Development and Evaluation of Mini- Tablets-filled-capsule system for chronotherapeutic delivery of salbutamol SULPHATE
M. Pharm. Dissertation Protocol
Submitted to the
Rajiv Gandhi University of Health Sciences, Karnataka
Bangalore.
By
vinod.d
B. Pharm.
Under the guidance of
Dr. N. G. RAGHAVENDRA RAO
Professor and HOD
PG Dept. of Pharmaceutics
DEPARTMENT OF PHARMACEUTICS
LUQMAN COLLEGE OF PHARMACY, GULBARGA
2011-12
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, KARNATAKA
BANGALORE
ANNEXURE - II
PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION
1. / Name of the Candidate and address (In block letters) / : /VINOD.D
107, BIDDAPUR COLONYOPP; KGB GULBAGA. PIN-585102
KARNATAKA.
2. / Name of the Institution / : / LUQMAN COLLEGE OF PHARMACY,
BEHIND P&T COLONY, OLD JEWARGI ROAD, GULBARGA, PIN - 585102
3. / Course of Study and Subject / : / M.PHARM. (PHARMACEUTICS)
4. / Date of Admission to Course / : / 27thJuly-2011
5. / Title of the Topic / : / Development and Evaluation of Mini-Tablets-filled-capsule system for chronotherapeutic delivery of salbutamol SULPHATE
6. / Brief resume of the intended work
6.1 / Need for the study:
Chronotherapeutic refers to a clinical practice of synchronizing drug delivery in a manner consistent with the body’s circadian rhythm including disease states to produce maximum health benefit and minimum harm. Asthma is a chronic obstructive lung disease characterized by airways, inflammation and hyperactivity. The worsening of asthma at night commonly referred to as nocturnal asthma (NA). Approximately two-thirds of asthmatics suffer from night time symptoms. In a large study involving 8,000 asthmatics it is observed that 70% awakened one night per week, 64% awakened 3 nights per week and 39% had their sleep disturbed on a nightly basis. The patients who self characterized their asthma as mild, 26% has nightly awakenings and 53% of asthma deaths occurred during the night time hours. A drug delivery system administered at bed time but releasing drug during morning hours would be ideal in this case 1, 2.
The oral route of administration still continues to be the most preferred route due to its manifold advantages including ease of ingestion, pain avoidance, versatility and most importantly patient compliance, accurate dosage, self medication3.
Oral controlled release drug delivery systems can be classified in two broad groups: single unit dosage forms such as tablets or capsules, and multiple unit dosage forms such as granules, pellets or mini-tablets3-5. The concept of multiple unit dosage form is characterized by the fact that the dose is administered as a number of subunits, each one containing the drug. The dose is then the sum of the quantity of the drug in each subunit and the functionality of the entire dose is directly correlated to the functionality of the individual subunits6.
Mini-tablets are small tablets with a diameter typically equal to or less than 3 mm that are typically filled into a capsule. It is possible to incorporate many different mini-tablets, each one formulated individually and programmed to release drug at different sites within the gastrointestinal track, into one capsule. These combinations may include immediate release, delayed release, and/or controlled release mini-tablets7.
Mini-tablets combine the advantages of multi particulate dosage forms with the established manufacturing techniques of tableting. Additional benefits of mini-tablets include excellent size uniformity, regular shape and a smooth surface, thereby offering an excellent substrate for coating with modified release polymeric systems. They can be produced via direct compression and can be manufactured using conventional tableting machines with only minor equipment modifications. Furthermore, mini-tablets can be coated using either perforated coating pan or a fluidized bed apparatus8-10.
Salbutamol sulphate is a drug widely used for the treatment of acute and chronic bronchitis patients11.Salbutamol sulphate is a selective β2- adrenergic agent, widely used in the treatment of bronchiole asthma, chronic bronchitis and emphysema. This is used as prophylactic drug as well as to prevent acute exacerbations of asthma in chronotherapy11.
The oral bioavailability of Salbutamol is 14.8% and half-life is 4 to 6 hour12-13. Salbutamol sulphate, a bronchodilator (β2 agonist) has a short half-life, hence frequent administration (4-6 times a day) is necessary. During acute attack of asthma it becomes difficult for a patient to take oral medications repeatedly. Hence, it is rational to administer Salbutamol sulphate in an immediate release as well as sustain release dosage form for chronotherapy, which will minimize repeated administration of drug.
Hence in the present work the attempt will be made to develop and evaluate the immediate release and extended release drug delivery of mini-tablets-filled-capsule systems using various water soluble and insoluble polymers like different grades of Hydroxy propyl methylcellulose, Microcrystalline cellulose, croscarmellose sodium, ethyl cellulose etc. and Salbutamol Sulphate as the model drug for its chronotherapeutic delivery whose physicochemical properties and short half life make it suitable candidate for controlled drug delivery system.
6.2 / Review of Literature:
Literature review shows that no work has been published on the Mini-Tablets-Filled-Capsule Systems for Chronotherapeutic Delivery of Terbutaline Sulphate. Some of the published reports of similar work for various medicinal agents are:
v Lopes CM et. al4., Formulated Compressed mini-tablets as a biphasic delivery system for zero-order sustained drug release. The outer layer (powder enrobing the mini-tablets) that fills the void spaces between the mini-tablets was formulated to release the drug in a very short time (fast release), while the mini-tablets provided a prolonged release.
v Brabander C et. al5., Formulated matrix mini-tablets based on starch: microcrystalline wax mixtures. The mini-tablets consisted of 60% ibuprofen, and in-vitro release was 4.5 hrs. For the mini-tablet and A significantly higher value of Cmax was seen for the mini-tablet formulation, resulting in a relative bioavailability of 116 ± 22.6% compared to the ibu-slow matrix. These data demonstrate that the experimental mini-tablets can be used to formulate sustained-release dosage forms.
v Vuong H et. al7., Carried out study on investigation of enteric coating of mini-tabs using a perforated pan or a fluid-bed machine. It is concluded that no significant differences in the appearance, physical and enteric properties of mini-tabs were observed when coated in a perforated pan or fluid-bed coating machines. The overall coating process time in the perforated pan machine was shorter than that in a fluid-bed coating machine. It was further determined that a minimum 30% enteric coating weight gain was required to provide acid resistance.
v Ishida M et. al8., Carried out study on A novel approach to sustained pseudoephedrine release: Differentially coated mini-tablets in HPMC capsules. The system comprises immediate-release mini-tablets (IRMT) and sustained-release mini-tablets (SRMT) contained in a hydroxy propyl methylcellulose (HPMC) capsule. The pseudoephedrine (PSE) in the IRMT dissolved within 60 min., whereas the PSE in the SRMT was released over 8-10 hrs. This system can be modified to yield various extended drug-release profiles, thereby harnessing the benefits of both SRMT and IRMT.
v Li Y et. al13., Carried out study on Modulation of combined-release behaviours from novel ‘‘tablets-in-capsule system’’. mini-tablets in a hard gelatine capsule, is developed by preparing rapid-release mini-tablets (RMTs), sustained-release mini-tablets (SMTs), Pulsatile mini-tablets (PMTs), and delayed-onset sustained-release mini-tablets (DSMTs), each with various lag times of release.
v Weyenberg W et. al.,14 Carried out study on characterization and in-vivo evaluation of ocular bio adhesive mini tablets compressed at different forces. The influence of the compression force on the physical properties, the in-vitro release and the in-vivo behaviour of ocular mini tablets is evaluated in this study. It is concluded that in-vivo relation release of ocular mini tablets is prolonged by increasing the compression force applied during manufacturing.
v Raghavendra Rao NG et al15., carried out study of Development and Evaluation of Tablets-Filled-Capsule System for Chronotherapeutic Delivery of Montelukast Sodium and proposed that fast/slow delivery devices show a wide flexibility in the modulation of the delivery program.
v Saettone MF et. al16., Formulated controlled release of timolol maleate from coated ophthalmic mini-tablets prepared by compression. Ophthalmic inserts for sustain release of Timolol were prepared by a standard compression and coating technique. An adequate control of the in-vitro drug release from the devices could be obtained by adjusting the type and amount of acrylic polymer coating.
v Raghavendra Rao NG et al17., carried out A novel approach to sustained montelukast sodium release: Differentially coated mini-tablets in HPMC capsules. Sustained release dosage form was developed by filling coated mini-tablets into an empty HPMC capsule shell which releases nearly 28.86% and 25.99% of the total dose within 60 min and the remaining dose was prolonged for a period of 24 h. This technology may be achieved by fast/slow delivery system.
6.3 / Objectives of the Study
The present study is planned with the following objectives:
1. Development of mini-tablets-filled-capsule system for chronotherapy consisting Salbutamol sulphate as model drug.
2. Development of different Mini-tablets consisting Salbutamol sulphate using various Hydrophilic and Hydrophobic polymers like different grades of hydroxy propyl methyl cellulose, ethyl cellulose and superdisintegrant croscarmellose Sodium, etc.
3. To evaluate the formulations with respect to various physical parameters (Weight variations, Hardness, Friability, etc.).
4. To evaluate the tablets with respect to content uniformity, in-vitro disintegration time and in-vitro dissolution rate studies.
5. To characterize the formulation with respect to drug-excipients interaction.
(Using DSC and FTIR).
6. To carry out stability studies as per ICH guidelines.
7 / MATERIAL AND METHODS
7.1 / Materials
Drugs : Salbutamol sulphate
Formulation additives: Different grades of hydroxy propyl methyl cellulose, croscarmellose sodium, ethyl cellulose, D-mannitol, anhydrous dibasic calcium phosphate, hydroxy propyl cellulose, magnesium stearate, talc, ethyl alcohol, etc.
All other chemicals and reagents used will be of analytical grade.
Equipments:
· UV/Visible spectrophotometer (Shimadzu).
· Electronic balance (Shimadzu Corporation BL-220 H, Pune).
· Thermostatic Hot plate with magnetic stirrer (Remi Motors Mumbai)
· Electro lab dissolution apparatus (USPXXIII) etc.
· Coating Pan, United Technologies, Mumbai, 6 inch.
7.2 / Methods
a) The powder blend was subjected for pre-compressional parameters like angle of repose, Bulk density and tapped density, Compressibility index and Hausner’s ratio.
b) Preparation of Salbutamol sulphate Mini-tablets: The system comprises immediate release Mini-tablets (IRMT) and sustained release Mini-tablets (SRMT) contained in a HPMC capsule. The IRMT will be compressed using disintegrants. The SRMT will be coated with a mixture of water soluble polymer (Different Grades of HPMC) and water insoluble polymer ethyl cellulose for controlling the release profile by varying thickness coat.
c) Evaluation of Salbutamol sulphate Mini-tablets: Mini-tablet formulations of Salbutamol sulphate will be evaluated for hardness, friability, weight variation, disintegration time, drug content, in-vitro dissolution rate, short-term stability and drug-excipients interaction (IR and DSC).
d) Formulation of Mini-tablets-filled-capsule system: Mini-tablets of Salbutamol sulphate will be filled with different combinations of immediate release Mini-tablets and sustained release Mini-tablets in the capsule.
e) Evaluation of the prepared Mini-tablets-filled-capsule system2,6: The prepared mini-tablets were evaluated for post-compressional parameters as hardness, friability, thickness, weight variation, drug content, in-vitro disintegration time, in-vitro dissolution studies.
7.3 / Does the study require any investigation or intervention to be conducted on patients or other humans or animals? If so please describe briefly.
Not under the plan of the work
7.4 / Has ethical clearance been obtained from your institution in case of 7.3?
Not applicable.
8. / List of References:
1. Shivakumar HN, Sarasija Suresh, Desai BG. Ind J Pharm Sci 2007, 69, 73-79.
2. Janugade BU, Patil SS, Patil SV, Lade PD. Int J Chem Tech Res2009, 1, 690-691.
3. Chien YW. Novel drug delivery systems.2nd Ed. New York: Marcel Dekker; 1992.
4. Lopes CM, Lobo JMS, Pinto JF, Costa P. Compressed mini-tablets as a biphasic delivery system. Int J of Pharm.: 2006; 323: 93–100.
5. Brabander C, Vervaet C, Gortz JP, Remon JP. Bioavailability of ibuprofen from matrix mini tablets based on a mixture of starch and microcrystalline wax. Int. J. Pharm.: 2000; 208: 81-86.
6. http://www.articlesbase.com/medicine-articles/minitablets-offer-mighty-advantages-to-the-pharmaceutical-industry-1056960.html
7. Vuong H, Palmer D, Levina M, Siahboomi AR. Investigation of Enteric Coating of Mini-Tabs Using a Perforated Pan or a Fluid-Bed Machine. Controlled Release Society Annul Meeting: 2008.
8. Ishida M, Abe k, Hashizume M and Kawamura M. A novel approach to sustained pseudoephedrine release: Differentially coated mini-tablets in HPMC capsules. Int. J. Pharm.: 2008; 359: 46–52.
9. Arvind K. Singh , Ramesh K. Singh, Sunil Kumar and M. K. Gupta Development and Evaluation of fast disintegrating tablets of Salbutamol Sulphate by superdisintegrating agents. IJPSR 2010; 01, (07): 46-53.
10. Martindale, The complete drug reference, 33rd edition, edited by Sean C Sweetman, Pharmaceutical Press, US 2002, pp. 770.3
11. Chanda R, Ghosh A, Biswas S and Choudary SR. Formulation of oral mucoadhesive tablets of Terbutaline sulphate using some natural materials and in-vitro and in-vivo evaluation. Journal of Pharmaceutical Research and Health Care: 2010; 2 (1): 32-45.
12. Saettone MF, Chetoni P, Mariotti BL, Giannaccini B, Conte U, Sangalli ME. Controlled release of Timolol maleate from coated ophthalmic Mini-tablets prepared by compression. Ind. J. Pharm: 1995; 126: 79-82.
13. Li Y, Zhu J. Modulation of combined-release behaviours from a novel ‘‘tablets-in-capsule system’’. Journal of Controlled Release: 2004; 95: 381– 389.
14. Weyenberga W, Vermeireb A, Remonb JP, Ludwiga A. Characterization and in vivo evaluation of ocular bioadhesive mini-tablets compressed at different forces. Journal of Controlled Release: 2003; 89: 329–340.
15. N. G. Raghavendra Rao, Mohd Abdul Hadi, Mansoori Wahid, M. R. Munde, Shrishail M. Ghurghure Development And Evaluation Of Tablets-Filled-Capsule System For Chronotherapeutic Delivery Of Montelukast Sodium. International Journal of Pharmacy and Technology.
16. Saettone MF, Chetoni P, Mariotti BL, Giannaccini B, Conte U, Sangalli ME. Controlled release of Timolol maleate from coated ophthalmic Mini-tablets prepared by compression. Ind. J. Pharm: 1995; 126: 79-82.
17. Raghavendra Rao NG, Mohd Abdul Hadi, Harsh A Panchal. A novel approach to sustained montelukast sodium release: Differentially coated mini-tablets in HPMC capsules. Pharma Sci Direct Int J Pharm Biomed Res 2011, 2(2), 90-97.