RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCESBANGALORE, KARNATAKA

ANNEXURE – II

PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

1. NAME OF THE CANDIDATE AND ADDRESS:

Permanent addressJAYA SHANKARA A.LS/O LakshaminarayanappaAnkathatty (V) Mathnahalli (P)Kolar Taluk, Kolar District-563101Karnataka

Postal addressKrupanidhi college of Pharmacy,Chikka Bellandure, Carmelaram Post,Varthur Hobli,Bangalore-560035Karnataka

2. NAME OF THE INSTITUTE: Krupanidhi College of Pharmacy,Chikka Bellandur, Carmelaram Post,Varthur Hobli,Bangalore – 560035,Karnataka

3. COURSE OF THE STUDY & SUBJECT:

MASTER OF PHARMACY IN PHARMACEUTICAL TECHNOLOGY

4. DATE OF ADMISSION TO THE COURSE:

7th July 2010

5. TITLE OF THE TOPIC:

“FORMULATION AND EVALUATION OF FAST RELEASE CAPSULES OF AN ANTI-DIABETIC DRUG USING SEMI SOLID MATRIX FILLING TECHNIQUE’’

6. BRIEF RESUME OF THE INTENDED WORK:

6.1 Need of Study:

Diabetes mellitus is a common and increasing health problems associated

with marked morbidity and mortality rate. Diabetes mellitus is characterized by

constant high levels of blood glucose1. Diabetes mellitus is a disorder of glucose

metabolism that results from an absolute or relative lack of insulin and it shows

complication of accelerated atherosclerosis, retinopathy and nephropathy.

Hereditary traits, age, poor diet, stress, drugs, infections, hypertension are the

major causes of diabetes2.

The survey of International Diabetes Federation in 2007, reported that India

was a country with the largest numbers of people with diabetes cases of 40.9

million. The statistics shows the mortality for diabetes is at the rate of one person

for ten seconds. As per the survey report the new cases of diabetes by the year

2025 many reach 7 million in the world3.

Anti-diabetic drugs such as glipizide, repaglinide, pioglitazone &

glibencamide are reported to posses less dose, poor aqueous solubility with

possible content uniformity problems. The poor aqueous solubility of these drugs

shows absorption problems and its dissolution rate is considered to be the rate

limiting step for absorption. During high blood glucose level conditions, an anti-

diabetic drugs should show quick and high oral bioavailability which can be

achieved by improving the solubility and rate of dissolution4.

Semi Solid Capsule filling is a novel method to incorporate liquid solution or

suspension of drug in to a hard gelatin capsules using a hydrophilic carriers. In this

method as the drug is dispersed molecularly in hydrophilic carriers, it results in the

enhancement of solubility and dissolution rate. Studies reported the improved rate

of dissolution of Nimodipine semi solid capsules by using plasdone as

polymer5.Semi solid matrix filling into hard gelatin capsules is a new technique is

being used more often because it has several advantages such as weight and

content uniformity, improvement in the dissolution of poorly water-soluble drugs

and creation of dust-free manufacturing process with minimal number of

manufacturing steps5.

Literature survey revealed that several techniques such as solid dispersion,

complexation, solubilizaion, particle size reduction etc has employed for

dissolution enhancement of anti diabetic drugs. Studies reported that an

improvement of solubility & dissolution rate for glibenclamide semi solid matrix

filled capsules using hydrophilic carriers like tetraglycol & gelucire6. Another

study reported enhancement of solubility and dissolution of glipizide using

different solubilization techniques7.

Formulation of low dose drug can be very challenging due to content

uniformity problems which can overcome by selecting suitable hydrophilic

additives excipients & there by formulating homogenous low dose formulation8.

In the present work we are making an attempt to improve solubility, dissolution

rate of an anti-diabetic drug employing semi solid matrix capsule fill technology in

hard gelatin capsules and to evaluate the optimized formulation.

6.2 Objective of Study:

The main objective of the present study is to enhance the dissolution rate of

poorly aqueous soluble drugs. To highlight this study liquid fill technology is

employed to prepare fast release capsule of an anti-diabetic drug using a

hydrophilic carrier.

The individual objective to be achieved include,

1. Selection of any one of the suitable water insoluble anti-diabetic drugs like

Glipizide, Repaglinide, Metformin & Pioglitazone etc.

2. Screening of the polymer and other excipients to be used in the

formulation are hydrophilic surfactants or polymers like Tween,

Poloxamer, PEG and Gelucire.

3. Preformulation compatibility studies on the drug and excipients.

4. Study of the physiochemical characteristics of the formulation.

5. Formulations of semi-solid matrix by liquid fill technology.

6. Evaluation studies like drug content, dissolution studies, moisture uptake

studies, solubility studies and thermal studies.

7. Accelerated stability profile as per ICH guidelines.

6.3 Review of Literature:

Seven Stegemann et al., provides an overview of the benefits for filling of two

piece hard gelatin capsules with liquid. The processes have also been proven to be

commercially viable for in-house manufacturing9.

Ewart T. Cole et al., described the use of hard gelatin capsules as an alternative for

liquid/semi solid formulation. A screening program has been described from which

a list of functional excipients compatible with the gelatin shell can be listed. The

process can be scaled-up and also kept in-house in a manner similar to the

operation of tableting or powder/pellet filling of hard gelatin capsules10.

Prameela Rani. A. et al., studied the phase solubility on oral anti-diabetic drugs

with β-cyclodextrin and Hydroxypropyl-β-cyclodextrin. They have reported the

improved solubility of Nateglinide, Repaglinide, & Glimepiride by complexation

with cyclodextrin11.

Adel M. Aly, et al., reported that enhancement of the dissolution rate and

bioavailability of glipizide through cyclodextrin inclusion complex by using

various carriers like PVP, NaCMC and PEG 6000. The formulation containing

cyclodextrin and cyclodextrin derivatives have proved as effective solubilizer for

glipizide12.

A. Smith et al., reported that dissolution rate of ibuprofen melt filled capsules was

markedly affected by incorporation of low levels of a variety of excipients. The

different carriers used for the semisolid dispersion were PEG 400, 4000 and 6000,

Acdisol, crosspovidone, Gelucire13.

A.B Dennis et al., developed both rapid and sustained release formulation of

ketoprofen. Rapid release was achieved by Gelucire 44/14 and prolonged release

was achieved by Gelucire 50/13. The formulation on comparing with conventional

showed similar plasma concentration14.

S.K Cole et al., designed a semi solid matrix capsule filled formulation of vitamin

E using non-ionic surfactants. The incompatibility occurring with non-ionic

surfactant in hard gelatin capsules was over come by including glycerol and water.

Dissolution and stability studies indicated efficient delivery of lipophilic drugs15.

NiluferYuksel et al., investigated the invitro and invivo performance of the semi

solid dispersion prepared with Gelucire 44/14 and Labrosol. The prepared

semisolid dispersion showed higher dissolution rate compared with pure piroxicam

and a commercially available tablets dosage form containing a piroxicam β-

cyclodextrincomplex16.

Barakat N.S et al., designed enteric coated liquid filled hard gelatin capsules of

propranol. It had a characteristic of biphasic rapid and sustained release with out

hepatic first-pass metabolism. Dissolution studies were carried out at both basic

and acidic pH, Significant alteration in release was achived17.

A Kattige et al., lactose/poloxamer dispersion exhibited thixotropic shear thinning

behaviour with an abrupt increase in apparent viscosity above a limiting

concentration of disperse phase. The rheological data was analyzed in detail using

empirical models and also used to identify capsule filling problems18

Ewart T Cole et al., encapsulation of liquid and semi solid provides solutions for

convenient delivery through improved oral absorption of poorly water soluble

drugs, low dose, highly potent, and low melting point drugs19.

N.S Barakat et al., formulated liquid filled dispersion of etodolac in hard gelatine

capsule using gelucire with an approach to increase the dissolution rate and

stability of poorly soluble drug.

E.L Massik M.A et al., semi solid fill bases were selected for the formulation of a

capsule. The filled material includes lipophilic bases and hydrophilic bases. The

dissolution rate study indicated that formulation contains lipophylic and

hydrophilic bases showed the best release profiles21.

7. Materials & Methods:

7.1 Source of Data:

Data will be obtained from Pubmed, Science Direct, Medline, US patent

office website and other Internet facilities, literature search and related articles

from library of Krupanidhi College of Pharmacy and Drug Information Centers.

7.2 Method of Collection of Data (including sampling procedure, if any):

The physiochemical properties of the drug will be collected from drug information

centre. Various standard books journals websites and other sources like research

literature databases like medline, sciencedirect, pubmed are followed.

The experimental data will be collected from the study of drug and literature. Its

formulation was done through investigation of process and product variables are

evaluated in laboratory of Krupanidhi college of pharmacy Bangalore.

Data on drugs will be collected from drug information center, standard books

physicochemical database and literature search. Extensive preformulation trial

provides the basis of selecting the excipients and system for final formulation

development and finally the system was evaluated.

The steps involved in the methodology is

1 Selection of suitable anti-diabetic drug

(Repaglinide or Glipizide or Metformin or Pioglitazone)

2 Selection of the polymer and other excipients to be used in the formulation

are hydrophilic surfactants and polymers like Tween, Poloxamer, PEG and

Gelucire.

3 Preformulation studies on the drug and excipients.

4 Formulation of semi solid matrix by liquid fills Technology.

5 To carry out in vitro evaluation of various formulations.

6 Optimization of the dosage form based on evaluated parameters.

7 To carry out accelerated stability profiling as per ICH guidelines.

7.3 Method of Screening:

z7.3 Does the study require any investigations or interventions to be

conducted on patients or other human or animals? If so please describe

briefly:

-NO-

7.4 Has the Ethical Clearance been obtained from your Institution in case of 7.3?

-NOT APPLICABLE-

8. LIST OF REFERENCES:

1)Lippincott, Williams & Wilkins. Remington. The science and practice of

pharmacy. 21st ed. B.I publications, 2006;1:1125.

2)Williams G. Management of non-insulin dependent diabetes mellitus. Lancet

1994; 343:95-100.Available From:

URL://www.ncbi.nlm.nih.gov/pubmed/7903785 [Access date: Nov 18]

3)Diabetes Statistics: India Is The Diabetes Capital Of The World 2008 Feb 25.

Available From:

URL:http://health.savvy-cafe.com/diabetis-statistics-india-is-the-diabetic-capital-

of -the-world-2008-02-25 [Access date: Nov 23]

4)D Choudhary, S Kumar, GD Gupta. Enhancement of solubility and

Dissolution of glipizide by solid dispersion (kneading) technique. Asian J Pharm

2009 Jul-Sep:245-51.

5)Sun Yunzhe, Yang Rui, Zhou Wenliang, Tang Xing. Nimodipine Semi-solid

capsules containing solid dispersion for improving dissolution.Int J Pharm Sci

2008;359:144-9.

6)Saly Galal, MagdaEL-Massik, Ossama Abdallah, Nabila Daabis. Formulation of

fast release glibenclamide liquid and semi-solid matrix filled capsules. Acta Pharm

2003;53:57-64.

7)Meenakshi Shukla, Priyanka Rathore, Ashish Jain, Satish Nayak. Enhanced

Solubility Study Of Glipizide Using Different Solubilization Techniques. Int J

Pharm Pharm Sci 2010;2(2):46-8.

8)Vipin Kukkar, Vikas Anand, Mahesh Kataria, Manoj Gera, Pratim Kumar

Choudhury.Mixing and formulation of low dose drugs: underlying problems and

solutions. Thai J Pharm Sci 2008;32:43-58.

9)Matt Richardson, Sven Stegemann. Filling Two- Piece Hard Gelatin Capsules

With Liquids. Tablets & Capsules 2007 Jan.Available From:

URL://www.Capsugel.Com/pdf/Filling-Two-Piece-Hard-Gelatin-Capsules-With-

Liquids.pdf

10)Ewart T Cole. Liquid filled and sealed hard gelatin capsules. Capsugl Library,

Warner-Lambertco, Switzerland;1-12.

URL: http://www.capsugel.com/pdf/brochure_liquid.pdf

11)Prameela Rani A, Siva Teja P, Archana N, BalaSekaran C. Phase Solubility

Studies On Oral Anti-diabetic Drugs with beta-Cyclodextrin and HP-beta

Cyclodextrin. Int J Pharm Tech Res 2009 Oct-Dec;1(4):1632-7.

12) Adel MAly,Mazen K Qato, Mahrous O Ahmad. Enhancement of the

Dissolution Rate and Bioavailability of Glipizide through Cyclodextrin inclusion

Complex. Pharm Tech 2003 June:54-62.

13) A Smith, JF Lampard, KM Carruthers, P Regan. The filling of Molten

ibuprofen into hard gelatin capsules. Int J Pharm 1990;59(2):115-9.

14) AB Dennis, SJ Farr, IW Kellaway, G Taylor, R Davidson. In vivo evaluation

of rapid release and sustained release Gelucire capsule formulation. Int J Pharm

1990;65(1-2):85-100.

15)SK Cole, MJ Story, D Attwood, T Laudanski, J Robertson, SG Barnwell.

Studies using a non-ionic surfactant-containing drug delivery system designed for

hard gelatin capsule compatibility. Int J Pharm 1992 Dec 8;88(1-3):211-20.

16)Nilufer Yuksel, Aysequl Karata, Yalcm Ozkan, Ayhan Savaer, SibelA.Ozkan,

Tamer Bayakara. Enhanced bioavailability of piroxicam using Gelucire 44/14 and

Labrosol. Eur J Pharma 2003;56(3):453-9.

17)SJ Burns, S Higginbottonm, D Corness, G Hay, I Whelan, D Attwood et al. A

study of enteric-coated liquid-filling hard gelatin capsules with biphasic release

characteristics. Int J Pharm 1994;110:291-6.

18)A Kattige, G Rowley. Influence of rheological behaviour of particulate polymer

dispersion on liquid-filling characteristic for hard gelatin capsules. Int J Pharm

2006Jun26;316(1-2):74-85.

19)Ewart T Cole, Dominique, Cade, Hassan Benameur. Challenges and

opportunities in the encapsulation of liquid and semi-solid formulation into

capsules for oral administration. Adv Drug Deliv Reviews 2008Mar17;60(6):747-

58.

20)NS Barakat. Etodolac-liquid-filled dispersion into hard gelatin capsules: An

approach to improve dissolution and stability of etodolac formulation. Letters in

Drug Desi Discov 2009;32:865-76.

21)EL Massik MA, Abdallah Oy, Galals, Daabis NA. Semi-solid matrix filled

capsules: An approach to improve dissolution stability of phenytion sodium

formulation. Drug Dev Ind Pharm 2003;29(5):531-43.

9. Signature of the Candidate

(JAYA SHANKARA A L) ((Rajesh

10. Remarks of the Guide:SjjjjjjjjIS OF SOME NOVEL DERIVATIVES OF S

Liquid formulations filled into two-piece hard capsules have attracted substantial

interest in the pharmaceutical industry over the last decade. Today’s challenges in

product development due to the poor aqueous solubility and high potency of the

new molecular entities are being addressed by several development groups that are

focused on liquid or semi-solid formulations. As filling and sealing of these

formulations into two-piece hard gelatin capsules can be done easily in-house with

improved rate of dissolution. Hence it is recommended for necessary clearance.

ELENO-o987lQUINAZOLONE AND EV

ALUATION OF THEIR ANTIOXIDANT AND ANTIMICROBIAL ACTIVITY”

to

c Mr. Rajesh

11. Name & Designation (in BLOCK LETTERS)

11.1 Guide Mrs. SARITHA ALLADI

ASSISTANT PROFESSOR

Department of Pharmaceutical Technology

Krupanidhi College of Pharmacy,

Bangalore-560035.

11.2 Signature of Guide

(Mrs. ROHINI R. M.)

11.3 Co-Guide

11.4 Signature of Co-Guide

11.5 Head of the Department Prof. Dr.R.S THAKUR

PROFESSOR AND HEAD

Department of PharmaceuticaTechnology

Krupanidhi College of Pharmacy

Bangalore – 560035.

11.6 Signature of HOD:

12. 12.1 Remark of the Principal:

12.2 Signature of the Principal Prof. Dr. N. PREM KUKAR

PRICIPAL

Krupanidhi college of pharmacy,

ChikkaBellandur, Carmelaram Post,

Varthur Hobli,

Bangalore – 560035

Karnataka