Formulation and Evaluation of Pulsatile Drug Delivery System of Rabeprazole

FORMULATION AND EVALUATION OF PULSATILE DRUG DELIVERY SYSTEM OF RABEPRAZOLE M.Pharm. dissertation protocol submitted to

Rajiv Gandhi University of Health Sciences, Karnataka Bangalore– 560041 By Mr. K. CHAITANYA DEEPAK B.pharm. Under the Guidance of DR. DIVAKAR GOLI M.pharm. Ph.D Professor Department of Pharmaceutics

2009-2010 Department of Pharmaceutics Acharya & B.M. Reddy College of Pharmacy Soldevanahalli, Chikkabanavara (Post), Hesarghatta main road, Bangalore– 560 090

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES KARNATAKA, BANGALORE. ANNNEXURE II PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

Mr. K. CHAITANYA DEEPAK 1 Name and address of s/o MR. K. BHOJAREDDY candidate NARSAOOR (DIST) Adilabad Nirmal Andhrapradesh

ACHARYA & B.M. REDDY COLLEGE OF PHARMACY 2 Name of institution Soldevanahalli, Hesaraghatta Main Road, Chikkabanavara post. Bangalore-560090 3 Course of study and M. Pharm subject (PHARMCEUTICS)

4 Date of admission 19th June– 2009

5 Title of the project FORMULATION AND EVALUATION OF PULSATILE DRUG DELIVERY SYSTEM OF RABEPRAZOLE 6 BRIEF RESUME OF THE INTENDED WORK:-

6.1 NEED FOR THE STUDY: Chronotherapeutic drug delivery systems (CRDDS) have been recognized as potentially beneficial to the chronotherapy (timeoptimized 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 to 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 behaviour where night time dosing is required and for the drugs having high first-pass effect and having specific site of absorption in GIT.

A pulsatile drug delivery system comprising a plurality of particles is able to deliver drug in any desired patterns. A plurality of particles with multi- layer core capable of short-pulse release interlaced with long-duration release is designed for delivery of multi-agents simultaneously or sequentially, or single agent, according to a pre-programmed profile.

Advantages of pulsatile drug delivery system: 1.Extended day time and night time activity 2.Reduced side effects 3.Reduced dosage frequency 4.Reduction in dose size 5.Improved patient compliance 6.Drug targeting specific site like colon 7.Protection of moucosa frm drug 8.Drug loss is prevented by extensive first pass effect

The Pulsincap system, developed and registered by R.P. Scherer International Corp. (MI, USA), is a special dosage form comprising a water insoluble capsule body enclosing a drug reservoir. The body is closed at the open end with a swellable hydrogel plug, which consists of insoluble, but permeable and swellable polymers (e.g., polymethacrylates), erodible compressed polymers (e.g., hydroxypropylmethyl cellulose, polyvinyl alcohol, polyvinyl acetate, polyethylene oxide), congealed melted polymers (e.g., saturated polyglycolated glycerides, glyceryl monooleate) and/or enzymatically controlled erodible polymers (e.g., pectin). When this capsule comes in to contact with the dissolution fluid, it swells and, after a lag time, the plug pushes itself outside the capsule and rapidly releases the drug. The length of the plug and its position of insertion into the capsule controls the lag time.4,

Rabeprazole works by blocking acid production in the stomach. This medication is known as a proton pump inhibitor (PPI). It is used to treat acid-related stomach/intestinal and throat (esophagus) problems (e.g., acid reflux or GERD, ulcers, erosive esophagitis, Zollinger-Ellison syndrome). This medication may also be used in combination with antibiotics to treat certain types of ulcers caused by bacterial infection.

6.2 REVIEW OF LITERATURE:- 1. To investigate 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 HPMC. No anomalous physical characteristics were detected with either the tablets or powder blends. MDA indicated water-dipole relaxation times of 2.9, 5.4 and 7.7 £ 1028 ms for 15, 24 and 30% HPMC concentrations, respectively, confirming that less free water was available for chain disentanglement at high concentrations. In conclusion, at low HPMC concentrations water mobility is at its greatest during the granulation process, such formulations are therefore more sensitive to processing techniques. Microwave dielectric analysis can be used to predict the degree of polymer spreading in an aqueous system, by determination of the water-dipole relaxation time.

2. In recent pharmaceutical applications involving pulsatile delivery, multiparticulate dosage forms are gaining much favor over single-unit dosage forms because of their potential benefits like predictable gastric emptying, no risk of dose dumping, flexible release patterns and increased bioavailability with less inter- and intra-subject variability. Based on these premises, the aim of the present review is to survey the main multiparticulate pulsatile delivery systems, for which the swelling and rupturing; dissolution or erosion; and changed permeability of the coating membrane are primarily involved in the control of release. The development of low density floating multiparticulate pulsed-release dosage forms possessing gastric retention capabilities has also been addressed with increasing focus on the upcoming multiparticulate-pulsatile technologies being exploited on an industrial scale. 3. Rupturable pulsatile drug delivery system based on soft gelatin capsules with or without a swelling layer and an external water-insoluble but -permeable polymer coating, which released the drug after a lag time (rupturing of the external polymer coating). The swelling of the gelatin capsule itself was insufficient to rupture the external polymer coating, an additional swelling layer was applied between the capsule and the polymer coating. Croscarmellose sodium (Ac-Di-Sol) was more effective as a swelling agent than low and high molecular weight hydroxypropylmethyl cellulose (HPMC; E5 or K100M). Brittle polymers, such as ethyl cellulose (EC) and cellulose acetate propionate (CAPr), led to a better rupturing and therefore more complete drug release than the flexible polymer coating, Eudragit RS. The lag time of the release system increased with higher polymer coating levels and decreased with the addition of a hydrophilic pore-former, HPMC E5 and also with an increasing amount of the intermediate swelling layer. The water uptake of the capsules was linear until rupture and was higher with CAPr than with EC. Soft gelatin capsule- based systems showed shorter lag times compared to hard gelatin capsules because of the higher hardness/filling state of the soft gelatin capsules. The swelling pressure was therefore more directed to the external polymer coating with the soft gelatin capsules. Typical pulsatile drug release profiles were obtained at lower polymer coating levels, while the release was slower and incomplete at the higher coating levels. CAPr-coated capsule resulted in a more complete release than EC-coated capsules.

4. The objective of this study was to develop a rupturable, capsule-based pulsatile drug delivery system with pH-independent properties prepared using aqueous coating. The drug release is induced by rupturing of the top-coating, resulting by expanding of swellable layer upon water penetration through the top-coating. Croscarmellose sodium (AcDiSol_) is a preferable superdisintegrant compared to low substituted hydroxypropylcellulose (L-HPC) and sodium starch glycolate (Explotab_), because of controlled lag time, followed by a quick and complete drug release. However, due to its anionic character, AcDiSol_ showed pH-dependent swelling characteristics (pH 7.4 >0.1 N HCl) resulting in a pH-dependent lag time. The pH dependency could be eliminated by the addition of fumaric acid to the swelling layer, which allowed to keep an acidic micro-environment. Formation of the rupturable top-coating was successfully performed using an aqueous dispersion of ethylcellulose (Aquacoat_ ECD), whereby sufficient drying during the coating was needed to avoid swelling of the AcDiSol_ layer. A higher coating level was required, when aqueous dispersion was used, compared to organic coatings. However, an advantageous aspect of the aqueous coating was the lower sensitivity of the lag time to a deviation in the coating level. 5. Present work conceptualizes a specific technology, based on combining floating and pulsatile principles to develop drug delivery system, intended for chronotherapy in nocturnal acid breakthrough. 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. percentageweight ratios of ethyl cellulose to hydroxypropyl methyl cellulose in the coating formulation and coating level (% weight gain) were optimized with a 32 full factorial design. Lag time prior to drug release and cumulative percentage drug release in 7 h were selected as responses. Results revealed that both, the coating composition and coating level, are significant factors affecting drug release profile. A second-order polynomial equation fitted to the data was used to predict the responses in the optimal region. The optimized formulation prepared according to computer-determined levels provided a release profile, which was close to the predicted values. The proposed mathematical model is found to be robust and accurate for optimization of time- lagged coating formulations for programmable pulsatile release of ranitidine hydrochloride, consistent with the demands of nocturnal acid breakthrough.

6. The objective of this study was to develop and evaluate a pulsatile multiparticulate drug delivery system (DDS), coated with aqueous dispersion Aquacoat ECD. A rupturable pulsatile drug delivery system consists of (i) a drug core; (ii) a swelling layer, comprising a superdisintegrant and a binder; and (iii) an insoluble, water-permeable polymeric coating. Upon water ingress, swellable layer expands, resulting in the rupturing of outer membrane with subsequent rapid drug release. Regarding the cores, the lag time was shorter, when 10% (w/w) theophylline was layered on sugar cores compared with cores consisting of 100% theophylline. Regarding swelling layer, the release after lag time was fast and complete, when cross-linked carboxymethyl cellulose (AcDiSol) was used as a swelling agent.

7. In this investigation a novel oral pulsatile drug delivery system based on a core-in-cup dry coated tablet, where the core tablet surrounded on the bottom and circumference wall with inactive material, is proposed. The system consists of three different parts, a core tablet, containing them active ingredient, an impermeable outer shell and a top cover layer-barrier of a soluble polymer. The core contained either diclofenac sodium or ketoprofen as model drugs. The impermeable coating cup consisted of cellulose acetate propionate and the top cover layer of hydrophilic swellable materials, such as polyethylene oxide, sodium alginate or sodium carboxymethyl cellulose. The effect of the core, the polymer characteristics and quantity at the top cover layer, on the lag time and drug release was investigated. The results show that the system release of the drug after a certain lag time generally due to the erosion of the top cover layer. The quantity of the material, its characteristics (viscosity, swelling, gel layer thickness) and the drug solubility was found to modify lag time and drug release. The lag time increased when the quantity of top layer increased, whereas drug release decreased. The use of sodium carboxymethyl cellulose resulted in the greatest swelling, gel thickness and lag time, but the lowest drug release from the system. Polyethylene oxide showed an intermediate behaviour while, the sodium alginate exhibited the smallest swelling, gel thickness and the shortest lag time, but the fastest release. These findings suggest that drug delivery can be controlled by manipulation of these formulations.

8. Biodegradable glucose-sensitive in situ gelling system based on chitosan for pulsatile delivery of insulin was developed. The sols/gels were thoroughly characterized for swelling properties, rheology, texture analysis and water content. The developed glucose-sensitive gels responded to varied glucose concentrations in vitro indicating their ability to function as environment-sensitive systems. Insulin load onto the gels was optimized and was found to affect the rheological behavior of these gels, the final preparation used for in vitro contained 1 IU/200 μl of the sol. These gels released the entrapped insulin in a pulsatile manner in response to the glucose concentration vitro. Furthermore, the formulations when evaluated for their in vivo efficacy in streptozotocin- induced diabetic rats at a dose of 3 IU/kg, demonstrated their ability to release insulin in response to glucose concentration and were preferred much better against subcutaneously given plain insulin formulation used as the control. Together, these preliminary results indicate that biosensitive chitosan in situ gelling systems have substantial potential as pulsatile delivery systems for insulin

9. A tablet system consisting of cores coated with two layers of swelling and rupturable coatings was prepared 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 system.

10. The objective of this study was to investigate 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-Sol)>low-substituted hydroxypropyl cellulose (L-HPC)>sodium starch glycolate (Explotab)>crospovidone (Kollidon CL)>hydroxypropyl methylcellulose (Methocel K100M). A linear correlation existed between the swelling energy and the water uptake. The swelling behavior of Ac-Di-Sol 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 tests.

11. Problems such as patient compliance and overdosing call for the development of pulsatile drug delivery devices. The in vitro and in vivo testing of a pulsatile delivery device for tetanus toxoid are described. In vitro release studies indicate that the delivery of the entrained active is dependent upon the driving mechanism, a fluid-activated swelling agent. The delivery profile is influenced by the physicochemical properties of the biomaterials used to construct the implant, such as polyethylene porosity, excipients and the design properties of the device. Solid formulations of tetanus toxoid antigen were intermittently released into the subcutaneous tissues in sheep using the delivery device. The in vivo release of the lyophilised and compressed powder of tetanus toxoid containing excipient materials (including lactose, cellulose and magnesium stearate) was monitored indirectly by measuring levels of antibodies against tetanus toxoid in sera of mice and sheep. The antibody titres generated by our devices were no different to the titres generated by subcutaneous injection of an alum-adjuvanted liquid formulation of tetanus toxoid. The pulsatile delivery devices described should facilitate the delivery of most vaccine antigens and pharmaceuticals

6.3 OBJECTIVE OF THE STUDY:

The main objective of the present study is to carry out formulation of pulsatile drug delivery system of drug rabeprazole and to evaluate it for: 1. To Develop of spectrophotometric method for the determination of the drug rabeprazole 2. Conduct Preformulation studies for possible drug/polymer/excipient interaction IR/DSC analysis. 3. Prepare of formulation using suitable polymers. 4. Evaluate of prepared tablets by different physicochemical studies such as a). Content uniformity b). Determination of drug entrapment efficiency c). Particle size and morphology study of microcapsules d). In vitro release profile of microcapsules 5. To carry out short term stability studies on the most satisfactory formulation as per ICH guidelines

7. MATERIALS AND METHODS: 7.1 SOURCE OF DATA:

Review of literature from:

a.i. Journals such as,

a.i.1. Indian Journal of Pharmaceutical Science

a.i.2. Current therapeutic research

a.i.3. International Journal of Pharmacy and pharmaceutical Sciences

a.i.4. International Journal of Pharmtech research

a.i.5. Europian Journal of Pharmacology

a.i.6. Text books

a.i.7. Europian Journal of Pharmaceutics and Biopharmaceutics

a.ii. World Wide Web.

a.iii. J-Gate@Helinet. 7.2 METHODS:

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 of pulsatile capsule a) Content uniformity b) Determination of drug entrapment efficiency c) Particle size and morphology study of microcapsules d) In vitro release profile of microcapsules

3) To carry out short term stability studies on the most satisfactory formulation as per ICH guidelines. 7.3 DOES THE STUDY REQUIRE ANY INVESTIGATIONS TO BE CONDUCTED ON PATIENT OR OTHER HUMANS OR ANIMALS?

“NO”

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

“NOT APPLICABLE” 8. REFERENCES:-

1. Jason T. McConvillea, Alistair C. Rossa, Alan R. Chambersa, Geoff Smithb, Alastair J. Florencea, Howard N.E. Stevens . The effect of wet granulation on the erosion behaviors of an HPMC–lactose tablet, used as a rate-controlling component in a pulsatile drug delivery capsule formulation .Eur. J. Pharm and Biopharm. 2004; 57: 541–549

2. Pallab Roy A, Aliasgar Shahiwala Multiparticulate formulation approach to pulsatile drug delivery: Current perspectives J.Control Release 2009; 134:74–80

3. Bussemer.T, R. Bodmeier Formulation parameters affecting the performance of coated gelatin capsules with pulsatile release profiles Int .J. Pharm 2003; 267:59–68

4. Ahmad Mohamad, Andrei Dashevsky pH-independent pulsatile drug delivery system based on hard gelatin capsules and coated with aqueous dispersion Aquacoat ECD. Eur. J. Pharm and Biopharm. 2006; 64:173–79

5. Pallab Roy, Aliasgar Shahiwala Statistical optimization of ranitidine HCl floating pulsatile delivery system for chronotherapy of nocturnal acid breakthrough. Eur.J. Pharm 2009; 37: 363–369

6. Andrei Dashevsky , Ahmad Mohamad Development of pulsatile multiparticulate drug delivery system coated with aqueous dispersion Aquacoat ECD. Int.J.Pharm 2006; 318: 124–131.

7. Efentakis .M ∗, S. Koligliati, M. Vlachou. Design and evaluation of a dry coated drug delivery system with an impermeable cup, swellable top layer and pulsatile release. Int.J.Pharm 2006; 311: 147–156

8. Kashyap. N, Viswanad .B, Sharma .G, Bhardwaj .V, Ramarao. P, Ravi Kumar .MNP Design and evaluation of biodegradable, biosensitive in situ gelling system for pulsatile delivery of insulin Biomaterials, , April 2007; 28: ( 11) 2051-2060

9. Srisagul Sungthongjeen, Satit Puttipipatkhachorn, Ornlaksana Paeratakul, Andrei Dashevsky, Roland Bodmeier. Development of pulsatile release tablets with swelling and rupturable layers. J.Control release. 2004 March 5; 95, ( 2) : 147-159.

10 .Busseme .T Peppas, R. Evaluation of the swelling, hydration and rupturing properties of the swelling layer of a rupturable pulsatile drug delivery system Eur.J.Pharm and Biopharm, 2003 SEP; 56 (2 ) 261-270

11. Michael Cardamone, Shari A. Lofthouse, Jane C. Lucas, Rogan P. Lee, Michael O'Donoghue, Mal R. Brandon. In vitro testing of a pulsatile delivery system and its in vivo application for immunisation against tetanus toxoid J. Control Release. 1997 Sep ;47(38): 205-219 9 Signature of the candidate:

10 Remarks of the Guide:

11 Name and Designation of:

DR. DIVAKAR GOLI M.pharm Ph.d 11.1 Institutional Guide: professor Dept. of pharmaceutics Acharya & B.M. Reddy College of Pharmacy, Bangalore-560 090

11.2 Signature:

11.3 Co-Guide:

11.4 Signature:

Dr. KALYANI PRAKASAM 11.5 Head of the Department: Professor & HOD Dept. of Pharmaceutics Acharya & B.M. Reddy College of Pharmacy, Bangalore-560 090

11.6 Signature

12 12.1 Remarks of the Principal

12.2 Signature

Dr. Goli Divakar Principal Acharya & B.M.Reddy College Of Pharmacy, Bangalore-560 090.