FORMULATION AND EVALUATION OF PINDOLOL PULSATILE DRUG DELIVERY SYSTEM FOR EFFECTIVE TREATMENT OF HYPERTENSION

M. PHARM DISSERTATION PROTOCOL

Submitted to

RajivGandhiUniversity of Health Sciences, Bangalore,

Karnataka

By :

Shridhar Sudhakar Palakhe

B.Pharm

Under the Guidance of:

Mr. Prashant A. Borgaonkar

M.Pharm (Ph.D.)

DEPARTMENT OF PHARMACEUTICS

R.M.E.S’S COLLEGE OF PHARMACY,

GULBARGA-585102

2013-2014

RAJIVGANDHIUNIVERSITY OF HEALTH SCIENCES, BANGALOREKARNATAKA

PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

1. / Name of the Candidate and address (In block letter) / SHRIDHAR SUDHAKAR PALAKHE
INDAPUR ROAD BEHIND MOTI HOSPITAL AKLUJ. DIST SOLAPUR
2. / Name of the Institution / R.M.E.S’S COLLEGE OF PHARMACY,
OLD JEWARGI ROAD,
GULBARGA-585102
KARNATAKA
3. / Course of study and subject / M. Pharm.
(Pharmaceutics)
4. / Date of Admission to course / 1/08/2013
5. / Title of the topic / FORMULATION AND EVALUATION OF PINDOLOL PULSATILE DRUG DELIVERY SYSTEM FOR EFFECTIVE TREATMENT OF HYPERTENSION
6.Brief resume of the intended work
6.1Need of the study:
In the field of modified release, there has been a growing interest in time specific oral delivery which generally refers to preprogrammed release of drug following administration to achieve improved therapeutic efficacy. These systems constitute a relatively new class of devices, the importance of which is specially connected with recent advances in Chronopharmacology1. It is well established that many of the body functions display circadian rhythms e.g. in peptic ulcer the acid secretion is high in afternoon and night, in case of asthma precipitation of symptom during night and early morning is high. Similarly in cardiovascular disease blood pressure is at its lowest during the sleep cycle and rises steeply during the early morning awaking period and in case of arthritis the pain is more in early morning. The other disorders that follow circadian rhythm are diabetic mellitus, angina pectoris, and rheumatic diseases2.
As well established, the physiology of the body is not uniform 24 hours a day. The delivery and therapy should be modified to achieve an effective drug level at the time required. This can be achieved by adopting a pulsatile drug delivery system of a suitable drug such type of formulation that are taken at bed time with preprogrammed start of drug release in early morning hours could offer a more effective therapy than a controlled conventional release drug delivery system.
Controlled releasethat display a pulse are mainly prepared by polymeric materials and systems that are made up of reservoir and covered with barrier. This barrier can be dissolved or eroded after which drug is released. The release from such formulation can be modified to get single pulse, double pulse and multi pulse release pattern.
The aim of present work is to develop a pulsatile drug release system of Pindolol forthe effective treatment of hypertension. Pindolol is a synthetic beta adrenergic receptor blocking agent with intrinsic sympathomimetic activity. It has an oral bioavailability of 50 to 95 % and has half life of 3-4 hours3.
6.2Review of Literature :
Literature survey was carried out on the proposed topic by referring various scientific journals, internet with helinet facility. The survey reveals that no such articles were reported on the proposed work and some related articles are mentioned below.
  1. Ina. Krogel et. Al., (1999)4 Formulation floating or pulsatile drug delivery system based on coated effervescent coat using Chlorpheniramine maleate. They have reported predetermined release pattern from above formulation.
  2. Jason T McConville et. (2002)5 Investigated the variability in the performance of pulsatile capsule delivery system induced by wet granulation of an erodible HPMC tablet, used to seal the contents within an insoluble capsule body. Erodible tablets with low concentration of HPMC (15%) showed a greater prolongation of log time followed by formulation containing wet granulation followed by formulation containing HPMC (24 & 30%)
  3. M Efentakis et. al., (2006)6 Formulated oral pulsatile drug delivery system based on a core-in-cup dry coated tablet, using Diclofenac sodium and Ketoprofen as model drug. Cellulose acetate propionate, Polyethlene oxide, sodium alginate were used to modulate the drug release. The concluded that these systems might offer a desired release profile for drug delivery at predetermined times.
  1. Evangelos Karavas et. al. (2006)7 Formulated pulsatile release formulations consisting of two layered tablets using Felodipine as model drug. PVP and HPMC blends were used to modulate the release. They have reported a pulse release after a lag period.
  2. Sameer Shamra et. al. (2006)8Formulated a multiparticulate floating pulsatile drug delivery system based on low density porous calcium silicate as drug carrier and pH responsive cross linked alginate polymer. This technique offers a pulse release of drug in upper part of small intestine
  3. V S Mastiholimath et al., (2007)9 formulated Time and pH dependent colon specific pulsatile delivery of Theophlylline for nocturnal asthma. The device was formulated with an insoluble hard gelatin capsule body, filled with Eudragit microcapsules of Theophylline and sealed with hydrogel plug. Programmable pulsatile colon specific release has been achieved.
  4. Badve S S et. al., (2007)10Developed hollowand porous calcium pectinate beads for floating pulsatile drug delivery. Desired preprogrammed release was obtained from the formulation.
  5. Hong-Laing Lin et. al, (2008)11 Formulated pulsatile drug relese system activated by membrane repture via osmotic pressure and swelling using Doxazosin mesylate as model drug. HPMC, E10M, Ethly cellulose and sodium chloride were used in the formulation. Predetermined lag time was obtained from the formulation
  6. Bin li al., (2008)12 Prepared a three pulse drug release based on ‘tablets in capsule’ device using Diclofenac sodium model drug. Ethyl cellulose was used to make the impermeable capsule body and sodium alginate, HPMC (E5) were used as a modulating barrier material. The result suggested that the formulation can be considered as promising technique to get a pulsatile drug release.
  7. Nayak Usha et. al., (2009)13Formulated pulsatile drug delivery system using valsartan as model drug. Ethyl cellulose coated hard gelatin capsule was used to modulate the drug release for the effective management of hypertension.
  8. Pallab Roy et. al., (2009)14 Formulated ranitidine HCI floating pulsatile delivery system for chronotherapy of nocturnal acid breakthrough. Ethly cellulose and HPMC were used to achieve the desired pulsed release. They have reported that the prepared formulation is very effective in management of nocturnal acidity as compare to conventional formulation.

6.3Objectives of the study:
Pindolol Pulsatile tablets will be prepared torelease the drug after apredetermined lag period, to meet the therapeutic requirement of the body.
The present research work is planned as mentioned below.
1.To prepare one pulse tablet drug delivery system consisting of three components which are core tablet, impermeable layer at the bottom and surrounding the tablet and hydrophilic swellable material on the top.
2.To evaluate the formulation with respect to various physical parameters.
3.To evaluate the formulation with respect to drug content uniformity in-vitro release swelling studies and drug excipients interaction studies.
4.The prepared formulation will be subjected to accelerated stability as per ICH guidelines
7.Materials and Methods:
Source of Data Collection :
Helient.
National and international journals.
7.1Materials
1.Drug – Pindolol
2.Polymers – Cellulose acetate propionate, hydroxyl propyl methyl cellulose , Sodium alginate, sodium carboxy methyl cellulose.
All other chemicals & reagents used will be of analytical grades.
7.2Method4:
The tablets will be prepared by using Karnavati Mini press with suitable flat faces punches. The system will consist of a core- in-cup tablet.
The core tablet consisting of Pindololwill be made by flat punches 8 mm. An impermeable coating cup consisting of cellulose acetate propionate will be applied at the bottom and core tablet is placed at the centre further the cellulose acetate propionate is placed at the sides of the tablet except the top.
On the top hydrophilic swellable material will be placed and total material will be compressed to produce core in cup system.
Evaluation parameters
Prepared tablet will be evaluated for drug content uniformity study, dissolution studies, drug excipients interaction study.
The prepared tablet will be subjected to accelerated stability studies as per ICH guideline.
I.PRECOMPRESSIONAL PARAMETERS
Bulk density and Tap densities: Exactly 50 gm of powder blend weighed on chemical balance and transferred into a 100 ml measuring cylinder. The cylinder dropped on a wooden platform from a height of 2.5 cm three times at 2 seconds interval. The volume occupied by the granules will be recorded as the bulk volume. The cylinder then tapped on the wooden platform until the volume occupied by the powder blend remained constant. This will be repeated three times for granules. The data generated used in calculating the Carr’s compressibility index and Haunser’s ratio.
Angle of repose: 50gm ofpowder blend placed in a plugged glass funnel which had a distance of 10 cm from the flat surface. The blend will be then allowedto flow through the 8mm funnel orifice by removing the cotton plug from the funnel orifice. The height of the heap (h) formed as well as the radius of the heap (r) noted.
II.POST COMPRESSIONAL METHODS
Tablet thickness: The thickness of 10 tablets selected at random will be determined using a vernier caliper and the mean of these readingswill be taken as the mean tablets thickness
Tablet weight uniformity: Twenty tablets weighed individually using a digital balance with the precision of 0.05 mg and readability of 0.1 mg, from which the mean calculated and percentage deviations determined
Hardness (Crushing Strength): The crushing strengths of tablets will be determined individually with the Monsanto hardness tester, 10 tablets used and the mean crushing strength will becalculated.
Friability : The friability of 10 tablets determine using Roche friabilator (Electrolab, Mumbai). This device subjects the tablets to the combined effect of abrasions and shock in a plastic chamber revolving at 25 rpm and dropping the tablets at a height of 6 inches in each revolution. Preweighed sample of tablets placed in the friabilator and subjected to 100 revolutions. Tablets will be dedusted using a soft muslin cloth and reweighed.
Drug content uniformity : The drug content of the tablets determined in triplicate by equilibrating an accurately weighed quantity of the Pindololin appropriate dissolution medium. The samples filtered, suitably diluted and assayed spectrophotometrically.
Swelling studies18. Five tablets will be weighed individually (w1) and place separately in plates with core facing the liquid surface and incubated at 37 ± 10C. At regular one hour time intervals until 6hrs. The tablets was removed from the petridish and excess surface water will be removed carefully with filter paper. The swollen tablet then reweighed (w2) and the swelling index (SI) will be calculated using the following formula.
Swelling Index SI= [(W2-W1)/W1]x100
In-Vitro dissolution studies5. Release of drug, from the Pindololtablet will be determined using USP dissolution apparatus with phosphate buffer 7.4 as dissolution medium.
Drug Polymer interaction study : Thedrug and different polymers will be used in this research work. There will be a chance of interaction between drug and polymer. To know any interaction between drug and polymer we planned to check it by FTIR and DSC studies.
Stability Studies: selected tablets will be strip packaged and kept at 450 C with 75% RH. Samples withdrawn at 0, 15,30 and 45 days for evaluation of appearance, drug content and in-vitro drug release.
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 plan of work --.
7.4Has ethical clearance been obtained from your institution in case of 7.3 ?
--Not Applicable--
8.LIST OF REFERENCES :
  1. Smolensky MH, Peppas N. Chronobiology, drug delivery and chronotherapeuitcs. Advanced drug delivery Review 2007; 59: 828-51.
  1. Survase S, Kumar N. Pulsatile drug delivery. Current Scenario Crips. 2007; Vol.8, No. 2:27-33.
  1. Reguel D. Pindolol overview 2000; 57:4-18.
  1. Krogel I, Bodmeier R. Floating or pulsatile drug delivery systems based on coated effervescent cores. International journal of Pharmaceutics 1999;187:175-84.
  1. McConville J, Ross AC, Chambers AR. The effect of wet granulation on the erosion behaviour of an HPMC-lactose tablet, used as a rate-controlling component in a pulsatile drug delivery capsule formulation. European journal of Pharmaceutics and Biopharmaceutics 2004;57:541-49.
  1. Efentakis M, Koligliati S, Vlachou M. Design and evaluation of dry coated drug delivery system with an impermeable cup, swell able top layer and pulsatile release international Journal of Pharmaceutics 2006, 311:147-56.
  1. Karavas E, Gerogarakis E, Bikiaris D. Application of PVP.HPMC miscible blends with enhanced mucoadhesive properties in predictable pulsatile chronotherapeutics. European Journal of Pharmaceutics and Biopharmaceutics 2006;64:115-26.
  1. Sharma S, Pawar A. Low density multiparticulate system for pulsatile release of Meloxicam. International Journal of Pharmaceutics 2006,313:150-58.
  1. Mastiholimath Vs, Danvagi PM, Jaoin SS. Time and pH dependent colon specific, pulsatile delivery of the ophylline for nocturnal asthma international journal of pharmaceutics 2007;328:49-56.
  1. Badve SS, Sher P. Korde A, Pawar AP. Development of hollow/ porous calcium pectinate beads for floating –pulsatile drug delivery. European Journal of Pharmaceutics and Biopharmaceutics 2007;65:85-93.
  1. Lin H L, Lin S.Y. Release characteristics and in vitro-in vivo correlation of pulsatile pattern for a pulsatile drug delivery system activated by membrane rupture via osmotic pressure and swelling. European Journal of pharmaceutics and Biopharmaceutics 2008, 70:289-301.
  1. Li B, Zhu J, Zheng C, Gong W. A novel system for three- pulse drug release based on ‘tablets – in-capsule device. International Journal of Pharmaceutics 2008;352159-64.
  1. Nayak UY. Shavi GV. Chronotherapeutic drug delivery for early morning surge in blood pressure. A programmable delivery system. Journal of Control Release 2009; 136:125-31.
  1. Roy P, Shahiwala A. Statistical optimization of ranitidine HC1 floating pulsatile delivery system for chronotherapy of nocturnal acid breakthrough. European Journal of Pharmaceutical Sciences 2009;37:363-69

9. / Signature of candidate
10. / Remark of the Guide / Pulsatile drug delivery system offers a noval drug delivery system for preprogrammed release of drug for improved therapeutic efficacy
Recommended for registration.
11. / Name & Designation
(in block letters)
11.1 Guide / Mr. PRASHANT A. BORGAONKAR
M.Pharm (Ph.D)
Assistant Professor
Department of Pharmaceutics.
R.M.E.S’s college of Pharmacy,
Gulbarga.
11.2 Signature
11.3Head of Department / Dr. MOHAMMED NAJMUDIN
M-Pharm Ph.D
Head of Department
Department of Pharmaceutics.
R.M.E.S.’s College of Pharmacy, Gulbarga
11.4 Signature
12 / 12.1 Remark of the Director / Principal / We will provide all necessary facility for the proposed research work.
Recommended for registration.
12.2 Signature

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