups of rate-controlled release,delayed-release and pulsed-release formulations. Delayed-release formulations includetime controlled release and site specific dosage forms. When constant drug plasma levels need to be avoided, as in

chronotherapy, time-controlled or pulsed-release formulations are preferable, especially in the treatment of earlymorning symptoms. By timing drug administration, plasma peak is obtained at an optimal time and the number of

doses per day can be reduced. Saturable first-pass metabolism and tolerance development can also be avoided.Various technologies to develop timecontrolled peroral drug delivery systems have been extensively studied in

recent decades. Some of these systems are discussed in the following subsections.Enteric-coated systems: Enteric coatings have traditionally been used to prevent the release of a drug in thestomach Enteric coatings are pHsensitive and drug is released when pH is raised above 5 in the intestinal fluid.

These formulations can be utilised in time-controlled drug administration when a lag time is needed. Because of the unpredictability of gastric residence, such systems cannot be the first choice when a time-controlled release isrequired. In the treatment of nocturnal asthma, a salbutamol formulation containing a barrier coating which is

dissolved in intestinal pH level above about 6, has been successfully used. The system contains a core which isfilm coated with two polymers, first with HPMC and then with a gastro-resistant polymer (Eudragit® L30D). In

this system the duration of the lag phase in absorption can be controlled by the thickness of the HPMC layer.

Figure.4.Schematic representation of Enteric coated systemLayered systems: These are one or two impermeable or semipermeable polymeric coatings (films or compressed)applied on both sides of the core. To allow biphasic drug release, a three-layer tablet system was developed . Thetwo layers both contain a drug dose. The outer drug layer contains the immediately available dose of drug. An

intermediate layer, made of swellable polymers,separates the drug layers. A film of an impermeable polymer


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coats the layer containing the otherdose of drug. The first layer may also incorporate a drug-free hydrophilic

polymer barrier providing delayed (5 h) drug absorption. Conte et al has also studied a multi-layer tablet system(Geomatrix®).It consists of a hydrophilic matrix core containing the drug dose. This kind of three layer devicehas been used in the treatment of Parkinsonian patients using L-- dopa/benserazide. Nighttime problems andearly-morning symptoms of Parkinsonism can be avoided by using a dualrelease Geomatrix@ formulation, whichallows daily doses of drug to be reduced and leads to extent of bioavailability 40 % greater than when a traditional

controlled release formulation is employed.

Figure.5. Geminex TIMERx technology based bilayered dual release tablet

Time-controlled explosion systems (TES): These have been developed for both single and multiple unit dosageforms

[80],[81]. In Both cases, the core contains the drug, an inert osmotic agent and suitable disintegrants.

Individual units can be coated with a protective layer and then with a semipermeable layer, which is the rate

controlling membrane for the influx of water into the osmotic core. As water reaches the core, osmotic pressure is built up. The core ultimately explodes, with immediate release of the drug. The explosion of the formulation can

also be achieved through the use of swelling agents. Lag time is controllable by varying the thickness of the outer polymer coating.Sigmoidal release systems (SRS): For the pellet-type multiple unit preparations, SRS containing an osmotically

active organic acid have been coated with insoluble polymer to achieve different lag-times. By applying differentcoating thicknesses, lag times in vivo of up to 5 hours can be achieved. Release rates from SRS, beyond the lag

time, has been found to be independent of coating thickness.Press-coated systems: Delayed-release and intermittent-release formulations can be achieved by press-- coating.Presscoating, also known as compression coating, is relatively simple and cheap, and may involve directcompression of both the core and the coat, obviating the need for a separate coating process and the use of coatingsolutions. Materials such as hydrophilic cellulose derivatives can be used and compression is easy on a laboratory

scale. On the other hand, for large-scale manufacture, special equipment is needed. The major drawbacks of thetechnique are that relatively large amounts of coating materials are needed and it is difficult to position the corescorrectly for the coating process. Conte et al have developed a press coated device in which the inner corecontains the drug and the outer coat is made of different types of polymers. The outer barrier, which controls drugrelease, can be either swellable or erodible. Lag times can be varied by changing the barrier formulation or the

coating thickness (Halsas M, 1998). Hydrophilic polymers such as hydroxypropyl methylcellulose and sodiumalginate have been used in the coat to control drug release.

In recent years, various controlled release, especially time-controlled release; drug delivery systems basedon compression coating technology have been studied. Most such Formulations release drug after a lag phase,followed by a rapid dissolution of a core. Tablets formulated with Penwest's TIMERx ® oral controlled release

technology comprise an inner core containing drug and an outer layer compression-coated with TIMERx, a

hydrophilic matrix of the heteropolysaccharides xanthan and locust bean gum (Baichwal A, 2002).

Figure.6. TIMERx based drug delivery system Examples of chronopharmaceutical technologies: Currently key technologies in chronopharmaceutics includes:CONTINR, physico-chemical modification of the active pharmaceutical ingredient (API), OROSR, CODASR,


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CEFORMR, DIFFUCAPSR, chronomodulating infusion pumps, TIMERxR, threedimensional printing,

controlled-release (CR) erodible polymer and CR microchip strategies. Readers may find advantages anddisadvantages of each technology depending on their specific needs on the website of each developer/marketer website before selection. Informations on FDA approval status and dosage formed were compiled from the FDAelectronic orange book.For asthma (CONTINR technology): In this technology, molecular coordination complexes are formed between

a cellulose polymer and a non-polar solid aliphatic alcohol optionally substituted with an aliphatic group bysolvating the polymer with a volatile polar solvent and reacting the solvated cellulose polymer directly with thealiphatic alcohol, preferably as a melt. This constitutes the complex having utility as a matrix in controlled releaseformulations since it has a uniform porosity (semipermeable matrixes) which may be varied. This technology hasconcretely enabled the development of tablet forms of sustained-release aminophylline, theophylline, morphine,

and other drugs. Research suggested that evening administration of UniphylR (anhydrous theophylline) tabletsrepresented a rational dosing schedule for patients with asthma who often exhibit increased bronchoconstriction in

the morning. Patients demonstrated improved pulmonary function in the morning compared with use of twice-daily theophylline when once-daily UniphylR was administered in the evening. Thus, evening administration of once-daily theophylline may block the morning dip in lung function commonly seen. CONTINR technology

provides for closer control over the amount of drug released to the bloodstream, and benefits patients in terms of reducing the number of doses they need to take every day, providing more effective control of their disease

(particularly at night), and reducing unwanted side effects.Marketed preparation for asthma till now

FDA approval date – Sept.01.1982 API- Theopylline Proprietary name dosage form - Uniphyl Chronopharmaceutical technology- CONTIN

CONCLUSION

Chronopharmaceutics will certainly improve patient outcome and optimize disease management in thefuture. Research in chronopharmacology has demonstrated the importance of biological rhythms in drug therapy

and this has led to a new approach to the development of drug delivery systems. Optimal clinical outcome cannot be achieved if drug plasma concentrations are constant. If symptoms of a disease display circadian variation, drugrelease should also vary over time. Different technologies have been applied to develop time-controlled, pulsed,

triggered and programmed drug delivery devices in recent years. Since it is seems that timing of drugadministration in disease therapy has significant impact upon treatment success, chronotherapeutics remains animportant area for continuing research. It is concluded that the treatment of asthma with the Chrono-optimized

preparation over night is more effective than treatment with a conventional preparation in twice-daily dosage. Inaddition, lung function showed greater stability, throughout the day, with once-daily evening therapy than with

traditional 12 hr dosing. It is well known that human body temperature, blood pressure, and pulse rate reach highvalues during the day and fall at night. Similarly, all other physiological functions and activities are subject to adaily cyclical variation known as their circadian rhythm. The respiratory function is no exception and is known toexperience a trough in activity from late night until early morning. In other words, in application once daily at

bedtime could be expected to prevent asthma attacks for practically the entire 24-hour period and, as maximum

blood concentration is reached in the early morning, would be particularly effective against attacks caused bymorning dip.

REFERENCES

Alexander A, Dulal KT, Ajazuddin, Mukesh S, Monesh S, Swarna. .Multidose Therapy (MDT) Treatment for

Helicobacter Pylori Infection Leading to Gastric Ulcer and Carcinoma: A Review; Res J PharmacolPharmacodynamics 3(3): 2011; 140-147.

Alexander A, Sharma S, Ajazuddin, Giri TK, Swarna, Shukla P. Various evaluation parameters used for theevaluation of different mucoadhesive dosage forms. A review. Inter. J.

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