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FORMULATION DEVELOPMENT AND

EVALUATION OF
FLOATING PULSATILE DRUG DELIVERY SYSTEM

Synopsis for M. Pharm Dissertation submitted to the


Rajiv Gandhi University of Health Sciences Karnataka, Bengaluru

Submitted By

Ms. ORCHU DURGA BHAVANI


1st Year M.Pharm

Under the guidance of


Dr. B. A.
VISHWANATH M. Pharm, Ph.D.,
HOD, DEPT. OF PHARMACEUTICS

DEPARTMENT OF PHARMACEUTICS
BENGALURU INSTITUTE OF PHARMACY EDUCATION AND RESEARCH,
KOGILU MAIN ROAD, YALAHANKA, BENGALURU-64
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,
KARNATAKA, BENGALURU.
ANNEXURE II
PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

1. NAME OF THE CANDIDATE ORCHU DURGA BHAVANI


AND ADDRESS (IN BLOCK M PHARM, PART I
LETTERS) DEPARTMENT OF PHARMACEUTICS
PRESENT ADDRESS:
ADITYA BENGALURU INSTITUTE OF
PHARMACY EDUCATION AND RESEARCH,
BEHIND ANNAPURNESWARI TEMPLE,
YELHANKA, KOGILU ROAD, BENGALURU-64,
KARNATAKA.
PERMANENT ADDRESS:
FLAT NO.401, SRI BALAJI TOWERS
PATTABIPURAM, NEAR R.T.O OFFICE,
MAIN ROAD GUNTUR, A.P.
2. NAME OF THE INSTITUTION ADITYA BANGLORE INSTITUTE OF
PHARMACY EDUCATION AND RESEARCH

3. COURSE OF STUDY AND SUBJECT MASTER OF PHARMACY IN


PHARMACEUTICS.

4. DATE OF ADMISSION OF COURSE 23rd July 2011

5. TITLE OF TOPIC

FORMULATION DEVELOPMENT AND EVALUATION OF FLOATING PULSATILE


DRUG DELIVERY SYSTEM

6. BRIEF RESUME OF THE INTENDED WORK


6.1 Need for the study :

Present work conceptualizes a specific technology, based on combining floating and


pulsatile principles to develop drug delivery system, intended for chronotherapy in
nocturnal antihypertensive activity. This approach will be achieved by using a programmed
delivery of ranitidine hydrochloride from a floating tablet with time-lagged coating. In this
study, investigation of the functionality of the outer polymer coating to predict lag time and
drug release was statistically analyzed using the response surface methodology (RSM).
RSM was employed for designing of the experiment, generation of mathematical models
and optimization study. The chosen independent variables, i.e. percentage weight ratios of
ethyl cellulose to hydroxypropyl methyl cellulose in the coating formulation and coating
level (% weight gain) were Lag time prior to drug release and cumulative percentage drug
release in 7 hours was selected. Optimization of time-lagged coating formulations for
programmable pulsatile release of antihypertensive drugs, consistent with the demands of
nocturnal antihypertensive activity. These considerations led to the development of pulsatile
release dosage forms possessing gastric retention capabilities.1

The objective of present investigation was to prepare and evaluate a floating pulsatile drug
delivery system of metoprolol tartrate. The prepared floating pulsatile delivery system
consisted of three different parts: a core tablet, containing the active ingredient, an erodible
outer shell and a top cover buoyant layer. The rapid release core tablet (RRCT) was
prepared by using superdisintegrants along with active ingredient. Dry coating of optimized
RRCT was done by using different grades of hydroxy propyl methyl cellulose (HPMC) E5,
E15, and E50 and upper most buoyant layer was prepared withHPMC K15M and sodium
bicarbonate. Developed formulations were evaluated for their physical characteristics, drug
content, in vitro disintegration time, in vitro drug release profile (lag time), floating lag
time, floating time and in vivo X-ray study. On the basis of these evaluation parameters it
was found that optimized floating pulsatile release formulation (FPRT) F9 showed floating
lag time of 4 min, floating time of 12 hrs and release lag time of 6 hrs. The F9 formulation
showed compliance with chronotherapeutic objective of hypertension.2

Floating systems or Hydrodynamically controlled systems are low-density systems that


have sufficient buoyancy to float over the gastric contents and remainbuoyant in the
stomach without affecting the gastric emptying rate for a prolonged period of time. While
the system is floating on the gastric contents, the drug is released slowly at the desired rate
from the system. After release of drug, the residual system is emptied from the stomach.
This results in an increased gastric retention time and a better control of the fluctuations in
plasma drug concentration. However, besides a minimal gastric content needed to allow the
proper achievement of the buoyancy retention principle, a minimal level of floating force
(F) is also required to keep the dosage form reliably buoyant on the surface of the meal.
Many buoyant systems have been developed based on granules, powders, capsules, tablets,
laminated films and hollow microspheres. These considerations have led to the development
of oral floating dosage forms possessing gastric retention capabilities. Thus when a drug
possesses a narrow absorption window design of sustained release preparation require both
prolongation of gastrointestinal transit time of dosage forms and controlled drug release.
Floating dosage form with prolonged residence time in stomach is highly desirable for drug
- That are locally active in stomach
- That have absorption window in stomach or in upper small intestine.
- That are unstable in intestinal or colonic environment
- Have low solubility at high pH value.3

6.2 Review of the literature :

1. Bulgarelli E et al., have formulated hydrophilic casein/gelatin beads using three different
cross-linker solvent compositions. The microspheres so obtained were studied for degree of
cross-linking comparing with the results of swelling process and degradation rate. It was
observed that the cross-linker solvent composition influences the penetration rate through
the matrix of the cross-linker, thus controlling the homogenicity of the matrix cross-linking.4

2. Gonzalez-Rodriguez M L et al., have prepared alginate/chitosan particulate systems


containing Diclofenac sodium. Alginate/chitosan particles were prepared by ionic gelation
(Ca2+ and Al3+) for the sodium diclofenac release. The ability to release the active substance
was examined as a function of some technological parameters and pH of the dissolution
medium. The release of sodium diclofenac is prevented at acidic pH, while is complete in a
few minutes when pH is raised to 6.4 and 7.2. The alginate/chitosan ratio and the nature of
the gelling cation allow a control release rate of the drug.5
3. Chowdary. K P R, el al., have designed mucoadhesive microcapsules of Glipizide for
oral controlled release. Microcapsules containing Glipizide were prepared by orifice ionic
gelation process employing alginate in combination with four mucoadhesive polymers such
as sodium CMC , mehylcellulose, carbopol and HPMC. The microcapsules so prepared
exhibited good mucoadhesive property, slow release of drug and followed zero order
kinetics after a lag period of 1 hour. These mucoadhesive microcapsules were thus suitable
for oral controlled release of Glipizide.6

4. Sanju Dhawan, et al., have prepared mucoadhesive micros, pheres of chitosan by


thermal cross-linking using citric acid and glutaraldehyde as cross-linking agent, by
emulsification and ionotropic gelation using sodium hydroxide. The microspheres were
evaluated for size, zeta potential, stability, mucous glycoprotein assay, adsorption of mucin
on microsphers. The statistical data displayed that the chitosan microspheres prepared by
ionotropic gelation and emulsification can be used as an excellent mucoadhesive delivery
system. The microspheres prepared by cross-linking method using glutaraldehyde showed
good stability.7

5. Jayavadan K, et al., have formulated mucoadhesive microspheres containing Glipizide


and produced by simple emulsification phase separation technique containing chitosan and
using glutaraldehyde as cross-linking agent. The microspheres are evaluated for polymer
drug ratio, mucoadhesive property, size of the microsphere. The results indicated that the
microspheres obtained were discrete, free flowing, spherical, with good mucoadhesive
property and entrapment efficiency of 75% and swelling index of 1.42. The drug release
was sustained for more than 12 hours and demonstrated significant hypoglycemic effect of
Glipizide.8

6. Anil K Anal, et al., have developed ionotropic cross-linked chitosan microspheres for
controlled release of Ampicillin. The beads were prepared with pentasodium
tripolyphosphate cross-linked chitosan microspheres having high acid resistance for
controlled release of Ampicillin. The microspheres were produced by emulsification and
spray drying method. The microspheres were characterized for their particle size, stability
and drug release patterns. The results indicated that the microspheres had size less than
10m and entrapment of Ampicillin was found to be 80%.9

7. Sunil K Jain, et al., has designed optimized floating microspheres of Repaglinide


containing calcium silicate as porous carrier and eudragit S as polymer. The gastroretentive
behavior of these optimized formulations was compared with non-floating microspheres
prepared from the identical polymer. The result displayed prolonged gastric residence time
over 6 hours, the relative bioavailability of loaded floating microspheres was found to be
increase by 3.17 times when compared to conventional dosage forms. The enhanced
bioavailability and elimination half lives of drug formulation observed in above studies
attributed to the floating nature of the designed formulations.10

8. Balasubramaniam J, et al., has prepared the sodium alginate microspheres of Metformin


hydrochloride. Metformin microspheres with sodium alginate and in combination with
gellan were prepared by emulsion cross-linking method. The prepared microspheres were
evaluated for their physicochemical properties like particle size, morphology using SEM,
incorporation efficiency, equilibrium water content (swelling) and invitro drug release. The
effect of various formulation variables like polymer concentration, drug loading, cross-
linking agent concentration and cross-linking time on the invitro dissolution of the prepared
microsphere were evaluated. The results showed that both the particle size and the
incorporation efficiency were proportional to the polymer concentration and the release
followed a biphasic profile characterized by an initial phase of moderate drug release
followed by phase of higher release.11

9. Srinatha A, J K, et al., have studied the invitro characterization of ionic cross-linked


beads for extended release of Ciprofloxacin. Chitosan beads with Ciprofloxacin
hydrochloride were fabricated by ionic cross-linking with sodiumtripolyphosphate. Beads
were evaluated for particle size, encapsulation efficiency, surface morphology, water uptake
studies, invitro degradation study, in vitro drug release study. The statistical results
displayed that the release of the drug from the beads increased with increase in
concentration of Ciprofloxacin and decrease in proportion of chitosan and drug release
followed both first order and higuchis root time kinetics showing non-Fickian release
mechanism.12

10. Das M K , el al, have prepared Furosemide loaded alginate microspheres using ionic
cross linking technique, with the incorporation efficiency of 65% to 93%. The effect of
sodium alginate concentration, cross linking agent and drying condition was evaluated with
respect to entrapment efficiency, particle size, surface characteristics and invitro release
behaviors. They found that the mean particle size and entrapment efficiency varied with
change in various formulation parameters and at the same time gave sustained release of
drug from the microsphere.13

6.3 Objectives of the study :


1. Preparation of floating core for burst release the core tablets containing ranitidine HCl
(75mg per tablet), glyceryl behenate (Compritol 888, 25%, w/w), hydroxypropyl methyl
cellulose (Methocel E5, 20%, w/w), croscarmellose sodium (Ac-Di-Sol, 5%, w/w) and
microcrystalline cellulose (Avicel PH101) were prepared by direct compression. Initially,
the core tablet excipients were dry blended in a double cone blender (Kalweka, Karnavati
Eng. Ltd., India) for 10min, followed by the addition of magnesium stearate (0.5%, w/w)
and Aerosil 200 (0.5%, w/w). The powder componentswere further blended for 5min. The
core tablets (diameter, 7.15mm; biconvex; hardness, 45 kg/cm2; average tablet weight,
180mg) were compressed using a singlepunch tableting machine (Cadmach, Ahmedabad,
India).

2. Time-lagged coating of floating core tablets for pulsatile release of drug coating solutions
of ethyl cellulose (rupturable polymer) combined with hydroxypropyl methyl cellulose
(erodible polymer) were prepared in isopropyl alcohol. The weight ratios of ethyl cellulose
(Aqualon EC N10) to hydroxypropyl methyl cellulose (Methocel E15) were 60:40%,
75:25% and 90:10% (w/w) based on the experimental design. The solution was plasticized
7. with triethyl citrate (20%, w/w, with respect to dry polymer), and then talc was added as
glidant (5%, w/w, related to dry polymer). The homogeneous dispersion was gently stirred
throughout the coating process. The polymer solution was sprayed onto the core tablets in a
conventional pan coating apparatus (Pharma R & D Coater, VJ Instruments Pvt. Ltd., India)
till the desired weight gain (5%, 10% and 15%, w/w). Coating conditions are maintained. At
each stage the coated tablets were further dried in the coating pan for 15min at 40 C. The
tablets were then placed in the oven at 40 C for 2h to remove the residual solvent

MATERIALS AND METHODS:


Drug : Antihypertensive drug
Polymer : Polyethylene glycol, Hydroxypropyl methyl cellulose (HPMC) different
grades, Eudragit different grades, Polyvinyl pyrrolidone (PVP), HPLC cellulose acetate
phthalate, ethyl cellulose, etc.
Ingredients : Sodium Bicarbonate ,citricacid ,tartaric acid, magenisum steriate ,talc ,
Lactose microcrystalline cellulose, magnesium stearate, colorant, etc. Solvent like ethanol,
dichloromethane etc.
Method : Floating pulsatile drug delivery system can be done by wet granulation ,dry
granulation ,direct compression method efflorescence system and non efflorescence.

7.1 Source Of Data :

a. Library: Aditya BIPER , Bengaluru.


b . e-library: Aditya BIPER, Bengaluru.
c. Practices datas based on laboratory studies.

7.2 Method of collection of data:


The data required for the study would be collected from the laboratory based on work
planned as follows

1. Phase solubility studies.

2. Stability studies.

3. In vitro dissolution studies.

4. Curve fitting analysis.

5. Pre formulation studies such as determination of melting point, identification of


Drugs, compatibility study.

8. 7.3 Does the study require any investigations or interventions to be Conducted on patients or
other humans or animals? If so, please Describe in brief.

Not applicable
7.4 Has ethical clearance been obtained from your institute in case 7.3?

Not applicable.

List of references:
1. Badve, S Sher P, Korde A, Pawar, A.P. Development of hollow/porous calcium pectinate
beads for floating-pulsatile drug delivery. Eur. J. Pharm. Biopharm 2009;65:8593.
2. Anuradha k.salukhe* ,Remeth J. Dias, Kailas K. Mali, Niranjan S.Mahanjan and
Vishwajeet S. Ghorpade . Formulation & Evalution of floating pulsatile drug delivery
system of Metoprolol tartrate Der Pharmacia letter 2011;3(3):147-60
3. Azahar Danish khan *,Meenakshi Bajpai floating drug delivery system ,An Overview
Inter J of pharm Tech res 2008;2(4):2497-505.
4. Basit, A., Lacey, L. Colonic metabolism of ranitidine: implications for its delivery and
absorption. Int. J. Pharm 2001;227:157165.
5. Bjorn, L. The clinical relevance of chronopharmacology in therapeutics. Pharmacol. Res
1996;33:10711.
9. NAME AND SIGNATURE OF THE
CANDIDTE
(ORCHU DURGABHAVANI)

10. REMARKS OF THE GUIDE RECOMMENDED AND FORWARDED

Dr. B. A. VISHWANATH M. Pharm, Ph.D.,


11.1 NAME OF THE GUIDE
HOD, DEPT. OF PHARMACEUTICS
ABIPER, BENGALURU-64

11.2 SIGNATURE OF GUIDE

NOT APPLICABLE
11.3 CO-GUIDE

Dr. B. A. VISHWANATH M. Pharm, Ph.D.,


12.1 HEAD OF THE DEPARTMENT HOD, DEPT. OF PHARMACEUTICS
ABIPER, BENGALURU-64

12.2 SIGNATURE OF HOD


(Dr. B. A. VISHWANATH)

13.1 REMARKS OF THE PRINCIPAL RECOMMENDED AND FORWARDED

Dr. B. A. VISHWANATH M. Pharm, Ph.D.,


12.2 PRINCIPAL PRINCIPAL
ABIPER, BENGALURU-64

13.3 SIGNATURE OF PRINCIPAL