* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download enclosure – ii
Survey
Document related concepts
Plateau principle wikipedia , lookup
Polysubstance dependence wikipedia , lookup
Compounding wikipedia , lookup
Discovery and development of proton pump inhibitors wikipedia , lookup
Pharmacogenomics wikipedia , lookup
Neuropharmacology wikipedia , lookup
Pharmaceutical industry wikipedia , lookup
Prescription costs wikipedia , lookup
Prescription drug prices in the United States wikipedia , lookup
Theralizumab wikipedia , lookup
Drug design wikipedia , lookup
Drug interaction wikipedia , lookup
Drug discovery wikipedia , lookup
Pharmacognosy wikipedia , lookup
Transcript
ENCLOSURE – I 6) BRIEF RESUME OF THE INTENDED WORK 6.1) NEED FOR THE STUDY Tablets represents the preferred class of pharmaceutical solid oral dosage forms because of their convenience in terms of self administration, compactness, unit dosage forms and ease in manufacturing. However, an important variable in any tablet system is the rate at which the drug substance dissolves and which in turn depends on disintegration of the dosage after administration. Such tablet fragmentation may be critical to the subsequent dissolution of the drug and to attainment of satisfactory drug bioavailability. Thus, the proper choice of disintegrants and its consistency of performance are of critical importance to the formulation development of such tablets1. Consequently, tablet disintegration has received considerable attention as an essential step in obtaining fast drug release by using superdisintegrants as they promote moisture penetration and dispersion of the tablet matrix. Superdisintegrants are the substances added to tablet and some encapsulated formulations to promote the breakup of the tablet and capsule “slugs’ into smaller fragments in an aqueous environment there by increasing the available surface area and promoting a more rapid release of the drug substance2. Various superdisintegrants like cross linked polyvinyl pyrrolidone (crospovidone), cross linked sodium carboxymethyl cellulose (AcDiSol, solutab), sodium starch glycolate (primogel), etc., are now frequently used in tablet formulation to ensure quick disintegration and dissolution of drug from the dosage form3. They are generally used at a low level in the solid dosage form, typically 1-10% by weight relative to the total weight of the dosage unit. They may be used alone or in combination with other superdisintegrants. However, the proper choice of superdisintegrants and its proportion are of significant importance in the development of tablets. There are three methods of incorporating disintegrating agents into the tablet: a) Internal addition (Intragranular). b) External addition (extragranular) and c) Partly internal and external. A disintegrant used in granulated formulation processes can be more effective if used both “intragranularly” and “extragranularly” thereby acting to break the tablet up into granules and having the granules further disintegrate to release the drug substance into solution. However, the portion of disintegrant added intragranularly (in wet granulation processes) is usually not as effective as that added extragranularly due to the fact that it is exposed to wetting and drying (as part of the granulation process) which reduces the activity of the disintegrant4,5. Thus, superdisintegrants play an important role to ensure quick disintegration and high dissolution rates of fast disintegrating drug delivery systems. So, it is essential to choose proper mode of addition of suitable superdisintegrants in an optimum concentration during the formulation of tablets. Hence, the aim of the present study is to develop fast disintegrating tablets of carbidopa which is used to treat Parkinson’s disease6 using various superdisintegrants. Further to study the effect of superdisintegrants on the tablet properties as well as to improve the patient compliance without compromising the therapeutic efficacy. ENCLOSURE – II 6.2) REVIEW OF LITERATURE Kulkarniet al7 formulated and evaluated taste masked fast disintegrating tablets of lisinopril to improve therapeutic efficacy of the drug. Tablets were evaluated for weight and thickness variation, disintegration time, drug content, in vitro dissolution, wetting time and water absorption ratio. The influence of superdisintegrants, crosspovidone, croscaremellose sodium on disintegration time, wetting time and water absorption ratio were studied. The in vitro disintegration time of the best fast disintegrating tablets was found to be within 32 seconds. Tablets containing crospovidone exhibit quick disintegration time than tablets containing croscaremellose sodium. The fast disintegrating tablets of lisinopril with shorter disintegration time, acceptable taste and sufficient hardness could be prepared using crospovidone and other excipients at an optimum concentration. Preetha B et al8 studied the effect of mode of incorporation of superdisintegrants like croscarmellose sodium, sodium starch glycolate and crospovidone (polyplasdone XL and XL-10) on dissolution of carbamazepine (poorly soluble), acetaminophen (sparingly soluble) and cetrizineHCl (soluble) tablet formulations prepared by wet granulation. The disintegrants were incorporated extragranularly or intragranularly or distributed equally between the two phases. The results indicated that crospovidone in general was effective in improving the dissolution of the drugs used in the study and generally extragranular mode of addition seemed to be the best mode of incorporation, irrespective of the solubility of the main tablet component. Shirsand SB et al9 designed fast disintegrating tablets of prochlorperazine maleate with a view to enhance patient compliance by direct compression method. In this method, crospovidone (up to 3% w/w) and croscarmellose sodium (up to 5% w/w) in combination were used as superdisintegrants. Then tablets were further evaluated for hardness, friability, drug content uniformity, in vitro dispersion time, wetting time and water absorption ratio. Based on in vitro dispersion time (approximately 12 s), one promising formulation was tested for in vitro drug release pattern in phosphate buffer pH 6.8 and short-term stability (at 40 degrees /70% RH for 3 mo), drug-excipient interaction (IR spectroscopy) were studied. Among the formulations tested, formulation DCPC(4) containing 5% w/w of croscarmellose sodium and 3% w/w of crospovidone as superdisintegrant, emerged as the overall best (t(50%) 7.0 min) based on drug release characteristics in pH 6.8 phosphate buffer compared to commercial conventional tablet formulation (t(50%) 17.4 min). Shortterm stability studies on the promising formulation indicated that there were no significant changes in drug content and in vitro dispersion time (p<0.05). Amit Modi et al10 formulated and evaluated fast dissolving tablets of Diclofenac sodium using different superdisintegrants by direct compression method. It was concluded that the batch which was prepared by using combination of crosspovidone and sodium starch glycolate as a superdisintegrant shows excellent disintegration time, enhance dissolution rate, taste masking and hence lead to improve efficacy and bioavailability of drug. Shirsand SB et al11 successfully prepared fast dissolving tablets of Clonazepam by direct compression method by using crospovidone, croscarmellose sodium and mannitol. They concluded that the formulation which was prepared by using 10%crospovidone and 35%w/w microcrystalline cellulose is the best formulation (t50% - 1.8 minutes). Arul Kumaran KSG et al12 prepared a levodopa- carbidopa combination of orally disintegration tablet by direct compression method and evaluated results were compared with marketed tablets. Effect of superdisintegrants (such as microcrystalline cellulose, sodium starch glycolate and crospovidone) on wetting time, disintegration time, drug content, in vitro release and stability parameters has been studied. Taste evaluation (palatability studies) was done for the formulation with the peppermint oil and evaluated for its better compliance than the other flavors used in the formulation. Taste and disintegration of optimized formulation (F5&F7) were found to be better than the marketed product. Drug release rate was more or less same as that of the marketed product. Patil C and Das S et al13 developed an orally disintegrating tablet (ODT) of lamotrigine and evaluated the effect of various superdisintegrants on its disintegration time and release profile. Tablets were prepared by direct compression technique using sodium starch glycolate, croscarmellose sodium and crosspovidone XL-10 in combinations to achieve optimum release profile, disintegration time and hardness. Direct compression process was selected for this formulation of ODT tablets, because porous nature is more in direct compression blend than wet granulation blend, so it will give faster disintegration. Microcrystalline cellulose was used as diluent and mannitol, mint flavor and sodium saccharin was used to enhance the organoleptic properties of tablets. The tablets were evaluated for weight variation, hardness, friability, in-vitro disintegration time and drug release characteristics. Hardness and friability data indicated good mechanical strength. The results of in-vitro disintegration time indicated that the tablets dispersed rapidly in mouth within 8 s. Dissolution study revealed release rate of drug from the tablets was comparable with marketed tablet formulation of lamotrigine. It was concluded that superdisintegrants addition technique is a useful method for preparing orally disintegrating tablets by direct compression method. Sarasija S et al14 prepared and evaluate mouth dissolving tablets of salbutamol sulphate. Fast dissolving tablets of salbutamol sulphate were prepared using sublimation ingredients. Selection of the filler also had an important role in deciding the disintegration time. Evaluation of the tablets showed that all the tablets were found to be within official limits and the disintegration time for the formulations ranged from 5 s to 40 s. amongst all, the formulation containing microcrystalline cellulose and ammonium bicarbonate showed the least disintegration time of 5 seconds. Chakraborty S et al15 studied on comparative effect of natural and synthetic superdisintegrants in the formulation of fast dissolving tablets. The effect of a natural superdisintgrant vis-a-vis isolated mucilage of Plantago ovata and synthetic superdisintegrants like sodium starch glycolate (SSG) and croscarmellose sodium (Ac-Di-Sol) were compared in the formulations of fast dissolving tablets. Fast dissolving tablets of Aceclofenac (modal drug) were prepared by direct compression method using microcrystalline cellulose as direct compressible vehicle. The present study revealed that this natural superdisintegrants Plantago Ovata mucilage showed better disintegrating property than the most widely used synthetic super disintegrants like SSG and Ac-Di-Sol in the formulation of fast dissolving tablets. Gudas GK et al16 prepared formulation and evaluation of fast dissolving tablets of Chlorpromazine HCL. The tablets were prepared with five superdisintegrants like sodium starch glycolate, crospovidone, croscarmellose, L-HPC, pregelatinised starch. The blend was examined for angle of repose, bulk density, tapped density, compressibility index and Hausners ratio. The tablets were evaluated for hardness, friability, disintegration time, dissolution rate, drug content. It was concluded that the fast dissolving tablets with proper hardness, rapidly disintegrating with enhanced dissolution can be made using selected superdisintegrants. Tayebi H and Mortazavi SA17 prepared a novel matrix-type buccal fast disintegrating ibuprofen tablet formulation using special polymers, water soluble excipients, super-disintegrants and quickly soluble granules. For this purpose different tablet formulations of ibuprofen were prepared. Eight groups of formulation were prepared (A-H series), accounting for a total number of 45 formulations. Formulations prepared were examined in terms of different physicochemical tests including powder/granule flowability, appearance, thickness, uniformity of weight, hardness, friability and disintegration time. Results of formulation F22a (in series F), was found to be acceptable, making it the chosen formulation for further studies. Then, by adding various flavorants and sweeteners to this formulation, complementary series of formulations, named G and H, were prepared. Following the comparison of their taste with each other through asking 10 volunteers, the most suitable formulation regarding the taste, being formulation F22s, was chosen as the ultimate formulation. This formulation had PVP, ibuprofen and croscarmellose as the intra-granular components and xylitol and saccharin as the extra-granular ingredients. Formulation F22s was found to be acceptable in terms of physicochemical tests conducted, showing quick disintegration within the buccal cavity, appropriate hardness and rather low friability. Hence formulation F22s was selected as the final formulation. Tapan KG et al18 developed tablets of diazepam-hydroxypropyl-β-cyclodextrin inclusion complex that disintegrate within 3 minutes and release 85% of drug within 30 minutes to provide rapid action of the drug through oro-mucosal route. Tablets of diazepam were prepared by direct compression method that disintegrated quickly (in 13.3 seconds) and released 85% drug rapidly (in 8.98 minutes). Comoglu T and Unal B19 developed new solution to incorporate higher doses of a model hydrophobic drug; meloxicam, without affecting the fast disintegrating properties of the formulation. In order to enhance the solubilization of meloxicam in fast disintegrating tablet (FDT) formulations, β cyclodextrin inclusion complex of the drug is prepared and FDTs containing meloxicam--β cyclodextrin inclusion complex (F1 A and F2 A) were compared and evaluated with the FDTs containing pure meloxicam (F1 and F2) by means of in vitro quality control tests. ENCLOSURE – III 6.3) OBJECTIVES OF THE STUDY The proposed work is planned with the following objectives: To carry out preformulation studies of drug and selected excipients. To formulate fast disintegrating tablets of carbidopa using various superdisintegrants like cross linked poly vinyl pyrrolidone (crospovidone), cross linked sodium carboxymethyl cellulose (AcDiSol, solutab), sodium starch glycolate (primogel) etc., by adopting wet granulation method. To carry out pre-compression and post-compression evaluation of the prepared formulations. To investigate the effect various superdisintegrants and their concentrations on release profile of the drug from carbidopa tablets. To investigate the effect of mode of addition of superdisintegrants on the tablet properties. To carry out in vitro disintegration and dissolution studies of prepared formulations. ENCLOSURE – IV 7) MATERIALS AND METHODS 7.1) SOURCE OF DATA: The primary data will be collected by conducting various experimental work and investigations in the laboratory and recording the observations. The secondary data will be collected by referring various national and international journals, books, Pharmacopoeia’s and professional websites like Helinet,Pubmed etc. ENCLOSURE –V 7.2) METHOD OF COLLECTION OF DATA 1) The physico-chemical parameters of the model drug will be determined in our laboratory using standard methodology. 2) Instruments like disintegration apparatus, friabulator, dissolution apparatus and UV spectrophotometer will be used to record the observations. 3) Compatibility between the drug and excipients will be studied using techniques such as DSC, FT-IR etc. 4) Tablets of carbidopa will be formulated by adopting suitable technique. 5) Tablets shall be evaluated for pre-compression parameters like bulk density, tapped density, Hausner’s ratio, Caurr’s index, particle size distribution (PSD) and post-compression parameters like thickness, weight variation, hardness, friability, drug content, in vitro disintegration and in vitro dissolution studies. 6) In vitro drug release profiles will be studied and data shall be analyzed statistically and kinetics of drug release shall be studied. 7) To carry out short term stability studies of tablet formulations as per ICH guidelines at 30 ± 2C (65 ± 5 %RH) and 40 ± 2C (75 ± 5 %RH). 7.3) Does the study require any investigations to be conducted on patients/ humans/ animals? NO ENCLOSURE –VI 8) LIST OF REFERENCES: 1. Na Zhao and Augsburger LL. Functionality comparison of 3 classes of superdisdintegrants in promoting aspirin tablet disintegration and dissolution. AAPS PharmSciTech 2005;6:E634-E640. 2. Ansel HC, Popvich NG, Allen LV. Pharmaceutical Dosage Forms and Drug Delivery System, First Edition, 1998, 78. 3. Shangraw R, Mitrevej A, Shah M. New era of tablet disintegrants. PharmTechnol 1980;4:49-57. 4. Lachman L, Liberman HA. Theory and Practice of Industrial Pharmacy, Third Edition, 1990, 293-294. 5. Caramella C, Colombo P, Conte U, Ferrari F, La Manna A, Van Kamp HV, Bolhuis GK. Water uptake and disintegrating force measurements: towards a general understanding of disintegration mechanisms. Drug Dev Ind Pharm 1986;12:1749-1766. 6. Block G, Liss C, Reines S, Irr J, Nibbelink D. Comparison of immediaterelease and controlled release Carbidopa/Levodopa in Parkinson's disease. A multicenter 5-year study. The CR First Study Group. Eur Neurol 1997;37: 23-27. 7. Kulkarni SV, Ranjit Kumar P, Basavaraj, SomeshwaraRao B, Ramesh B, Ashok Kumar P. Effect of superdisintegrants on formulation of taste masked fast disintigratinglisinopril tablets. Int J Curr Pharm Res 2011;3(1):11-14. 8. Preetha B, Pandit JK, Rao VU, Bindu K, Rajesh YV, BalasubramaniamJ. Comparative Evaluation of Mode of Incorporation of Superdisintegrants on Dissolution of Model drugs from wet granulated tablets. Acta Pharmaceutica Sciencia 2008;50: 229-236. 9. Shirsand SB, Suresh S, Swamy PV, Para MS, Nagendra Kumar D. Formulation design of fast disintegrating tablets using disintegrant blends. Indian J Pharm Sci 2010;72(1):130-3. 10. Amit M, Vandana S, Arun G, Ashish A. Formulation and Evaluation of Fast Dissolving Tablets of Diclofenac Sodium Using Different Superdisintegrants by Direct Compression Method. Int J Pharm Biol Arch 2012; 3(4):10031007. 11. Shirsand SB, Sarasija S, Swamy PV, Nagendra KD, Rampure MV. Design and Evaluation of Fast Dissolving Tablets of Clonazepam. Indian J Pharm Sci 2008; 11:791-795. 12. Arul Kumaran KSG, Sreekanth J, Palanisamy S. Formulation development and evaluation of Levodopa-Carbidopa orally disintegration tablets J Chem Pharm Res 2011;3(3):169-175. 13. Patil C and Das S. Effect of various superdisintegrants on the drug release profile and disintegration time of Lamotrigine orally disintegrating tablets. African Journal of Pharmacy and Pharmacology 2011;5(1):76-82. 14. Sarasija S, Pandit V, Joshi HP. Preparation and evaluation of mouth dissolving tablets of salbutamol sulphate. Ind J Pharm Sci 2007;69(3):467469. 15. Chakraborty S, Khandai M, Singh SP, Patra NC, Int J Green Pharmacy 2008; 2(1), 22-25. 16. Gudas GK, Manasa B, Rajesham VV, Kumar SK, Kumari JP. J Pharm Sci Tech 2010;2(1):99-102. 17. Tayebi H, Mortazavi SA. Formulation and evaluation of a novel matrix-type orally disintegrating Ibuprofen tablet. Iran J Pharm Res 2011;10(3):469-79. 18. Tapan KG, Biswanath Sa. Preparation and Evaluation of Rapidly Disintegrating Fast Release Tablet of Diazepam-Hydroxypropyl-β- Cyclodextrin Inclusion Complex. Pharmacology & Pharmacy 2010;1:18-26. 19. Comoglu T, Unal B. Preparation and evaluation of an orally fast disintegrating tablet formulation containing a hydrophobic drug. Pharm Dev Technol 2013;Dec 3 [Epub ahead of print].