Volume 1 Issue 4 www.ijrpb.com July - August 2013
Indian Journal of Research in Pharmacy and Biotechnology
ISSN: 2320-3471...
Volume 1 Issue 4 www.ijrpb.com July - August 2013
INDIAN JOURNAL OF RESEARCH IN PHARMACY AND BIOTECHNOLOGY
Instructions to...
Indian Journal of Research in Pharmacy and Biotechnology
ISSN: 2320-3471 (Online)
ISSN: 2321-5674 (Print)
Volume 1 Issue 4...
Indian Journal of Research in Pharmacy and Biotechnology
ISSN: 2320-3471 (Online)
ISSN: 2321-5674 (Print)
Volume 1 Issue 4...
ISSN: 2321-5674(Print)
ISSN: 2320 – 3471(Online)
Mahesh and Praveen Indian Journal of Research in Pharmacy and Biotechnolo...
ISSN: 2321-5674(Print)
ISSN: 2320 – 3471(Online)
Mahesh and Praveen Indian Journal of Research in Pharmacy and Biotechnolo...
ISSN: 2321-5674(Print)
ISSN: 2320 – 3471(Online)
Mahesh and Praveen Indian Journal of Research in Pharmacy and Biotechnolo...
ISSN: 2321-5674(Print)
ISSN: 2320 – 3471(Online)
Shoba Krushnan et.al Indian Journal of Research in Pharmacy and Biotechno...
ISSN: 2321-5674(Print)
ISSN: 2320 – 3471(Online)
Shoba Krushnan et.al Indian Journal of Research in Pharmacy and Biotechno...
ISSN: 2321-5674(Print)
ISSN: 2320 – 3471(Online)
Shoba Krushnan et.al Indian Journal of Research in Pharmacy and Biotechno...
ISSN: 2321-5674(Print)
ISSN: 2320 – 3471(Online)
Shoba Krushnan et.al Indian Journal of Research in Pharmacy and Biotechno...
ISSN: 2321-5674(Print)
ISSN: 2320 – 3471(Online)
Shoba Krushnan et.al Indian Journal of Research in Pharmacy and Biotechno...
ISSN: 2321-5674(Print)
ISSN: 2320 – 3471(Online)
Shoba Krushnan et.al Indian Journal of Research in Pharmacy and Biotechno...
ISSN: 2321-5674(Print)
ISSN: 2320 – 3471(Online)
Srinivas et.al Indian Journal of Research in Pharmacy and Biotechnology
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ISSN: 2321-5674(Print)
ISSN: 2320 – 3471(Online)
Srinivas et.al Indian Journal of Research in Pharmacy and Biotechnology
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ISSN: 2321-5674(Print)
ISSN: 2320 – 3471(Online)
Srinivas et.al Indian Journal of Research in Pharmacy and Biotechnology
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ISSN: 2321-5674(Print)
ISSN: 2320 – 3471(Online)
Srinivas et.al Indian Journal of Research in Pharmacy and Biotechnology
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ISSN: 2321-5674(Print)
ISSN: 2320 – 3471(Online)
Srinivas et.al Indian Journal of Research in Pharmacy and Biotechnology
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ISSN: 2321-5674(Print)
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Srinivas et.al Indian Journal of Research in Pharmacy and Biotechnology
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Harish et.al Indian Journal of Research in Pharmacy and Biotechnology
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Harish et.al Indian Journal of Research in Pharmacy and Biotechnology
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ISSN: 2321-5674(Print)
ISSN: 2320 – 3471(Online)
Harish et.al Indian Journal of Research in Pharmacy and Biotechnology
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Harish et.al Indian Journal of Research in Pharmacy and Biotechnology
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Sowjanya et.al Indian Journal of Research in Pharmacy and Biotechnology
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ISSN: 2320 – 3471(Online)
Sowjanya et.al Indian Journal of Research in Pharmacy and Biotechnology
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Sowjanya et.al Indian Journal of Research in Pharmacy and Biotechnology
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Sowjanya et.al Indian Journal of Research in Pharmacy and Biotechnology
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Sowjanya et.al Indian Journal of Research in Pharmacy and Biotechnology
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Sowjanya et.al Indian Journal of Research in Pharmacy and Biotechnology
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Sowjanya et.al Indian Journal of Research in Pharmacy and Biotechnology
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Navin et.al Indian Journal of Research in Pharmacy and Biotechnology
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Indian journal of research in pharmacy and biotechnology  4
Indian journal of research in pharmacy and biotechnology  4
Indian journal of research in pharmacy and biotechnology  4
Indian journal of research in pharmacy and biotechnology  4
Indian journal of research in pharmacy and biotechnology  4
Indian journal of research in pharmacy and biotechnology  4
Indian journal of research in pharmacy and biotechnology  4
Indian journal of research in pharmacy and biotechnology  4
Indian journal of research in pharmacy and biotechnology  4
Indian journal of research in pharmacy and biotechnology  4
Indian journal of research in pharmacy and biotechnology  4
Indian journal of research in pharmacy and biotechnology  4
Indian journal of research in pharmacy and biotechnology  4
Indian journal of research in pharmacy and biotechnology  4
Indian journal of research in pharmacy and biotechnology  4
Indian journal of research in pharmacy and biotechnology  4
Indian journal of research in pharmacy and biotechnology  4
Indian journal of research in pharmacy and biotechnology  4
Indian journal of research in pharmacy and biotechnology  4
Indian journal of research in pharmacy and biotechnology  4
Indian journal of research in pharmacy and biotechnology  4
Indian journal of research in pharmacy and biotechnology  4
Indian journal of research in pharmacy and biotechnology  4
Indian journal of research in pharmacy and biotechnology  4
Indian journal of research in pharmacy and biotechnology  4
Indian journal of research in pharmacy and biotechnology  4
Indian journal of research in pharmacy and biotechnology  4
Indian journal of research in pharmacy and biotechnology  4
Indian journal of research in pharmacy and biotechnology  4
Indian journal of research in pharmacy and biotechnology  4
Indian journal of research in pharmacy and biotechnology  4
Indian journal of research in pharmacy and biotechnology  4
Indian journal of research in pharmacy and biotechnology  4
Indian journal of research in pharmacy and biotechnology  4
Indian journal of research in pharmacy and biotechnology  4
Indian journal of research in pharmacy and biotechnology  4
Indian journal of research in pharmacy and biotechnology  4
Indian journal of research in pharmacy and biotechnology  4
Indian journal of research in pharmacy and biotechnology  4
Indian journal of research in pharmacy and biotechnology  4
Indian journal of research in pharmacy and biotechnology  4
Indian journal of research in pharmacy and biotechnology  4
Indian journal of research in pharmacy and biotechnology  4
Indian journal of research in pharmacy and biotechnology  4
Indian journal of research in pharmacy and biotechnology  4
Indian journal of research in pharmacy and biotechnology  4
Indian journal of research in pharmacy and biotechnology  4
Indian journal of research in pharmacy and biotechnology  4
Indian journal of research in pharmacy and biotechnology  4
Indian journal of research in pharmacy and biotechnology  4
Indian journal of research in pharmacy and biotechnology  4
Indian journal of research in pharmacy and biotechnology  4
Indian journal of research in pharmacy and biotechnology  4
Indian journal of research in pharmacy and biotechnology  4
Indian journal of research in pharmacy and biotechnology  4
Indian journal of research in pharmacy and biotechnology  4
Indian journal of research in pharmacy and biotechnology  4
Indian journal of research in pharmacy and biotechnology  4
Indian journal of research in pharmacy and biotechnology  4
Indian journal of research in pharmacy and biotechnology  4
Indian journal of research in pharmacy and biotechnology  4
Indian journal of research in pharmacy and biotechnology  4
Indian journal of research in pharmacy and biotechnology  4
Indian journal of research in pharmacy and biotechnology  4
Indian journal of research in pharmacy and biotechnology  4
Indian journal of research in pharmacy and biotechnology  4
Indian journal of research in pharmacy and biotechnology  4
Indian journal of research in pharmacy and biotechnology  4
Indian journal of research in pharmacy and biotechnology  4
Indian journal of research in pharmacy and biotechnology  4
Indian journal of research in pharmacy and biotechnology  4
Indian journal of research in pharmacy and biotechnology  4
Indian journal of research in pharmacy and biotechnology  4
Indian journal of research in pharmacy and biotechnology  4
Indian journal of research in pharmacy and biotechnology  4
Indian journal of research in pharmacy and biotechnology  4
Indian journal of research in pharmacy and biotechnology  4
Indian journal of research in pharmacy and biotechnology  4
Indian journal of research in pharmacy and biotechnology  4
Indian journal of research in pharmacy and biotechnology  4
Indian journal of research in pharmacy and biotechnology  4
Indian journal of research in pharmacy and biotechnology  4
Indian journal of research in pharmacy and biotechnology  4
Indian journal of research in pharmacy and biotechnology  4
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  1. 1. Volume 1 Issue 4 www.ijrpb.com July - August 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 4 www.ijrpb.com July - August 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 4 www.ijrpb.com July – August 2013 S.No. Contents Page No. 1. Controversial role of antipsychotics in the treatment of Alzheimer’s disease Mahesh G, G Praveen Kumar 469-471 2. Formulation and evaluation of oro dispersible tablets of Amlodipine besylate Shobha Krushnan G, Ravi M Britto, Perianayagam J, Rajendra Prasad R 472-477 3. Comparision of potency of anti bacterial activity and anti inflammatory activity of 10 years and 100 years old bark extracts of Azadirachta indica Vijaya Kumar G, Srinivas N, P Sravanthi, Sravani B 478-483 4. Development and evaluation of carisoprodol tablets with improved dissolution efficiency using solid dispersion technique Mogili Daya Sagar, Mohammed Shahidullah, Shaik Rabbani Basha, Shaik Shahnaz, Harish.G 484-487 5. Transdermal drug delivery systems R.sowjanya, Salman Khan, D.Bhowmik, Harish.G, S.Duraivel 488-495 6. Synthesis of new thiazolidine-2,4-dione derivatives and their antimicrobial and antitubercular activity Faiyazalam M Shaikh, Navin B Patel and Dhanji Rajani 496-503 7. Effects of permeability characteristics of different polymethacrylates on the pharmaceutical characteristics of diltiazem hcl-loaded microspheres V. Kamalakkannan, K.S.G.Arul Kumaran, C. Kannan, S.Bhama, R. Sambath Kumar 504-511 8. Importance of safety health environment in preventing occupational health hazards in indian industries Murty TN, Md Aasif Siddique Ahmed Khan, Abhinov T, Abhilash T 512-516 9. Optimization of Thiocolchicoside tablet with permeation enhancers using 32 factorial design Devendra Singh, Pankaj Kumar Sharma, Udai Vir Singh Sara 517-524 10. Method development and validation for the simultaneous estimation of Desvenlafaxine and Clonazepam in bulk & tablet formulation by RP-HPLC method Regalagadda Mallikarjuna, Nanda Kishore Agarwal, Prem Kumar Bichala, Sukhen Som 525-532 11. Plant seeds used for anthelmintic activity: A review Shambaditya Goswami, Sanjeev Nishad, Mayank Rai, Sarvesh Madhesiya, Ankita Malviya, Pawan Pandey, Vikram Gautam, Sujeet Yadav 533-536 12. Development and validation of pemetrexed by RP-HPLC method in bulk drug and pharmaceutical dosage forms Suresh Kumar Agrawal, Devendra Singh Rathore 537-542 13. Stability indicating RP-HPLC method for the estimation of Ceftazidime pentahydrate and Tazobactam sodium in bulk and dosage forms S. Amareswari, Nandakishore Agarwal, Md Aasif Siddique Ahmed Khan 543-548 14. Effect of hydrotropic solute on in-vitro charecterization of Valsartan fast disintegrating tablets Madhu Sudhan Reddy A, Kishore Babu G, Srinivasa Babu P, Bhardwaj G 549-553 15. A review on Gloriosa superba l as a medicinal plant Kavithamani D, Umadevi M, Geetha S 554-557 16. Formulation and evaluation of floating drug delivery system of Clarithromycin tablets Priyanka Shukla, Ajay Yadav 558-561 17. Antifungal activity of ethanolic extract of Eupatorium adenophorum leaves Dharmendra Kumar Singh, Ranjeet Singh 562-564
  4. 4. Indian Journal of Research in Pharmacy and Biotechnology ISSN: 2320-3471 (Online) ISSN: 2321-5674 (Print) Volume 1 Issue 4 www.ijrpb.com July – August 2013 18. Formulation of mouth dissolving tablets of Naproxen Rajesh Reddy K, Nagamahesh Nandru, Desam Asha Latha, Srinivasa Rao Chekuri 565-569 19. Preparation of immediate release Atorvastatin and sustained release matrix tablets of Gliclazide using retardant hydroxypropyl methyl cellulose Vinod Raghuvanshi, Jayakar B, Debjit Bhowmik, Harish G, Dureivel S 570-574 20. Phytochemical sreening and antidiabetic antioxidant effect of Ecbolium ligustrinum flowers extracts Ranjitsingh B Rathor, Rama Rao D, Prasad Rao 575-580
  5. 5. ISSN: 2321-5674(Print) ISSN: 2320 – 3471(Online) Mahesh and Praveen Indian Journal of Research in Pharmacy and Biotechnology Volume 1(4) July-August 2013 Page 469 CONTROVERSIAL ROLE OF ANTIPSYCHOTICS IN THE TREATMENT OF ALZHEIMER’S DISEASE Mahesh G*1 , G Praveen kumar2 1. School of Pharmaceutical sciences, Vels University, Chennai. 2. C.L. Baid Metha College of Pharmacy, Chennai, Tamil Nadu. *Corresponding author: Mail Id: udaynagamahesh@hotmail.com ABSTRACT Antipsychotics are the commonly prescribed drugs in the treatment of Alzheimer’s disease, which is the most common form of dementia. Atypical antipsychotics are an effective short-term (6-12 weeks) treatment in relieving the depression, psychotic symptoms (hallucinations and delusions) and behavioral disturbances (physical and verbal aggression, motor hyperactivity, repetitive mannerisms and activities, and combativeness). But several placebo studies & clinical based evidences which recorded the deaths of the patients concluded that this medication nearly doubles the risk of death in patients over two to three years by developing cerebrovascular adverse events, upper respiratory infections, oedema or extra pyramidal symptoms. The use of selective serotonin reuptake inhibitors (SSRI’s), Nor- epinephrine reuptake inhibitors (NERI’s) and Tricyclic antidepressants (TCA’S) may relieve depression but still they are associated with serious adverse effects such as insomnia, agitation, confusion and GI adverse effects. So there is a need for applying non-pharmacological treatment i.e. Psychotherapy rather than the Pharmacotherapy in minimizing the symptoms & anticipates further research in developing the appropriate medication, alternative to the antipsychotics which minimizes the suffering of the patient. Typical antipsychotics were the first generation of the drugs aimed to treat psychosis by antagonizing D2 receptors. As a result, they reduce dopaminergic neurotransmission in the four dopamine pathways. Typical Antipsychotics include Chlorpromazine, Chlorprothixene, and Haloperidol etc. Atypical Antipsychotics are the drugs which not only block dopamine receptors but also serotonin receptors.Risperidone, Olanzapine, Quetiapine, Aripiprazole, Clozapine, Ziprasidone include Atypical Antipsychotics. Key words: Antipsychotics, Alzheimer’s disease, Atypical Antipsychotics, Typical antipsychotics INTRODUCTION Atypical antipsychotics are not the FDA approved drugs for the treatment of behavioral & psychotic symptoms in dementia (BPSD). Placebo-controlled trials revealed increased mortality rate in patients those treated with Atypical Antipsychotics. The mostly prescribed Antipsychotics include Risperidone, olanzapine, quetiapine & Haloperidol (Typical Antipsychotic). Alzheimer’s disease majorly affects the Hippocampus & Cerebral cortex of the brain with the formation of Neurofibrillary tangles & Neuritic plaques which leads to the degeneration of cortex, cholinergic & other neurons (Amresh Shrivastava, 1999). 15 out of 17 Placebos controlled trials showed increased mortality in the drug treated group compared to the Placebo treated patients (Monasterio E, 2011). It involves Risperidone (7trials), Olanzapine (5trials), Quetiapine (2 trials) & Aripiprazole (3 trials). 1.6-1.7 fold (i.e almost 2 times) increase in mortality is observed in active treatment over placebo (Forbes DA, 2005). Rate of death in drug treated patients was about 4.5%, compared to rate of about 2.6% in placebo group (Ballard, 2009). Specific causes of these deaths are cerebrovascular adverse events (heart failure with sudden death) or infections (mostly pneumonia). In 2005, FDA approved the Black box warning that “Atypical Antipsychotics increase the risk of death in dementia patients” (Cummings JL, 2002). The only FDA approved drugs for the treatment of Alzheimer’s disease is for improving the cognition i.e. for cognitive symptoms (memory loss, disorientation, impaired executive functions such as poor problem solving, planning, and attention, thinking, remembering & reasoning). Examples of drugs used for improving cognitive symptoms are Donepezil, Rivastigmine, Galantamine (Cholinesterase Inhibitors) and Memantine (N-methyl D-aspartate receptor antagonist).
  6. 6. ISSN: 2321-5674(Print) ISSN: 2320 – 3471(Online) Mahesh and Praveen Indian Journal of Research in Pharmacy and Biotechnology Volume 1(4) July-August 2013 Page 470 The U.S. Food and Drug Administration (FDA) have approved only five medications till now to treat the symptoms of Alzheimer's disease (Rayner AV, 2006). Slow titration of drugs with continuous monitoring of patient is essential to minimize the risk of adverse effects. The common adverse effects of AD medications include depression, insomnia, confusion, decreased weight, and diarrhea. So the Cholinesterase inhibitors, NMDA receptor antagonist & Atypical antipsychotics which are used in treating cognitive & non-cognitive symptoms (BPSD & depression) have wide side effects & high risk of adverse effects (Steffens, 2008) CONCLUSION The serious adverse effects due to the use of Atypical Antipsychotics in treating Behavioral & Psychotic symptoms in Dementia (BPSD) of Alzheimer’s disease concludes the limitation for the use of atypical-antipsychotics and their controversial role in the current existing treatment. Despite the FDA black box warning, antipsychotic use in dementia has remained remarkably frequent; a recent study of 16,586 nursing home patients reported that 29% receive at least one antipsychotic medication. As the warnings initially slowed the rate of increase in new prescriptions for atypical antipsychotics in patients with dementia, but there is no decrease in the overall prescription rate. (Devanand, 2011) Non pharmacological interventions which include Psychotherapy should be the primary intervention in treatment. The care giver should simplify the tasks to the patient by providing 3 R’s-Repeat, Reassure & Redirect. This improves the activities of daily living. The current existing medication only slows down the worsening of cognition & minimizes the BPSD but cant arrest the progression of Alzheimer’s disease. So there is an immediate need for developing new drugs which curbs & reverses the neuro degeneration with a cost effective treatment for Alzheimer’s disease (Treloar, 2010). Table.1.FDA approved medications for treating Alzheimer’s disease. Drug name Approved For FDA Approved Memantine Moderate to severe 2003 Galantamine Mild to moderate 2001 Rivastigmine Mild to moderate 2000 Donepezil All stages 1996 Tacrine Mild to moderate 1993 Figure 1: showing the presence of neurofibrillary tangles & neuritic plaques Figure 2: Comparison of Normal brain, early & late Alzheimer brain by Positron emission tomography (PET SCAN)
  7. 7. ISSN: 2321-5674(Print) ISSN: 2320 – 3471(Online) Mahesh and Praveen Indian Journal of Research in Pharmacy and Biotechnology Volume 1(4) July-August 2013 Page 471 Figure 3: Risk Perception In Typical & Atypical Antipsychotics Table 2: Cardiovascular risk factors associated with Atypical Antipsychotics REFERENCES Amresh Shrivastava, Megan Johnston, Kristen Terpstra, Larry Stitt, and Nilesh Shah, Atypical antipsychotics usage in long-term follow-up of first episode schizophrenia, Indian J Psychiatry, 54(3), 2012, 248–252. Ballard CG, Gauthier S, Cummings JL, Brodaty H, Grossberg GT, Robert P, Cyketsos CG, Management of agitation and aggression associated with Alzheimer’s disease, Nature Reviews, 5, 2009, 245-255. Cummings JL, Frank JC, Cherry D, Guidelines for managing Alzheimer's disease: part I. Assessment, Am Fam Physician, 65, 2002, 2263-2272 Devanand D P, Susan M D, Schultz K, Consequences of Antipsychotic Medications for the Dementia Patient, Am J Psychiatry, 168, 2011, 767-769. Forbes DA, Peacock S, Morgan D, Nonpharmacological management of agitated behaviors associated with dementia, Geriatrics and Aging, 8, 2005, 26-30. Monasterio E, McKean A, Off-label use of atypical antipsychotic medications in Canterbury, New Zealand, N Z Med J, 124, 2011, 1336. Rayner AV, O'Brien JG, Schoenbachler B, Behavior disorders of dementia: recognition and treatment, Am Fam Physician, 73, 2006, 647-652. Steinberg, M., Shao, H., Zandi, P., Lyketsos, C.G., Welsh-Bohmer, K.A., Norton, M.C.,Breitner, Steffens JC, Tschanz DC, Point and 5-year period prevalence of neuropsychiatric symptoms in dementia: the Cache County study, International Journal of Geriatric Psychiatry, 23(2), 2008, 170-177. Treloar A, Crugel M, Prasanna A, Solomons L, Fox C, Paton C, Katona C, Ethical dilemmas: should anti-psychotics ever be prescribed for people with dementia? British Journal of Psychiatry, 197(2), 2010, 88-90.
  8. 8. ISSN: 2321-5674(Print) ISSN: 2320 – 3471(Online) Shoba Krushnan et.al Indian Journal of Research in Pharmacy and Biotechnology Volume 1(4) July-August 2013 Page 472 FORMULATION AND EVALUATION OF ORO DISPERSIBLE TABLETS OF AMLODIPINE BESYLATE Shobha Krushnan G*, Ravi M Britto, Perianayagam J, Rajendra Prasad R Department of pharmaceutics, Aurobindo College of Pharmaceutical Sciences, Gangadevipally, Geesugonda, Warangal, Andhra Pradesh, India *Corresponding author: E.Mail: avinashjipz@gmail.com ABSTRACT Recent advances in technology have presented viable dosage forms alternative for patients who may have difficulty in swallowing tablets or capsules. Oro-dispersible tablet is one such approach in which the tablets were dispersed in the mouth rapidly. Amlodipine is a calcium channel blocker used in the treatment of hypertension and angina pectoris, where ultra-rapid action is required. In the present study Amlodipine Oro-dispersible tablets are formulated using sodium starch glycolate, croscarmellose sodium, crospovidone superdisintegrants. The tablets were prepared by direct compression technique and were evaluated for weight variation, friability, hardness, drug content, in-vitro disintegration time, wetting time, in-vitro dissolution studies. All the formulations follow compendia specifications. Formulations containing higher concentrations of sodium starch glycolate and cross povidone as superdisintegrant showed better dissolution profile and disintegration time. The bioavailability of amlodipine was increased by formulating amlodipine as ODT. Differential Scanning calorimetric study (DSC) and Fourier transform infrared spectroscopy (FTIR) were conducted for drug excipient compatibility study. Key words: Orodispersible tablets, Amlodipine, hypertension INTRODUCTION United States of America food and drug administration (FDA) defines oral dispersible tablet (ODT) as “A solid dosage form containing medicinal substances (or) active ingredient which disintegrates rapidly usually within a matter of seconds when placed upon a tongue”. Oral route of drug administration have widely accepted up to 50-60% of total dosage forms. Solid dosage forms are popular because of ease of administration, accurate dosage, self-medication, pain avoidance and most importantly the patient compliance. The most popular solid dosage forms are tablets and capsules having the drawback of these dosage forms for some patients, is the difficulty to swallow. Drinking water plays an important role in the swallowing of oral dosage forms. Often people experience inconvenience in swallowing conventional dosage forms such as tablet when water is not available, in the case of the motion sickness and sudden episodes of coughing during common cold, allergic condition and bronchitis. For these reasons, tablets that can rapidly dissolve or disintegrate in the oral cavity have attracted a great deal of attention. Oro- dispersible tablets are not only indicated for people who have swallowing difficulties, but also are ideal for active people (Valleri M, 2004). Fast dissolving tablets are also called as mouth-dissolving tablets, melt-in mouth tablets, oro- dispersible tablets, rapimelts, porous tablets, quick dissolving etc. Fast dissolving tablets are those when put on tongue disintegrate instantaneously releasing the drug, which dissolve or disperses in the saliva (Fu Y, 2004).The faster the drug into solution, quicker the absorption and onset of clinical effect. Some drugs are absorbed from the mouth, pharynx and esophagus as the saliva passes down into the stomach. In such cases, bio-availability of drug is significantly greater than those observed from conventional tablets dosage form (Ghosh TK, 2005, Deepak K, 2004). The basic approach in development of ODT is the use of superdisintegrants like cross linked carboxymethyl cellulose (croscarmellose), sodium starch glycolate (primogel, explotab), polyvinyl pyrollidone (Crosspovidone) etc, which provide instantaneous disintegration of tablet after placing on tongue, there by release the drug in saliva. The bioavailability of some drugs may be increased due to absorption of drug in oral cavity and also due to pre-gastric absorption of saliva containing dispersed drugs that pass down into the stomach. Moreover, the amount of drug that is subjected to first pass metabolism is reduced as compared to conventional tablet. The advantage of mouth dissolving dosage forms are increasingly being recognized in both, industry and academics. Their growing importance was underlined recently when European pharmacopoeia adopted the term “Oro-dispersible tablet” as a tablet that to be placed in the mouth where it disperses rapidly before swallowing. According to
  9. 9. ISSN: 2321-5674(Print) ISSN: 2320 – 3471(Online) Shoba Krushnan et.al Indian Journal of Research in Pharmacy and Biotechnology Volume 1(4) July-August 2013 Page 473 European pharmacopoeia, the ODT should disperse/disintegrate in less than three minutes. MATERIALS AND METHODS Amlodipine Besylate was received as gift sample from Micro labs, Hosur, Tamilnadu, India. Crospovidone(CP),Croscarmellosesodium(CCS),Sodiu mstarchglycolate(SSG),Lactose, Magnesium stearate and talc were used. And all other chemicals/solvents used were of analytical grade. Formulation of Amlodipine oro-dispersible tablets by direct compression method: The drug and all other excipients were accurately weighed and sifted through #40 sieves and mixed thoroughly. The above blend was lubricated with magnesium stearate. The formulation development of Amlodipine ODT was initially developed with different super-disintegrants, SSG, CCS and CP in the concentration range of 5%, 7.5% and 10%. The tablets were prepared by direct compression method. The tablets were compressed on 8 station rotary tablet punching machine (Rimek manufacturers, Gujarat, India) using 6mm round punch and the individual tablet weight was100mg. The prepared tablets were evaluated for different parameters like weight variation, friability, hardness, thickness, disintegration time, wetting time, assay and in vitro dissolution studies. Weight variation: Twenty tablets were randomly selected from each batch and individually weighed. The average weight of these selected tablets was calculated (Indian Pharmacopoeia, Vol ‐ I, 1996). Tablet thickness: Tablet thickness is an important characteristic in reproducing appearance and also in counting by using filling equipment. Thickness was recorded using vernier calliper. Friability: Friability is a measure of mechanical strength of the tablet. If a tablet has more friability it may not remain intact during packaging,transport or handling. Roche friabilator is used to determine the friability by following procedure. Pre weighed tablets are placed in the friabilator. Friabilator consist of a plastic chamber that revolves at 25 rpm, dropping those tablets at a distance of 6 inches with each revolution (Lachman L, 1987). The tablets are rotated in the friabilator for at least 4 minutes. At the end of test tablets are dusted and reweighed; the loss in the weight of tablet is the measure of friability. Crushing strength: Tablet crushing strength, which is the force required to break the tablet, was measured with a Pfizer tablet hardness tester. The hardness (crushing strength) of three tablets per batch was determined and mean taken. Drug content: Drug content was determined by taking randomly ten tablets per batch. An amount equivalent to 10 mg amlodipine was dissolved in methanol, suitably diluted with PH 7.2 Phosphate buffer and filtered (British pharmacopoeia commission 2007). The absorbance of the solution was measured spectrophotometrically against the blank (PH 7.2 Phosphate buffer) at 239 nm using a U.V.spectrophotometer (Shimazdu-1800, Japan). Wetting time: The wetting time of the tablet was measured by placing five circular tissue papers (10 cm in diameter) in a Petri dish of 10 cm diameter. Water (10 ml) containing methylene blue (0.1% w/v) was added to the Petri dish. A tablet was carefully placed on the surface of the tissue paper and the time required for the dye to reach the upper surface of the tablet was recorded as wetting time (Radke RS et al, 2009). The measurements were carried out in triplicate. Disintegration time: One tablet each was placed in each of the six tubes of the apparatus and time in seconds taken for complete disintegration of the tablet with no palatable mass remaining in the apparatus was measured. The tablet was considered disintegrated completely when all the particles passed through the screen. The disintegration time of 6 individual tablets were recorded and the average was reported. The disintegration time set by U.S. Food and Drug Administration (FDA) for all the ODT formulations (60 s) were considered as a specification limit (Bi Y, 1999). In-vitro drug release: In vitro drug release studies were carried out using USP type II apparatus at 50 rpm. Phosphate buffer (500 ml) at 7.2 was used as the dissolution medium. The temperature of the dissolution medium was maintained at 37±0.50 C (Bhagwati ST, 2000). An aliqout (5 ml) of dissolution medium was withdrawn at specific time intervals, filtered and suitably diluted prior to spectrophotometric analysis. Sink condition were maintained by replenishing the medium with an equal amount (5 ml) of dissolution fluid. Absorption of the solution was measured by UV spectroscopy (Shimadzu-1800, Japan) at 239 nm. Drug-Excipient Compatibility Study: Drug-excipient compatibility was performed by FTIR and DSC studies,
  10. 10. ISSN: 2321-5674(Print) ISSN: 2320 – 3471(Online) Shoba Krushnan et.al Indian Journal of Research in Pharmacy and Biotechnology Volume 1(4) July-August 2013 Page 474 a) Fourier Transform Infrared Spectroscopy (FT- IR): The FT-IR spectrums of pure drug and physical mixtures of drug with SSG, CCS and CP. FT-IR (Thermo Nicolet 670 spectrometer) was used for the analysis in the frequency range between 4000 and 400 cm-1 resolution. A quantity equivalent to 2 mg of pure drug was used for the study. b) Differential scanning calorimetric study (DSC study): Thermal properties of pure drug and physical mixtures of drug with SSG and CP were evaluated by Differential scanning calorimetry (DSC) using a Diamond DSC (Mettler Star SW 8.10). The analysis was performed at a rate 50 C min-1 from 500 C to 2000 C temperature range under nitrogen flow of 25 ml min-1. RESULTS AND DISCUSSION Weight variation and Thickness: The weight variation of all the formulations was within the range and the Thickness of the tablets found to be 2.7mm to 2.92mm. Hardness and Friability: The hardness was constantly maintained between 3-3.5 kg / cm2 during compression and Friability for all the formulation shown less than 1% which is in the acceptable limits which indicates formulations have good mechanical strength. Drug content and Wetting time: The drug content of Amlodipine from all the formulations was found in the range of 98% to 99% and Wetting time in above formulations found to be between 41-56 seconds Disintegration time: Disintegration time of formulations containing 5% SSG (F1),5% CCS (F2),5% CP (F3), found to be between 36-39 seconds. Disintegration time of formulations containing 7.5%SSG (F4), 7.5%CCS (F5), 7.5% CP (F6), found to 18-28 seconds. And disintegration time of formulations containing 10% SSG (F7), 10% CCS (F8), 10% CP (F9) found to be 9-13 seconds. Based on the above results it was clearly observed that the above formulations improved the disintegration with increased concentration of superdisintegrants. In-vitro dissolution: In this work the table No 5 shows dissolution profile of different formulation in which F7 and F9shows maximum % released and increases bioavailability hypothetically.As per USFDA guidelines ODT tablets, the tablets should disintegrate in less than 60 seconds, it should directly reflect on the mouth disintegration. Based on these considerations it was decided to increase the concentration of super- disintegrants in the further study. Fourier Transform Infrared Spectroscopy (FT-IR): The FTIR spectrum peak points of pure drug Amlodipine at 561.52, 613.36, 667.66, 753.76, 996.54, 1031.94, 1090.98, 1202.19, 1263.25, 1300.93, 1364.91, 1432.65, 1468.64, 1614.45, 1672.20, 1696.53, 2979.01 and 3154.55. Similar spectrum peak points were observed in all the formulations. This clearly indicates that there is no drug excipient interaction. Table 2 shows the spectrum peak points of the pure drug and the formulations of Amlodipine. Differential scanning calorimetric study (DSC): DSC study was conducted on the selected formulations. The DSC results shows sharp endothermic peak for pure Amlodipine at 209.98 °C. Similar sharp endothermic peaks were observed in the formulations at almost similar temperatures. This clearly indicates that there is no drug excipient interaction. CONCLUSION This present research work demonstrates that orodispersible tablet with higher percentage of superdisintegrant by direct compression technique yields a good pharmaceutically accepted dosage forms and show increased dissolution profiles which reflects enhanced bioavailability. ACKNOWLEDGEMENT The authors are thankful to Micro labs, Hour, Tamilnadu, India for providing gift sample of Amlodipine besylate and thankful to Principal of Aurobindo college of Pharmaceutical sciences, Gangadevipally, Warangal, Andhra Pradesh.
  11. 11. ISSN: 2321-5674(Print) ISSN: 2320 – 3471(Online) Shoba Krushnan et.al Indian Journal of Research in Pharmacy and Biotechnology Volume 1(4) July-August 2013 Page 475 Table 1: Formulation of Amlodipine Oro-dispersible tablet Ingredients (mg) F1 F2 F3 F4 F5 F6 F7 F8 F9 AMLODIPINE 10 10 10 10 10 10 10 10 10 SSG 5 - 7.5 - 10 - CCS - 5 - - 7.5 - - 10 - CP - - 5 - - 7.5 - - 10 LACTOSE 81 81 81 78.5 78.5 78.5 76 76 76 TALC 3 3 3 3 3 3 3 3 3 MG. STEARATE 1 1 1 1 1 1 1 1 1 Total Weight 100mg 100mg 100mg 100mg 100mg 100mg 100mg 100mg 100mg Table 2: FTIR spectrum peak points of pure drug and the formulation of Amlodipine Table 3: DSC melting points of the selected formulations Formulations DSC melting point in °C PURE AMLODIPINE 209.98 AMD -SSG 208.19 AMD -CP 206.12 Pure AMD WITH SSG WITH CCS WITH CP 561.52 561.09 561.58 559.55 613.36 613.38 613.20 609.53 667.66 666.54 667.22 665.63 727.94 727.22 726.36 726.37 753.76 753.48 752.92 752.59 996.54 998.12 997.24 997.02 1031.94 1032.81 1029.36 1029.22 1090.98 1089.94 1089.86 1089.70 1202.19 1202.44 1201.99 1202.13 1263.25 1263.89 1262.43 1262.77 1300.93 1301.42 1301.39 1299.89 1364.91 1365.00 1365.27 1365.22 1432.65 1431.33 1431.76 1431.61 1468.64 1470.12 1469.56 1469.56 1614.45 1613.36 1613.28 1613.12 1672.20 1672.98 1672.99 1672.18 1696.53 1695.30 1695.39 1694.80 2979.01 2980.52 2980.96 2980.34 3154.55 3155.03 3155.64 3155.42
  12. 12. ISSN: 2321-5674(Print) ISSN: 2320 – 3471(Online) Shoba Krushnan et.al Indian Journal of Research in Pharmacy and Biotechnology Volume 1(4) July-August 2013 Page 476 Table 4: Physicochemical Parameters of Amlodipine ODT Parameter F1 F2 F3 F4 F5 F6 F7 F8 F9 Weight Variation 100.1 101 102 100.3 102 102 100.2 100 101 Friability (%) 0.47 0.58 0.78 0.56 0.64 0.87 0.68 0.72 0.92 Hardness(Kg/Cm2 ) 3.0 3.1 3.0 3.0 3.5 3.0 3.5 3.2 3.5 Thickness (mm) 2.78 2.84 2.81 2.78 2.81 2.92 2.8 2.8 2.7 Disintegration time(Sec) 37.6 39.49 36.04 25.9 28.5 18.81 9.3 12.57 9.26 Wetting time(sec) 52 56 50 41 46 43 42 45 42 Drug content (%) 99 98 99 99 98 99 99 99 99 Table 5: In-vitro dissolution data Amlodipine ODT Time (min) F1 F2 F3 F4 F5 F6 F7 F8 F9 5 66.70 64.90 65.15 75.26 72.67 74.63 83.24 80.28 82.56 10 76.51 75.15 75.00 81.82 79.82 80.68 89.90 87.57 88.98 15 81.90 79.40 80.20 88.81 85.85 87.94 93.3 92.79 93.1 20 87.65 85.28 86.1 93.96 90.78 92.96 95.4 94.5 95.1 30 96.90 93.67 95.98 97.96 96.72 97.86 98.82 96.5 98.9 Fig 1: FTIR of pure Amlodipine Fig 2: FTIR of AMD + SSG Fig 3: FTIR of AMD +CCS Fig 4: FTIR of AMD + CP
  13. 13. ISSN: 2321-5674(Print) ISSN: 2320 – 3471(Online) Shoba Krushnan et.al Indian Journal of Research in Pharmacy and Biotechnology Volume 1(4) July-August 2013 Page 477 Fig 7: DSC of AMD + CP REFERENCES Bhagwati ST, Hiremath SN, Sreenivas SA, Comparative evaluation of disintegrants by formulating cefixime dispersible tablets, Indian J. Pharm.Edu.Res, 39, 2000, 194‐197. Bi Y, Evaluation of rapidly disintegrating tablets prepared by direct compression method, Drug Dev Ind Pharm, 25(5), 1999, 571‐581. Deepak K, Orally disintegrating tablets, Tablets Capsule 7, 2004, 30-35. Fu Y, Yang S, Jeong SH, Kimura S, Park K, Orally fast disintegrating tablets: Developments, technologies, taste masking and clinical studies, Crit Rev Ther Drug Carrier Syst, 21, 2004, 433–76. Ghosh TK, Pfister WR, Quickdissolving oral dosage forms: Scientific and regulatory considerations from a clinical pharmacology and biopharmaceuticals perspective; In: Drug delivery to the oral cavity: Molecules to market. New York, CRC Press, 2005, 337-356. Indian Pharmacopoeia, Vol ‐ I, 4th ed. Controller of publication, Govt. of India, New Delhi, 1996, 736. Lachman L, Liberman H, Kanig J, The theory and practice of industrial pharmacy, Varghese Publishing House, Mumbai, 3rd Edn, 1987, 297. Radke RS., Jadhav JK., Chajeed MR. Formulation and evaluation of orodispersible tablets of baclofen. International Journal of Chemtech Research, 1, 2009, 517‐521. Valleri M, Mura P, Maestrelli F, Cirri M, Ballerini R, Development and evaluation of glyburide fast dissolving tablets using solid dispersion technique, Drug Dev Ind Pharm, 30(5), 2004, 525-534. Fig 5: DSC of Pure Amlodipine Fig 6: DSC of AMD + SSG
  14. 14. ISSN: 2321-5674(Print) ISSN: 2320 – 3471(Online) Srinivas et.al Indian Journal of Research in Pharmacy and Biotechnology Volume 1(4) July-August 2013 Page 478 COMPARISION OF POTENCY OF ANTI BACTERIAL ACTIVITY AND ANTI INFLAMMATORY ACTIVITY OF 10 YEARS AND 100 YEARS OLD BARK EXTRACTS OF AZADIRACHTA INDICA Vijaya Kumar G, Srinivas N*, P Sravanthi, Sravani B Department of Pharmacology, A.K.R.G College of Pharmacy, Nallajerla, W.G. Dist, A.P, India. *Corresponding author: Email: srnvs_87@rediffmail.com, 8019189741 ABSTRACT Azadirachta indica (Meliaceae) commonly known as neem contains many biologically active compounds including alkaloids, flavonoids, triterpenoids, phenolic compounds, Carotenoids, steroids and ketones, azadirachtin. Oil from the leaves, seeds and bark possesses a wide spectrum of antibacterial action against Gram-negative and Gram-positive microorganisms, including M. tuberculosis and streptomycin resistant strains. The present study was undertaken to evaluate the comparision of potency of anti bacterial and anti-inflammatory activities of 10 and 100 years old bark extract of Azadirachta indica. The antibacterial activity was performed by using both gram positive and gram negative organisms viz., Bacillus Subtilis, E. coli and Staphylococcus Aureus. The anti-inflammatory activity was evaluated by using carrageenan induced paw edema method in rats. From the results of anti bacterial activity and anti-inflammatory activity, it has been concluded that 100 years old neem bark extract showed greater activities than the 10 years old neem bark extract. Key words: Azadirachta indica, Anti bacterial activity, Anti-inflammatory activity, 10 years and 100 years old plants. 1. INTRODUCTION Azadirachta indica (Meliaceae) commonly known as neem is native of India and naturalized in most of tropical and subtropical countries is of great medicinal value and distributed widespread in the world. The Chemical constituents contain many biologically active compounds that can be extracted from neem, including alkaloids, flavonoids, triterpenoids, phenolic compounds, Carotenoids, steroids and ketones, Azadirachtin is actually a mixture of seven isomeric compounds labeled as azadirachtin A-G and azadirachtin E is more effective (P Sudhir Kumar, 2010). Other compounds that have a biological activity are salannin, volatile oils, meliantriol and nimbin. Oil from the leaves, seeds and bark possesses a wide spectrum of antibacterial action against Gram- negative and Gram-positive microorganisms, including M. tuberculosis and streptomycin resistant strains. In vitro, it inhibits Vibrio cholerae, Klebsiella pneumoniae, M. tuberculosis and M. pyogenes. Antimicrobial effects of neem extract have been demonstrated against Streptococcus mutans and S. faecalis. NIM-76, a new vaginal contraceptive from neem oil showed inhibitory effect on the growth of various pathogens, including bacteria, fungi and virus. Recently, the antibacterial activity of neem seed oil was assessed in vitro against 14 strains of pathogenic bacteria. (Baswa M, 2001) The present study was undertaken to evaluate the comparision of potency of anti bacterial activity of 10 and 100 years old acetonic bark extract of azadiracta indica by using agar disc diffusion method on Bacillus subtilis, Escherichia coli, Staphylococus aureus and also to evaluate the comparision of potency of anti- inflammatory activity of 10 and 100 years old aqueous bark extract of azadiracta indica on carrageenan induced paw edema in rats. 2. MATERIALS Both the 10 years old and 100 years old neem plants were collected from Bapatla, Guntur district, Andhra Pradesh. Gentamycin (Nicholas piramil ltd, Mumbai), Penicillin (Alembic labs, Ahmedabad) and Diclofenac sodium (Novartis pharma ltd, Ahmedabad) were purchased from local medical stores, Nallajerla. Carrageenan was procured from Ozone internation, Mumbai. 2.1. Animals: Albino Wistar rats weighing 180–200g of either sex were obtained from the animal house of A.K.R.G. College of Pharmacy, Nallajerla, Andhra Pradesh, were used for this study. The animals were housed in separate groups (six rats in each cage) in clean sanitized polypropylene cages containing sterile paddy husk as bedding. The bedding material of the cages was changed every day. They had free accessed to standard pellet diet and water ad libitum. The animals were maintained under day and night 12:12 h cycles and with maintenance of room temperature 25 ±
  15. 15. ISSN: 2321-5674(Print) ISSN: 2320 – 3471(Online) Srinivas et.al Indian Journal of Research in Pharmacy and Biotechnology Volume 1(4) July-August 2013 Page 479 2◦ C. All procedures were performed in accordance with the Institutional Animal Ethics Committee (IAEC) constituted as per the direction of the Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA), under ministry of Animal Welfare Division, government of India, New Delhi IAEC approved the experimental protocol (AKRGCP/IAEC/03/2011-12) dated 11/02/2012. 3. METHODS 3.1. Preparation of neem bark extracts (NBEs): The stem bark of neem plants was peeled with sharp knife and chopped into pieces which was sun dried and ground into powder using a blender. The resulting powder stored at room temperature in clean, air tight and wide mouth container. 3.2. Preparation of acetonic neem bark extract: Twenty grams of neem bark was mixed with 200ml of acetone in a conical flask. The mixture was then magnetically stirred for 24hrs at room temperature. The homogenate was vacuum filtered through filter paper. The clarified filtrate was evaporated using at about 35o C and the residue was collected. 3.3. Preparation of aqueoes neem bark extract: Twenty grams of neem bark was mixed with 200ml of distilled water in a conical flask. The mixture was then magnetically stirred for 60hrs at room temperature. The homogenate was vacuum filtered through filter paper. The clarified filtrate was evaporated using at about 350 C and the residue was collected. 3.4. Antimicrobial Studies (A Kottai Muthu, 2010) 3.4.1. Test solution: Test solution of each extract was prepared by dissolving 100mg of each extract separately in 1ml of sterile dimethyl formamide (DMF) in a specific gravity bottle and stored in refrigerator. The solution was removed from the refrigerator one hour prior to each use and allow warming at room temperature. 3.4.2. Standard solution: The standard drugs Gentamycin (200µg/ml) and Pencillin (750µg/ml) was prepared in sterile water for injection. These were used as standard drugs for Antimicrobial studies. 3.4.3. Preparation of medium: Nutrient broth was used for preparation of inoculum of bacteria. Nutrient agar was used for preparation of medium for Antimicrobial screening. The composition of nutrient agar medium was as follows. Peptone - 5.0g Beef extract - 1.5g Yeast extract - 1.5g Agar - 1.5g Distilled water - 1000 ml pH adjusted -7.2 3.4.4. Preparation of inoculums: Inoculum was prepared by transferring a loopful of stock culture to a 150ml of Erlenmeyer containing 80ml of nutrient broth. The composition of inoculum broth was same as that of stock culture with exception of agar. The inoculum flasks were incubated at 370 C for 24 hrs and used for experiments. 3.4.5. Inoculation: The nutrient agar medium was sterilized by autoclaving at 121o C for 15 min. The petridishes and pipette were sterilized in an oven at 150o C for one hour. About 25ml melted nutrient agar medium (40o -50o C) was poured in each sterilized petridishes and 0.5ml of inoculum broth of bacteria was added to the respective petridishes. The content petridishes were thoroughly maintained at rotary motion. The medium containing inoculum was allowed to solidify at room temperature. After solidification of the medium, fine whattman filter paper disc were made it equal distance. The whattman filter paper discs were dipped in test and standard solution and kept in the petridish and the petridish undisturbed for one hour at room temperature. The petridish were incubated at 37o C for 24 hours and the zone of inhibition was recorded in mm. The experiment was performed in triplicate and the average readings are recorded. 3.5. Anti inflammatory activity (A M Mujumdar, 2000) 3.5.1. Experimental design: Male Wistar rats weighing 180-200 g were divided into four groups of six animals each. The treatment groups are designated as follows Group Treatment Group I Control (Solvent) Group II 100 yrs old NBE (200mg/kg) Group III 10 yrs old NBE (200mg/kg) Group IV Standard (Diclofenac 100mg/kg) 3.5.2. Experimental procedure: Male Wistar rats weighing 200 g are starved for 48 h. having access to drinking water ad libitum. The test compounds and standard drugs are administered by oral route. Thirty min later the rat are challenged by a sub-contentious injection of 0.05ml of 1% solution of carrageenan on the plantar surface of the left hind paw. The paw is
  16. 16. ISSN: 2321-5674(Print) ISSN: 2320 – 3471(Online) Srinivas et.al Indian Journal of Research in Pharmacy and Biotechnology Volume 1(4) July-August 2013 Page 480 marked with ink at the level of lateral malleolus and immersed in the mercury column of a plethysmometer for measuring the paw volume after carrageenin injection and then at 0.5, 1, 2, 3 and 4 hrs. The increase in paw volume at each time interval is calculated as percentage compared with the volume measured immediately after the injection of carrageenan for each animal. The percentage edema inhibition was calculated by sing the following formula Table 1: Percentage yield data of 100 yrs and 10 yrs old plants with different solvents Solvent Percentage Yield 100 Yrs 10yrs Acetone 1.5 1.9 Water 1.2 1.6 Figure 1: Percentage yield profile of 100 yrs and 10 yrs old plants with different solvents Table 2: Comparison of inhibition zones of acetonic neem bark extracts of 100 yrs and 10 yrs old plants against different standard organisms Organism Zone of inhibition (mm) 100 Yrs 10yrs Penicillin Gentamicin DMF Bacillus subtilis 31 14 25 22 - E. coli 35 15 19 30 - Staphylococcus aureus 27 10 21 18 - (-) No zone of inhibition DMF – dimethyl Formamide Figure 2: Comparison of inhibition zones of acetonic neem bark extracts of 100 yrs and 10 yrs old plants against different standard organisms 0 0.5 1 1.5 2 Acetone Water PecentageYieldof NeemBarkExtract 100 Yrs 10yrs 0 10 20 30 40 100 Yrs 10yrs Gentamicin Penicillin Zoneofinhibition (mm) Bacillus Subtilis E. coli
  17. 17. ISSN: 2321-5674(Print) ISSN: 2320 – 3471(Online) Srinivas et.al Indian Journal of Research in Pharmacy and Biotechnology Volume 1(4) July-August 2013 Page 481 Table 3: Paw volume data of test and standard drugs on carrageenan induced rat paw edema Group Treatment Change in paw volume (ml) measured by mercury displacement at different time intervals (hrs) (mean±S.D) 0 0.5 1 2 3 4 Group I Control 0 0.13±0.001 0.3±0.002 0.4±0.001 0.5±0.002 0.5±0.001 Group II 100 yrs old NBE 0 0.11±0.002 0.2±0.001 0.2±0.001 0.11±0.002 0.1±0.001 Group III 10 yrs old NBE 0 0.11±0.001 0.23±0.002 0.3±0.001 0.27±0.001 0.2±0.002 Group IV Standard 0 0.1±0.001 0.2±0.001 0.19±0.002 0.1±0.001 0.1±0.001 Figure 3: Paw volume profiles of test and standard drugs on carrageenin induced rat paw edema Table 4: Percentage oedema inhibition of test and standard drugs on carrageenan induced rat paw edema Group Treatment Percentage of edema inhibition measured by mercury displacement at different time intervals (hrs) 0 0.5 1 2 3 4 Group I Control 0 0 0 0 0 0 Group II 100 yrs old NBE 0 15.38 33.3 50 78 80 Group III 10 yrs old NBE 0 15.38 23.33 25 46 60 Group IV Standard 0 23 33.33 52.5 80 80 Figure 4: Percentage oedema inhibition of test and standard drugs on carrageenin induced rat paw edema 0 0.1 0.2 0.3 0.4 0.5 0.6 0 1 2 3 4 5 changeinpawvolume (ml) Time (hrs) Control 100 yrs 10 yrs Standard 0 20 40 60 80 100 0 1 2 3 4 5 Percentageinhibition ofoedema Time (hrs) 100 yrs 10 yrs Standard
  18. 18. ISSN: 2321-5674(Print) ISSN: 2320 – 3471(Online) Srinivas et.al Indian Journal of Research in Pharmacy and Biotechnology Volume 1(4) July-August 2013 Page 482 4. DISCUSSION The present study has been undertaken to compare the potency of anti microbial and anti-inflammatory activities of 100 years and 10 years old neem bark extracts. In this study acetone, and aqueous extracts were used for anti microbial and anti-inflammatory activities respectively. The percentage yield of different extracts were calculated and tabulated in table 1. The inhibition zones of acetonic neem bark extracts of 100 years and 10 years old plants against different standard organisms (Bacillus subtilis, E. coli and Staphylococcus aureus) were measured. Similarly the inhibition zones of standard drugs that are Gentamicin and Penicillin against the same organisms were also measured and data shown in table 2. The data was treated statistically and the statistical interaction implies that the difference in zone of inhibition was statistically significant between 100 years and 10 years old neem plants. It is clear that the both test drugs (100 years and 10 years old) are showed anti microbial activity against gram positive micro organisms (Bacillus Subtilis and Staphylococcus Aureus) and gram negative micro organisms (E. coli). The solvent (DMF) used as vehicle did not showed anti microbial activity and confirmed there is no solvent action on the micro organisms. Anti inflammatory activity was evaluated by using carrageenan induced rat paw oedema method. A single subcutaneous injection of 0.1 ml of 2% formalin in rats produced inflammation significantly (p<0.001). Paw volume was measured by mercury displacement at different time intervals and right leg considered as control for left leg which is received carrageenan on plantar region. The change in paw volume (L-R) was measured and data shown in table 3. From this data percentage oedema inhibition of test and standard drugs was calculated and tabulated in table 4. The data was treated statistically and the statistical interaction implies that the difference in paw volume was statistically significant between 100 years and 10 years old neem plants. At the time of 3 hours the percentages of oedema inhibition were 0, 78, 46 and 80 for control, 100 years old plant extract, 10 years old plant extract and standard drugs respectively. 5. CONCLUSION The bark extracts were extracted by different solvents. All these activities are evaluated and observed that the age of plant is influenced the index of activity. It is may be due to the age of plant influence the chemical cinstients or their potency. The young plant (10 years age neem plant) showed high percentage yield when compared with old plant (100 years age neem plant). The crude extracts are sparingly soluble in water; hence DMF (dimethyl formamide) used as solvent for the test dose preparations. From the results of anti microbial activity, it has been concluded that 100 years old neem bark acetonic extract showed greater anti microbial activity than the 10 years old neem bark acetonic extract and both the drugs showed broad spectrum anti bacterial activity. From the results of anti inflammatory activity, it has been concluded that 100 years old neem bark aqueous extract showed greater anti inflammatory activity than the 10 years old neem bark aqueous extract and the results met the standard NSAID drug that is diclofenac sodium. From this investigation it was concluded that the selection of age of plant is important to their significant pharmacological action. 6. AKNOWLEDGEMENTS The authors are thankful to Management, A.K.R.G College of Pharmacy, Nallajerla, Andhra Pradesh, India for permitting and providing necessary facilities for carrying out to do the project work. REFERENCES A Kottai Muthu, Penugonda Sravanthi, D Sathesh Kumar, A Anton Smith and R Manavalan, International Journal of Pharma Sciences and Research, 1(2), 2010, 127-130. A M Mujumdar, D G Naik, C N Dandge, H M Puntambekar, Anti inflammatory activity of curcuma amada Roxb in albino rats. Indian Journal of Pharmacology, 32, 2000, 375-377. Ara I, Siddiqui B S, Faizi S, Siddiqui S, Diterpenoids from stem bark of Azadirachta indica, Phytochemistry, 28, 1989, 1177-1180. Baswa M, Rath CC, Dash SK, Mishra RK, Antibacterial activity of Karanj (Pngamia pinnata) and neem (Azadirachta indica) seed oil: a preliminary report, Microbios, 105, 2001, 183-189. Biswas, Kausik, Ishita Chattopadhyay, Ranajit K, Banerjee and Uday Bandyopadhyay, Biological activities and medicinal properties of Neem (Azadirachta indica), Current Science, 82(11), 2002, 1336-1345. Naqvi S N H, Pharmacological importance of neem Azadiracta indica A Juss (Meliacae), J. Baqai Med. Uni, 1(2), 1998, 39-50.
  19. 19. ISSN: 2321-5674(Print) ISSN: 2320 – 3471(Online) Srinivas et.al Indian Journal of Research in Pharmacy and Biotechnology Volume 1(4) July-August 2013 Page 483 P Sudhir Kumar Debasis Mishra, Goutam Ghosh and Chandra S Panda, Biological action and medicinal properties of various constituent of Azadirachta indica (Meliaceae) an Overview, Annals of Biological Research, 1 (3), 2010, 24-34. Siddiqui S, Siddiqui B S, Faizi S, Mahmood T, Isolation of a tetranortriepenoid from Azadirachta indica. Phytochemistry, 23, 1984, 2899-2901. Thaker A M and Anjaria JV, Antimicrobial and infected wound healing response of some traditional drugs, Indian Journal of Pharmacology, 18, 1986, 171-174.
  20. 20. ISSN: 2321-5674(Print) ISSN: 2320 – 3471(Online) Harish et.al Indian Journal of Research in Pharmacy and Biotechnology Volume 1(4) July-August 2013 Page 484 DEVELOPMENT AND EVALUATION OF CARISOPRODOL TABLETS WITH IMPROVED DISSOLUTION EFFICIENCY USING SOLID DISPERSION TECHNIQUE Mogili Daya Sagar, Mohammed Shahidullah, Shaik Rabbani Basha, Shaik Shahnaz, Harish.G* Department of Pharmaceutics, Nimra college of Pharmacy, Vijayawada, AP, India *Corresponding author: E.Mail: harishgopinath4u@gmail.com ABSTRACT Carisoprodol is indicated in patients with acute muscular pain. Carisoprodol is typically prescribed as 350 mg tablets. The aim of the present study is to design and development Carisoprodol tablets with improved dissolution efficiency using solid dispersion technique. The present work is planned to prepare solid dispersion system consisting of Carisoprodol with hydrophilic carriers by employing different methods, to study the physicochemical properties of Carisoprodol solid dispersions, develop fast dissolving tablets of Carisoprodol solid dispersions by using super- disintegrant such as starch, Croscarmelose sodium, sodium starch glycolate and to study the effect of the preparation methods of solid dispersions on dissolution characteristics. Key words: Carisoprodol, Solid dispersion, super-disintegrant. INTRODUCTION The potential drug candidates are characterized by a low oral bioavailability. Often poor drug dissolution/solubility rather than limited permeation through the epithelia of the gastrointestinal tract are responsible for low oral bioavailability (Vasconcelos TF, 2007). Thus aqueous solubility of any therapeutically active substance is a key property as it governs dissolution, absorption and thus the in-vivo efficacy (Vemula VR, 2010). Drugs with low aqueous solubility have low dissolution rates and hence suffer from oral bioavailability problems. The rate and extent of dissolution of the active ingredient from any dosage form often determines the rate of extent of absorption of the drug. When an active agent is given orally, it must first dissolve in gastric acid and/or intestinal fluids before it can then permeate the membranes of the GI tract to reach systemic circulation. Therefore, a drug with poor aqueous solubility will typically exhibit dissolution rate limited absorption, and a drug with poor membrane permeability will typically exhibit permeation rate limited absorption. Hence, two areas focus on improving the oral bioavailability of active agents include:  Enhancing solubility and dissolution rate of poorly water-soluble drugs  Enhancing permeability of poorly permeable drugs There are various techniques available to improve the solubility of poorly soluble drugs, such Micronization, Nanosuspension, Modification of the crystal habits, Eutectic mixtures, Solid dispersions, Microemulsions, Self micro emulsifying drug delivery systems, cyclodextrin inclusion and lipid based delivery systems etc (Sharma D, 2010). Solid dispersion is one of the most promising approaches for solubility enhancement. In the biopharmaceutical classification system (BCS) drugs with low aqueous solubility and high membrane permeability are categorized as Class II drugs. Therefore, solid dispersion technologies are particularly promising for improving the oral absorption and bioavailability of BCS Class II drugs. In case of solid dispersion drug disperse in the matrix generally a hydrophilic matrix and a hydrophobic drug, thereby forming a solid dispersion. When the solid dispersion is exposed to aqueous media, the carrier dissolves and the drug releases as fine colloidal particles. The resulting enhanced surface area produces higher dissolution rate and bioavailability of poorly water-soluble drugs. Solid dispersion: Solid dispersion technology is the science of dispersing one or more active ingredients in an inert matrix in the solid stage in order to achieve increased dissolution rate, sustained release of drugs, altered solid state properties, and enhanced release of drugs from ointment and suppository bases, and improved solubility and stability (Mohanachandran PS, 2010). MATERIALS AND METHODS Materials: Carisoprodol was obtained as gift sample from SYNED LABS LIMITED, Medak, AP, Starch, SSG, Cross carmelose sodium, Crospovidone, MCC, Lactose was obtained as a gift sample from ICPAHealthcare, Ankaleshwar. PVP, Talc and Magnesium Stearate were obtained from Signet Mumbai. All other chemicals and Solvents used in this study are of analytical grade.
  21. 21. ISSN: 2321-5674(Print) ISSN: 2320 – 3471(Online) Harish et.al Indian Journal of Research in Pharmacy and Biotechnology Volume 1(4) July-August 2013 Page 485 Pre-formulation Studies: Pre-formulation study relates to pharmaceutical and analytical investigation carried out proceeding and supporting formulation development effort of the dosage forms of the drug substance. Pre-formulation studies yield basic knowledge necessary to develop suitable formulation. It gives information needed to define the nature of the drug substance and provide frame work for the drug combination with pharmaceutical excipients in the dosage forms. Hence the following pre-formulation studies were performed on the obtained sample of drug such as Solubility, bulk density, tapped density, Percentage compressibility, Identification of drug sample, Drug excipient compatibility studies (Patidar Kalpana, 2010). Formulation of Carisoprodol Solid dispersion: The accurately weighed quantity of the drug and polymer in various ratios has been formulated by melting the polymer and dispersing the drug in it. The formulated SD has been dried and grounded by passing through mesh #22. Formulation of Carisoprodol Tablet: Preparation of the Fast dissolving tablet of Carisoprodol: Fast dissolving tablets of Carisoprodol had been formulated by direct Compression method using Super-disintegrants such as SSG, CP, Starch, CCS etc. in various ratios. These ingredients were weighed and mixed stoichometrically to obtain the final formulation. The weight of the tablet in all formulations was kept constant to 130mg. All the batches were prepared by direct compression method using the 16-station rotary punch tablet compression machine using 7 mm biconvex plain on both side die-punches set. The variables maintained in the formulation were the different types of super-disintegrant and their concentration (in mg) in the formulation. Completely dried complex used for the preparation of fast dissolving tablet. Tablets were prepared from blends by direct compression method. All the ingredients including drug were passed through mesh no. 60 excepting lubricants. Lubricants were passed through mesh no.80. Lubricants were added at the time of compression. Blend is mixed uniformly by manually for 30 minutes. Tablets of convex faced weighing 130mg each with 3.3mm thickness and 7mm in diameter. Evaluation of Post-Compression Characteristics: The formulated Carisoprodol SD has been compressed in to tablet and the following evaluation has been performed as per BP pharmacopoeia. The following evaluation of tablets was performed such as Drug content, Weight variation, Hardness, Friability, Content uniformity, Thickness, In-Vitro Dissolution. Table.1. Formulation of Carisoprodol solid dispersion Drug:Polymer (Urea) Drug:Polymer (Mannitol) 1:1 1:1 1:2 1:2 1:3 1:3 Table.2. Formulation of Fast dissolving tablet of Carisoprodol SD INGREDIENTS F1 F2 F3 X4 X5 X6 Z7 Z8 Z9 C10 C11 Carisoprodol SD (mg) 10 10 10 10 10 10 10 10 10 10 10 Starch 62.5 62.5 62.5 62.5 62.5 62.5 62.5 62.5 62.5 62.5 SSG 2 4 6 - - - - - - - - CCS - - - 2 4 6 - - - - CP - - - - - - 2 4 6 - - MCC - - - - - - - - - - 41 PVP 16 16 16 16 16 16 16 16 16 16 16 Lactose 11.5 10.5 8.5 12.5 10.5 8.5 12.5 10.5 8.5 14.5 36 Talc 10 10 10 10 10 10 10 10 10 10 10 Magnesium Stearate 18 17 17 17 17 17 17 17 17 17 17 Total Weight 130 130 130 130 130 130 130 130 130 130 130
  22. 22. ISSN: 2321-5674(Print) ISSN: 2320 – 3471(Online) Harish et.al Indian Journal of Research in Pharmacy and Biotechnology Volume 1(4) July-August 2013 Page 486 RESULTS AND DISCUSSION Evaluation of Blend: Table.3. Pre-compression parameters of Carisoprodol SD Formulation Series Bulk Density(gm/ml) Tapped Density(gm/ml) Compressibility Index Hausner’s Ratio Angle of Repose F1 0.510 0.598 15.81 1.17 26o 28’ F2 0.512 0.597 15.38 1.18 26 o 85’ F3 0.512 0.60 14.87 1.17 27 o 14’ X4 0.505 0.591 14.64 1.17 27 o 75’ X5 0.507 0.595 14.72 1.17 28 o 07’ X6 0.507 0.597 14.97 1.17 28 o 07’ Z7 0.512 0.595 13.84 1.16 29 o 39’ Z8 0.515 0.598 13.91 1.16 29 o 74’ Z9 0.515 0.602 14.43 1.16 29 o 02’ C10 0.510 0.641 20.40 1.22 32 o 82’ C11 0.534 0.714 25.13 1.33 34 o 59’ Table.4. Evaluation of Formulation Series Batch no. Weight variation Hardnes kg/cm2 Thickness (mm) Friability (%) Disintegration time (sec) Wetting time (sec) Water absorption ratio Drug Content (%) F-1 Passes 3.1 2.1 0.41 42 63 75 99.78 F-2 Passes 3.2 2.1 o.37 31 55 88.72 99.62 F-3 Passes 3.1 2.1 0.37 25 49 96.29 100.8 X-4 Passes 2.9 2.1 0.38 48 69 67.40 100.2 X-5 Passes 3.1 2.1 0.4 35 59 85.82 100.4 X-6 Passes 3 2.1 0.41 29 50 94.77 100.3 Z-7 Passes 2.8 2.1 0.41 55 71 64.70 99.9 Z-8 Passes 2.9 2.1 0.41 41 65 82.82 99.7 Z-9 Passes 2.9 2.1 0.43 34 56 93.28 100.1 C-10 Passes 3.5 2.1 0.41 74 79 58.33 99.6 C-11 Passes 4.1 2.1 0.32 161 93 42.69 99.5 M-1 - 5.3 - - 257 429 68.33 101.1 M-2 - 5.6 - - 291 486 63.01 99.7 M1:- Marketed Tablet of Carisoprodol; M2:- Marketed Tablet of Carisoprodol Fig.1.Percentage Drug release profile of Carisoprodol formulations CONCLUSION The Mannitol and Urea is used as polymer for the enhancement of the solubility of Carisoprodol solid dispersion and improve the rate of dissolution by fast dissolving tablet using various super disintegrates which shows rapid onset of action and faster rate of drug delivery. The formulation F3 and X6 showed faster disintegration time a faster rate of in-vitro dissolution above 99% at the end of 8min. hence formulation of Carisoprodol SD using the SSG (6%) and CCS (6%) showed a rapid onset of drug release. Hence, formulation of the poorly soluble drug with improved solubility using solid dispersion
  23. 23. ISSN: 2321-5674(Print) ISSN: 2320 – 3471(Online) Harish et.al Indian Journal of Research in Pharmacy and Biotechnology Volume 1(4) July-August 2013 Page 487 and faster rate of action can be developed by following the method discussed so far in this study. REFERENCES Aggarwal S, Gupta GD and Chaudhary S, Solid dispersion as an eminent strategic approach in solubility enhancement of poorly soluble drugs. International Journal of Pharmaceutical Sciences and Research, 1, 2010, 1-13. Batra V, Shirolkar VS, Mahaparale PR, Kasture PV, Deshpande AD, Solubility and Dissolution Enhancement of Glipizide by Solid Dispersion Technique, Indian J Pharm Educ Res, 42(4), 2008, 373-378. Chaulang G, Patil K, Ghodke D, Khan S, Yeole P, Preparation and Characterization of Solid Dispersion Tablet of Furosemidewith Crospovidone, Research J Pharm andTech, 1(4), 2008, 386-389. Kumar DS, Solubility improvement using solid dispersion; strategy, mechanism and characteristics: responsiveness and prospect way outs. International Research Journal of Pharmacy, 2, 2011, 55-60. Mohanachandran PS, Sindhumo PG and Kiran TS, Enhancement of solubility anddissolution rate: an overview, International Journal of Comprehensive Pharmacy, 4, 2010, 1-10. Patidar Kalpana, Solid Dispersion: Approaches, Technology involved, Unmet need & Challenges in Drug Invention Today, 2(7), 2010, 349-357. Sharma D, Soni M, Kumar S and Gupta GD, Solubility Enhancement –Eminent Role in Poorly Soluble Drugs. Research Journal of Pharmacy and Technology, 2, 2009, 220-224. Vanshiv SD, Rao MRP, Sonar GS, Gogad VK, Borate SG, Physicochemical Characterization and In Vitro Dissolution of Domperidone by Solid Dispersion Technique, Indian J Pharm Educ Res, 43 (1), 2009, 86-90. Vemula VR, LagishettyV and Lingala S, Solubility enhancement techniques, International Journal of Pharmaceutical Sciences Review and Research, 5, 2010, 41-51.
  24. 24. ISSN: 2321-5674(Print) ISSN: 2320 – 3471(Online) Sowjanya et.al Indian Journal of Research in Pharmacy and Biotechnology Volume 1(4) July-August 2013 Page 489 TRANSDERMAL DRUG DELIVERY SYSTEMS R.Sowjanya*, Salman Khan, D.Bhowmik, Harish.G, S.Duraivel Department of pharmaceutics, Nimra college of pharmacy, Nimranagar, Ibhrahimpatnam, Vijayawada, Andhra Pradesh. *Coreesponding author: E. Mail id:debjit_cr@yahoo.com ABSTRACT Transdermal therapeutic systems have been designed to provide controlled continuous delivery of drugs via the skin to the systemic circulation. The relative impermeability of skin is well known, and this is associated with its functions as a dual protective barrier against invasion by microorganism and the prevention of the loss of physiologically essential substances such as water. Elucidation of factors that contribute to this impermeability has made the use of skin as a route for controlled systemic drug delivery possible. The market for Transdermal devices is currently estimated at US$ 1.2 billion, approximately 10% of the entire US $ 28 billion drug delivery market. In addition, Transdermal drug delivery market is currently based on only 10 drugs. Hence, Pharmaceutical scientists are striving to add new deliverables to the short list of approved Transdermal products. Keywords Therapeutic activity, Bioavailability, First pass metabolism, Ionophoresis. 1. INTRODUCTION For many decades, medication of an acute disease or a chronic illness has been accomplished by delivering drugs to the patients via various pharmaceutical dosage forms like tablets, capsules, pills, creams, ointments, liquid aerosols, injectable and suppositories, as carriers. Recently, several technical advancements have been made. They have resulted in the development of new techniques of drug delivery. These techniques are capable of controlling the rate of drug delivery, sustaining the duration of therapeutic activity, and/or targeting the delivery of drug to a tissue. In responses to these advances, several transdermal drug delivery systems have recently been developed, aiming to achieve the objective of systemic medication through topical application on the intact skin surface. The principal of transdermal drug delivery systems is that they could provide sustained drug delivery (and hence constant drug concentrations in plasma) over a prolonged period of time. For these attributes, it is often extrapolated that sustained therapeutic activity will also be obtained with transdermal drug delivery systems. Thus, it is anticipated that transdermal drug delivery systems can be designed to input drugs at appropriate rates to maintain suitable plasma-drug levels for therapeutic efficacy, without the periodic sojourns into plasma concentrations that would accompany toxicity or lack of efficacy. Today, four drugs have been successfully incorporated into transdermal drug delivery systems for clinical use (Scopolamine, Nitroglycerine, Clonidine and Estradiol), which establishes the dermal route for systemic drug delivery. Ultimately, the success of all transdermal systems depends on the ability of the drug to permeate skin in sufficient quantities to achieve its desired therapeutic effect. (Roberts MS, 1997) 1.1. Advantages of TDDS: 1. Avoids the risk and inconveniences of intravenous therapy 2. Bypass the variation in the absorption and metabolism associated with oral administration 3. Permit continuous drug administration and the use of drugs with a short biological half-life. 4. Increase the bioavailability and efficacy of drugs and bypass of hepatic first pass metabolism. 5. Treatment can be continued or discontinued according to the desire of the physician. 6. Greater patient compliance due to the elimination of multiple dosing schedules. 1.2. Selection of drug candidate for transdermal delivery: The transdermal route of administration cannot be employed for a large number of drugs. Judicious choice of the drug substance is the most important decision in the successful development of a transdermal system. The drug candidate should have following ideas characteristics: 1.2.1. Adequate skin permeability:  Drugs with low molecular weight  Drugs with low melting point  Drugs with moderate oil and water solubility 1.2.2. Adequate skin acceptability:
  25. 25. ISSN: 2321-5674(Print) ISSN: 2320 – 3471(Online) Sowjanya et.al Indian Journal of Research in Pharmacy and Biotechnology Volume 1(4) July-August 2013 Page 490  Non-irritating drugs  Non-irritating drugs  Non-metabolizing drugs 1.2.3. Adequate clinical need:  Need to prolong administration  Need to reduce side effects on target tissues  Need to increase patient compliance 1.3. Factors affecting transdermal permeation: The principle transport mechanism across mammalian skin is by passive diffusion through primarily the transepidermal route at steady state or through trans- appendageal route ay initial non-steady state. The factors controlling transdermal permeability can be broadly placed in the following cases 1.3.1. Physico-chemical properties of the penetrant molecules: Partition co-efficient: Drugs possessing both lipid and water solubility are favorably absorbed through the skin. Transdermal permeability co-efficient shows a linear dependency on partition co-efficient. A lipid/water partition co-efficient of one or greater is generally required. 1.3.2. pH conditions: The pH value of very high or very low can be destructive to the skin. With moderate pH values, the flux of ionisable drugs can be affected by changes in pH that alter the ratio of charged and uncharged species and their transdermal permeability. 1.3.3. Penetrant concentration: Increasing concentration of dissolved drug causes a proportional increase in flux. At higher concentrations, excess solid drug functions as a reservoir and prolonged period of time. 1.3.4. Physico-chemical properties of drug molecule: Release characteristics: solubility of the drug in the vehicle determines the release rate. The mechanism of drug release depends on the following factors. Whether the drug molecules are dissolved or suspended in the delivery system. 1.3.5. Enhancement of transdermal permeation: Majority of drugs will not penetrate the skin at the rates sufficiently high for therapeutic efficacy; the permeation can be improved by the addition of permeation enhancer like dimethyl sulfoxide, dimethyl formamide, propylene glycol, etc into the system 1.4. Physiological and pathological conditions of skin: 1.4.1. Reservoir effect of horny layer: The horny layer is deeper layer, can sometimes act as depot and modify the transdermal permeation of drugs. The reservoir effect is due to irreversible binding of a part of the applied drug with the skin. 1.4.2. Lipid film: The lipid film on the skin surface acts as a protective layer to prevent the removal of moisture from the skin and helps in maintaining the barrier function of stratum corneum. 1.4.3. Skin hydration: Hydration of stratum corneum can enhance permeability. Skin hydration can be achieved simply by covering or occluding the skin with plastic sheeting, leading to accumulation of sweat. Increased hydration appears to open up the dense, closely packed cells of the skin and increase its porosity. 1.4.3. Skin temperature: Raising the skin temperature results in an increase in the rate of skin permeation; this may be due to availability of energy required for diffusivity. 1.4.4. Regional variation: Differences in nature and thickness of the barrier of skin causes variation in permeability. 1.4.5. Pathological injuries to the skin: Injuries that disrupt the continuity of the stratum corneum, increases permeability due to increased vasodilatation caused by removal of the barrier layer. 1.4.6. Cutaneous self-metabolism: catabolic enzymes present in the epidermis may render the drug inactive by metabolism and thus the topical bioavailability of the drug. 1.4.7. Penetration enhancers and their use in transdermal therapeutic system: The transdermal route for drug administration is limited by the barrier properties of the skin. Only the most potent drugs with low daily dose and appropriate physicochemical characteristics are candidates for transdermal delivery. To circumvent the low permeability nature of human skin, pharmaceutical scientists are searching for safe and effective skin penetration enhancers. Development of penetration enhancer is important to improve the low permeability of drug across the skin. Although many penetration enhancers are known, their mode of action is still not fully understood. The penetration enhancers are agents that increase the permeability of the skin or substances that reduce the impermeability of the skin. According to Chien et.al., penetration enhancers or promoters or promoters are agents that
  26. 26. ISSN: 2321-5674(Print) ISSN: 2320 – 3471(Online) Sowjanya et.al Indian Journal of Research in Pharmacy and Biotechnology Volume 1(4) July-August 2013 Page 491 have no therapeutic properties of their own but can transport the sorption of drugs from drug delivery systems onto the skin and/or their subsequent transdermal permeation through skin. The accelerant causes the keratin to swell and leaches out essential structural material from the stratum corneum, thus reducing the diffusional resistance and increasing the permeability of drugs through skin. 1.5. Mechanisms of transdermal permeation: For a systemically active drug to reach a target tissue, it has to possess some physicochemical properties which facilitate the sorption of the drug through the skin and enter the microcirculation. The rate of permeation, dq/dt, across various layers of skin tissues can be expressed as: dq/dt = Ps (Cd—Cr) .......... (1) Where Cd and Cr are respectively, the concentrations of a skin penetrant in the donor phase (stratum corneum) and in the receptor phase (systemic circulation), and Ps is the overall permeability coefficient of the skin and is defined by Ps = Ks Dss/ hs ...........(2) Where, Ks = partition coefficient of the penetrant. Dss = apparent diffusivity of penetrant, hs = thickness of skin Thus, permeability coefficient (Ps) may be a constant, if Ks, Dss and hs terms in equation (2) are constant under a given set of conditions. A constant rate of drug permeation is achieved if Cd >> Cr, then the equation (1) may be reduced to dq / dt = Ps Cd Molecular penetration through the various regions of the skin is limited by the diffusional resistances encountered. The total diffusional resistance (Rskin) to permeation through the skin has been described by Chien as: R skin = Rsc + Re + Rpd .............. (4) Where R is the diffusional resistance and subscripts sc, e , pd refer to stratum corneum, epidermis and papillary layer of the dermis respectively. Of these layers, the greatest resistance is put up by the stratum corneum and tends to be the rate –limiting step in percutaneous absorption. When more than one phase of the membrane is capable of supporting separate diffusional currents through each transdermal patch, then the pathways are configured in parallel to one another and the total fluxes of matter across the membrane is the sum of the fluxes of each route and is expressed by: J = A (f1 p1 + f2 p2 + ..........+ fn pn) C Where J = diffusional flux and the term f1p1 + f2p2 + ..........fnpn, defines the overall permeability coefficient, C being the concentration drop. 1.6. Components of transdermal devices: Transdermal drug delivery devices have come of age. It is 24 years since the first US patents were issued to these systems; today more than 100 patents describing transdermal devices have been issued. Transdermal devices are of 3 types, they are adhesive device, monolithic matrix device and the reservoir system. These devices basically contain: 1. Backing layer 2. Drug reservoir 3. Release control layer (polymer matrix) 4. Adhesive and peel strip 5. Enhancers and excipients. The backing layer/membrane is flexible and they provide a good bond to the drug reservoir, prevent drug from leaving the dosage form through the top, and accept printing. It is impermeable substance that protects the product during use on the skin. Eg., metallic plastic laminate, plastic backing with absorbent pad and Occlusive base plate (aluminium foil), adhesive foam pad (flexible polyurethane) with occlusive base plate (aluminium foil disc) etc. The drug reservoir is generally made up of adhesives and allow for the transport of drug at a desired rate. The drug should be selected depending upon clinical need and its physicochemical properties. The following are some of the desirable properties of a drug for transdermal delivery. 1.7. Physicochemical properties: 1. The drug should have a molecular weight less than approximately 1000 daltons. 2. The drug should have affinity for both lipophilic and hydrophilic phases. 3. The drug should have a low melting point. 1.8. Biological properties: 1. The drug should be potent with a daily dose of the order of a few mg/day. 2. The half life (t1/2) of the drug should be short. 3. The drug must not induce a cutaneous irritant or allergic response.
  27. 27. ISSN: 2321-5674(Print) ISSN: 2320 – 3471(Online) Sowjanya et.al Indian Journal of Research in Pharmacy and Biotechnology Volume 1(4) July-August 2013 Page 492 4. Drugs which degrade in the GI tract or/are inactivated by hepatic first-pass effect are suitable candidates for transdermal delivery. 5. Tolerance to the drug must not develop under the near zero-order release profile of transdermal delivery. 6. Drugs which have to administer for a long period of time or which cause adverse effects to non-target tissues can also be formulated for transdermal delivery. 1.9. Polymer Matrix: The polymer controls the release of the drug from the device. The following criteria should be satisfied for a polymer to be used in a transdermal system. 1. Molecular weight, glass transition temperature and chemical functionality of the polymer should be such that the specific drug diffuses properly and gets released through it. 2. The polymer should be stable, non-reactive with the drug, easily manufactured and fabricated into the desired product; and inexpensive. 3. The polymer and its degradation products must be non-toxic or non-antagonistic to the host. 4. The mechanical properties of the polymer should not deteriorate excessively when large amounts of active agent are incorporated into it. 1.10. Possible useful polymers for Transdermal devices are: 1.10.1. Natural Polymers: Cellulose derivatives, Zein, Gelatin, Shellac, Waxes, Proteins, Gums and their derivatives, Natural rubber, Starch etc. 1.10.2. Synthetic elastomers: Polybutadiene, Hydrin rubber, Polysiloxane, Silicone rubber, Nitrile, Acrylonitrile, Butyl rubber, Neoprene etc. 1.10.3. Synthetic Polymers: Polyvinyl alcohol, Polyvinyl chloride, Polyethylene, Polypropylene, Polyacrylate, Polyamide, Polyurea, Polyvinylpyrrolidine, Polymethylmethacrylate, Epoxy etc. 1.10.4. Adhesives: The fastening of all transdermal devices to the skin has so far been done by using a pressure sensitive adhesive. The pressure sensitive adhesive can be positioned on the face of the device or in the back of the device and extending peripherally. Both adhesive systems should fulfil the following criteria. Should not irritate or sensitize the skin or cause an imbalance in the normal skin flora during its contact time with the skin. It should adhere to the skin aggressively during the dosing interval without its position being disturbed by activities such as bathing, exercise etc. It should be removed easily from the skin. It should not leave a un washable residue on the skin. It should have excellent (intimate) contact with the skin at macroscopic and microscopic level. 1.10.4.1. The face adhesive system should also fulfill the following criteria: 1. Physical and chemical compatibility with the drug, excipients and enhancers of the device of which it is a part. 2. Permeation of drug should not be affected. 3. The delivery of simple or blended permeation enhancers should not be affected. 4. Some widely used pressure sensitive adhesives include polyisobutylenes, acrylics and silicones. 1.11. Permeation Enhancers: These are compounds which promote skin permeability by altering the skin as a barrier to the flux of a desired penetrant. Permeation enhancers are hypothesized to affect one or more of these layers to achieve skin penetration enhancement. A large number of compounds have been investigated for their ability to enhance stratum corneum permeability. These may be conveniently be classified under the following main headings 1.11.1. Solvents: These compounds increase penetration possibly by swelling the polar pathway and/or by fluidizing lipids. Eg.,water alcohols- methanol and ethanol ; alkyl methyl sulfoxides- dimethyl sulfoxide, dimethyl acetamide and dimethyl formamide, miscellaneous solvents-propylene glycol, glycerol, isopropyl palmitate. 1.11.2. Surfactants: These compounds are proposed to enhance polar pathway transport, especially of hydrophilic drugs. Anionic surfactants can penetrate and interact strongly with the skin. Cationic surfactants are reportedly more irritant than the anionic surfactants and they have not been widely studied as skin permeation enhancers. Of the 3 major classes of surfactants, the nonionics have long been recognised as those with the least potential for irritation and have been widely studied. Egs., of commonly used surfactants are :
  28. 28. ISSN: 2321-5674(Print) ISSN: 2320 – 3471(Online) Sowjanya et.al Indian Journal of Research in Pharmacy and Biotechnology Volume 1(4) July-August 2013 Page 493 1.11.3. Anionic surfactants: Dioctyl sulphosuccinate, Sodium lauryl sulphate, Decodecylmethyl sulphoxide etc. 1.11.4. Nonionic surfactants: Pluronic F127, Pluronic F68, etc. 1.11.5. Bile salts: Sodium taurocholate, Sodium deoxycholate, Sodium tauroglycocholate. Binary systems systems apparently open up the heterogeneous multilaminate pathway as well as the continuous pathways. Eg. Propylene glycol-oleic acid and 1,4-butane diol-linoleic acid. 1.11.6. Miscellaneous chemicals: Urea, N,N- dimethyl-m-toluamide, Calcium thioglycolate, 1.11.7. Anticholinergic agents: The enhancers used should be pharmacologically inert, non-toxic, non- allergenic and non-irritating. They should show a quick onset of action, reduction of barrier function of the skin only in one direction. On removal from skin, the tissues should quickly and fully recover normal barrier function. It should be compatible with all the formulation components and should be an excellent solvent for drugs. 2. TECHNOLOGIES OF DIFFERENT TYPES OF TRANSDERMAL DRUG DELIVERY SYSTEM Several technologies have been successfully developed to provide a rate-control over the release and skin permeation of drugs. These technologies can be classified into the following approaches. 2.1. Membrane permeation controlled TDDS: In this system, the drug reservoir is sandwiched between a backing membrane and a rate-controlling membrane, through which the drug is released. In the drug reservoir, drugs are either dispersed uniformly in the solid adhesive matrix (polyisobutylene) or suspended in a viscous, leachable liquid (silicone fluid) or dissolved in a releasable solvent (alkyl alcohol). The rate controlling membrane can be either microporous or non-porous membrane (Ethylene vinyl acetate copolymers) 2.2. Adhesive type TDDS: In this system, the drug resrvoir is formulated by directly dispersing the drug in an adhesive polymer (polyisobutylene or polyacrylate), then spreading the medicated adhesive by solvent casting or hot melt, onto a backing support to form a single layer or multiple layers of drug reservoir 2.3. Matrix type TDDS: The drug reservoir here is formed by homogeneously dispersing the drug in a hydrophilic or lipophilic polymer matrix and the medicated polymer formed is then moulded into medicated discs with a defined surface area and controlled thickness. This is then mounted onto a backing membrane and the adhesive is applied outside the disc along the circumference to form a strip of adhesive rim. 2.4. Microreservoir TDDS: This type of drug delivery system is formed by first suspending the drug in the aqueous solution of a water-soluble polymer (eg.PEG) and then dispersing homogeneously, the drug suspension in a lipophilic polymer, by high shear force, to form unleachable microscopic drug reservoirs. These are also known as ‘Microsealed Delivery Devices. 2.5. Poroplastic or Moleculon Type Devices: These systems, developed at Moleculon, (Cambridge, Massachusetts) utilise poroplastic films. The film is made utilizing the concept of water coagulation of cellulose triacetate solution in organic acids at low temperature. The coagulation is performed under controlled conditions and the extent of water content may be varied to a great condition and degree. 2.6. Penetration enhancement: The permeation of drugs across the skin is enhanced by physical means like pulsed DC iotophorosis or effect of ultrasounds may have synergistic effect depending upon the current density of pulse current applied and ultrasound intensity time (Chien YW, 1992). 2.6.1. Iontophoresis: It is a process that utilizes bipolar electric fields to propel ionic drug molecules across the intact skin into the underlying tissues. Positively charged drug ions in solution are transferred from a positive polarity chamber and vice versa. Delivery of positively charged compounds is easier than negatively charged compounds as the skin itself possesses a net negative charge. Iontophoresis can enhance transport across skin by a number of ways including an electrophoretic driving force and an electro-osmotic driving force and thus transiently increasing skin permeability. The transdermal transport can be increased by orders of magnitude relative to passive diffusion-based methods and can be modulated by controlling electrical parameters. Food and Drug Adminstration (FDA) has approved a number of products based on this technique like pilocarpine and lidocaine patches. The delivery of
  29. 29. ISSN: 2321-5674(Print) ISSN: 2320 – 3471(Online) Sowjanya et.al Indian Journal of Research in Pharmacy and Biotechnology Volume 1(4) July-August 2013 Page 494 proteins and peptides and other small macromolecules has been demonstrated in various articles. An iontophoretic electrode, Trans-Q has been developed such that the charge is delivered to a hydrogel pad loaded with the drug solution. Most of the work is going on to develop novel bioadhesive drug containing electrodes for use in iontophoretic drug delivery. Iontopatch SP transdermal drug delivery system is a self-constrained ultra-thin technology that eliminates the need of wires or batteries. It has an active area of 15.5 cm2 containing 40 mcg of the medicament. Mostly this technology has been introduced as an alternative to traditional treatment with injections. Non-steroidal anti-inflammatory drugs and corticosteroids are delivered by this mechanism. Alza Corporation Ltd., has developed electro transport system (E-Trans) for delivering fentanyl to treat acute and post operative pain. The patient has to push the button on the device which causes current to flow between two electrodes and a predetermined amount of drug is released through the skin. Also, a disposable kind of iontophoretic patch called Power Patch for delivering calcitonin to treat osteoporosis is under clinical trial. 2.6.2. Sonophoresis: It involves the introduction of substance into the body by ultrasound energy. Ultrasound energy vibrates molecules and creates tiny holes in the skin surface through ultrasound technology. The pores remain open for 12 hrs only.SonoPrep transdermal system from Sontra Medical uses low frequency ultrasound for skin permeation of lidocaine. It involves exposing the skin to a coat of lipids and then applying ultrasound at a frequency of 55,000 cycles per second causing creation of tiny bubbles which expands both in the liquid layer applied and the lipids of the skin. Thus, the skin of that area becomes leaky and remains as such. However, the pores get changed once the sound is turned off. Similarly, ImaRx Therapeutics has developed ultrasound assisted transdermal system utilizing ultrasound transducers to activate a drug and to open the skin pores for enhanced transdermal delivery. This technique has been employed for large molecular weight drugs such as peptides or proteins having molecular weight between 6000 to 48000 Daltons. 2.6.3. Electroporation: It is known that the mammalian skin is having intercellular lipids arranged in bilayers, which do not allow the transport of the drug transdermally. Electroporation is the technique by which aqueous pores are created by electric pulse of milliseconds causing transient permeability in the outer membrane which facilitates transport of drug. Flux increase upto four orders of magnitude was observed with human skin in vitro for three polar molecules having charges between –1 and –4 and molecular weights up to slightly more than 1000 daltons. Similar increase in flux was observed in- vivo with animal skin. The commercial product MedPulser (Genetronics Biomedical) is used on electroporation therapy system for use in delivering pharmaceuticals and genes. This electroporation system takes about 30 minutes and uses very small dose of the drug. The flux values of the model drugs increases exponentially and reaches the steady state flux. The examples are heparin and leutinizing hormone releasing hormone (LHRH), which show increased transdermal absorption with this technique. 2.6.4. Heat and Microneedles: Heat is also now expected to enhance the transdermal delivery of various drugs by increasing skin permeability, body circulation, blood vessel wall permeability, rate limiting membrane permeability and drug solubility.Heating prior to or during topical application of a drug will dilate penetration pathways in the skin, increase kinetic energy and the movement of particles in the treated area and facilitate drug absorption. Heating the skin after topical application of a drug will increase the drug absorption into vascular network, enhancing the systemic delivery but decreasing the local delivery as drug molecule is carried away from local site. Tempera are necessary to cause measurable changes in cell permeability. Recently, some researchers have reported the use of pressure driven jets for the intradermal delivery of a variety of drugs. The pressure and velocity of the jet were measured using calibrated pressure transducers and high-speed photography and showed the dependence on the drug delivery. Another innovation in this field is controlled heat aided drug delivery system (CHADD), which uses a thin heating device, attached to the top of the transdermal patch. The heat and temperature are controlled to deliver the drug either as bolus or to match circadian rhythms. S- Caine, a pediatric formulation of lidocaine and tetracaine uses CHADD technology for attaining a dense anesthetic effect in 15 to 20 minutes. Another product-Titragesia, uses the same technology to deliver fentanyl for treating pain.
  30. 30. ISSN: 2321-5674(Print) ISSN: 2320 – 3471(Online) Sowjanya et.al Indian Journal of Research in Pharmacy and Biotechnology Volume 1(4) July-August 2013 Page 495 3. CONCLUSION The novel drug delivery system has brought renaissance into the pharmaceutical industry for controlled drug delivery. The novel drug delivery systems include transdermal drug delivery system, mucoadhesive drug delivery system, nasal drug delivery system etc. The transdermal route of drug delivery is gaining accolade with the demonstration of percutaneous absorption of a large number of drugs. This type of drug delivery with the intention of maintaining constant plasma levels, zero order drug input and serves as a constant I.V. infusion. Several transdermal drug delivery systems (TDDS) have recently been developed aiming to achieve the objective of systemic medication through application to the intact skin. The intensity of interest in the pontential bio-medical application of transdermal controlled drug administration is demonstrated in the increasing research activities in a number of health care institutions in the development of various types of transdermal therapeutic systems(TTS) for long term continuous infusion of therapeutic agents including antihypertensives, antianginal, anti-histamine, anti- inflammatory , analgesic drugs etc. REFERNCES Brahmankar DM, Jaiswal SB, Biopharmaceutics and pharmacokinetics A Teatise, Vallabh Prakashan, Delhi, 1995, 335-371. Chien YW, Novel drug delivery systems, Drugs and the Pharmaceutical Sciences, Vol.50, Marcel Dekker, New York, 1992, 797. Roberts MS, Targeted drug delivery to the skin and deeper tissues: role of physiology, solute structure and disease, Clin Exp Pharmacol Physiol, 24(11), 1997, 874-9. Amgaokar MY, Chikhale RV, Lade UB, Biyani DM, Umekar MJ, Design formulation and evaluation of transdermal drug delivery system of budesonide, Dig J Nanomater and Biostruct, 6(2), 2011, 475-97. Patel MP, Patel KN, Patel DR, Patel UL, Formulation and evaluation of transdermal patches of glibenclamide, Int J Pharm Res, 1(2), 2009, 34-42 Jamakandi VG, Mulla JS, Vinay BL, Shivakumar HN, Formulation, characterization and evaluation of matrix- type transdermal patches of a model antihypertensive drug, Asian J Pharm, 3(1), 2009, 59-65. Irfani G, Raj R S, Tondare A, Noola, Design and Evaluation of transdermal drug delivery system of valsartan using glycerine as plasticizer, IJPRD, 3(2), 2011, 185-92 Shivaraj A, Selvam RP, Mani TT, T Sivakumar, Design and evaluation of transdermal drug delivery of ketotifen fumarate Int J Pharm Biomed Res, 1(2), 2010, 42-47 Ashok KJ, Pullakanda N, Prabu SL, V Gopal, Transdermal drug delivery system an overview, IJPSRR, 3(2), 2010, 49-54
  31. 31. ISSN: 2321-5674(Print) ISSN: 2320 – 3471(Online) Navin et.al Indian Journal of Research in Pharmacy and Biotechnology Volume 1(4) July-August 2013 Page 496 SYNTHESIS OF NEW THIAZOLIDINE-2,4-DIONE DERIVATIVES AND THEIR ANTIMICROBIAL AND ANTITUBERCULAR ACTIVITY Faiyazalam M Shaikh1 , Navin B. Patel1* and Dhanji Rajani2 1. Veer Narmad South Gujarat University, Udhana-Magdalla Road, Surat-395 007, Gujarat, India. 2. Microcare Laboratory and Tuberculosis diagnosis & Research Centre, Surat. * Corresponding author: E-mail: faiyaz_online007@yahoo.co.in; drnavin@satyam.net.in, Mobile: +919825350484 ABSTRACT New 1,3-thiazolidine-2,4-dione (TZD) derivatives 16-29 have been prepared by Knoevenagel condensation reaction between TZD and aromatic aldehydes followed by condensation with 3,4- dichloro benzoyl chloride. The structures of the newly synthesized compounds were assigned on the basis of elemental analysis, IR, 1 H NMR and 13 C NMR spectral data. All the synthesized compounds were tested for antibacterial activity against Gram-positive cocci and Gram-negative rods, antifungal activity and antitubercular activity. Moderate to good activity results were found for the newly synthesized compounds. Key Words: 1,3-thiazolidine-2,4-dione, Knoevenagel condensation, antibacterial, antifungal, antitubercular activity 1. INTRODUCTION One of the main objectives of organic and medicinal chemistry is to design, synthesize and produce molecules possessing value as human therapeutic agents. Compounds containing heterocyclic ring systems are of great importance receiving special attention as they belong to a class of compounds with proven utility in medicinal chemistry. Thiazolidine-2,4-dione (TZD) is a heterocyclic ring system with multiple applications. Thiazolidine-2,4-dione inhibits corrosion of mild steels in acidic solution. These are also used in analytical chemistry as highly sensitive reagents for heavy metals and as a brighter in electroplating industry. In 1982 a number of TZDs were intensively studied for their anti-hyperglycaemic property. The first representative of this class was ciglitazone, whereas other derivatives like englitazone, pioglitazone and troglitazone followed soon. The thiazolidine-2,4-dione nucleus has been reported for being responsible for majority of their pharmacological actions. Henceforth, thiazolidine- 2,4-dione derivatives have been studied extensively and found to have diverse chemical reactivities and broad spectrum of biological activities (Jain, 2013). Thiazolidinediones (TZD) are biologically active compounds having five membered rings, with two heteroatoms. Thiazolidinediones displayed a broad spectrum of biological activities including antimicrobial (Gouveia, 2009; Tuncbilek and Altanlar, 2006), antidiabetic (Murugan, 2009; Pattan, 2005), antiobesity (Bhattarai, 2009), anti- inflammatory (Youssef, 2010), antioxidant (Bozdag- Dundar, 2009), antiproliferative (Patil, 2010), antitumor (Shimazaki, 2008), etc. Currently, the antibiotic era is threatened by the convergence of three adverse circumstances: high levels of antibiotic resistance among important pathogens, an uneven supply of novel classes of antibiotics, and a dramatic reduction in the number of pharmaceutical companies engaged in the discovery and development of anti-infective agents (Wenzel, 2004). As a result, multidrug-resistant, and therefore difficult-to-treat, infections continue to occur and are clearly increasing in some areas. New antibiotics can help stave off the catastrophe. But since 1987, no major antibiotic has been discovered. In this regard, it is important to develop new and safe nuclei to combat with multidrug-resistant bacterial and fungal infections. Substantial investment and research in the field of anti-infectives are now desperately needed if a public health crisis is to be averted. Looking towards this turmoil of situation in the field of antibiotics, we are reporting herewith synthesis and antibacterial, antifungal and antitubercular activity of new thiazolidinediones. 2. MATERIALS AND METHODS 2.1. General: Laboratory Chemicals were supplied by Rankem India Ltd. and Ficher Scientific Ltd. Melting points were determined by the open tube capillary method and are uncorrected. The purity of the compounds was determined by thin layer chromatography (TLC) plates (silica gel G) in the solvent system n-hexane: ethyl acetate (7.5:2.5). The spots were observed by exposure to iodine vapors or by UV light. The IR spectra were obtained on Thermo Scientific Nicolet iS10 FT-IR spectrometer (using KBr pellets). The 1 H-NMR & 13 C-NMR spectra were recorded on a Varian Gemini 200 spectrometer using TMS as an internal standard in DMSO-d6. Elemental analyses of the newly

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