ENCLOSURE – I
6. BRIEF RESUME OF THIS INTENDED WORK
6.1 NEED FOR THE STUDY
Nowadays, the emphasis of pharmaceutical 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 1,2. In modified drug delivery much of research is being done in time specific oral delivery involving a pre programmed release to increase the therapeutic efficacy of the drug. Such system constitutes a new class of formulation which has significance in chronopharmaceutics.
Chronopharmaceutics, the drug delivery based on circadian rhythm is recently gaining much attention worldwide. In chronopharmaceutics modified drug delivery systems suitable for diseases that have peak symptoms in the specific time and exhibit circadian rhythm. Bronchial asthma is characterized by airway inflammation resulting in hyper responsiveness of lower respiratory tract in early morning3. In cardiovascular diseases capillary resistance and vascular reactivity are higher in the morning and decreases latter in the day, myocardial infraction and sudden cardiac death are more porn in early morning4.Carcadian rhythm also exists in arthritic pain and in case of rheumatoid arthritis patient experience more pain in the morning and patient with osteoarthritis have more pain in the evening hours5. Circadian rhythm can also be observed in acid seacration6, diabeties and allergic rhinitis7.
However, because of circadian rhythms in physiological parameters and pathological conditions (e.g. asthma, angina pectoris etc), the conventional paradigm concerning drug concentrations “the flatter the better” may not be what the organism may need. Instead, to correlate with our biological needs, precisely timed drug delivery is required ‘pulsatile drug delivery’ is one such novel approach, which may maximize therapeutic efficacy, minimize dose frequency and reduce toxicity by avoiding side effects and drug tolerance.
Pulsed drug release is defined as the rapid and transient release of a drug after a predetermined off release period. One way to classify pulsed drug delivery systems is based on the physicochemical and biological principles that trigger the release. These devices are classified into programmed and triggered drug delivery systems. In programmed delivery systems the release is completely governed by the inner mechanism of the device, i.e. the lag time prior to the drug release is controlled primarily by the delivery system. In ‘triggered’ delivery systems the release is governed by changes in the physiological environment of the device (biologically triggered systems) or by external stimuli (externally triggered systems).Various studies on pulsatile drug delivery systems were reported in the literature8.
Arthritic pain and rheumatoid arthritis patient experience more pain in the morning and patient with osteoarthritis have more pain in the evening hours. Celecoxib is a sulfonamide nonsteroidal antiinflammatory drug (NSAID) and selective COX-2 inhibitor used in the treatment of osteoarthritis, rheumatoid arthritis, acute pain9-11. Keeping all in discussion the following research work is planned.
The proposed research work is plannedto prepare celecoxib core in cup pulsatile drug delivery tablets using swellable and rupturable hydrophilic polymers and evaluate their precompressional and post compressional properties.
ENCLOSURE - II
6.2 REVIEW OF LITERATURE
Prashant A et al12 formulated a core in cup pulsatile drug delivery system containing metoprolol tartarate using cellulose acetate propionate as impermeable membrane and sodium alginate 500 cps and sodium alginate 2000 cps as soluble hydrophilic polymer layer. The top cover layer is prepared using 32 factorial designs. Quantification of water uptake, top layer expansion, in vitro dissolution studies, radial and axial expansion, stereomicroscopic image and short term stability studies are performed. The concentration of top layer of hydrophilic polymer is a critical factor governing the release pattern, increase in the concentration increased lag time and delay the release. It can be concluded from the study that pulsatile drug delivery system useful in chronotherapy of hypertension.
Gao W et al13 developed a pulsatile candesartan cilexitil core in cup tablets. The factors influencing t lag were evaluated by invitro drug release and tablet erosion observations. In addition, the jugular artery pressures vs. times courses of rabbits were recorded after oral administration of marketed candesartan celixitil tablets or core in cup tablets. In vivo studies showed that the onset times indicating the decreases in the blood pressures of commercial tablets and core in cup tablets were (98±17) min and (278±27) min respectively.
Khadabadi SS et al14developed press coated tablet for pulsatile drug delivery of ketoprofen used for chronotherapy of rheumatoid arthritis. The press coated tablets containing ketoprofen in the inner core were formulated by direct compression method with an outer coating of different amounts of HPMC K4M. The release profile of press coated tablet exhibited a lag time depending upon the amount of HPMC K4M in compression coating, followed by burst release. Optimization was done using 32 factorial design considering two independent factors at three levels. Data was evaluated statistically by Stat Ease Design Expert 7.1.4 software.
Li CJ et al15developed verapamil hydrochloride core-in-cup tablets to provide pulsatile drug release. Core tablets were prepared by direct compression method, and core-in-cup tablets by dry-compression coated technology. The parameter, time-lag was used to evaluate the influence of factors, such as the weight of the top cover layer, the amount of hydroxypropylmethylcellulose (HPMC), and the compression load on verapamil hydrochloride release. With the increase of the weight and HPMC amount of the top cover layer, the first lag time was prolonged. The second lag time of core-in-cup tablet with four-layered tablet as core tablet increased with the increasing amount of HPMC K100M. With the increase of compression load, the two lag times were prolonged.
Archana SP et al16 designed chronomodulated pulsatile drug delivery system of captopril intended to release the drug after a lag time of 6h by using rupturable coating polymers. The core containing captopril was prepared by direct compression method and then coated sequentially with an inner swelling layer containing hydrocolloid HPMC E5 and an outer rupturable layer consisted of eudragit RL/RS (1:1). In vitro drug release and rupture tests were performed using USP Type II method at 50 rpm in 0.1N HCl and phosphate buffer of pH 6.8. The results showed that as the amount of inner swelling layer increases, the lag time decreases and as the eudragit coating level increases, the lag time increases and percent water uptake of time dependent pulsatile release system decreases. The presence of an osmotic agent and effervescent agent helped in shortening of lag time.
Swati Jet al17 designed pulsatile drug delivery system of atenolol consisting of core coated with two layers of swelling and rupturable polymers. Cores containing atenolol were prepared by direct compression using different ratios of lactose and microcrystalline cellulose and were then coated sequentially with an inner swelling layer containing a super disintegrants KYRON T 314 and an outer rupturable layer of ethyl cellulose. The effect of level of swelling layer and rupturable coating was investigated. Rupture and dissolution tests were performed using the USP Type II 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 ethyl cellulose coating.
Rane AB et al18 investigated a press coated tablet for pulsatile drug delivery of ketoprofen using hydrophilic and hydrophobic polymers. The press coated tablets containing ketoprofen in the inner core was formulated with an outer shell by different weight ratio of hydrophobic polymer (micronized ethyl cellulose powder) and hydrophilic polymers (glycinemax husk or sodium alginate). The release profile of press coated tablet exhibited a lag time followed by burst release, in which outer shell ruptured into two halves. The surface morphology of the tablet was examined by a scanning electron microscopy. Differential scanning calorimeter and fourier transformed infrared spectroscopy study showed compatibility between ketoprofen and coating material.
ENCLOSURE - III
6.3 Objectives of the study
The present research investigation is planed with the following objectives.
1)To develop core-in-cup tablet system containing celecoxib using different combination of swellable and rupturable polymers that will release drug atspecifictime (chronotherapeutic approach).
2)To obtain the precompressional and postcompressional evaluation data of core tablets.
3)To study the in vitrotime lagged drug release from formulated pulsatile core-in-cup tablet.
4)To study the statistical interpretation of the dissolution release data and model fitting by using dissolution software Disso V3.0.
ENCLOSURE – IV
7. MATERIALS AND METHODS
7.1 Source of data
The primary data will be collected by performing various tests and investigations in the laboratory. The secondary data will be collected by referring various national and International Journals, Books, Pharmacopeia’s and Websites.
ENCLOSURE – V
7.2 METHOD OF COLLECTION OF DATA
The data for the study is planned to collect from following stages.
- The bulk density, granular density, Carr’s ratio, compressibility index and angle of repose were collected during preformulation stages.
- The drug polymer interaction data were collected from FTIR and DSC.
- The thickness, diameter, drug content, weight variation, hardness, friability, disintegration, water uptake, rupture test, swelling studies, in vitro dissolution data were collected during formulation and evaluation stages.
ENCLOSURE-VI
LIST OF REFERENCES
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12.Prashant AB, Bushetti SS, Najmuddin M. Formulation and evaluation of pulsatile drug delivery system of Metoprolol tartarate using core in cup tablet. Am J Med Med Sci 2012; 2(6): 114-122.
13.Gao W, Zhonghong WU, Chen Q, Bin YU. Preparation of Candesartan celexitil core in cup tablets with pulsatile release properties and its effects on the blood pressure of rabbits. J China Pharm Uni 2010; 41 (2): 124-129.
14.Khadabadi SS, Nahid HC, Farhan MK, Akeel AT. Formulation and evaluation of press coated tablet of ketoprofen- a chronotherapeutic approach.Int J Pharm Pharm Sci 2012; 5(3): 733-740.
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18.Rane AB,Gattani SG,Kadam VD,Tekade AR Formulation and evaluation of press coated tablets for pulsatile drug delivery using hydrophilic and hydrophobic polymers. Chem Pharm Bull (Tokyo)2009; 57(11):1213-1217.