FORMULATION AND EVALUATION OF
FLOATING-PULSATILE DRUG DELIVERY SYSTEM OF FAMOTIDINE
M. Pharm Dissertation Protocol Submitted to
RajivGandhiUniversity of Health Sciences, Karnataka
Bangalore– 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 Candidateand Address / Mr. RAJ KISHOR PANJIYAR
SHREEPUR-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 OF
FLOATING-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 ofFamotidine 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 stomachonly and are not affected by variability of pH, local environmentor gastric emptying rate. These dosage forms are also specificallyadvantageous for drugs either absorbed from the stomachor requiring local delivery in stomach. These considerations ledto the development of pulsatile release dosage forms possessinggastric retention capabilities.Normal gastric acid secretion follows a circadian rhythm with a sudden surge of gastric acidity when gastric pH level goes far below4 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 treatmentfailure 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 overcomeby 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 dosingwould 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 isnot affected by variability of pH, local environmentor gastric emptying rate.
6.These dosage forms are also specifically advantageous for drugs either absorbed from thestomach 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 areservoir system consisting of a drug-containing effervescent core and a polymeric coating. Preliminary studieswere carried out to identify core and coating properties for the two systems. The mechanical properties (puncture strengthand elongation) of acrylic (Eudragit® RS, RL or NE) and cellulosic (cellulose acetate, ethyl cellulose) polymers, whichprimarily determined the type of delivery system, were characterized with a puncture test in the dry and wet state. Forthe floating system, a polymer coating with a high elongation value and high water and low CO2 permeabilities wasselected (Eudragit® RL:acetyltributyl citrate 20%, w:w) in order to initiate the effervescent reaction and the floatingprocess rapidly.For the pulsatile DDS, a weak, semipermeable film, which ruptured after a certain lag time wasselected (ethyl cellulose:dibutyl sebacate 20%, w:w). With the floating system, the polymeric coating did not retard thedrug release. A polymer (cellulose acetate or HPMC) was added to the core to control the drugrelease. The time to flotation could be controlled by the composition (type of filler, concentration of effervescentagents) and hardness of the tablet core and the composition (type of polymer and plasticizer) and thickness of thecoating. For the pulsatile system, a quick releasing core was formulated in order to obtain a rapid drug release afterthe rupture of the polymer coating. The lag time prior to the rapid drug release phase increased with increasing corehardness and coating level1.
Evangelos Karavaset al., prepared pulsatile release formulations consisting of two-layered tablets appropriate for preventingischemic heart diseases. The active core of tablet wasconstituted by a FELO/PVP 10/90 w/w solid dispersion while for the adjustmentof the drug release time the coating layer was composed of PVP/HPMC blends at different compositions, acting as a stimulusresponsible layer. These blends are miscible in the entire composition range, ensured by the interactionstaking place between hydroxyl groups of HPMC and carbonyl groups of PVP. The miscibility of the system enhances the mucoadhesiveproperties of the blends, compared with those of pure HPMC, which is desired for such applications. Upon exposure ofthe prepared tablets to the release medium it was found that the coating layer disintegrates first, followed by the immediate release ofFELO 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 beeffectively 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 thatPulsatile drug delivery systems (PDDS) are gaining importance as these systems deliver the drug at specific time as per thepathophysiological need of the disease, resulting in improved patient therapeutic efficacy and compliance. Diseases whereinPDDS are promising include asthma, peptic ulcer, cardiovascular diseases, arthritis andhypercholesterolemia. They focused on the diseasesrequiring 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 vivocorrelations 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 ethylcellulosemembrane plasticized with HPMC 606 (Pharmacoat 606) at different ratios with/without adding various amounts of water todissolve it in the coating solution. Drug release behaviors were investigated using apparatus II in four media of pH 1.2 solution, pH6.8 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 swellingwhich activated drug release with a lag time. The lag time was not influenced by the pH value of the release medium or by the rotationspeeds. 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. Therelease rate after the lag time was determined by the extent of retardation of gelation of HPMC in the core tablet based on the ionicstrength of the medium4.
Dr. S. D. Barhateet al., prepared bilayer floating tablets of famotidine by usingHPMC K100LV, HPMC K4MCR, sodium bicarbonate, sodium alginate, sodium starch glycolate,croscarmellose, crospovidone and lactose. Box-Behnken factorial design was used to statisticallyoptimize the controlled release layer composition and evaluation of the effect of amount of HPMCK100LV, amount of HPMC K4MC and amount of sodium bicarbonate on release rateof 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. Theprognostic ability of Response Surface Methodology involving multiple response optimizations wasproved in designing and optimization of controlled release pharmaceutical formulations5.
Srisagul Sungthongjeenaet al., prepareda 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 Kikuchiet 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 pulsedor transient release of bioactive substances at a specific site and time. Thus it is important to develop new drug deliverydevices to achieve pulsed delivery of a certain amount of drugs in order to mimic the function of the living systems, whileminimizing undesired side effects. Thermal stimuli-regulated pulsed drug release is established through the design of drug deliverydevices, hydrogels, and micelles7.
JasonTMcConvilleetal.,investigatedthevariabilityintheperformanceofapulsatilecapsuledelivery systeminduced by wet granulation of an erodible HPMC tablet, used to seal the contentswithinaninsoluble capsule body. Erodible tablets containing HPMC and lactose were prepared by direct compression (DC) and wet granulation (WG) techniques and used to seal the modeldrugpropranololinside an insoluble capsulebody. 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.Bussemeret al.,investigated the swelling characteristics of various swellable polymers in swelling layers that induce therupturing of an outer polymer coating in pulsatile drug delivery systems (DDS). An apparatus was designed to measure simultaneously theswelling energy/force and water uptake of discs, made of polymers. The swelling energy of several excipients decreased in the followingorder: 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 betweenthe swelling energy and the water uptake. The swelling behavior of Ac-Di-Solw depended on the ionic strength and the pH of the medium dueto a competition for free water and the acidic nature of this polymer. Analysis of the time-dependent swelling force data with a previouslydeveloped exponential equation confirmed a diffusion-controlled swelling force development, predominantly controlled by the penetrationrate of the medium. The swelling behavior and the rupture of the outer polymeric coating of a pulsatile DDS were demonstrated in simulationtests10.
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.
MATERIALS AND METHODS:-
SOURCE OF DATA:-
1)Review of literature from:
- Journals – such as
- European Journal of Pharmaceutical Sciences
- Asian Journal ofPharmaceutics
- International Journal of Pharmaceutics
- Journal of Controlled Release
- International Journal of Pharmacy and Pharmaceutical Sciences
- Iranian Journal of Pharmaceutical Research
- J-Gate@Helinet
METHOD OF COLLECTION OF DATA :-
1)To carry out preformulation study
- Drug polymer interaction
- Micromeritic study
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
3)Statistical analysis of the results
4)Stability studies, etc.
7.3 / DOSE THE STUDY REQUIRES ANY INVESTIGATION TOBE 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 PharmBiopharm; 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; 2010Oct-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 ControlRelease; 2004 Mar 5; 95(2):147-59
7. Kikuchi A, Okano T. Pulsatile drug release control using hydrogels. AdvDrug DeliverRev;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 componentin a pulsatile drug delivery capsule formulation.Eur J Pharm Biopharm; 2004;57: 541–49