FORMULATION AND EVALUATION OFFLOATING-PULSATILE DRUG DELIVERY SYSTEM OF FAMOTIDINE

M. Pharm Dissertation Protocol Submitted to

Rajiv Gandhi University of Health Sciences, KarnatakaBangalore– 560 041

By

Mr. RAJ KISHOR PANJIYAR B.Pharm Under the Guidance of

Mr. ANUP KUMAR ROY M.Pharm, (Ph.D)Asst. Professor & HOD

Dept. of Industrial pharmacy

Department of Industrial Pharmacy,Acharya & B.M. Reddy College of Pharmacy,

Soldevanahalli, Chikkabanavara (Post)Hesaraghatta, Main Road, Bangalore – 560 090.

2010-2012

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,

KARNATAKA, BANGALORE.

ANNEXURE - II

PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

1. Name of the Candidate and Address

Mr. RAJ KISHOR PANJIYARSHREEPUR-14 ;BIRGUNJ (NEPAL)PIN CODE: 00977

2. Name of the Institution

ACHARYA & B.M. REDDY COLLEGE OF PHARMACY,Soldevanahalli, Hesaraghatta Main Road, Chikkabanavara Post.Bangalore-560090

3.Course of Study and Subject M. Pharm

(Industrial pharmacy)

4. Date of Admission 4 -May-2010

5. TITLE OF PROJECT:

FORMULATION AND EVALUATION OFFLOATING-PULSATILE DRUG DELIVERY SYSTEM OF FAMOTIDINE

6.

6.1

BRIEF RESUME OF THE INTENDED WORK:

NEED FOR THE STUDY:

The objective of this investigation is to develop floating-pulsatile release of Famotidine for

chronotherapy of nocturnal acid breakthrough. Development of simple floating pulsaltile drug delivery

system of famotidine is to provide night time relief from gastric acid breakthrough. It is aimed to

modulate the pulsatile release profile from time-lagged coating using a combination of rupturable (ethyl

cellulose) and erodible (hydroxypropyl methyl cellulose) polymer.

Chronotherapeutic drug delivery systems (CRDDS) have been recognized as potentially beneficial

to the chronotherapy (time optimized therapy) of widespread chronic diseases that display time-

dependent symptoms, such as ulcers, asthma, cardiovascular diseases and arthritis. CRDDS control drug

release according to circadian rhythms and the timing of symptoms. A number of CRDDS have been

developed to synchronize medication with the intrinsic biorhythm of the disease; with conventional and

modified release formulations being administered at different times of the day in accordance with the

circadian onset of the disease.

Pulsatile systems are gaining a lot of interest as they deliver the drug at the right site of action at

the right time and in the right amount, thus providing spatial and temporal delivery and increasing

patient compliance. These systems are designed according to the circadian rhythm of the body. The

principle rationale for the use of Pulsatile release is for the drugs where a constant drug release, i.e., a

zero-order release is not desired. The release of the drug as a pulse after a lag time has to be designed in

such a way that a complete and rapid drug release follows the lag time.

These systems are beneficial for the drugs having chronopharmacological behavior where night

time dosing is required and for the drugs having high first-pass effect and having specific site of

absorption in GIT.

In contrary, gastro-retentive dosage forms reside in stomach only and are not affected by variability

of pH, local environment or gastric emptying rate. These dosage forms are also specifically

advantageous for drugs either absorbed from the stomach or requiring local delivery in stomach. These

considerations led to the development of pulsatile release dosage forms possessing gastric retention

capabilities. Normal gastric acid secretion follows a circadian rhythm with a sudden surge of gastric

acidity when gastric pH level goes far below 4 for at least 1 hr in the midnight. Heartburn, coughing or

choking due to fluid in the throat, breathlessness, wheezing and morning phlegm are common symptoms

frequently reported during this time. This pathophysiological condition is termed as nocturnal acid

breakthrough (NAB) and is even more prolonged and clinically critical for H. pylori-negative patients on

proton pump inhibitor (PPI) therapy. NAB is one of the main reasons of treatment failure in gastro

oesophageal reflux disease (GERD) compromising therapeutic goals in patient.

Study reveals that up to 70% patients appear to be resistant to even high doses of PPIs taken twice

daily; and thus brings forth failure of PPI in providing necessary nocturnal acid suppression .It is

demonstrated that adding a bed-time dose of H2 antagonist to an evening dose of proton pump inhibitor

provides nocturnal recovery of gastric acid secretion. However, the long-time efficacy of the

combination therapy is still debatable due to possible development of tolerance on regular dosing. This

limitation, however, can be overcome by a chronotherapeutic approach which will ensure that the highest

blood levels of the drug coincide with the peak symptoms in early morning hours. This limited exposure

of the drug to the biological system, thereby will minimize the chances of development of tolerance.

Hence, a bed-time dosing of H2 antagonist from a pulsatile delivery system combined with normal twice

a day PPI dosing would be a promising therapeutic regimen.

Advantages of pulsatile-floating drug delivery system:

1. Improved patient compliance.

2. Extended night time activity.

3. Reduced side effects.

4. Reduced dosage frequency.

5. Drug is not affected by variability of pH, local environment or gastric emptying rate.

6. These dosage forms are also specifically advantageous for drugs either absorbed from the  stomach or

requiring local delivery in stomach.

6.2 REVIEW OF LITERATURE:

Ina Krogel et al., developed and evaluated floating and pulsatile drug delivery systems based on a

reservoir system consisting of a drug-containing effervescent core and a polymeric coating. Preliminary

studies were carried out to identify core and coating properties for the two systems. The mechanical

properties (puncture strength and elongation) of acrylic (Eudragit® RS, RL or NE) and cellulosic

(cellulose acetate, ethyl cellulose) polymers, which primarily determined the type of delivery system,

were characterized with a puncture test in the dry and wet state. For the floating system, a polymer

coating with a high elongation value and high water and low CO2 permeabilities was selected (Eudragit®

RL:acetyltributyl citrate 20%, w:w) in order to initiate the effervescent reaction and the floating process

rapidly. For the pulsatile DDS, a weak, semipermeable film, which ruptured after a certain lag time was

selected (ethyl cellulose:dibutyl sebacate 20%, w:w). With the floating system, the polymeric coating did

not retard the drug release. A polymer (cellulose acetate or HPMC) was added to the core to control the

drug release. The time to flotation could be controlled by the composition (type of filler, concentration of

effervescent agents) and hardness of the tablet core and the composition (type of polymer and

plasticizer) and thickness of the coating. For the pulsatile system, a quick releasing core was formulated

in order to obtain a rapid drug release after the rupture of the polymer coating. The lag time prior to the

rapid drug release phase increased with increasing core hardness and coating level1 .

Evangelos Karavas et al., prepared pulsatile release formulations consisting of two-layered tablets

appropriate for preventing ischemic heart diseases. The active core of tablet was constituted by a

FELO/PVP 10/90 w/w solid dispersion while for the adjustment of the drug release time the coating

layer was composed of PVP/HPMC blends at different compositions, acting as a stimulus responsible

layer. These blends are miscible in the entire composition range, ensured by the interactions taking place

between hydroxyl groups of HPMC and carbonyl groups of PVP. The miscibility of the system enhances

the mucoadhesive properties of the blends, compared with those of pure HPMC, which is desired for

such applications. Upon exposure of the prepared tablets to the release medium it was found that the

coating layer disintegrates first, followed by the immediate release of FELO from the active core. The

delaying time is based on a complicated mechanism, which is a combination of swelling and erosion of

the PVP/HPMC polymer blends. Varying the PVP/HPMC blend ratios, the exact time that FELO is

released during a daytime can be effectively adjusted and this ability is expressed mathematically by the

equation t = 0.028 C1.5, where C is the concentration of HPMC in the blend2.

Sachin Survase et al., studied that Pulsatile drug delivery systems (PDDS) are gaining importance as

these systems deliver the drug at specific time as per the pathophysiological need of the disease,

resulting in improved patient therapeutic efficacy and compliance. Diseases wherein PDDS are

promising include asthma, peptic ulcer, cardiovascular diseases, arthritis and hypercholesterolemia. They

focused on the diseases requiring PDDS, methodologies involved for the existing systems, recent update

and PDDS product currently available in the market3.

Lin HL et al., characterized the influence of core and coating formulations on the release profiles to

establish in vitro/in vivo correlations of pulsatile pattern for a pulsatile drug delivery system activated by

membrane rupture based on three core tablet formulations (A-core: HPMC 50+4000 cps, B-core: E10M,

and C-core: K100M) coated with various thicknesses of a semipermeable ethylcellulose membrane

plasticized with HPMC 606 (Pharmacoat 606) at different ratios with/without adding various amounts of

water to dissolve it in the coating solution. Drug release behaviors were investigated using apparatus II

in four media of pH 1.2 solution, pH 6.8 buffer, deionized water, and a NaCl solution rotated at 75, 100,

and 150 rpm. Dissolution of coated tablets showed that the controlling membrane was ruptured by

osmotic pressure and swelling which activated drug release with a lag time. The lag time was not

influenced by the pH value of the release medium or by the rotation speeds. The lag time increased with

a higher coating level, but decreased with the addition of the hydrophilic plasticizer, Pharmacoat 606,

and of the water amount in the coating solution. The lag time also increased with a higher concentration

of NaCl in the medium. The release rate after the lag time was determined by the extent of retardation of

gelation of HPMC in the core tablet based on the ionic strength of the medium4.

Dr. S. D. Barhate et al., prepared bilayer floating tablets of famotidine by using HPMC K100LV, HPMC

K4MCR, sodium bicarbonate, sodium alginate, sodium starch glycolate, croscarmellose, crospovidone

and lactose. Box-Behnken factorial design was used to statistically optimize the controlled release layer

composition and evaluation of the effect of amount of HPMC K100LV, amount of HPMC K4MC and

amount of sodium bicarbonate on release rate of famotidine. The polymers HPMC K100LV, HPMC

K4MCR showed better control over drug release. The formulated formulations of Box-Behnken factorial

design showed zero-order drug release. The prognostic ability of Response Surface Methodology

involving multiple response optimizations was proved in designing and optimization of controlled

release pharmaceutical formulations5.

Srisagul Sungthongjeena et al., prepared a tablet system consisting of cores coated with two layers of

swelling and rupturable coatings and evaluated as pulsatile drug delivery system. Cores containing

buflomedil HCl as model drug were prepared by direct compression of different ratios of spray-dried

lactose and microcrystalline cellulose and were then coated sequentially with an inner swelling layer

containing a superdisintegrant (croscarmellose sodium) and an outer rupturable layer of ethylcellulose.

The effect of core composition, level of swelling layer and rupturable coating, and magnesium stearate in

rupturable layer was investigated. Mechanical properties of ethylcellulose films in the dry and wet state

were characterized with a puncture test. Rupture and dissolution tests were performed using the USP

XXIV paddle method at 50 rpm in 0.1 N HCl. The lag time of the pulsatile release tablets decreased with

increasing amount of microcrystalline cellulose in the cores and increased with increasing levels of both

swelling layer and rupturable ethylcellulose coating. Increasing levels of the ethylcellulose coating

retarded the water uptake and thus prolonged the lag time. Addition of magnesium stearate to the

ethylcellulose coating lowered the mechanical strength of the film and improved the robustness of the

system6.

Akihiko Kikuchi et al., studied several types of drug delivery systems using hydrogels that showed

pulsatile drug delivery characteristics. As it is frequently found in the living body, many vital functions

are regulated by pulsed or transient release of bioactive substances at a specific site and time. Thus it is

important to develop new drug delivery devices to achieve pulsed delivery of a certain amount of drugs

in order to mimic the function of the living systems, while minimizing undesired side effects. Thermal

stimuli-regulated pulsed drug release is established through the design of drug delivery devices,

hydrogels, and micelles7.

Jason   T   McConville   et al., investigated the variability in the performance of a 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 containing HPMC and lactose were prepared

by direct compression (DC) and wet granulation (WG) techniques and used to seal the

model drug propranolol inside an insoluble capsule body. Dissolution testing of capsules was performed.

Physical characterisation of the tablets and powder blends used to form the tablets was undertaken using

a range of experimental techniques. The wet granulations were also examined using the novel technique

of microwave dielectric analysis (MDA). WG tablets eroded slower and produced longer lag-times than

those prepared by DC, the greatest difference was observed with low concentrations of HPMC8.

VD Havaldar et al., prepared the floating tablet of prolonged the gastric residence time of atenolol by

designing its floating tablets and studied the influence of different polymers on its release rate. Nine

formulations of atenolol containing varying concentrations of polymers were designed by optimization.

The floating matrix tablets of atenolol were prepared by direct compression method. The prepared tablets

were evaluated for physicochemical parameters such as hardness, floating properties (floating lag time,

floating time and matrix integrity), swelling studies and drug content. The physicochemical parameters

(P < 0.0001) and floating lag time ( P < 0.005) at 0.5, one, four and eight hrs were observed. The

floating lag time of all the formulation was within the prescribed limit (<10 minutes). All the

formulations showed good matrix integrity and retarded the release of drug for eight hours. The release

pattern of atenolol was fitted to different models based on coefficient of correlation (r). The swelling

studies of all the formulations showed that formulations containing Xanthan gum has higher swelling

indices than HPMC K100M and HPMC K4M. It can be concluded that formulations with higher

swelling indices retarded the release of drugs more than those with lower swelling indices9.

T. Bussemer et al., investigated the swelling characteristics of various swellable polymers in swelling

layers that induce the rupturing of an outer polymer coating in pulsatile drug delivery systems (DDS).

An apparatus was designed to measure simultaneously the swelling energy/force and water uptake of

discs, made of polymers. The swelling energy of several excipients decreased in the following order:

croscarmellose sodium (Ac-Di-Solw), low-substituted hydroxypropyl cellulose (L-HPC), sodium starch

glycolate (Explotabw), crospovidone (Kollidonw CL), hydroxypropyl methylcellulose (Methocelw

K100M). A linear correlation existed between the swelling energy and the water uptake. The swelling

behavior of Ac-Di-Solw depended on the ionic strength and the pH of the medium due to a competition

for free water and the acidic nature of this polymer. Analysis of the time-dependent swelling force data

with a previously developed exponential equation confirmed a diffusion-controlled swelling force

development, predominantly controlled by the penetration rate of the medium. The swelling behavior

and the rupture of the outer polymeric coating of a pulsatile DDS were demonstrated in simulation

tests10.

OBJECTIVE OF THE STUDY:

The main objective of the present study is to carry out formulation of floating- pulsatile drug delivery

system of famotidine and to evaluate it for:

Selection of drugs, polymers and other excipients.

Characterisation of drug, polymer and excipients for the intended work.

Carry out compatibility studies for the selected drug, polymer and excipients by FTIR.

Development of floating pulsatile delivery formulation of famotidine.

Characterisation of the formulation for various in vitro parameters.

Statistical assessment of all the results.

To carry out short term stability studies on the most satisfactory formulation as per ICH

guidelines.

6.3

MATERIALS AND METHODS:-

SOURCE OF DATA:-

1) Review of literature from:

a. Journals – such as

European Journal of Pharmaceutical Sciences

Asian Journal of Pharmaceutics

International Journal of Pharmaceutics

Journal of Controlled Release

International Journal of Pharmacy and Pharmaceutical Sciences

Iranian Journal of Pharmaceutical Research

b. J-Gate@Helinet

c. www.sciencedirect.com

7.1

7.

METHOD OF COLLECTION OF DATA :-

1) To carry out preformulation study

A. Drug polymer interaction

B. Micromeritic study

a) Angle of repose

b) Bulk density

c) Porosity and Percentage compressibility

2) Evaluation of the various properties of the formulation

A. Physical evaluation & drug content

a) Thickness

b) Weight variation

c) Hardness

d) Friability

B. In vitro floating behaviour

a) Floating lag time

b) Total floating time

C. In vitro dissolution study

7.2

3) Statistical analysis of the results

4) Stability studies, etc.

7.3 DOSE THE STUDY REQUIRES ANY INVESTIGATION TO BE CONDUCTED ON PATIENT

OR OTHER HUMANS OR ANIMALS?

“NO”

7.4 HAS ETHICAL CLEARANCE BEEN OBTAINED FROM YOUR INSTITUTION IN CASE OF

7.3?

“NOT APPLICABLE”

8. REFERENCES:-

1. Krogel I, Bodmeier R. Floating or pulsatile drug delivery system based on coated  effervescent cores.

Int J Pharm; 1999; 187: 175-84

2. Karavas E, Georgarakis E, Bikiaris D. Application of PVP/HPMC miscible blends with enhanced

mucoadhesive properties for adjusting drug release in predictable pulsatile chronotherapeutics.

    Eur J  Pharm Biopharm; 2006; 64: 115-26

3. Survase S, Kumar N. Pulsatile drug delivery : Current scenario. CRIPS; 2007 Apr-Jun; 8 (2): 27-33

4. Lin HL, Lin SY, Lin YK, Ho HO, Lo YW, Sheu MT. 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. Eur J  Pharm Biopharm; 2008; 70: 289-301

5. Barhate SD, Rupnar Y, Rahane R, Patel MM. Formulation optimization of bilayer floating  tablet of

famotidine. Int J Pharm Bio Sci; 2010 Oct-Dec; 1 (4): 613-21

6.  Sungthongjeena S, Puttipipatkhachorn S, Paeratakulc O, Dashevskyb A, Bodmeier R. Development

of pulsatile release tablets with swelling and rupturable layers.  J Control Release; 2004 Mar 5; 95

(2):147-59

7.  Kikuchi A, Okano T. Pulsatile drug release control using hydrogels. Adv Drug Deliver Rev; 2002;

54: 53–77

8. McConvillea TJ, Rossa AC, Chambersa AR, Smithb G, Florencea AJ, Howard NE. 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. Eur J Pharm Biopharm; 2004; 57: 541– 49

9.  Havaldar VD, Kulkarni AS, Dias RJ, Aloorkar NH, Mali KK. Floating matrix tablets of  atenolol.

Formulation and in vitro evaluation. Asian J Pharm; 2009; 3 (4): 286-91

10. Bussemera T, Peppasb NA, Bodmeier R. Evaluation of the swelling, hydration and  rupturing

properties of the swelling layer of a rupturable pulsatile drug delivery system.

      Eur J Pharm Biopharm; 2003;56: 261–70

9. Signature of the candidate

10. Remark of the Guide

11. Name and designation of:

11.1 Institutional Guide:

Mr. Anup Kumar Roy M.Pharm, ( Ph.D)

Asst. Professor & HOD

Dept. Of Industrial Pharmacy

11.2 Signature

11.5 Head of the Department:

Mr. Anup Kumar Roy M.Pharm, (Ph.D)

Asst. Professor & HOD

Dept. of Industrial Pharmacy

11.6 Signature

12.

12.1 Remarks of Principal

12.2 Signature

Dr. DIVAKAR GOLI M.Pharm, Ph.D

Principal

Acharya & B.M.Reddy College Of Pharmacy