DESIGN AND ASSESSMENT OF COLON SPECIFIC DRUG DELIVERY OF CELECOXIB USING PULSINCAP TECHNIQUE

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Microcrystals, Pulsincap Drug Delivery, Celecoxib.

Microcrystals, Pulsincap Drug Delivery, Celecoxib.

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  • 1. DESIGN AND ASSESSMENT OF COLON SPECIFIC DRUG DELIVERY OF CELECOXIB USING PULSINCAP TECHNIQUE Dissertation submitted to Jawaharlal Nehru Technological University, Anantapur. Presented by LAKSHMI K Regd. No. (11421S0304) M. Pharm (Pharmaceutics) IInd year Under the guidance of Mr. RAJESH KAZA, M. Pharm., (Ph.D.) Associate professor Dept. of pharmaceutics SRI PADMAVATHI SCHOOL OF PHARMACY MOHAN GARDENS, TIRUCHANOOR, TIRUPATHI-517503 JUNE-2013 1
  • 2. PULSATILE DRUG DELIVERY SYSTEM  Pulsatile drug delivery system delivers drug in a rapid and burst manner within a short time period immediately after a programmable lag phase.  Pulsatile drug delivery aims to release drug in a programmed pattern i.e., at appropriate time and appropriate site of action. Drug release profile of pulsatile drug delivery system A: Ideal sigmoidal release B and C: Delayed release after a lag time 2
  • 3. ADVANTAGES Drug targeting to specific site Improved patient compliance Bypassing first pass metabolism ADVANTAGES No risk of dose dumping Drug adapts to suit circadian rhythms of diseases Limited risk of local irritation Reducing dose frequency 3
  • 4. disADVANTAGES Large number of process variables Lack of manufacturing reproducibility and efficacy Multiple formulation steps ADVANTAGES Need of advanced technology Higher cost of production Trained/skilled personal needed for manufacturing 4
  • 5. Drug release mechanism from pulsincap system 5
  • 6. RHEUMATOID ARTHRITIS  Rheumatoid arthritis is an autoimmune disorder in which various joints in the body are inflamed which leads to swelling, pain, morning stiffness and severe pain at joints.  It is a chronic disease which initially attacks the synovium, a connective tissue membrane that lines the capsule around joints and secretes a lubricating fluid.  In rheumatoid arthritis, an abnormal immune system response produces destructive molecules that causes continuous inflammation to the synovium and thereby narrowing the joint space and eventually damaging the bone. 6
  • 7. ETIOLOGY OF RHEUMATOID ARTHRITIS GENETIC FACTORS AGE GENDER SMOKING FAMILY HISTORY 7
  • 8. Treatment FOR RHEUMATOID ARTHRITIS • Celecoxib • Joint replacement surgery • Prednisone • Unicondylar knee arthroplasty • Methotrexate • Synovectomy • Infliximab • Arthroscopy Surgery Life Style Changes • Regular exercise • Managing psychological and emotional conditions Drug Therapy Alternative Therapies • Acupuncture, • Mineral baths (Balneotherapy) • Proper dietary intake 8
  • 9. LITERATURE REVIEW Punitha et al., (2009) have worked on increasing the solubility of poorly water soluble drug celecoxib with solid dispersion technique using urea as water soluble carrier by physical mixture, solvent evaporation and fusion method. Solid dispersions were prepared by using 1:1, 1:3 and 1:5 ratios of drug and polymer respectively. The dissolution studies were carried out using USP paddle type dissolution apparatus. Solid dispersion of drug and polymer in 1:5 ratio prepared by fusion method showed faster dissolution rate i.e., 79.08% when compared to that of other formulations prepared by physical mixture and solvent evaporation method. The FT-IR studies revealed that no interaction of drug with carrier. Finally solid dispersions of drug and polymer in 1:5 ratios respectively prepared by fusion method showed excellent physicochemical characteristics and was found to be described by first order release kinetics. Ram Mohan Gupta et al., (2011) carried out an experiment to increase the solubility and dissolution rate of celecoxib by preparing the spherical crystals of celecoxib using polymers like polyethylene glycol 4000, sodium carboxy methylcellulose, sodium alginate and polyvinyl pyrrolidone K30 in different ratios i.e., 1:1, 1:2, 1:3 and 1:4 respectively. All the formulations were characterized for micromeritic properties. FT-IR spectra and differential scanning calorimetry studies revealed that compatibility between drug and polymer. X-ray diffraction studies revealed the occurrence of decrease in crystallinity of spherical agglomerates of celecoxib. From the results of dissolution study, spherical agglomerates of celecoxib prepared with polyvinyl pyrrolidone K30 in 1:4 ratio respectively showed maximum drug release when compared to that of pure drug and 9 other batches of spherical agglomerates.
  • 10. LITERATURE REVIEW Gohel et al., (2002) studied a programmed drug delivery of ketoprofen from hard gelatin capsules containing a hydrophilic plug made up of polymers like HPMC K15M or guar gum. The significance of factors such as plug thickness and the formulation of fill material on the release pattern of diltiazem hydrochloride were investigated. In order to accelerate the drug release after a lag time of 4 hrs, an effervescent blend, sodium bicarbonate and citric acid in the capsules were added. The plugs of HPMC K15M in tablet form, were used for obtaining immediate drug release after lag time. The results indicated that the drug release was dependent on the type of swellable hydrophilic agent, HPMC K15M or guar gum for achieving predetermined lag time. Putta Rajesh Kumar et al., (2012) developed the pulsatile drug delivery system for verapamil hydrochloride to release the drug after a predictable lag time. The verapamil hydrochloride pulsincaps were prepared by physical mixture with lactose by varying drug to polymer ratio and evaluated for percentage yield, drug content, IR and in vitro drug release studies. Sodium alginate and xanthan gum were used as hydrogel plugs to maintain a suitable lag period. The in vitro drug release studies were carried out by using buffer of pH 1.2 for a period of 2 hrs, phosphate buffer of pH 7.4 for a period of 4 hrs and phosphate buffer of pH 6.8 for a period of 6 hrs simultaneously. Results showed that the optimized formulation containing guar gum as hydrogel plug releases 94.5% of drug at 12 hrs with 4 hrs lag time. Thus programmable pulsatile drug release has been achieved from optimized formulation over a period of 12 hrs and is consistent with the demands of pulsincap drug delivery system. 10
  • 11. AIM OF the WORK The aim of present work is to improve the solubility of celecoxib by rapid solvent change method and the prepared microcrystals were used for the development of pulsatile drug delivery using pulsincap technique. 11
  • 12. OBJECTIVEs OF THE WORK 1. 2. 3. 4. 5. 6. • To enhance the solubility of celecoxib by rapid solvent change method . • To synchronize the drug delivery to the circadian rhythms of rheumatoid arthritis. • To provide maximum drug release when sharp increase of symptoms of rheumatoid arthritis occurs . • To bypass the gastric degradation and first pass metabolism of drug. • To minimize the frequency of drug administration . • To improve the patient compliance. 12
  • 13. DRUG PROFILE CELECOXIB • Molecular formula: C17H14F3N3O2 • Category: Selective COX-2 inhibitor (NSAID) • Bioavailability: 25-30% • Half life: 7.5-8 hrs • Solubility: It is freely soluble in methanol, ethanol, PEG 400, DMSO and acetone. It is poorly soluble in water and nonpolar hydrocarbons. • Melting point: 1571580C • Dose: 100-200 mg • Uses:Rheumatoid  Used for the treatment of arthritis  Osteoarthritis  Ankylosing spondylitis 13
  • 14. POLYMER PROFILE S. No. 1. 2. 3. NAME OF THE POLYMER Guar gum Maltodextrin PVP K30 FUNCTIONAL CATEGORY USES  Stabilizing agent  Suspending agent  Tablet binder and disintegrant  Viscosity enhancer  In colonic drug delivery  Used in cosmetics, food and pharmaceutical formulations.      Tablet film former in aqueous film coating.  Carrier to increase the viscosity of solutions.  Osmolarity regulator for solutions. Stabilizing agent Tablet binder Viscosity enhancer Diluent  Stabilizing agent  Tablet binder and disintegrant  Dissolution enhancer  Suspending agent  Solubilizer  Coating agent 14
  • 15. EXCIPIENT PROFILE S. No. 1. NAME OF THE EXCIPIENT HPMC K100 M FUNCTIONAL CATEGORY      Controlled release agent Film former Suspending agent Viscosity enhancer Sustained release agent 2. Sodium starch glycolate  Tablet and capsule disintegrant 3. Lactose  Dry powder inhaler  Carrier USES  Emulsifier  Used in oral, ophthalmic, nasal and topical pharmaceutical formulations.  Suspending agent in topical gels and ointments  Super disintegrant  Tablet and capsule diluent 15
  • 16. PLAN OF WORK • Drug-polymer compatibility studies • Preparation of calibration curve for drug PREFORMULATION STUDIES PREPARATION AND EVALUATION OF CELECOXIB MICROCRYSTALS • Preparation of microcrystals • Evaluation of microcrystals • Characterization of microcrystals • Physicochemical characterization of formaldehyde treated capsules • Preparation of pulsincaps • Evaluation of pulsincaps PREPARATION AND EVALUATION OF CELECOXIB PULSINCAPS 16
  • 17. Experimental methodology Pre-formulation studies 1. 2. • Preformulation studies for drug • Drug-excipient compatibility studies by FT-IR 17
  • 18. Preparation of celecoxib microcrystals BY RAPID SOLVENT CHANGE METHOD Drug solution Hydrophilic stabilizer Non solvent Crystallization Drying at 500C for 1 hr Celecoxib microcrystals 18
  • 19. Working formula of celecoxib microcrystals Formulation code S. No. Ingredients F1 1. 2. 3. 4. Celecoxib (gms) Guar gum (gms) Maltodextrin (gms) PVP K30 (gms) F2 F3 F4 F5 F6 F7 F8 F9 1.76 1.76 1.76 1.76 1.76 1.76 1.76 1.76 1.76 0.02 0.04 0.06 --- --- --- --- --- --- --- --- --- 0.02 0.04 0.06 --- --- --- --- --- --- --- --- --- 0.02 0.04 0.06 5. Methanol (solvent) (ml) 10 10 10 10 10 10 10 10 10 6. Water (anti-solvent) (ml) 20 40 60 20 40 60 20 40 60 19
  • 20. EVALUATION OF microcrystals Percentage crystal yield Particle size distribution EVALUATION STUDIES Percentage drug content In vitro drug release studies 20
  • 21. CHARACTERIZATION OF microcrystals Differential scanning calorimetry (DSC) CHARACTERIZATI ON STUDIES X-Ray diffractometry (XRD) Scanning electron microscopy (SEM) 21
  • 22. Preparation of celecoxib pulsincaps Preparation of cross-linked hard gelatin capsule bodies Separation of cap and bodies of capsules. Treatment of capsule bodies with 15% v/v formaldehyde solution for 12 hrs in dessicator. Drying for a period of 3 hrs at 50 C. Preparation of hydrogel plug Different weight ratios (1:1, 1:2, 1:3 and 1:4) of HPMC and guar gum respectively were taken Subject to direct compression method using 6 mm punches and dies on rotary tablet punching machine. Capsule Filling Sealing and coating of capsules 200mg of optimized celecoxib microcrystal formulation were taken. Joint of capsule body and cap was sealed with a small amount of 3% ethyl cellulose ethanolic solution. To this, add appropriate quantities of sodium starch glycolate (super disintegrant) and lactose (diluent) Coating of capsules with 3% ethyl cellulose ethanolic solution by dip coating method. Filling of above mixture in capsule bodies Coating was repeated until 8-12% increase in total weight of capsule was obtained. 22
  • 23. Composition of pulsincaps S. No. Ingredients Weight taken (per capsule) 1. Optimized microcrystal formulation (mg) Equivalent to 200 mg of drug (w/w) 2. Sodium starch glycolate (mg) (4%) (w/w) 3. Lactose (mg) Quantity sufficient (q.s) Total weight (mg) 300 mg Composition of different formulations of hydrogel plug Formulation code S. No. Ingredients H1 H2 H3 H4 1. HPMC (mg) 150 100 75 60 2. Guar gum (mg) 150 200 225 240 Total weight (mg) 300 300 300 300 23
  • 24. evaluATION OF pulsincaps Solubility test Disintegration test EVALUATION STUDIES Evaluation of hydrogel plugs In vitro drug release studies 24
  • 25. EVALUATION OF hydrogel plugs Thickness test Harness test EVALUATION STUDIES Friability test Weight variation test 25
  • 26. RESULTS AND DISCUSSION Standard curve of celecoxib S. No. Concentration (µg/ml) Absorbance 1. 0 0 2. 2 0.085 3. 4 0.181 4. 6 0.275 5. 8 0.365 6. 10 0.450 26
  • 27. Preformulation studies of celecoxib Colour • White crystalline Taste • Bitter Melting point • 1570C 27
  • 28. Drug-excipient compatibility study by FT-IR . Functional group Celecoxib CX:GG CX:MD C-C (Aromatic bending) 792.84 cm-1 797.84 cm-1 796.84 cm-1 794.84 cm-1 C=C (Aromatic stretching) 1446.79 cm-1 1443.79 cm-1 1445.79 cm-1 1442.79 cm-1 3098.05 cm-1 3099.98 cm-1 3097.98 cm-1 3094.98 cm-1 1228.81 cm-1 1230.73 cm-1 1233.73 cm-1 1232.73 cm-1 3343.04 cm-1 3341.12 cm-1 3339.19 cm-1 3342.04 cm-1 S=O (Stretching) 1165.15 cm-1 1162.15 cm-1 1164.15 cm-1 1163.15 cm-1 C-N (Stretching) 1348.41 cm-1 1346.48 cm-1 1347.41 cm-1 1350.34 cm-1 C-F (Stretching) 3233.09 cm-1 3235.02 cm-1 3234.02 cm-1 3236.95 cm-1 C-H (Aromatic stretching) C-H (Aromatic bending) N-H (Aromatic stretching) CX:PVP K30  Same peaks of N-H, C-N, C-F and S=O bonds were present as that of pure drug without much shifting in the spectra of celecoxib microcrystals suggested that no chemical interaction between the drug and stabilizing agent. 28
  • 29. 0.4 0.8 0.3 0.6 1647.41, 0.27 0.4 0.2 3098.05, 0.3015 3343.04, 0.08878 0.2 3233.09, 0.08552 763.90, 0.1538 1228.81, 0.02133 1165.15, 0.0006996 1348.41, 0.00338 0.0 576.79, 0.09064 1155.50, 0.06075 1078.34, 0.04968 1446.79, 0.08247 792.84, 0.07979 1000 1458.36, 0.161 929.80, 0.154 0.1 1500 2000 2500 3000 600 800 1000 1200 1400 1600 FT-IR spectrum of maltodextrin FT-IR spectrum of celecoxib 0.65 0.8 0.60 0.6 1655.13, 0.5447 0.55 870.00, 0.5693 0.4 0.50 812.13, 0.5192 673.24, 0.5179 0.2 3339.19, 0.05435 0.45 3235.02, 0.04854 3099.98, 0.2359 1230.73, 0.009505 1165.15, 0.0008563 1348.41, 0.001917 1155.50, 0.4384 605.72, 0.4378 0.0 792.84, 0.0495 1000 0.40 1446.79, 0.04871 1500 2000 2500 3000 600 FT-IR spectrum of celecoxib microcrystals containing maltodextrin 800 1000 1200 1400 FT-IR spectrum of guar gum 1600 29
  • 30. 0.6 0.8 0.5 0.6 1016.61, 0.5022 846.85, 0.4899 0.4 0.4 733.04, 0.4388 1169.00, 0.4199 1371.55, 0.4082 3099.98, 0.4106 2955.31, 0.3278 3341.12, 0.171 1230.73, 0.3758 648.16, 0.3709 3235.02, 0.1632 0.2 0.3 792.84, 0.157 1165.15, 0.01194 0.0 1348.41, 0.02018 1446.79, 0.1692 1288.61, 0.2841 1230.73, 0.06457 1000 1500 1000 2000 2500 1500 2000 2500 3000 3000 FT-IR spectrum of celecoxib microcrystals containing guar gum FT-IR spectrum of PVP K30 0.8 0.6 3099.98, 0.6003 3343.04, 0.3396 3236.95, 0.3268 0.4 1446.79, 0.325 792.84, 0.3178 0.2 1165.15, 0.03449 1230.73, 0.152 1350.34, 0.08314 0.0 1000 1500 2000 2500 3000 FT-IR spectrum of celecoxib microcrystals containing PVP K30 30
  • 31. Evaluation of celecoxib microcrystals S. No. Formulation code % Crystal yield % Drug content % Cumulative drug release at 60 min 1. F1 93.25 86.31 54.69 0.98 2. F2 95.55 91.63 74.33 1.32 3. F3 96.30 94.99 85.12 0.78 4. F4 92.69 86.87 63.06 0.76 5. F5 94.44 92.03 78.67 0.92 6. F6 96.70 95.36 89.33 0.89 7. F7 91.57 85.70 42.70 0.96 8. F8 95.55 90.22 69.65 0.45 9. F9 96.15 94.60 82.03 0.65 31
  • 32. Particle Size Distribution Celecoxib F6 Formulation F3 Formulation F9 Formulation 32
  • 33. Dissolution profile of celecoxib microcrystals  From the results, it was revealed that the enhancement in the dissolution rate of microcrystals occurs due the presence of stabilizing agent, which has the ability to reduce the crystallinity of drug by adsorption onto the specific faces of the growing crystal surface of crystalline drug which results in the passage of solvent towards the faces and interiors of drug particles and leads to increased solubility and subsequent dissolution. 33
  • 34. DSC STUDIES Celecoxib CX:MD CX:GG CX:PVP K30 34
  • 35. DSC STUDIES From DSC thermograms, the melting point of pure celecoxib, microcrystals containing guar gum, maltodextrin and PVP K30 showed a sharp melting endothermic peak at 170.01, 163.08, 161.70 and 162.370C respectively. Melting endotherm is not appreciably changed in celecoxib microcrystals prepared in the presence of hydrophilic stabilizing agents i.e., guar gum, maltodextrin and PVP K30 but with a slight reduction that did not seem to be significant. This observation confirmed the absence of chemical interaction of drug with stabilizing agents during crystallization process. 35
  • 36. XRD STUDIES Celecoxib CX:MD CX:GG CX:PVP K30 36
  • 37. XRD STUDIES Characteristic peaks appeared in the XRD for celecoxib showed sharp intensity peaks at 2θ values of 10, 22, 27, 29, 31, 36, 41, 46, 49, 54 and 74.  In case of celecoxib microcrystals containing guar gum, sharp intensity peaks were exhibited at 25, 31, 36, 39 and 46. In case of celecoxib microcrystals containing maltodextrin, sharp intensity peaks were exhibited at 41, 53, 59 and 74. In case of celecoxib microcrystals containing PVP K30, sharp intensity peaks were exhibited at 31, 41, 49 and 74. The lack of numerous distinctive peaks of the drug in case of celecoxib microcrystals indicates the reduced crystallinity when compared to that of pure drug. This may be due to partial conversion of the drug to amorphous state from crystalline state and thus enhances the solubility 37
  • 38. SEM STUDIES 20KV 20KV 9.7mm×500SE 9.7mm×500SE 28µm 100µm 17/06/2013 17/06/2013 SEM of celecoxib 12:39 10:43 SEM of celecoxib microcrystals 38
  • 39. SEM STUDIES  Microcrystals containing maltodextrin as stabilizing agent at 0.1% w/v concentration with 1:6 ratios of solvent to anti-solvent (v/v) respectively (F6 formulation) showed small platy crystals with particle size of 28µm diameter. From the results, it was observed that the particle size of drug decreases three folds by rapid solvent change method. This may be due to face specific adsorption of stabilizing agent alters the growth rate of the crystal faces where adsorption takes place and thus changes the morphology of the crystal. Modification of crystal habit can improve the dissolution rate by promoting the growth of more hydrophilic faces or inhibiting the growth of more hydrophobic faces. 39
  • 40. Evaluation of celecoxib pulsincaps Physico-chemical characterization of capsules: Color S. No. Capsule type 1. Dimensions Odor Length (mm) Diameter (mm) Red Odorless 21.6 0.20 3.24 0.03 Blue Red Odorless 19.8 0.15 3.22 0.11 White White Odorless 19.9 0.20 3.27 0.06 Body Cap Untreated capsules without coating Blue 2. Formaldehyde treated capsules without coating 3. Formaldehyde treated capsules with coating Solubility and disintegration time: S. No. Capsule type Solubility test Disintegration time 1. Untreated capsules without coating Whole capsule-≤15 min Whole capsule-3 min 2. Formaldehyde treated capsules without coating Cap-≤15 min Cap-3 min Body-2 hrs Body-10 hours 40
  • 41. Evaluation of hydrogel plugs Hydrogel S. No. Plug code (HPMC:Guar gum) Mean thickness (mm) Mean hardness (kg/cm2) % Friability % Weight variation test 1. H1 (1:1) 2.99 4.50 0.78 Passes the test. 2. H2 (1:2) 3.06 4.50 0.74 Passes the test. 3. H3 (1:3) 2.82 4.50 0.63 Passes the test. 4. H4 (1:4) 3.11 4.50 0.81 Passes the test. 41
  • 42. Dissolution data of celecoxib pulsincap formulations Percent cumulative drug release (mean±S.D.) Time S. No. (Hr:min) PH1 PH2 PH3 PH4 1. 00:30 0.00 0.00 0.00 0.00 2. 01:00 0.00 0.00 0.00 0.00 3. 01:30 0.00 0.00 0.00 0.00 4. 02:00 0.00 0.00 0.00 0.00 5. 02:30 0.00 0.00 0.00 0.00 6. 03:00 6.32±0.13 0.00 0.00 0.00 7. 03:30 14.35±1.04 0.00 0.00 0.00 8. 04:00 29.73±0.34 5.93±1.02 0.00 0.00 9. 04:30 45.65±0.45 17.35±0.32 0.00 0.00 10. 05:00 57.76±0.14 30.73±0.44 6.11±0.67 0.00 11. 05:30 68.34±0.67 45.65±1.32 22.72±1.18 0.00 12. 06:00 76.88±1.32 60.76±0.89 45.77±0.44 0.00 13. 06:15 79.05±1.15 64.34±0.37 51.23±0.63 0.00 14. 06:30 79.92±0.44 67.88±1.29 55.48±1.23 9.30±1.22 15. 06:45 80.32±1.38 70.95±0.44 59.61±1.32 22.49±1.42 16. 07:00 81.11±1.29 72.89±1.06 64.42±0.12 56.03±0.38 17. 07:15 81.89±0.54 73.99±0.42 67.38±1.27 67.35±1.17 18. 07:30 82.12±0.25 74.96±0.23 68.03±0.21 86.17±0.23 19. 07:45 82.46±0.36 76.83±0.18 70.01±0.32 87.36±0.61 20. 08:00 82.86±0.41 78.32±0.53 72.83±0.22 87.89±0.38 42
  • 43. Dissolution profile of celecoxib pulsincap formulations 100 % Cumulative drug release 90 80 70 60 PH1 50 PH2 40 30 PH3 20 PH4 10 0 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6 6.5 7 7.5 8 Time (hrs)  Out of four pulsincap formulations prepared (PH1-PH4), PH4 formulation showed highest percentage drug release i.e., 87.89% at the end of 8th hr and maximum lag time of 6 hrs when compared to other pulsincap formulations. 43
  • 44. Lag time profile of celecoxib pulsincap formulations Formulation code PH4 PH3 PH2 PH1 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6 Lag time (hrs)  Increase in lag time of pulsincap formulation with increased concentration of guar gum occurs may be due to the presence of high viscosity for guar gum which further retards the release of drug by increasing the erosion time of hydrogel plug.  Therefore, in case of PH4 pulsincap formulation, due to the presence of higher amount of guar gum in hydrogel plug, plug possesses high viscous nature and takes more time for complete erosion. Hence it maintains a maximum lag time of 6 hrs when compared to other pulsincap formulations 44
  • 45.  Celecoxib microcrystals were prepared by rapid solvent change method using guar gum, maltodextrin and PVP K30 as a hydrophilic stabilizing agents. 1:6 ratio of solvent to antisolvent (methanol/water) and 0.1% stabilizing agent were optimum parameters for microcrystallization of celecoxib.  The optimized microcrystals were exploited in the development of pulsincaps. Amongst the pulsincap formulations prepared (PH1-PH4), PH4 formulation containing hydrogel plug made of HPMC and guar gum in 1:4 ratio respectively was considered as optimized formulation in which percentage drug release was found to be 87.89% at the end of 8th hour and maximum lag time of 6 hrs when compared to that of other pulsincap formulations.  The studies have clearly indicated that pulsatile drug release of celecoxib from time dependent pulsincaps can be helpful for chronomodulated therapy for treating rheumatoid arthritis as well as declining the frequency of dose administration by preventing the drug from gastric degradation and first pass metabolism. 45
  • 46. Publications  “Design and Characterization of Microcrystals for Enhanced Dissolution Rate of Celecoxib” Lakshmi K, Pranav Kumar Reddy and Rajesh Kaza. Current Drug Discovery Technologies, 2013, 10(4), 305314.  “Design and Assessment of Colon Specific Drug Delivery of Celecoxib Microcrystals Using Pulsincap Technique” . Rajesh Kaza and Lakshmi K. Current Drug Delivery. [Accepted and Article in Press]. 46
  • 47.  Gothoskar A.V and Joshi N.H. A review on pulsatile drug delivery systems. Drug Delivery Technology, 2004; 4(5): 1-11.  Shiva kumar H.G, Pramod kumar T.M and Kashyapa G.D. Pulsatile drug delivery system. Indian J Pharm Educ., 2003; 37(3): 125-128.  Sarasija, S and Hota, A. Colon-specific drug delivery systems. Indian J Pharm Sci., 2000; 62(1): 1-8.  Jain N.K, Krishnaiah Y.S.R and Satyanarayana S. Colon-specific drug delivery systems. Advances in controlled and novel drug delivery (1st edition). CBS publishers and distributors, New Delhi, 2000; pp. 89-119.  http://www.drugs.com/celecoxib.html  http://www.rxlist.com/cgi/generic/coxib.html  Smolinske S.C. Handbook of food, drug and cosmetic excipients. Boca Raton, CRC Press, New York, 1992; pp. 303–305. 47
  • 48.  Rajesh A Keraliya, Tejal G Soni, Vaishali T Thakkar, Tejal R Gandhi and Rajanikant C Patel. Formulation and physical characterization of microcrystals for dissolution rate enhancement of tolbutamide. Int J Pharm Sci Res., 2010; 1(1): 69-77.  Nighute A.B and Bhise S.B. Enhancement of dissolution rate of rifambutin by preparation. of microcrystals using solvent change method. Int J Pharm Tech Res., 2009; 1(2): 142-148.  Hancock B and Zografi G. Characterization and significance of the amorphous state in pharmaceutical systems. Int J Pharm Sci.,1997; 8(6): 1–12.  Franenkel Conrat H and Olcott H.S. Reaction of formaldehyde with proteins II participation of guanidyl groups and evidence of crosslinking. J American Chem Soc., 1946; 6(8):34-38.  Kikuchi A and Okano T. Pulsatile drug release control using hydrogel plugs. Adv Drug Del Rev., 2002; 54: 53-77.  Meena A, Kumar B, Surya Prakash T.N.K and Senthamarai R. Development and evaluation of of pulsatile drug delivery system of lornoxicam. Int J Pharm world Res., 2011; 2(2): 1-14. 48
  • 49. 49