Successfully reported this slideshow.

1(3) ijrpb

6,446 views

Published on

Published in: Business, Technology
  • Be the first to comment

  • Be the first to like this

1(3) ijrpb

  1. 1. 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) Editor B.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), Phd Research 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
  2. 2. Volume 1 Issue 3 www.ijrpb.com May-June 2013 INDIAN JOURNAL OF RESEARCH IN PHARMACY AND BIOTECHNOLOGY Instructions to Authors Manuscripts will be subjected to peer review process to determine their suitability for publication provided they fulfill the requirements of the journal as laid out in the instructions to authors. After the review, manuscripts will be returned for revision along with reviewer’s and/or editor’s comments. Don’t copy and paste the article content from internet or other sources like e-books etc. Authors are the sole responsible persons for the article, article content; results of the research conducted and copy right issues if any. The editor and the editorial board are not entitled to change the article content, results and diagrammatic representations which are given by authors. The article will be published only after getting the approved galley proof from the authors. Kindly follow the below guidelines for preparing the manuscript: 1. Prepare the manuscript in Times New Roman font using a font size of 12. There shall not be any decorative borders anywhere in the text including the title page. 2. Don’t leave any space between the paragraphs. 3. Divide the research article into a. Abstract b. Introduction c. Materials and Methods d. Results e. Discussion f. conclusion g. References 4. References should include the following in the same order given below a) Author name followed by initials b) Title of the book/ if the reference is an article then title of the article c) Edition of the book/ if the reference is an article then Journal name d) Volume followed by issue of the journal e) Year of publication followed by page numbers 5. Download the author declaration form from the web site www.ijrpb.com, fill it and submit it after signing by corresponding and co-authors to IJRPB. You can send the filled in form by post or scanned attachment to ijrpb@yahoo.com. 6. Keep in touch with the editor through mail or through phone for further clarifications as well as for timely publication of your article. Indian Journal of Research in Pharmacy and Biotechnology is a bimonthly journal, developed and published in collaboration with Nimra College of Pharmacy, Ibrahimpatnam, Vijayawada, Krishna District, Andhra Pradesh, India-521456 Printed at: F. No: 501, Parameswari Towers, Ibrahimpatnam, Vijayawada, India -521456 Visit us at www.ijrpb.com Contact us/ send your articles to: Email: ijrpb@yahoo.com Phone no: 9490717845; 9704660406
  3. 3. Indian Journal of Research in Pharmacy and Biotechnology ISSN: 2320-3471 (Online) ISSN: 2321-5674 (Print) Volume 1 Issue 3 www.ijrpb.com May-June 2013 S.No. Contents Page No. 1. Development and evaluation of drotoverine taste masked tablets with improved dissolution efficiency using solid dispersion technique Anusha P, Nirajana V.A, Syed Mohammed, Shaik Jilani, Ch. Murali Krishna, Harish.G 275-280 2. Effect of different disintegrants on Ciprofloxacin conventional tablets Harish.G, Ch.Bhargavi, A.Riyajune, Md.Yasmeen, Syed Mohammed, Ch.Murali Krishna, Sk.Jilani, Nirajana.V.A 281-287 3. Chronotherapy for nocturnal asthama Papola Vibhooti , Rajan G, Bisht Seema , Dr. Kothiyal Preeti 288-298 4. Recent trends in scope and opportunity of clinical research in India Hemant Singh, Abhinav Srivastva 299-304 5. Sustained release drug delivery system Navin Dixit, Sheo Dutt Maurya, Bhanu P.S.Sagar 305-310 6. Antibacterial activity of ethanolic extracts of Nyctanthes arbortristis and Nerium oleander A.Ravi Kumar, Ch.S.D.Phani Deepthi Yadav 311-313 7. Food poisoning and its safety precaution M. Umadevi, K.P.Sampath Kumar, Sai Pavan, Sd.Gosia Sultana, D. Bhowmik 314-323 8. Microencapsulation technology K.P.Sampath Kumar,Tejbe.Sk, Shameem Banu, P.Naga Lakshmi , D.Bhowmik 324-328 9. An overview about pharmacy education in India Praneta Desale 329-332 10. Phytochemical evaluation of Nyctanthes arbortristis, Nerium oleander and Catharathnus roseus Ch.S.D. Phani Deepthi Yadav, N.S.P. Bharadwaj, M. Yedukondalu, Ch. Methushala, A. Ravi Kumar 333-338 11. Angina pectoris epidemic in India: a comprehensive review of clinical features, differential diagnosis, and remedies Shravan Paswan, Ranjan Kumar Sharma, Alok Ranjan Gaur, Avinash Sachan, Mahendra Singh Yadav, Preeti Sharma, Mrinmoy Gautam 339-345 12. Stability Indicating HPLC method for the estimation of Cinacalcet hydrochloride API Manikandan Krishnan, Santhana Lakshmi Karunanidhi, Gayathri Sola, Akshitha .Y 346-350 13. Bioavailability: criteria for approving a drug product for marketing Sandhya Singh, Faheem Ajmal Ansari, Shravan Paswan, Rnjan Kumar Sharma, Alok Ranjan Gaur 351-359 14. The effect of superdisintegrants on the dissolution of calcium carbonate fast dissolving tablets Mohammed Farhana, J.Preeti, Md Faizulla, Budda Chellibabu, Harish.G, Rajnesh Kumar Singh 360-364 15. Phytochemical and pharmacological studies on whole plant of Asystasia gangetica T.K.Gopal, Megha.G, D.Chamundeeswari, C.Umamaheswara Reddy 365-370 16. Investigation of in-vitro anti-oxidant, anti-inflammatory and anti-arthritic activity of aerial parts of Securinega leucopyrus (willd.) Muell T.K.Gopal, T.Sheela, D.Chamundeeswari, C.Umamaheswara Reddy 371-378
  4. 4. Indian Journal of Research in Pharmacy and Biotechnology ISSN: 2320-3471 (Online) ISSN: 2321-5674 (Print) Volume 1 Issue 3 www.ijrpb.com May-June 2013 17. Transdermal sonophoresis technique- an approach for controlled drug delivery K.P.Sampath Kumar, Debjit Bhowmik, M.Komala 379-381 18. A comprehensive review of Eladi Vati Navin Dixit, Sheo Dutt Maurya , Bhanu P.S.Sagar 382-384 19. Preparation and characterization of some herbal ointment formulations with evaluation of antimicrobial property Pulak Majumder and Susmita Majumder 385-390 20. The effects of air pollution on the environment and human health Shyam Bihari Sharma, Suman Jain, Praveen Khirwadkar, Sunisha Kulkarni 391-396 21. Formulation and evaluation of orodispersible tablets of Cinnarizine by super disintegrants addition method Praveen Khirwadkar, Kamlesh Dashora, Shyam Bihari Sharma 397-400 22. Effective hypoglycemic action of metformin combinations against Dexamethasone induced diabetes mellitus in rats Mohanraghupathy.S, Jayabharath N, Bhuvana Tejay, Hameera Khanam B, Lavanya Lahari B 401-403 23. A review on medicinal plants having antioxidant potential Prof.S.K Sharma, Mr. Lalit Singh, Suruchi Singh 404-409 24. Invitro anti-inflammatory activity of Strychnos potatorum linn seed by HRBC membrane stabilization V.Vijayakumar, Dr C.K.Hindumathy 410-412 25. Synthesis and characterization of 1, 3, 4-oxadiazole and 1,3,4- thiadiazole Ramanji Naik 413-419 26. Preparation, characterization and evaluation of Olmesartan medoxomil β- cyclodextrin complexes V. Prudhvi Raj, Subhashis Debnath, Maleswari, M. Niranjan Babu 420-427 27. Wafers technology – a newer approacah to smart drug dilevery system Papola Vibhooti*, Kothiyal Preeti 428-439 28. Evaluation of anti-ulcer effects of ethanolic extract of Delonix regia flower Samaresh 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 for pharmacist intervention for improving patient adherence Dr. Praveen Kumar G 446-447 30. Recent trends in positive and negative aspects of food on bioavalabilty of drugs Gowthami B, Sk Nahida Fazilath, Sanaulla Md, K Prudhvi Raj, Dastagiriah G, Tabassum Sk 448-460 31. A review on collagen based drug delivery systems Sahithi B, Ansari Sk, Hameeda Sk, Sahithya G, Durga Prasad M, Yogitha Lakshmi 461-468
  5. 5. ISSN: 2321-5674(Print) ISSN: 2320 – 3471(Online) Anusha P et.al Indian 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 TECHNIQUE Anusha P*1 , Nirajana V.A2 , Syed Mohammed1 , Shaik Jilani1 , Ch. Murali Krishna, Harish.G1 1. Nimra college of Pharmacy, Jupudi, Vijayawada, Andhra Pradesh, India 2. Faculty of Pharmacy, Sri Ramachandra University, Porur, Chennai. *Corresponding author: E.Mail:anupharma88@gmail.com ABSTRACT The purpose of this research is to mask the bitter taste of the drug, Drotoverine using solid dispersion technique. The taste-masked drug is formulated in to a conventional tablet by direct compression method for ease of administration. Taste masking was done by solid dispersion using polymer such as urea and mannitol by melting/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, hardness and 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 demonstrated successful 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. Several oral 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 drug in order to improve the Palatability of the drug, which in turn improves patience compliance. Drotoverine is a novel 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 and intracellular increase of cAMP level. Its oral bioavailability is about 100% with a biologic half- life of about 7 to 12 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 oral administration. This is due to a large fraction of the dose remaining undissolved for absorption. Under such conditions, 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 face difficulty 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 drotoverine with 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 and improved dissolution rate. 2. MATERIALS AND METHODS 2.1. Materials: Drotoverine was obtained as a gift sample from Apex laboratory ltd, Chennai; sodium starch glycolate, aspartame, magnesium stearate and micro crystalline cellulose was obtained as a gift sample from Intex chemicals, Chennai.
  6. 6. ISSN: 2321-5674(Print) ISSN: 2320 – 3471(Online) Anusha P et.al Indian Journal of Research in Pharmacy and Biotechnology Volume 1(3) May-June 2013 Page 276 2.2. Methods 2.2.1. Preparation of Drotoverine Solid Dispersion Using Mannitol and Urea as Carriers: The solid dispersion 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 directly until it melted. The melted mixture is then solidified orally in an ice-bath under vigorous stirring. The final solid mass is crushed, pulverized and sieved. 2.2.2. Characterization of solid dispersion: The prepared drotoverine and mannitol, drotoverine and urea solid dispersions 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 were compressed on an eight-station single rotary tabletting press (GMC, using a flat punch with break line by direct compression technique. 3. Characterization of Prepared Tablets: The prepared tablets were evaluated for its physical characteristics like hardness thickness, weight variation, friability, disintegration test. 3.1. In 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 (Stimulated gastric 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 plug and 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 amounts released were expressed as a percentage of the drug content in each dissolution medium. The dissolution test was carried 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 1:3 F4 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
  7. 7. ISSN: 2321-5674(Print) ISSN: 2320 – 3471(Online) Anusha P et.al Indian Journal of Research in Pharmacy and Biotechnology Volume 1(3) May-June 2013 Page 277 Table.5. In-vitro dissolution study for Drotoverine solid dispersion Time 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 products Time in min Percent drug release 0 0 5 24.36 10 35.12 15 54.32 20 67.75 25 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 45.35 15 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 0 0=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
  8. 8. ISSN: 2321-5674(Print) ISSN: 2320 – 3471(Online) Anusha P et.al Indian Journal of Research in Pharmacy and Biotechnology Volume 1(3) May-June 2013 Page 278 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
  9. 9. ISSN: 2321-5674(Print) ISSN: 2320 – 3471(Online) Anusha P et.al Indian Journal of Research in Pharmacy and Biotechnology Volume 1(3) May-June 2013 Page 279 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 was done 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 the formulations. In all the formulations, the friability value is less than 1% giving an indication that tablets formulated 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 drug release. For the formulation f7 the percentage amount of drug release was found to be with the pharmacopeial limits.the comparission of dissolution profiles for formulated drotaverine and marketed drotaverine tablets were shown in the table no 8 and it was concluded that percent drug release for formulated drotaverine tablets was more when comparared to marketed drotaverine tablets. Taste evaluation of all formulations: The time intensity study for taste in human volunteers of the formulated drotaverine hydrochloride with the polymer SD revealed considerable masking of the bitter taste of drotaverine HCl 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. CONCLUSION This 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 palatable form 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 and geriatric 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
  10. 10. ISSN: 2321-5674(Print) ISSN: 2320 – 3471(Online) Anusha P et.al Indian Journal of Research in Pharmacy and Biotechnology Volume 1(3) May-June 2013 Page 280 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,
  11. 11. ISSN: 2321-5674(Print) ISSN: 2320 – 3471(Online) Harish G et.al Indian Journal of Research in Pharmacy and Biotechnology Volume 1(3) May-June 2013 Page 281 EFFECT OF DIFFERENT DISINTEGRANTS ON CIPROFLOXACIN CONVENTIONAL TABLETS Harish.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: harishgopinath4u@gmail.com ABSTRACT The objective of the present study is to design and evaluate the effect of disintegrating agents such as Starch, 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 the drug 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 by stability studies for a period of 3 months. INTRODUCTION Despite increasing interest in controlled-release drug delivery systems, the most common tablets are those intended 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 is of 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 tablets that 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 ciprofloxacin conventional 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 disintegrate rapidly when compared to other disintegrating agents such as Starch, SSG, and CCS with ciprofloxacin. MATERIALS AND METHODS Ciprofloxacin obtained as a gift sample from Intex chemicals Pvt ltd, Chennai. Starch, Cross Caramellose Sodium 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 using kBr 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
  12. 12. ISSN: 2321-5674(Print) ISSN: 2320 – 3471(Online) Harish G et.al Indian Journal of Research in Pharmacy and Biotechnology Volume 1(3) May-June 2013 Page 282 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 weighed and passed through 40# sieve, blended in a Poly Bag except Magnesium Stearate for 10 minutes. Mix half the part of the disintegrated with the above mixture after passing through the sieve. The resultant mixture was wet massed using 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 tablets and quantity equivalent to 45mg was taken and determined using 0.1M Hcl using UV spectrophotometer at about 276nm Weight Variation: The USP weight variation test was run by weighing 20 tablets individually, calculating the average 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 with thumb 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 and shock by utilizing a plastic chamber that revolves at 25RPM for minutes dropping the from a distance of six inches 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, Ciprofloxacin Hydrochloride 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 were measured for their thickness and diameter with a Caliper, Thickness Gauge. Average thickness and diameter were calculated. Disintegration Test: Disintegration time is considered to be one of the important criteria in selecting the best formulation. 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 the 1000ml beaker containing water maintained at 37 ± 2o C 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 are disintegrated. 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 rpm and 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 was determined 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 and Hausner’s Ratio. The results of disintegration time of all the tablets prepared by wet granulation found to be varied with change in concentration of disintegrating agents from few seconds to several minutes. Formulations FD 1 and FE1 disintegrated within 3min and found to be more effective. The disintegration time of the tablets using different disintegrants 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 intra and extra granulation method found to be more effective in comparison with formulation prepared by only extra
  13. 13. ISSN: 2321-5674(Print) ISSN: 2320 – 3471(Online) Harish G et.al Indian Journal of Research in Pharmacy and Biotechnology Volume 1(3) May-June 2013 Page 283 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 range of 0.37 to 0.38 g/cm3 and 0.44 to 0.45g/cm3 respectively. 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 the range of 5-15 hence falls within the excellent range. The results were tabulated in table 15. The pre-formulation characteristics results for all the formulation of ciprofloxacin tablets using FB as disintegrating agent found to be within the range, compressibility index for FB1 and FB3 was found to be with in good range of 12-16 were as FB2 was in excellent range. The angle of repose of prepared 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 0.34 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 than 1.25 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 be within 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 index was within the range of 5-15 hence falls within the excellent range. The results were tabulated in table 17. The formulation of ciprofloxacin using 4% B.C disintegrant found to be within the limits for both FD1 and FD2 and falls 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 index was 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 density were 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. The compressibility 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 the formulations indicating good mechanical strength with an ability indicating physical and mechanical strength with an 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 tablet formulations 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 3min and 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, 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 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 FA as 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 was determined 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-
  14. 14. ISSN: 2321-5674(Print) ISSN: 2320 – 3471(Online) Harish G et.al Indian Journal of Research in Pharmacy and Biotechnology Volume 1(3) May-June 2013 Page 284 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 time interval 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 as disintegrant 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 but this 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 see how 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 each formulation 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 method called “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 from unwanted 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 3 months from 4th month onwards up to one year, every 6 month in the second year of storage, afterwards once in a year till shelf life is completed. ICH guidelines also demands for storing samples at 40 ° c and 75 % RH (stress condition or accelerated stability study) for relatively short period of time (3-6 months) which depends on claimed shelf 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
  15. 15. ISSN: 2321-5674(Print) ISSN: 2320 – 3471(Online) Harish G et.al Indian Journal of Research in Pharmacy and Biotechnology Volume 1(3) May-June 2013 Page 285 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
  16. 16. ISSN: 2321-5674(Print) ISSN: 2320 – 3471(Online) Harish G et.al Indian Journal of Research in Pharmacy and Biotechnology Volume 1(3) May-June 2013 Page 286 0 20 40 60 80 100 0 10 20 30 40 %Cumulativeamountofdrug release Time in Minutes FA1 FA2 FA3 FB1 FB2 FB3 0 20 40 60 80 100 0 20 40 %Cumulativeamountofdrug release Time in minutes FC1 FC2 FC3 0 20 40 60 80 100 120 0 20 40 %Cumulativeamountofdrug release 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 cause the tablet to disrupt, not only into the granules from which it was compressed, but also into powder particles from which 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
  17. 17. ISSN: 2321-5674(Print) ISSN: 2320 – 3471(Online) Harish G et.al Indian Journal of Research in Pharmacy and Biotechnology Volume 1(3) May-June 2013 Page 287 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, Indian J. 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 as Disintegrants 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 Natural Disintegrants, 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.
  18. 18. ISSN: 2321-5674(Print) ISSN: 2320 – 3471(Online) Papola Vibhooti Indian Journal of Research in Pharmacy and Biotechnology Volume 1(3) May-June 2013 Page 288 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:papola.vibhooti47@gmail.com 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 between midnight 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 is currently controlled by taking either a long-acting β2 agonists like salmetrol inhalers, sustained release theophylline. 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 worse events of nocturnal asthma. Thus, a smart drug delivery that is administrated before sleep and maintains high 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 drugs are 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. Chronotherapy considers 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. Chronotherapy considers 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. To understanding the biological time keeping the idea came that these rhythms must affect how the 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 adverse effects. 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 a day like menstrual cycles) and seasonal rhythms (such as seasonal affective disorders causing more depression in
  19. 19. ISSN: 2321-5674(Print) ISSN: 2320 – 3471(Online) Papola Vibhooti Indian Journal of Research in Pharmacy and Biotechnology Volume 1(3) May-June 2013 Page 289 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 undergoes rhythmic changes in time. Perhaps the best known and studied chronobiology frequency is the circadian rhythm which approximates the earth's 24-hour rotation around the sun. Researchers have recently concluded that both disease 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 that there 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 control of 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 chronotherapies have since been widely used in clinical medicine in the U S, Europe, and Asia; These include special evening theophylline systems for chronic obstructive pulmonary disease, conventional evening H2 -receptor ant agonists for 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 the observation that there is an interdependent relationship between the peak-to trough rhythmic activity in disease symptoms 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 24 hours.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 but also influences the absorption, distribution, metabolism, and elimination (ADME) of drugs, leading to changes in drug availability and target cell responsiveness.
  20. 20. ISSN: 2321-5674(Print) ISSN: 2320 – 3471(Online) Papola Vibhooti Indian Journal of Research in Pharmacy and Biotechnology Volume 1(3) May-June 2013 Page 290 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 when symptoms of disease are most frequent .Variation in the severity of many diseases over a 24-hour period is well known diseases such as bronchial asthma, myocardial infarction, angina pectoris, rheumatic disease, ulcers 43, diabetes, and attention deficit syndrome, hypercholesterolemia and hypertension show symptomatic changes due to circadian rhythm city. Aggravation of asthmatic attacks occur after midnight or in the early morning due to limited 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 making difficulty in breathing. Such a constriction is often called as bronchospasm and is followed by excess production of mucus and inflammation in the membranes lining the walls of the airways. “Breathing through a straw” is a commonly 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 considerably in the impact of illness on their life, response to treatment and severity of symptoms. Because asthma has such a striking circadian variation, several types of chronotherapy have been tried. In one study, use of a timed-release formulation of theophylline (Theo- 24) achieved therapeutic drug concentrations during the night and avoided toxic levels during the day. Asthma is well suited for chronotherapy, with beta 2- agonists and oral corticosteroids.
  21. 21. ISSN: 2321-5674(Print) ISSN: 2320 – 3471(Online) Papola Vibhooti Indian Journal of Research in Pharmacy and Biotechnology Volume 1(3) May-June 2013 Page 291 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. The activity of the lung exhibits a circadian rhythm with a maximum around 4 p.m. and a minimum around 4 a.m. In asthmatic patients, the intensity of variation in lung function is as much as 50% in a day. Bronchial reactivity generally follows the same circadian cycle in Asthmatic patients. It can be defined as any sleep-related Worsening of 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 nocturnal asthmatic attacks is rare in the first part of night 80% of asthmatic attacks occur between midnight and 8 a.m., and deaths from asthma are more common during these 9 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. 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 exposure to allergens in the bedroom during sleep. A series of physiological events from three to eight hours are poorest about 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 % by allergen 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 airway secretions. About 70 % of asthmatics experience postnasal drip and/or chronic sinusitis. Asthma often improves when 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 reverse this. 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 that measures 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 respiratory symptoms, 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 circadian rhythm 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 the observations 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 the afternoon, and declines as sleep pressure dissipates during sleep. Effect of nocturnal asthma on daytime performance, morbidity, and mortality: With the decreased sleep efficiency 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 asthmatic subjects 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 the nocturnal worsening of lung function, which may be related to a blunted arousal mechanism caused by fragmented sleep. Interestingly, in one study of asthma mortality, 79% of the 168 patients who died had a sleep disturbance 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%).
  22. 22. ISSN: 2321-5674(Print) ISSN: 2320 – 3471(Online) Papola Vibhooti Indian Journal of Research in Pharmacy and Biotechnology Volume 1(3) May-June 2013 Page 292 Circadian/sleep physiologic and challenge response: Lung function and thoracic blood volume: It has been shown that sleep enhances the nocturnal increases in airway resistance and also leads to marked reduction in the volume of hyperinflated lungs in patients with nocturnal asthma. Such volume changes do not account directly for all of the nocturnal change in airway resistance. However, artificially reducing lung volumes in awake asthmatic individuals to their typical levels during 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 by several 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 on intrapulmonary 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 evening and a nadir between 5:00 and 11:00 in the morning. There are conflicting data as to whether esophageal acid causes a decrease in airway function. In one study of sleeping individuals with nocturnal asthma, no significant acute or sustained change was observed in airflow resistance relative to periods of increased esophageal acid content, 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 the nocturnal cycle, the exact role of circadian/sleep effects in esophageal acid-induced bronchoconstriction remains unclear. Nasal-Sinus–Lung Interaction: There is evidence that upper-airway disease (i.e., allergic rhinitis, sinusitis, and nasal 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 the asthma 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. Chronotherapy General Principles: Bodily functions have been incorrectly assumed to be relatively constant throughout the 24 h of 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 on special 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 adverse effects are reduced. For this purpose, SR theophylline is administered once daily, in the evening, for the management 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 information exists about comparing the effects of or adding a long-acting b2-agonist oral preparation to an inhaled corticosteroid using chronotherapeutic techniques. Salmeterol has been shown to control symptoms of nocturnal asthma to a substantial degree, and to improve sleep quality and daytime cognitive performance in patients with chronic 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.
  23. 23. ISSN: 2321-5674(Print) ISSN: 2320 – 3471(Online) Papola Vibhooti Indian Journal of Research in Pharmacy and Biotechnology Volume 1(3) May-June 2013 Page 293 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 in controlling nocturnal asthma than the same doses given at 3:00 P.M. and 8:00 P.M. Other studies have shown that a single 3:00 P.M. dose of prednisone improved lung function and reduced airway inflammation more effectively than the same single dose given at 8:00 A.M. and 8:00 P.M (Beam, 1992). Not only can oral steroids be dosed chronotherapeutically, 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 the treatment of asthma, they have been shown to alleviate the symptoms and the decrement in lung function seen in nocturnal 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 decrease nighttime 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 include time 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 early morning 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 the stomach 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 is required. 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 is film 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 system Layered 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 . The two 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
  24. 24. ISSN: 2321-5674(Print) ISSN: 2320 – 3471(Online) Papola Vibhooti Indian Journal of Research in Pharmacy and Biotechnology Volume 1(3) May-June 2013 Page 294 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 device has been used in the treatment of Parkinsonian patients using L-- dopa/benserazide. Nighttime problems and early-morning symptoms of Parkinsonism can be avoided by using a dualrelease Geomatrix@ formulation, which allows 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 dosage forms [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 different coating 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 direct compression of both the core and the coat, obviating the need for a separate coating process and the use of coating solutions. 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 the technique are that relatively large amounts of coating materials are needed and it is difficult to position the cores correctly for the coating process. Conte et al have developed a press coated device in which the inner core contains the drug and the outer coat is made of different types of polymers. The outer barrier, which controls drug release, 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 sodium alginate have been used in the coat to control drug release. In recent years, various controlled release, especially time-controlled release; drug delivery systems based on 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,
  25. 25. ISSN: 2321-5674(Print) ISSN: 2320 – 3471(Online) Papola Vibhooti Indian Journal of Research in Pharmacy and Biotechnology Volume 1(3) May-June 2013 Page 295 CEFORMR, DIFFUCAPSR, chronomodulating infusion pumps, TIMERxR, threedimensional printing, controlled-release (CR) erodible polymer and CR microchip strategies. Readers may find advantages and disadvantages 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 FDA electronic 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 by solvating the polymer with a volatile polar solvent and reacting the solvated cellulose polymer directly with the aliphatic alcohol, preferably as a melt. This constitutes the complex having utility as a matrix in controlled release formulations since it has a uniform porosity (semipermeable matrixes) which may be varied. This technology has concretely enabled the development of tablet forms of sustained-release aminophylline, theophylline, morphine, and other drugs. Research suggested that evening administration of UniphylR (anhydrous theophylline) tablets represented 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 the future. 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, drug release 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 drug administration in disease therapy has significant impact upon treatment success, chronotherapeutics remains an important 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. In addition, 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 high values during the day and fall at night. Similarly, all other physiological functions and activities are subject to a daily cyclical variation known as their circadian rhythm. The respiratory function is no exception and is known to experience 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 by morning 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 Pharmacol Pharmacodynamics 3(3): 2011; 140-147. Alexander A, Sharma S, Ajazuddin, Giri TK, Swarna, Shukla P. Various evaluation parameters used for the evaluation of different mucoadhesive dosage forms. A review. Inter. J. Drug Formulation res 2011; 2:1-26. Ali J, Baboota S, Ahuja A, Saigal N. Distinctive features of “chronotherapeutic” and “pulsatile” drug delivery
  26. 26. ISSN: 2321-5674(Print) ISSN: 2320 – 3471(Online) Papola Vibhooti Indian Journal of Research in Pharmacy and Biotechnology Volume 1(3) May-June 2013 Page 296 systems negating the practice of their interchangeable terminology. J. Drug Target 2010; 18 (6):413–419. Awasthi R, Kumar P, Pawar VK. Chronotherapy: science and technology of drug scheduling on the basis of biological rhythm. JChrDD 2010; 1: 09-18. Ballard R. D, Pak J,White D.P, Influence of posture and sustained loss of lung volume on pulmonary function in asthmatics. Am. Rev. Respir. Dis. 144, 1991, 499–503 Ballard R. D., Saathoff M. C., Patel D. K., Kelly P. L, Martin RJ, Effect of sleep on nocturnal bronchoconstriction and ventilatory patterns in asthmatics. J. Appl. Physiol. 67, 1989, 243–249. Ballard R. D.,Irvin C. G., Martin R. J., Pak J.,Pandey R., White D.P, Influence of sleep on lung volumes in asthmatic patients and normal subjects, J. Appl. Physiol, 68, 1990, 2034–2041 Ballard, R.D., M. C. Saathoff, D. K. Patel, P. L. Kelly, and R. J. Martin, Effect of sleep on nocturnal bronchoconstriction and ventilator patterns in asthmatics, J. Appl. Physiol. 67, 1989, 243–249. Beam, W. R., D. E. Weiner, and R. J. Martin, Timing of prednisone and alterations of airways inflammation in nocturnal asthma, Am. Rev. Respir. Dis, 146, 1992, 1524–1530. Bellofiore, S., G. U. diMaria, and J. G. Martin, Changes in upper and lower airway resistance after inhalation of antigen in sensitized rats, Am. Rev. Respir. Dis, 136, 1987, 363–368. Brugman S. M.,Larsen G. L.,Henson P.M, Honor J.,Irvin CG, Increased lower airways responsiveness associated with sinusitis in a rabbit model. Am. Rev. Respir. Dis. 147, 1993, 314–320 Catterall, J. R., G. B. Rhind, and I. C. Stewart, Effect of sleep deprivation on overnight bronchial constriction in nocturnal asthma, Thorax 41, 1986, 676–680. Clark, T. J. H., and M. R. Hetzel, Diurnal variation of asthma, Br. J. Dis. Chest 71, 1977, 87–92 Corren J, Adinoff A.D., Irvin CG, Changes in bronchial responsiveness following nasal provocation with allergen, J. Allergy Clin. Immunol, 89, 1992, 611–618. D’Alonzo, G. E, M. H. Smolensky, S. Feldman, Y. Gnosspelius, and K Karlsson, Bambuterol in the treatment of asthma, Chest, 107, 1995, 406– 412. D’Alonzo, G. E., M. H. Smolensky, S. Feldman, L. A. Gianotti, M. B.Emerson, H. Staudinger, and V. W. Steinijans, Twenty-fourhour lung function in adult patients with asthma, Am. Rev. Respir. Dis, 142, 1990, 84–90 Desjardin J. A, Sutarik J. M, Suh B. Y, Ballard R.D, Influence of sleep on pulmonary capillary blood volume in normal and asthmatic subjects. Am. J. Respir. Crit. Care Med. 152, 1995, 193–198 DevdhawalaMehulG.and Seth Avinash K. Current status of chronotherapeutic drug delivery system: An overview. J Chem Pharm Res 2010; 2(3):312-328. Elliott WJ. Timing treatment to the rhythm of disease, A short course in chronotherapeutics. Postgrad Med 2001; 110: 119–212 (1125–126, 129). Fitzpatrick, M. F., H. Engelman, K. F. Whyte, I. J. Deary, C. M. Shapiro, and N. J. Douglas, Morbidity in nocturnal asthma: sleep quality and daytime cognitive performance, Thorax 46, 1991, 569–573. Fitzpatrick, M. F., T. Mackay, H. Driver, and N. J. Douglas, Salmeterol in nocturnal asthma: a double-blind, placebo-controlled trial of a long-acting inhaled b2 agonist, Br. Med. J. 301, 1990, 1365–1368 Halberg F, Haus E, Cardoso SS, Scheving LE, Kuhl JFW, Shiotsuka R, Toward a chronotherapy of neoplasia: tolerance of treatment depends upon host rhythms, Experientia, 29, 1973, 909 - 1044. Halberg F, Stephens AN. Susceptibility to ouabain and physiologic circadian periodicity, Proc Minn Acad Sci, 27, 1959, 139 - 43. Haus E, Chronobiology in the endocrine system, Advanced Drug Delivery Reviews, 59, 2007, 985 - 1014.
  27. 27. ISSN: 2321-5674(Print) ISSN: 2320 – 3471(Online) Papola Vibhooti Indian Journal of Research in Pharmacy and Biotechnology Volume 1(3) May-June 2013 Page 297 Hetzel, M. R., and T. J. H. Clark, Comparison of normal and asthmatic circadian rhythms in peak expiratory flow rate, Thorax, 35, 1980, 732– 738. Hizli FG, Agar gun MY. Delayed Sleep Phase Type Sleep Disorder and Chronotherapy. Turkish Journal of Psychiatry 2009:1 - 5. Hrushesky WJM, Von Roemeling R, Lanning RM, Rabatin JT, Circadian-shaped infusion of floxuridine for progressive metastatic renal cell carcinoma, J ClinOncol, 8, 1990, 1504 - 1513. Lemmer B, The clinical relevance of chronopharmacology in therapeutics. Pharmacol Res, 33, 1996, 107–115. Lin SY. Chronotherapeutic approach to design a thermo responsive membrane for transdermal drug delivery. Curr Drug Deliv 2004; 1: 249–263. Litinski M, Scheer FA, Shea SA. Influence of the circadian system on Disease severity. Sleep Med Clin 2009; 4: 143–163. Montplaisir, J., J. Walsh, and J. L. Malo, Nocturnal asthma: features of attacks, sleep and breathing patterns. Am. Rev. Respir. Dis,125, 1982, 18–22. Moore J. G., Englert E, Circadian rhythm of gastric acid secretion in man. Nature 226, 1970, 1261–1262. Morrison, J. F. J., and S. B. Pearson, The effect of the circadian rhythm of vagal activity on bronchomotor tone in asthma, Br. J. Clin. Pharmacol, 28, 1989, 545–549. Ohdo S. Changes in Toxicity and Effectiveness with Timing of Drug administration Implications for Drug Safety Drug Safety. 2003; 26 (14): 999-1010. Ohdo S. Chronopharmaceutics: pharmaceutics focused on biological rhythm. Biol Pharm Bull 2010; 33:159–167. Ohdo S. Chronotherapeutic strategy: rhythm monitoring, manipulation and disruption. Adv Drug Deliv Rev 2010; 62: 859–875. Pincus, D. J., S. J. Szefler, L. M. Ackerson, and R. J. Martin, Chronotherapy of asthma with inhaled steroids: the effect of dosage timing on drug efficacy, J. Allergy Clin. Immunol, 95, 1995, 1172–1178. Reinberg, A., P. Gervais, M. Chaussade, G. Fraboulet, and B. Duburque, Circadian changes in effectiveness of corticosteroids in eight patients with allergic asthma, J. Allergy Clin. Immunol, 71, 1983, 425–433. Ritschel W.A. and Sabouni A, Permeability of [3H] water across a porous polymer material used as rate-limiting shell in compression-coated tablets, J. Controlled Release 12, 1990, 97-102. Robertson, C. E., A. R. Rubinfeld, and G. Bowej, Deaths from asthma in Victoria: a 12-month study. Med. J. Austr. 152, 1990, 511–517 Robertson, C.E., Rubinfeld, A.R., Bowej G, Deaths from asthma in Victoria: a 12-month study. Med. J. Austr. 152, 1990, 511-517 Saigal N, Baboota S, Ahuja A, Ali J. Site Specific Chronotherapeutic Drug Delivery Systems: A Patent Review. Recent Patents on Drug Delivery & Formulation. 2009; 3: 64-70. Selby, C., H. M. Engleman, M. F. Fitzpatrick, P. M. Sime, T. W. MacKay, and N. J. Douglas, Inhaled salmeterol or oral theophylline in nocturnal asthma? Am. J. Respir. Crit. Care Med, 155, 1997, 104–108 Smolensky M.H, Chronobiology and chronotherapeutics: Applications to cardiovascular medicine, Am J Hypertens, 9, 1986, 11S-21 S. Tan W. C.,Martin R. J.,Pandey R.,Ballard R. D, Effects of spontaneous and simulated gastroesophageal reflux on sleeping asthmatics. Am. Rev. Respir. Dis. 141, 1990, 1394–1399. Traynor K, Newton DW, Hrushesky JM, Reiter RJ. A pharmacist's primer on chronotherapeutics. American Pharmacy1992; 3:261-269. Vener KJ, Reddy A. Timed treatment of the arthritic diseases: a review and hypothesis, Arthritis Rheum, 22,
  28. 28. ISSN: 2321-5674(Print) ISSN: 2320 – 3471(Online) Papola Vibhooti Indian Journal of Research in Pharmacy and Biotechnology Volume 1(3) May-June 2013 Page 298 1992, 83– 97. Watson W. T. A., Becker A. B., Simons F. E. R, Treatment of allergic rhinitis with intranasal corticosteroids in patients with mild asthma: effect on lower airway responsiveness, J. Allergy Clin. Immunol, 91, 1993, 97–101. Wenzel, S. E., J. B. Trudeau, D. A. Kaminsky, J. Cohn, R. J. Martin, and J. Y. Westcott, Effect of 5-lipoxygenase inhibition on bronchoconstriction and airway inflammation in nocturnal asthma, Am. J. Respir. Crit. Care Med, 152, 1995, 897–905. Youan BIBC. Chronopharmaceutics: Gimmick or clinically relevant approach to drug delivery. J Controlled Release. 2004; 98: 337 - 53. Youan BIBC. Chronopharmaceutics: Gimmick or clinically relevant approach to drug delivery. J Controlled Release 2004; 98: 337 - 53.
  29. 29. ISSN: 2321-5674(Print) ISSN: 2320 – 3471(Online) Hemant Singh Indian Journal of Research in Pharmacy and Biotechnology Volume 1(3) May-June 2013 Page 299 RECENT TRENDS IN SCOPE AND OPPORTUNITY OF CLINICAL RESEARCH IN INDIA Hemant Singh* , Abhinav Srivastva I.E.C. College of Eng & Technology, Greater Noida. *Corresponding author:hemanthsingh198611@gmail.com ABSTRACT Clinical Research is one of the most knowledge-intensive industry. It is complete biography of drug from its inception in the lab to its introduction to the consumer market and beyond. Any molecule is identified is subjected to pre-clinical and clinical trials before entering in to market. Though post marketing surveillance is also part of the same. Pre-clinical studies are associated with effect of drug on animals. All the toxicological studies, tests for teratogenicity, carcinogenicity are carried out.After this, the data obtained from the studies are submitted as an IND (Investigational Drug Application) to take permission for human studies. Then, it is enter in to clinical trials. There are 4 phases in it. It is very clear that India has become a very preferred destination for clinical research. The industry is growing exponentially and is expected to reach Rs. 7000 Cr by 2010. Statics shows that if India's clinical trial business grows to 10% of that in US by 2015, the industry will need approximately 50,000 clinical research professionals. Key Words: Clinical Research, healthy volunteers, Clinical Trial Phases. INTRODUCTION Clinical Research is a systematic study to evaluate the effectiveness and safety of medications or medical devices by monitoring their effects on large groups of people. Clinical research has become a multi-billion and multidisciplinary industry. A number of factors favor India as a clinical research hub. There are numerous government-funded medical and pharmaceutical institutions with state-of-the-art facilities, which can serve as ideal centers for multi-centered clinical trials.India boasts of well-trained and qualified manpower, well versed in English. The research and the development process in India can be done at a more affordable price. More importantly, there is vast clinical material, which can be utilised, due to the prevalence of a large variety of diseases, including widespread cases of cancer and diabetes, India is viewed the world over as the ideal location for clinical research trials for the pharmaceutical industry.India is becoming a hub for clinical research; the demand for professionals in this field is growing rapidly. Clinical research business in India will be worth $1 billion by 2010. Thus, there will soon be a massive demand for clinical research professionals, making it an interesting career option with massive growth potential. According to a survey, there are 2,50,000 vacancies available worldwide 50,000 job openings in India by 2010. Highest remuneration packages owing to the shortage of skilled professionals.There are high demand for trained professionals in this field; the pay package is impressive at the entry level. Freshers can expect a pay packet of around three lakhs or more per anum. If you have a master’s degree backing your qualifications, then the amount is almost doubles. Clinical research is an industry where experience counts, thus the longer you are in this field; higher the salary you can expect.So there is really a very good scope for clinical research in India. HUMAN CLINICAL TRIAL PHASES Phase I: Studies assess the safety of a drug or device. This initial phase of testing, which can take several months to complete, usually includes a small number of healthy volunteers (20 to 100), who are generally paid for participating in the study. The study is designed to determine the effects of the drug or device on humans including how it is absorbed, metabolized, and excreted. This phase also investigates the side effects that occur as dosage levels are increased. About 70% of experimental drugs pass this phase of testing. Phase II: Studies test the efficacy of a drug or device. This second phase of testing can last from several months to two years, and involves up to several hundred patients. Most phase II studies are randomized trials where one group of patients receives the experimental drug, while a second "control" group receives a standard treatment or placebo. Often these studies are "blinded" which means that neither the patients nor the researchers know who has received the experimental drug. This allows investigators to provide the pharmaceutical company and the FDA with comparative information about the relative safety and effectiveness of the new drug. About one-third of experimental drugs successfully complete both Phase I and Phase II studies.
  30. 30. ISSN: 2321-5674(Print) ISSN: 2320 – 3471(Online) Hemant Singh Indian Journal of Research in Pharmacy and Biotechnology Volume 1(3) May-June 2013 Page 300 Phase III: Studies involve randomized and blind testing in several hundred to several thousand patients. This large-scale testing, which can last several years, provides the pharmaceutical company and the FDA with a more thorough understanding of the effectiveness of the drug or device, the benefits and the range of possible adverse reactions. 70% to 90% of drugs that enter Phase III studies successfully complete this phase of testing. Once Phase III is complete, a pharmaceutical company can request FDA approval for marketing the drug. Phase IV: Studies, often called Post Marketing Surveillance Trials, are conducted after a drug or device has been approved for consumer sale. Pharmaceutical companies have several objectives at this stage to compare a drug with other drugs already in the market; to monitor a drug's long-term effectiveness and impact on a patient's quality of life; and to determine the cost-effectiveness of a drug therapy relative to other traditional and new therapies. Phase IV studies can result in a drug or device being taken off the market or restrictions of use could be placed on the product depending on the findings in the study. SCOPE FOR CLINICAL RESEARCH IN SOUTH ASIAN NATIONS With a very large number of drugs, worth more than $50 billion in annual revenues, coming off patent in the next few years, many western pharma companies are now increasingly relinquishing business activities that are not considered core, such as clinical research, and are moving towards contract research. Since in the western countries, clinical research is characterized by extremely high costs and long gestation periods and the same work can be performed in developing countries at a fraction of the cost and much faster, many global pharma companies are increasingly turning their attention to Asia to benefit from low R&D costs in the region and also to gain access to Asia's drug markets. Clinical trials have thus gone ‘global,’ because CROs find it easier to conduct them in underdeveloped countries, as this is cheaper or has less ethical encumbrances or legal risks. Naïve patient populations, English speaking doctors, low costs and other advantages offered by developing countries have opened up new avenues for the clinical trials market. Hence there is lot of scope for clinical research activities for the South Asian nations if they make use of the upcoming opportunities in this field. India: The future of clinical research in India continues to be hazy. While on the one hand there are predictions that India will be the next hotspot for clinical trials, on the other , industry forums speak of ongoing challenges and stagnant growth for a variety of reasons, such as regulatory delays in approval, escalating costs, inconsistent quality, ethical irregularities etc. While several CROs have started operations in India basing their future on the rosy predictions, it is equally true that existing players are struggling to grow or even sustain their current business. Since registration of clinical trials in Clinical Trial Registry of India (CTRI) was made mandatory from mid-2009 onwards, close to 1800 trials have been registered in this database. Of these, about 69 per cent are sponsored by the pharmaceutical industry (both multinational and Indian companies), the rest being funded by grants from various government and not-for-profit institutions (e.g. DBT, CSIR, AIIMS, ICMR, Ministry of Defence,). Indian CROs can now look forward for more opportunities to conduct clinical studies within the generic space. For drugs that are not absorbed in the GI tract, plasma concentrations are not useful to determine delivery of the drug to the site of activity, and hence bioequivalence of the generic product to the innovator cannot be established by BA/BE studies. In such cases, one needs to demonstrate therapeutic equivalence with clinical or pharmaco-dynamic studies. Assocham had predicted that India would garner about 15 per cent of the global clinical trials opportunity. However, out of over 1,00,000 human trials being conducted in 178 countries, less than 2,000 (two per cent) are being done in India compared to over 9,000 (nine per cent) in China. Some of the advantages that India offers as a clinical trial destination are : availability of diverse patient population across major therapeutic segments such as oncology, metabolics, neurology etc; high degree of compliance to international guidelines such as the ICH GCP and the regulations laid down by the US FDA; availability of well qualified, English speaking research professionals including physicians; lower costs compared to the west; increasing prevalence of illnesses common to both developed and developing countries; availability of good infrastructure and changes in Patent Laws since January 2005. Bangladesh: According to an article in The Pharma World, leading health Journal in Bangladesh, notwithstanding its potential, clinical research is still underdeveloped in Bangladesh. There is a lack of capacity for bioequivalence studies, no analytical capacity (samples have to be shipped to foreign countries such as Singapore for any analytical treatment) and limited bio-banking and documentation of clinical specimens. There

×