6.1 NEED FOR THE STUDY:
- Oral drug delivery is the most desirable and preferred method of administering therapeutic agents for providing both systemic as well as local effects in various regions of gastrointestinal tract.
- Colon specific drug delivery system is a site specific formulation for targeting drug delivery to the colon. It is a site where both local and systemic drug delivery takes place.
- Targeted drug delivery into the colon is highly desirable for local treatment of a variety of bowel diseases such as ulcerative colitis, crohn’s disease, amoebiasis, colon cancer etc and for systemic delivery of proteins and peptides.
- Colon specific systems can also be used in conditions in which a diurnal rhythm is evident.
- Colon targeted drug delivery ensures direct treatment at the disease site, lower dosing and lesser systemic side effects.
- In addition to local therapy, the colon can also be utilized as a portal for the entry of drugs into the systemic circulation.
- Rectal route is also used for colon targeting but they show poor patient compliance, so there is a need to develop a widely accepted dosage form like tablet which can reach the colon and provide local action.
- In the current project, an attempt will be made to develop compression coated tablets to deliver drugs to colon in treatment of conditions like amoebiasis and other protozoal infections.
1. Carla Martins Lopez, Jose M Sousa Lobo, Joao F Pinto, Paulo C Costa., fabricated a dual component tablet of ibuprofen made of a sustained release tableted core and an immediate release tableted coat by direct compression method. The sustained release effect was achieved with a polymer [HPMC or Ethyl cellulose] to modulate the release of the drug. The in vitro drug release showed that the ibuprofen contained in the fast releasing component was dissolved within 2 minutes, whereas the drug in the core tablet was released at different times [16 or > 24 hrs], depending on the composition of the matrix tablet. It was concluded that HPMC core was suitable for providing a constant and controlled release [zero order] for a long period of time11.
2.Iskandar S Moussa, Louis H Cartilier., prepared dry coated tablets of Diltiazem HCL and Acetaminophen for time independent and complex drug release based on physic-chemical properties of cross-linked amylase[CLA], a hydrophilic polymer. To make cores CLA was mixed with drug in different proportions and then compressed. The cores were coated manually, consisting of either pure CLA or a mixture of CLA with a small proportion of solute.CLA dry coated tablets acts as reservoir systems where as the outer gel layer acts as a solution-diffusion membrane, through which transport occurs by a process of dissolution of the permeating drug in the polymer at one interface and diffusion down a gradient in thermodynamic activity. After the drug established a uniform concentration gradient within outer membrane [lag time],drug is linear for the range of constant thermodynamic activity in the core. By decreasing coating thickness or incorporating small amounts of sodium chloride in the shell shortens the release lag time and increases the releases rate10.
3. Y S R Krishnaiah , S Satyanarayana, Y V Rama Prasad, S Narasimha Rao., prepared Indomethacin compression coat tablets using guar gum. In vitro drug release showed that guar gum as compression coat protects the drug from being released under conditions mimicking mouth to colon transit. Studies in pH 6.8 phosphate buffered saline [PBS] containing 4% w/v rat caecal contents showed the susceptibility of guar gum to colonic bacterial enzyme action with consequent drug release. Gamma scintiographic studies in human volunteers with technetium-99m-DTPA as a tracer in sodium chloride tablets shows that gum coat protects the drug [tracer in present study] from being released in stomach and small intestine1.
4.Kapse Pankaj, Mandore Paresh, Patil Bharat, Tekade B W, Thakare V M, Dr Patil V R., Prepared an oral press coated tablet of Diltiazem HCL by direct compression to produce sustained drug delivery. The tablet contained Diltiazem in the inner core and was formulated with an outer shell by different weight ratios of low viscosity grade hydrophilic polymer of HPMC 3-cps, 5-cps, 6-cps powder respectively and weight ratio of that used 1:2.86, 1:3, 1:4, 1:5 for each press coated polymer to core tablet. The release profile exhibited a lagtime period without drug release in pH 1.2 and followed by sustained release in pH 6.8. The 1:3 weight ratios shows better sustained release action compared to other9.
5. V R Sinha, B R Mittal, K K Bhutani, Rachana Kumria., prepared rapid disintegrating core tablets containing 5-fluorouracil with compression coating of granules containing a mixture of xanthan gum [XG] and guar gum [GG] in varying proportions. The aim was to develop a reduced coat weight and gum concentration formulation for colonic delivery of 5-fluorouracil to treat colorectal cancer. With 175 mg of coat weight, a highly retarded drug release was observed. After 24 hours of dissolution the mean percentage release from compression coated XG: GG 20:20, 20:10, 10:20 were found to be around 18+1.23%, 20+1.54%, and 30+1.77% respectively. When the coat weight was reduced to 150 mg, initial drug release was not affected and percent drug release from above compression coat XG: GG ratios were found to be increased to 25+1.22%, 36.6+1.89%, and 42.6+2.22% respectively4.
6. M Halsas, P Ervasti, P Veski, H Jurjenson, M Marvola., prepared a press coated modified release tablet of ibuprofen in which the drug is in the core or is divided between core and coat. The coat contains polymer [sodium alginate or HPMC] to control drug release. By altering the proportion of drug between core and coat the pharmacokinetic profile of the drug was studied and also the effect of amount of polymer in the coat was also studied. Bioavailability tests were done on healthy volunteers. In vivo absorption curves of tablets containing 50%, 67%, and 80% of drug in core and 180 mg HPMC in coat revealed bimodal release and in vitro studies failed to show the same. When whole dose was in core the absorption curve has only one clear tmax value at about 10 hours. Doubling HPMC coat decreases drug absorption, finally to get slightly reduced tmax value, the viscosity grade of HPMC used should be lowered2.
7. Shan Yang Lin, Mei Jane Li, Kung, Hsu Lin., formulated an oral press coated tablet containing Diclofenac sodium in the inner core with an outer shell by different weight ratios of hydrophobic polymer of micronized ethyl cellulose powder and hydrophilic excipients such as spray dried lactose [SDL] or HPMC by direct compression to achieve time controlled disintegrating function with predetermined lag time. The effect of formulation of an outer shell comprising both hydrophobic polymer and hydrophilic excipients on the time lag of drug release was studied. The release profile of tablet showed a time period without drug release [time lag] followed by rapid and complete release phase, in which outer shell broke into 2 halves. The lag phase dependent on weight ratios of EC/SDL or EC/HPMC in outer shell. A semi log plot of time load of tablet vs. weight ratio of EC/SDL or EC/HPMC gave a good linear relationship, with r=0.976 and r=0.982 respectively. Different time lags from 1 to 16.3 hours can be modulated by changing the type of polymers and excipients ratios7.
8. Toyohiro Sawada, Hiromu Kondo, Hiroshi Nakashima, Kazuhiro Sako, Masahiro Hayashi., prepared compression-coated time-release tablets (CC tablets) of nifedipine by dry coating method with different polyethylene oxide-polyethylene glycol mixtures. Each formulation showed a clear lag period before drug release initiation, followed by sustained drug release lasting up to 24hrs. The lag time was increased as the amount of polyethylene oxide in the outer layer increased. To study the applicability of CC tablets for chronopharmacotherapy, the pharmacokinetics of CC-1 and CC-2 with difference in vivo lag time were compared with pharmacokinetics of sustained release (SR) tablet in dogs. The data showed a significant difference in in- vivo lag time (P<0.0). Additionally, higher plasma drug concentrations were observed at 8h after administration of CC-2 than that observed for SR-tablet. These results indicates that a CC-tablet with a lag time before drug release is useful for chronopharmacotherapy that can control time and duration of plasma drug concentration better than existing SR technologies6.
9. T Sawada, K Sako , M. Fukui, S Yokohama, M Hayashi., prepared acetaminophen compression coated tablets to study the effect of their core composition in vivo pharmacokinetics on bioavailability. First, the extent of mass reduction of cores in different compression coated tablet core formulations was used to establish a new index, the core erosion ratio. The data showed adding high water soluble excipients to the core results in greater core erosion ratio. Next, to elucidate the effect of core erosion ratio on in vivo acetaminophen release, 3 Compression controlled tablet formulation with similar in vitro acetaminophen release but different core erosion ratio were administered to 4 fasted dogs. The results showed in vivo lag time was same for all formulations. The necroscopy revealed that 3hrs after oral administration, the tablets were located in ileum and colon and all 3 formulations had identical GI transit times. The area under acetaminophen plasma concentration-time curve was greater in dogs with larger core erosion ratios formulation. This showed that larger core erosion ratio increases in vivo drug release, leading to increased absorption from GI tract5.
10. Rudiger Groning, Michael Berntgen, Manolis Georgarakis., prepared peroral acyclovir 200 mg depot tablets with internal magnets. An extracorporal magnet was used to prolong gastric residence time of dosage form and to influence the duration of absorption of acyclovir. In a 3 way cross over in-vivo study with five healthy male subjects, the plasma concentration in the presence and absence of extracorporal magnets were determined. A commercially available immediate release preparation was used as a reference. In the presence of extracorporal magnet, placed in stomach region, the plasma concentrations of drug were higher after 7, 8, 10 and 12 hours. The mean area under the plasma concentration time curve[AUC0-24 hours],in the presence of extracorporal magnet was 2802.7 ngh/ml and in the absence 1598.8 ngh/ml was achieved8.
11.Erica Sundy, Michael Paul Danckwerts., prepared doughnut shaped tablets of caffeine and Ibuprofen compressed using specially designed punches and studied whether the drug release was zero order. HPMC K 15M mixed with gelatin was found to be most suitable coating material with respect to its disintegration and adherence properties. The adherence of the coating tablet to ibuprofen cores was not optimal, so different concentration of gelatin, to act as a plasticizer and enhance adherence, were studied. Friability results of coated doughnut shaped tablets indicate that coating tablets containing 20% and 30% gelatin had a percentage weight loss of less than 1% after 100 revolutions in a Roche friabilator. For all the concentration of gelatin, the angle of repose values in the range of 22.01-17.8 degrees. The compressibility factor were 121.91+2.36, 132.64+3.60 and 88.54+11.52 for the coating tablet granules containing 10%, 20%, and 30% gelatin in HPMC K 15M respectively. The composition of coating tablets did not affect the rate of release of both caffeine and Ibuprofen from the coated doughnut shaped tablets. The coating was adhered to the core tablets for entire duration of drug release1.
6.3 MAIN OBJECTIVE OF STUDY:
The present work is an attempt,
. To formulate a compression coated tablet containing a model anti-protozoal agent.
. Preparation of compression coated tablets:
It can be prepared by any of the following methods,
A] Wet granulation method.
B] Dry granulation method.
C] Direct compression method
The commonly used polymers in the preparation of press coated tablets are;
- Hydroxypropyl methylcellulose
- Hydroxyethylcellulose
- Polyvinylpyrrolidine
- Carboxymethylcellulose calcium
- Ethylcellulose
- Calcium citrate
- Magnesium stearate etc
-> Pre compression parameters.
1.Bulk density
2. Bulkiness
3. porosity
4. True volume
5.Tapped density
6.Angle of repose
7.Compressibility ratio
8.Hausners ratio
-> Post compression parameters.
1. General appearance
2. Size and shape
3. Uniformity of weight
4. Tablet hardness
5. Friability
6. In vitro drug release
7. Stability studies [as per ICH guidelines ]
MATERIALS AND METHODS
7.1 SOURCE OF DATA:
.The data required for the work will be collected from different books, journals and articles available in the library of Government College of pharmacy.
. Journals available at Jgate – Helinet of the Rajiv Gandhi University of health sciences website and through various internet sources.
7.2 METHOD OF COLLECTION OF DATA
The data will be collected from the prepared formulation by subjecting the formulation to different studies like hardness, friability, drug content, lag period, in-vitro dissolution drug release and stability studies and other tests as necessary during the evaluation.
7.3 Does the study require any investigations or interventions to be conducted on patients or other humans or animals? If so, please describe in brief?
NOT APPLICABLE
7.4 Has ethical clearance been obtained from your institute?
NOT APPLICABLE
LIST OF REFERENCES
1. Iskandar S Moussa, Louis H Cartilier. Evaluation of cross linked amylase press coated tablets for sustained drug delivery. International Journal of Pharmaceutics 1997 (149): 139-149.
2. Rudiger Groning , Michael Berntgen , Manolis Georgarakis. Acyclovir serum concentrations following peroral administration of magnetic depot tablets and the influence of extracorporal magnets to control gastrointestinal transit. European Journal of Pharmaceutics and Biopharmaceutics. 1998(46): 285-291.
3. Y S R Krishnaiah , S Satyanarayana , Y V Rama Prasad, S Narasimha Rao. Evaluation of guar gum as a compression coat for drug targeting to colon. International Journal of Pharmaceutics 1998(171) 137-146.
4. M Halsas, P Ervasti, P Veski, H Jurjenson, M Marvola. Biopharmaceutical evaluation of time controlled press coated tablets containing polymers to adjust drug release. European Journal of drug metabolism and pharmacokinetics. 1998(23): 190-196.
5. T Sawada , K Sako , M Fukui , S Yokohama , M Hayashi. A new index, the core erosion ratio, of compression coated timed release tablets predicts the bioavailability of acetaminophen. International Journal of Pharmaceutics. 2003(265): 55-63.
6. Toyohiro Sawada , Hiromu Kondo , Hiroshi Nakashima , Kazuhiro Sako , Masahiro Hayashi. Time release compression coated core tablet containing nifedipine for chronopharmacotherapy. International Journal of Pharmaceutics 2004(280): 103-111.
7. Shan Yang Lin, Mei Jane Li, Kung Hsu Lin. Hydrophilic excipients modulate the time lag of time controlled disintegrating press coated tablets. AAPS PharmScitech 2004; 5 [4] 54:1-5
8. V R Sinha , B R Mittal , K K Bhutani , Rachana Kumria. Colonic drug delivery of 5-fluorouracil: an in vitro evaluation. International Journal of Pharmaceutics 2004(269): 101-108
9. Kapse Pankaj , Mandore Paresh , Patil Bharat , Tekade B W, Thakare V M , Dr Patil V R Formulation and evaluation of Diltiazem HCL press coated tablet. 2004;3:2:26-35
10. Erica Sundy, Michael Paul Danckwerts. A novel compression coated doughnut shaped tablet design for zero order sustained release. European Journal of Pharmaceutical sciences. 2004(22): 477-485.
11. Carla Martins Lopez, Jose M Sousa Lobo, Joao F Pinto, Paulo C Costa .Compressed matrix core tablet as a quick/slow dual component delivery system containing Ibuprofen. AAPS PharmScitech 2007; 8 (3):76:E1-E8
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