RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES



RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES

BANGALORE

KARNATAKA

ANNEXURE – II

PROFORMA OF REGISTRATION OF SUBJECT OF DISSERTATION

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| | |PARASHURAME GOWDA J B |

|1. |NAME OF THE CANDIDATE AND ADDRESS |JANARDHANAPURA |

| | |MAYASANDRA |

| | |TURUVEKERE(T) |

| | |TUMKUR(D) |

| | |572221 |

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|2. |NAME OF THE INSTITUTION |VISVESWARAPURA INSTITUTE OF PHARMACEUTICAL SCIENCES |

| | |BANGALORE – 560070 |

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|3. |COURSE OF THE STUDY AND SUBJECT |MASTER OF PHARMACY IN |

| | |PHARMACEUTICS |

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|4. |DATE OF ADMISSION OF THE COURSE |30-05-2009 |

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| | |FORMULATION AND EVALUATION OF PULSATILE DRUG DELIVERY SYSTEM FOR |

| | |SELECTED ANTI-ANGINAL DRUG |

|5. |TITLE OF THE TOPIC | |

|6. |BRIEF RESUME OF THE PROJECT STUDY |

| |6.1 NEED FOR THE STUDY: |

| |With the advancement of the technologies in the pharmaceutical field, drug delivery systems have drawn an increasing interest|

| |over the last few decades. Nowadays, the emphasis of pharmaceutical galenic research is turned towards the development of |

| |more efficacious drug delivery systems with already existing molecule rather going for new drug discovery because of the |

| |inherent hurdles posed in drug discovery and development process. |

| |In recent years, people have got better understanding on the circadian rhythms of many diseases, such as angina, |

| |hypertension, bronchial asthma and rheumatic disease. The process of these diseases has a close relationship to the day–night|

| |rhythm. Take angina for example, the fatal heart attack is prone to stroke in the midnight due to its circadian rhythm.1 This|

| |will give rise to the failure of survival and brings new challenge to the drug delivery systems. The typical oral sustained |

| |release systems keep the in vivo drug concentration in the therapeutic level for a prolonged period of time, and this is |

| |necessary but not sufficient for treatment of circadian rhythm diseases. Therefore, a novel delivery system designed for this|

| |kind of diseases, called pulsatile system, has drawn much interest in recent years. Pulsatile drug delivery systems can be |

| |characterized by a predetermined lag time after which the drug release is triggered automatically or by the change of |

| |physiological circumstances. The drug release pattern corresponds to the requirement of circadian rhythm treatment, so as to |

| |achieve the ideal therapeutic effect and minimize the adverse effects.2 |

| |In the present study a capsule based pulsatile release formulations will be developed for anti-anginal drugs. Instead of |

| |normal trial and error method, a standard statistical tool of optimization3 will be adapted to study the effect of |

| |formulation and process variables in the development of pulsatile dosage form. The principal advantage of pulsatile |

| |pharmaceuticals is to provide optimum plasma levels of drug, resulting in maximum health benefits and minimize the undesired |

| |ones. As a consequence there is reduction of dose requirement and this likely to improve patient compliance.4 |

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| |REVIEW OF LITERATURE: |

| |A pulsatile drug delivery system based on rupturable coated hard gelatin capsules was developed, comprising of |

| |drug-containing hard gelatin capsules which were coated with a swelling layer and an outer insoluble, water-permeable |

| |polymeric coating. The result demonstrated that an inner pressure developed by the swelling layer resulted in the rupture of |

| |the outer coating. Simulated rupture test demonstrated the dependence of the lag time prior to rupture on the properties of |

| |the coating, such as its water permeability and mechanical strength. The lag time increased with a higher coating level. The |

| |coated capsules took up release medium at a nearly constant rate until a critical maximum was reached, where the swelling |

| |pressure was sufficient to rupture the outer coating. The rate of medium uptake decreased with increasing coating level. |

| |Hydrophobic particulate material, magnesium stearate, was added to the coating layer to reduce the mechanical strength and |

| |therefore the lag time.5 |

| |Delayed-release osmotic capsule of acetaminophen was designed by using hard gelatin capsule containing, osmotic agent |

| |(sorbitol), a release promoter (sodium dodecyl sulfate), coated with a semipermeable cellulose acetate membrane containing a |

| |hydrophobic plasticizer (castor oil) and sealed with white bees wax plug. When placed in the sink water penetrates the |

| |membrane, dissolves the osmotic agent and increases the osmotic pressure inside the capsule, pressure is high enough it |

| |expels out the plug and the drug release commences. The statistical analysis revealed that castor oil concentrations in the |

| |range of 3-4% (w/w) did not affect the lag time but by adjusting the thickness of the membrane, the onset of release could be|

| |adjusted from 2 to 7 h. A theoretical basis for such system, which can be used to express quantitatively the effect of the |

| |semipermeable membrane thickness on the onset of action and rapid release of drug after lag time can be achieved.6 |

| |A three-layered, pH-independent pulsatile release pellets system containing Isosorbide-5-mononitrate (ISMN) were reported. |

| |Pellets containing ISMN were prepared as the core, and then layered with a swelling layer followed by a water insoluble |

| |control layer. The core pellets were formulated with microcrystalline cellulose (MCC) and lactose, and were prepared by |

| |extrusion-spheronization. The preparation was optimized by Box–Behnken experimental design by taking MCC/lactose ratio as |

| |well as the operating conditions of extrusion-spheronization as variables. The core pellets were coated by a fluidized bed |

| |coater, and pellets with various coating types and coating levels were studied by in vitro dissolution tests. The effects of |

| |both swelling layer and control layer on the lag time and the drug release time were studied, in order to predetermine the |

| |lag time and release time. The pellets were also evaluated in vivo by studying the pharmacokinetics after oral administration|

| |in beagle dogs. The pellets achieved a lag time of 4.1 h in vivo, which had a good consistency with the in vitro results, and|

| |the relative bioavailability was nearly 100% comparing to the normal tablets. 7 |

| |An oral ChronotopicTM system was developed to achieve time and/or site-specific release. Cores contained the antipyrine drug |

| |coated by a hydrophilic swellable polymer which is responsible for a lag phase in the onset of release. The release tests |

| |were carried out in a USP 24 paddle apparatus. The in vivo testing, performed on healthy volunteers, envisaged the HPLC |

| |determination of antipyrine salivary concentration and a gamma-scintigraphic investigation. The in vitro release curves |

| |presented a lag phase preceding drug release and the in vivo pharmacokinetic data showed a lag time prior to the detection of|

| |model drug in saliva. Both in vitro and in vivo lag times correlate well with the applied amount of the hydrophilic retarding|

| |polymer. The gamma-scintigraphic study pointed out that the break-up of the units occurred in the colon. The experimental |

| |results showed the delaying drug release for a programmable period of time and delay to attain colon-targeted delivery |

| |according to a time-dependent approach. 8 |

| |A pulsatile release drug delivery system contain different swellable/rupturable materials are reported. The system consists |

| |of the drug core coated with two layers of swelling and rupturable coatings were prepared and evaluated. Cores containing the|

| |drug were prepared by direct compression using microcrystalline cellulose and Ludipress as hydrophilic excipients with the |

| |ratio of 1:1. Cores were then coated sequentially with an inner swelling layer of different swellable materials; Explotab, |

| |Croscarmellose sodium, or Starch RX 1500, and an outer rupturable layer of different levels of ethylcellulose. Results showed|

| |the dependence of the lag time and water uptake prior to tablet rupture on the nature of the swelling layer and the coating |

| |levels. Explotab showed a significant decrease in the lag time, followed by Croscarmellose sodium and finally by Starch RX |

| |1500. Increasing the level of ethylcellulose coating retarded the diffusion of the release medium to the swelling layer and |

| |the rupture of the coat, thus prolonging the lag time. 9 |

| |A novel tablet in capsule system for programmed drug delivery of diltiazem HCL as a model drug have been investigated. In |

| |this study, various factors like type of plug, plug thickness and fill materials were evaluated on the release pattern of |

| |drug. The body portion of the hard gelatin capsules was cross-linked by the combined effect of formaldehyde and heat |

| |treatment. A decrease in drug release was observed when the plug is of powder form, but as the powder is replaced with tablet|

| |form with or without additional soluble adjuvant exhibited burst release after a prolonged lag time. The capsule containing |

| |200mg of HPMC tablet plug and 35mg of effervescent blend in the body portion of capsule exhibited a lag time of 4hrs and |

| |burst release thereafter. 10 |

| |A capsule based pH-independent pulsatile drug delivery system coated with aqueous dispersion of Aquacoat ECD have been |

| |reported. AcDiSol, Explotab and L-HPC as superdisintegrant were evaluated and based on the result it was found that AcDiSol |

| |is the preferred one than the other superdisintegrant for controlled system followed by quick complete drug release. The pH |

| |depend of the dosage form was eliminated by the addition of fumaric acid which maintains an acidic micro environment in the |

| |alkaline pH. Similarly a higher coating level of Aquacoat was required when used in aqueous phase than in organic phase for |

| |controlled lag time with quick drug release. 11 |

| |An osmotic capsule coated with cellulose acetate for controlled onset of release for propranolol HLC in the presence of |

| |osmotic agent have been studied. In this study, white bees wax used as plug to control the onset for drug release. It was |

| |identified that plug thickness is most important parameters for onset of drug release followed by presence castor oil in the |

| |coating solution. Finally it was concluded that the onset of release varied from 0.6 to 10.5hr which could be useful for |

| |chronotherapeutic purpose. 12 |

| |An alternative pulsatile drug delivery system have been proposed consisting of a drug containing impermeable capsule body |

| |closed with an enzyme degradable plug. The plug was prepared by direct compression of pectin and pectinase in different |

| |ratios. The disintegration times of the plugs, lag times and the release profiles of the pulsatile system were determined. |

| |The disintegration times of the plugs, respectively the lag times prior to drug release was controlled by pectin: enzyme |

| |ratio and the plug weight. The inclusion of a buffering agent within the plug leads to plug disintegration independent of the|

| |surrounding pH. The addition of Na-EDTA hindered the formation of non-insoluble calcium pectinate in the presence of calcium |

| |ions in the environment. The addition of effervescent agents to the capsule content resulted in a rapid emptying of the |

| |capsule content after plug degradation. From the results it was concluded that the drug release was controlled by enzymatic |

| |degradation and dissolution of pectin. 13 |

| |A Pulsatile drug delivery system was designed based on an impermeable capsule body filled with drug and an erodible plug |

| |placed in the opening of the capsule body. The erodible plugs were either prepared by direct compression followed by placing |

| |the tablets in the capsule opening. The disintegration/erosion properties of these plugs were determined and optimized for |

| |the final delivery system. In order to assure rapid drug release of the capsule content after erosion of the plug, various |

| |excipients (fillers, effervescent agents) and the drug with different solubilities were evaluated. The lag time prior to drug|

| |release and the subsequent drug release were investigated as function of capsule content, plug composition, plug preparation |

| |technique, plug hardness, weight, and thickness. The erosion time of the compressed plugs increased with increasing molecular|

| |weight of the hydrophilic polymer (HPMC, polyethylene oxide), deceasing filler content (lactose) and decreased with |

| |congealable lipidic plugs with increasing HLB-value and inclusion of surfactants. For complete and rapid release of the drug |

| |from the capsule body, effervescent agents had to be included in the capsule content. The drug delivery showed the typical |

| |pulsatile release profiles with a lag time followed by a rapid release phase.14 |

| | |

| |OBJECTIVES OF THE STUDY: |

| |The present investigation is concerned to study the effect of formulation and process variables in the development of |

| |pulsatile drug delivery system by application of statistical design of experiments. |

| | |

| |Application of screening design of experiment to select various excipients and polymers |

| |Formulation development by utilizing a suitable experimental design (CCD/ Mixture design) |

| |To carry out various in vitro studies |

| |To carry out curve fitting analysis and Optimization studies |

| |To carry out a short term stability studies as per ICH guidelines for the optimized formulation |

| |To carry out in vivo studies for the selected formulation by using a suitable animal model |

| |MATERIALS AND METHODS |

| |7.1 SOURCE OF DATA |

| |Journals, Internet, Text books, Web resources and E journals (European Journal of Pharmaceutics |

| |and Biopharmaceutics, International Journal of Pharmaceutics, Journal of controlled release, J Pharma Biomed Analysis, |

| |Journal of National Cancer Institute) and experimental work- which includes formulation, evaluation and stability studies. |

| |7.2 METHOD OF COLLECTION OF DATA |

| |The data related to physiochemical details of the drug will be collected from drug information center, various standard |

| |books, journals & other sources like research literature, data bases such as science direct etc and laboratory experiments. |

| |Materials & Methods : |

| |Drug: / / verampamil HCL, Nifedipine, Amlodipine. |

| |Polymers: Hydrophilic and Hydrophobic polymers eg. HPMC, HPC, cellulose acetate phthalate, EC, Eudragit RS 100 & RL 100 etc. |

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| |Method: |

| |Preparation of coating of capsule body: Transparent and colorless size hard gelatin capsules were coated with semipermeable |

| |polymer by dip coat method at room temperature. The coated capsules were then dried at different temperatures ranging from |

| |approximately 25 to 500C for 15 to 30 min. |

| |Filling of capsule body: The coated capsules were hand filled with drug, other excipients and magnesium stearate as lubricant|

| |for improving powder flow property. |

| |Preparation of plugs: The plugs are prepared by direct compression method by using appropriate amount of suitable |

| |swellable/hydrophobic polymers and these plugs are placed manually within the capsule body. |

| |Evaluation: |

| |I) Evaluation of powder blend for capsule filling:- |

| |Bulk density |

| |Trapped density |

| |Angle of repose |

| |II) Evaluation of semipermeable membrane thickness. |

| |III) |

| |Weight variation |

| |Plug thickness |

| |Swelling index |

| |Drug content |

| |IV) In vitro dissolution studies following suitable pharmacopoeial method. |

| |V) Optimization studies: Various selected response parameters will be subjected to numerical optimization technique. |

| |VI) Validation: The optimized formula thus obtained will be validated to check the reproducibility of the model. |

| |VII) Stability studies: The optimized formulation will be subjected to short term stability studies as per ICH guidelines. |

| |VIII) In vivo studies: - It is performed for optimized formulation by using a suitable animal model. |

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| |7.3 DOES THE STUDY REQUIRE ANY INVESTIGATIONS OR |

| |INTERVENTIONS TO BE CONDUCTED ON PATIENTS OR OTHER |

| |HUMANS OR ANIMALS? IF SO PLEASE DESCRIBE BRIEFLY |

| |Yes: Bioavailability and pharmacokinetic studies will be performed for both standard preparation (marketed) and optimized |

| |formulation for comparative evaluation. |

| |7.4 ETHICAL CLEARENCE: |

| |Applied for clearance. |

| | |

| |7.5 PLACE OF STUDY: |

| |Visveswarapura Institute of Pharmaceutical Sciences, Bangalore-70. |

| | |

| |LIST OF REFERENCES: |

| |Francesco P, Bjorn L. Chronobiology and chronotherapy of ischemic heart disease. Adv Drug Deliv Rev 2007;(59):952-65. |

| |Sachin S, Neeraj K. Pulsatile drug delivery: current scenario. CRIPS 2007;8(2):27-33. |

| |Narendra C, Srinath MS, Rao BP. Development of three layered buccal compact containing metoprolol tartrate by statistical |

| |optimization technique. Int J Pharm 2005;304:102-14. |

| |McConville JT, Ross AC, Florence AJ, Stevens HNE. Erosion characteristics of an erodible tablet incorporated in a |

| |time-delayed capsule device. Drug Dev Ind Pharm 2005;31:79-89. |

| |Bussemer T, Dashevsky A, Bodmeier R. A pulsatile drug delivery system based on rupturable coated hard gelatin capsules. J |

| |Controlled Rel 2003;93: 331-39. |

| |Mohammad BJ, Mohammad RS, Azim BJ, Khosro A, Ghobad M, Behnaz A, et al. Design and evaluation of delayed-release osmotic |

| |capsule of acetaminophen. Iranian J Pharm Sci 2006;2(2):65-72. |

| |Yao L, Songqing L, Qing D. Design and evaluation of pH-independent pulsatile release pellets containing |

| |isosorbide-5-mononitrate. Chem Pharm Bull 2009;57(1):55-60. |

| |Sangalli M E, Maroni A, Zema L, Busetti C, Giordano F, Gazzaniga A. In vitro and in vivo evaluation of an oral system for |

| |time and/or site-specific drug delivery. J Controlled Rel 2001;73:103-10. |

| |Hoda AM. Modulation of a pulsatile release drug delivery system using different swellable/rupturable materials. Drug Delivery|

| |2007;14:539-46. |

| |Mukesh CG, Manhapra SG. Modulation of active pharmaceutical material release from a novel tablet in capsule system containing|

| |an effervescent blend. J Controlled Rel 2002;79:157-64. |

| |Ahmad M, Andrei D. pH-independent pulsatile drug delivery system based on hard gelatin capsules and coated with aqueous |

| |dispersion AquacoatECD. Eur J Pharm and Biopharm 2006;64:173-9. |

| |Mohammad BJ, Khosro A, Ghobad M, Mahdi Zeraati, Behnaz AGB, Ali N. Propranolol hydrochloride osmotic capsule with controlled |

| |onset of release. Drug Delivery 2007;14:461-8. |

| |Jna K, Roland B. Evaluation of an enzyme-containing capsular shaped pulsatile release drug delivery system. Pharm Research |

| |1999;16:1424-81. |

| |Jna K, Roland B. Pulsatile drug release from an insoluble body controlled by an erodible plug. Pharm Research 1998;15:474-81.|

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|8. | |

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| |Reg. No. | |

|9. | | |

| |SIGNATURE OF THE CANDIDATE | |

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| | |The proposed research work is advantageous in regulating symptoms |

|10. |REMARKS OF THE GUIDE |of nocturnal heart attack hence it can be further navigated. |

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|11. |NAME AND DESIGNATION OF |

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| |11.1 GUIDE |Mr. NARENDRA C. |

| | |Asst. Professor, |

| | |Department of Pharmaceutics, |

| | |V.I.P.S., Bangalore-560070 |

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| |SIGNATURE | |

| | | |

| | |Dr. PRAKASH RAO. B |

| |11.2 HEAD OF THE DEPARTMENT |Professor, |

| | |Department of Pharmaceutics, |

| | |V.I.P.S., Bangalore-560070 |

| | | |

| |SIGNATURE | |

| | | |

| | |Dr.D.H. Harish kumar |

|12. |12.1 PRINCIPAL |M.pharm,PhD |

| | |V.I.P.S.BANGALORE-560070 |

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| |SIGNATURE WITH SEAL | |

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