RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, BANGALORE,

KARNATAKA.

ANNEXURE II

PROFORMA FOR REGISTRATION OF SUBJECT FOR DISSERTATION

1. Name of the candidate and address

(in block letters)SUNIL LAKSHAMAN RAYKAR

BAPUJI PHARMACY COLLEGE

S.S. LAYOUT, SHAMANUR ROAD

DAVANGERE – 577 004

2. Name of the institution BAPUJI PHARMACY COLLEGE

3. Course of study and subjectM. PHARMACY

(INDUSTRIAL PHARMACY)

4. Date of admission to course 29-12-2012

5. Title of the topicFABRICATION AND IN VITRO

EVALUATION OF MINOXIDIL

MATRIX TABLETS

6. BRIEF RESUME OF THE INTENDED WORK

6.1 Need for the study

The word new or novel with respect to drug delivery system is a search for

something out of necessity. An appropriately designed sustained or controlled release

drug delivery system can be major advance towards solving the problem associated with

the existing drug delivery systems.1

The oral route is the most common route of drug administration because of its

advantages in terms of convenient administration, thus leading to increased patient

compliance. Extended release formulations in many cases provide further significant

advantages, including improved therapeutic effect, increased patient compliance by

reducing dosing frequency and decrease in incidence and or intensity of adverse effect

by constant plasma drug concentration.2

Conventional immediate release tablet has to be administered, three to four times in a

day. most of the patients to maintain the therapeutic plasma drug concentration

throughout the dosing intervals 3. This increased complications and expense involved in

marketing of new drug entities has focused greater attention on development of

sustained release (SR) or controlled release (CR) drug delivery systems. Sustained or

controlled release delivery systems can achieve predictable and reproducible release

rates, extended duration of activity, decreased toxicity, reduction of required dose,

optimized therapy limiting fluctuation within the therapeutic range, decreasing dosage

frequency and better patient compliance. Matrix type sustained delivery systems are

popular because of their ease of manufacturing.4-5

The simplest way to retard drug release is to disperse it in a solid matrix. The matrix

system is commonly used for manufacturing sustained release dosage forms especially

tablets because it makes such manufacturing easy.6

Minoxidil is an orally effective vasodilator with antihypertensive activity, which

is more potent than hydralazine. More than 95% of the drug is absorbed from the

gastrointestinal tract and a plasma elimination half-life is 4.2 hr. Administration of

minoxidil in a sustained release dosage would be more desirable for antihypertensive

effects by maintaining the therapeutic plasma drug concentrations. To reduce the

frequency of administration and to improve patient compliance, a once-daily sustained-

release formulation of minoxidil is desirable.

Previously, studies have been carried out to formulate various sustained release drug

delivery devices, including Gel7, Transdermal patches,8 Niosomes, cream or ointment9

sustained release drug delivery offers safe and ease method of drug utilization, because

can be promptly terminated in case of toxicity by removing other dosage form from

sustained release.

Minoxidil is a potent direct vasodilator, which reduces both systolic and diastolic

blood pressure by lowering peripheral resistance. The drug acts predominantly on the

arterioles and has little effect on the venous capacitance vessels. In patients with benign

hypertension not responding well to traditional therapy, better control of blood pressure

with minoxidil may prevent the deterioration of renal function which occurs in the

majority of such patients.

6.2 Review of the study

Literature review for undertaking the study was done by referring to articles published in

various National and International Journals, official standard books and referring to

various websites on the internet. Review of literature indicates that enormous work has

been reported on matrix tablets. More relevant works are explained systematically as

follows

. Khan Arshadbashir, et al., Formulattion and Evaluation of sustained release matrix

tablets of Propranolol Hydrochloride using Sodium Carboxy Methyl Guar (SCMG) as

rate sustaining polymer. SCMG is a guar gum derivative, which was investigated as a

sustaining material to formulate sustained release tablets of the model drug, Propranolol

Hydrochloride. 10

Prajapatib G et.al. Prepared and Evaluated in vitro formulations of once-daily

sustained-release matrix tablets of Losartan Potassium. Objective of the present study

was to develop Hydrophilic polymer and Hydrophobic polymer based matrix Losartan

Potassium sustained release tablet which can release the drug up to time of 24 hr in

predetermined rate. It is readily absorbed from the gastrointestinal tractwith oral

bioavailability of about 33% and a plasma elimination half-life ranging from 1.5 to 2.5

hr. Administration of LP in a sustained release dosage would be more desirable for

antihypertensive effects by maintaining the plasma concentrations of the drug well

above the therapeutic concentration. From in vitro dissolution profile, Batch B4 was

prepared with blend of HPMC K4M (67.2 mg), HPMC K200M(90mg) and Eudragit

RSPO(112.5 mg), where drug release was about 94-98%. Batch B4 showed highest

similarity factor values (f2 = 67.76). 11

Dhirendrakumar, et al. Designed and evaluated sustained-release matrix once-

daily formulation of Stavudine, to increase therapeutic efficacy, reduce frequency of

administration and improve patient compliance. The sustained release tablets were

prepared by Direct Compression and formulated using different drug: polymer ratios,

formulations such as F1to F15. Hydrophilic polymers like Hydroxy Propyl Methyl

Cellulose (HPMC), Carboxymethyl Cellulose (CMC) and Starch 1500 were used. SEM

studies of the formulations were carried out for the confirmation of mechanism of drug

release. The in vitro drug release characteristics were studied in both simulated gastric

and intestinal fluids for a period of 24 hr using USP Type 2 dissolution apparatus.

Mathematical analysis of the release kinetics indicated a coupling of diffusion and

erosion mechanisms. The study proves that the developed sustained release tablet is

capable of releasing the drug in a sustained manner for 24 hr.12

Jaberemami, et al. Prepared and evaluated in-vitro of sustained-release matrix

tablets of Flutamide using Synthetic and Naturally occurring polymers. The sustained-

release matrix tablets of Flutamide were prepared by direct compression method using

different polymers. Cellulose ethers (HPMC and NaCMC), Natural gums (Guar and

Xanthan gums) and compressible Eudragits (RSPO and RLPO) and their combinations

were used in different ratios to examine their influence on tablet properties and drug

release profile Frequent dosing of the potent anti-androgen, flutamide, is necessary to

reach a therapeutic level for the treatment of prostatic carcinoma. Sustained delivery of

the drug could reduce the adverse effects such as gastrointestinal disorders and improve

patient compliance.13

Anton Smith, et al. Developed and Evaluated of Ondansetron Hydrochloride

sustained release matrix tablets. The objective of the present study was to develop

sustained release matrix tablets of Ondansetron Hydrochloride [5mg] formulated

employing Hydroxy Propyl Methyl Cellulose polymer and the sustained release

behaviour of the tablets was investigated. Tablets were prepared by Wet Granulation

methodsThe granules were evaluated for angle of repose, bulk density and drug

content .The tablets were subjected to thickness, diameter, weight variation test,

hardness, friability, drug content and in vitro release studies. Formulation was optimized

on

the basis of acceptable tablet properties and in vitro drug release. The results of

dissolution studies indicated that formulation FV (drug to polymer ratio 1:3) the most

successful of the study, exhibited drug release pattern very close to theoretical release

profile. All the formulations (except FV) exhibited diffusion – dominated drug

release.The mechanism of drug release from FV was diffusion coupled with erosion.14

V N. Deshmukh, et al.,15 Designed and evaluated sustained release Metoprolol

Succinate tablet using Hydrophilic gums As release modifiers. The objective of this

study was to design and evaluate oral sustained drug delivery system for Metoprolol

Succinate using Natural hydrophilic gums such as Karaya gum and Xanthan gum as a

release modifier. Matrix tablets were prepared by wet granulation method and were

evaluated physical & chemical parameters, and Stereo Photography. No chemical

interaction between drug and gums was seen as confirmed by IR studies. The matrix

formulation F8showed sustained release of Metotprolol succinate by the diffusion

mechanism.

Saleha. Alsuwayeh, et al. Carried out in-vitro and in-vivo Evaluation of sustained

release Hydralazine Hydrochloride tablets prepared by Thermal Granulation Technique,

the aim of this work was to use the Thermal Granulation Technique to formulate

Hydralazine Hydrochloride (HLZ) as sustained release tablets using Hydroxyl Propyl

methyl Cellulose (HPMC) and Poly Ethylene Glycol 6000 (PEG 6000) blend as

hydrophilic heterogeneous matrices.16

K. Raghuram Reddy, et al. Developed once-daily sustained-release matrix tablets

of Nicorandil: formulation and In vitro evaluation. The objective of the present study

was to develop once-daily sustained-release matrix tablets of Nicorandil, a Novel

Potassium channel opener used in cardiovascular diseases. The tablets were prepared by

the wet granulation method. The results of dissolution studies indicated that formulation

F-I (drug-to-HPMC, 1 4; ethanol as granulating agent) could extend the drug release up

to 24 hours. In the further formulation development process, F-IX (drug-to-HPMC, 1 4;

EC 4% wt/vol as granulating agent), the most successful formulation of the study,

exhibited satisfactory drug release in the initial hours, and the total release pattern was

very close to the theoretical release profile. All the formulations (except F-IX) exhibited

diffusion-dominated drug release. The mechanism of drug release from F-IX was

diffusion coupled with erosion.17

P. Khemariya, et al. Developed and carried out studies evaluation of sustained-

release matrix tablets of Diltiazem. The purpose of the present research work was

develop once-daily sustained-release matrix tablet containing water-soluble drug

(Diltiazem) that is a Novel Calcium channel blocker used in cardiovascular diseases.18

. P R. Radhikaa, et al. Formulated and evaluated sustained release matrix tablets of

Glipizide. The purpose of this study was to develop a new monolithic matrix tablet to

completely deliver Glipizide in a zero order manner over a sustained period. The

granules were prepared by wet granulation method and thereby formulated as F-1, F-2.

F-3 and F-4 by using the above bring up polymers with other ingredients. The granules

of different formulations were evaluated for angle of repose, loose bulk density and

tapped density, compressibility index, total porosity, and drug content.19

Dr. Umesh. D. Shivhare, et al. Formulated and evaluated sustained release tablets

of Aceclofenac. The objective of the present study was to develop “once daily” sustained

release tablets of Aceclofenac by Wet Granulation using Carboxy Poly Methylene

polymer. The physicochemical properties of tablets were found within the limits.

Formulation F2 & F9containing Carbopol 971P and Carbopol 974P were found to

release the drug in sustained manner up to 24 hr and were stable under accelerated

conditions of temperature for 6 months since there were no significant changes in drug

content and physical parameters.20

R. Nagaraju, et al. Formulated and Evaluated bilayer sustained release tablets of

Salbutamol and Theophylline. They are available in conventional dosage forms,

administered four times a day, leading to saw tooth kinetics and resulting in ineffective

therapy. The combination of these two drugs in a single dosage form will enhance the

patient compliance and prolong broncho dilation pients are Povidone Micro Crystalline

Cellulose in different ratios. 21

6.3 Objectives of the study

The objectives of the present research study are:

Pre-formulation studies includes,

Determination of melting of minoxidil, Drug- excipients compatability study,

Interference of polymer in uv determination of drug compressibility index, etc

Development of suitable analytical method.

Screening of excipients for suitability.

Formulation of Minoxidil sustained release matrix tablets with different polymer

7.

composition.

Evaluation of the physico-chemical characteristics of the prepared sustained

release matrix tablets.

To determine in vitro of drug release from the matrix tablets

To evaluate the drug release kinetics and mechanism for the prepared

formulations.

To assess the stability of the prepared formulations.

Evaluation of pre compression and post compression parameters for formulated

dosage forms.

MATERIALS AND METHODS

7.1 Source of data

The physicochemical properties of drug and polymers will be collected from the

national and International journals, internet facilities, related articles, and standard books

from library of the college.

7.2 Methods of collection of data

(Including sampling procedure, if any)

a. Analytical method for the estimation of Minoxidil will be developed in

phosphate buffer of PH 7.4

b. Evaluation of physical properties of powder blend of tablet batches such as,

angle of repose, bulk density, compressibility index, etc.

c. Formulation of sustained release matrix tablets of the minoxidil using different

polymers.

d. The sustained release matrix tablets were evaluated for in process and finished

product quality control tests such as, appearance, dimensions (diameter and

thickness), uniformity of weight, hardness, friability, content uniformity, etc.

e. In vitro evaluation of prepared sustained release matrix tablets of minoxidil for

the drug release characteristics.

7.3 Does the study require any investigations or interventions to be conducted

on patients or other humans or animals? If so, please describe briefly.

Not required.

7.4 Has ethical clearance been obtained from your institution in case of 7.3?

Not applicable.

8 LIST OF REFERENCES

1. Najmuddin M, Vishal P, Aejazahmed,Shelar S, Khan T. Preparation and

Evaluation of Flurbiprofen Microcapsules for Colonic Drug Delivery System,

Int J Pharmacy and Pharmaceu Sci, 2010;2(2):83-7.

2. Dhirendra k, Vivek D, Shaila L, Brajesh P, Kavita R. Gajbhiye, Sarvesh P,

Design and Evaluation of Sustained-Release Matrix Once-daily Formulation of

Stavudine, Int J of Drug Del, 2010;2:125-34.

3. Saleha, Mohammed H. El-Shaboury, Saeed M. Al-Baraki, Abubakar S. Elg,et,.al

In-vitro and in-vivo Evaluation of Sustained Release Hydralazine Hydrochloride

Tablets prepared by Thermal Granulation Technique. Australian j of Basic and

Applied Sci, 2009;3(3):2866-75.

4. Radhikaa PR, Pala TK, Sivakumar B.Formulation and Evaluation of Sustained

Release Matrix Tablets of Glipizide. Iranian J of Pharmaceut Sci Autumn, 2009;

5(4):205-14.

5. Subal C. Basa k, Karthikeyan J, Bharati B. In-vitro evaluation and Release Rate

Kinetics of Matrix Type Sustained Release Tablet containing Aceclofenac.The

Internet J of Pharmacol, 2010;8(2):6

6. Deshmukh VN, Singh SP, Sakarkar DM. Formulation and Evaluation of

Sustained Release Metoprolol Succinate Tablet using Hydrophilic Gums as

Release Modifiers, Inter J of Pharm-Tech Research, 2009;1(2):159-163.

7. Sunil G, Sadhana S, Imran T, Nityanand Z, Shekhar T, Uttara S. Gov. Coll of

Pharmacy, Aurangabad, MH, India. Int J Pharmacy Research and Allied Sci

(2012),1(1) 41-47.

8. Venna D, Thakur RS, Arshad Bk. Krupanidhi Coll of Pharmacy, Asian J of

Pharma and Life Sci , 2013;3(1):22-31

9. Chia-Ming C, Flynn GC, Weiner ND , Addicks WJ, Szpunar GJ. University

of Michigan. Int J Pharmaceu, 1989;(49):109-14

10. Khanarshad B, Nanjundaswamy NG. Formulation and Evaluation of Sustained

Release Matrix tablets of Propranolol Hydrochloride using Sodium Carboxy

Methyl Guar as rate sustaining polymer, Arch Pharm Sci& Res, 2009;1(2):203 -

06.

11. Prajapatib G, Patel KR. Formulation and in-vitro evaluation Once-daily

Sustained-Release Matrix Tablets of Losartan Potassium, Int J of Medical and

Clinical Research, 2010;1(1);01-7.

12. Dhirendra K, Vivek D, Shaila L, Brajesh P, Kavita R. Gajbhiye, Arvesh P.

Design and Evaluation of Sustained-Release Matrix Once-Daily formulation of

Stavudine, Int J of Drug Del, 2010;2:125-34.

13. Emami J, Tajeeddin M, Ahmadi F. Preparation and In-vitro Evaluation of

Sustained-Release Matrix Tablets of Flutamide using Synthetic and naturally

occurring polymers, Iranian J of Pharmaceu Research, 2008;7(4):247-57.

14. Anton S, Kottaimuthu A, Waghbhushan P, Manavalan R, Formulation

Development and Evaluation of Ondansetron Hydrochloride Sustained Release

Matrix Tablets. J Pharmaceu. Sci & Research, 2009;1(4):48-54

15. Deshmukh VN, Singh SP, Sakarkar DM. Formulation and evaluation of

sustained release metoprolol Succinate tablet using hydrophilic gums as Release

Modifiers, Int J of Pharm tech Research, 2009;1(2):159-63.

16. Saleha. mohammed H. El-shaboury, Saeed M. Al-Baraki, Abubakar et,.al In-

vitro and In-vivo Evaluation of Sustained Release Hydralazine Hydrochloride

Tablets prepared by Thermal Granulation Technique, Australian J of Basic and

Applied Sci, 2009;3(3):2866-75

17. Raghuramreddy K, Srinivas M, Srinivas R. Formulation & in vitro evaluation

Once-daily Sustained-Release Matrix Tablets of Nicorandil, AAPS pharma sci

tech, 2003;4(4):1-9.

18. Khemariya P, Jain AK, Bhargava M, Singhai SK, Goswami S, Goswami R.

Preparation and In-vitro Evaluation of Sustained-Release Matrix Tablets of

Diltiazem. Int J of Advances in Pharmaceu Sci, 2010;1:267-3.

19. Radhika PR, Pala TK, Sivakumar T. Formulation and Evaluation of Sustained

Release Matrix tablets of Glipizide. Iranian J of Pharmaceu Sci Autumn, 2009;

5(4):205-14.

20. Dr.Umesh D, Shivhare, Nandkishord A, Dr. Kishore PB, Dr. Vijay BM,

Digvijay UA, Formulation Development, Evaluation and Validation of Sustained

Release Tablets of Aceclofenac, Int J of Pharmacy and Pharmaceu Sci, 2009;

1(2):74-80.

21. Nagaraju R, Rajeshkaza. Formulation and Evaluation of Bilayer Sustained

Release Tablets of Salbutamol and Theophylline, Int J of Pharmaceu Sci and

Nanotechnology, 2009;2(3):638-46

9. Signature of the Candidate

10. Remarks of the Guide:

11. Name and Designation of (In block letters)11.1 Guide

11.2 Signature

11.3 Co guide (If any)

11.4 Signature

11.5 Head of the Department

11.6 Signature

Mr. MANJUNATHA K M. M. Pharm

senior lecturerDepartment of Industrial PharmacyBapuji Pharmacy College, Davangere.

Dr. J. THIMMASETTY M. Pharm, ph. D

Head of the Department of Industrial Pharmacy

Bapuji Pharmacy College, Davangere.

12. 12.1 Remarks of the Principal

12.2 Signature