Research articles
 

By Dr. Rakesh Patel , Mr. Hitesh Patel , Mr. Ashok Baria
Corresponding Author Dr. Rakesh Patel
Dept of Pharmaceutics, S. K. Patel College of Pharmaceutical Education & Research, Ganpat University - India 382711
Submitting Author Dr. Rakesh Patel
Other Authors Mr. Hitesh Patel
Pharmaceutics, S. K. Patel College of Pharmaceutical Education and Research, - India

Mr. Ashok Baria
Department of Pharmaceutics, S. J. Thakkar Pharmacy College, - India

PHARMACEUTICAL SCIENCES

Prednisolone, Eudragit polymers, Colon targeting, Inflammatory bowel diseases

Patel R, Patel H, Baria A. Design Optimization and Evaluation of pH Responsive Prednisolone Sustained Release Tablet for Ileo-colonic Delivery. WebmedCentral PHARMACEUTICAL SCIENCES 2010;1(9):WMC00830
doi: 10.9754/journal.wmc.2010.00830
No
Submitted on: 30 Sep 2010 08:04:51 AM GMT
Published on: 30 Sep 2010 03:25:20 PM GMT

Abstract


The focus of this work is to provide accurate and effective treatment of inflammatory bowel disorders like ulcerative colitis. The necessity and advantages of colon-specific drug delivery systems have been well recognized and documented. Generally, the single approaches to obtain colon-specific delivery achieved limited success. So new combined oral drug delivery system for colon targeting of Prednisolone was developed which contains sustained drug release system of hydroxypropylmethylcellulose, ethyl cellulose, pectin, starch and polymeric coating of Eudragit polymers. DSC, FTIR and accelerated stability studies indicates no possibility of interaction between Prednisolone and other ingredients. The results of the in vitro dissolution tests in 1st fluid (pH 1.2), 2nd fluid (pH 4.5) and 3rd fluid (pH 7.2) indicated absence of drug release in stomach and small intestine and controlled release in colonic medium up to 8 hrs.

Introduction


The most extensive application of a formulation strategy for colonic delivery has been the employment of enteric coatings on solid substrates. This is a natural development of conventional coating technologies to avoid gastric release thus preventing problems such as degradation, pharmacological effects including gastric irritation and nausea. The underlying principle of this approach has been employment of polymers that are able to withstand the lower pH values of the stomach, but disintegrate and release the drug as the pH in the small bowel increases. Targeted delivery of drugs to the colon is usually to achieve one or more of four objectives likes (a) To reduce dosing frequency (b) To delay delivery to the colon to achieve high local concentrations in the treatment of diseases of the distal gut (c) To delay delivery to a time appropriate to treat acute phases of disease, (d) To deliver to a region that is less hostile metabolically.
Ulcerative colitis is characterized by diffuse mucosal inflammation limited to the colon. Disease extent can be broadly divided into distal and more extensive disease. ‘‘Distal’’ disease refers to colitis confined to the rectum (proctitis) or rectum and sigmoid colon (proctosigmoiditis). More extensive disease includes left sided colitis, extensive colitis and pancolitis (affecting the whole colon). Crohn disease and ulcerative colitis are chronic relapsing disorders of unknown origin. These diseases share many common features and are collectively known as idiopathic inflammatory bowel disease.
Prednisolone (PDS), a typical glucocorticoid has been used for the treatment of inflammatory bowel disorders. However, when PDS is orally administered, a large amount of the drug is absorbed from upper gastrointestinal tracts and enters into the systemic circulation. This deteriorates the therapeutic efficacy of PDS and causes systemic side effects such as adrenosuppression, hypertension and osteoporosis. Therefore, it is preferable for treatment of inflammatory bowel disorders to deliver the drug site-specifically to colon.
Among the various types of cellulose ether derivatives, HPMC polymers are popular in controlled release matrices due to their compatibility with numerous drugs. HPMC offers the advantage that, although wet massing may be used to conventionally granulate the material direct compression of the drug blended drug with HPMC is easily accomplished.
The objective of this work was to formulate, optimize and evaluate sustained release tablet of PDS for ileo-colonic delivery. Matrix tablet of PDS was prepared with pectin, hydroxypropyl methylcellulose, ethyl cellulose and this tablet formulation is coated with eudragit polymer to prevent drug release in upper gastrointestinal tract and improve therapeutic effect for treatment of inflammatory bowel disorder.

Methods


Materials
Prednisolone (PDS) was received as gift sample from Lincoln Pharmaceuticals Ltd, Ahmedabad. Starch was received from Shital Chemicals Ltd. Hydroxypropyl methylcellulose K-4M (HPMC K-4M), hydroxypropyl methylcellulose K-100M (HPMC K-100M) and ethyl cellulose were received from Ranchem Ltd, Mumbai. Eudragit FS 30D was received from Corel Pharma Ltd, Ahmedabad. All other chemical and reagent were of analytical grade and used as received.
Methods
1) Drug-Excipients Interaction studies
Assessment of possible incompatibilities between an active drug substance and different excipients forms an important part of the preformulation stage during the development of solid dosage form.Differential Scanning Calorimeter (DSC) allows the fast Evaluation of possible incompatibilities, because it shows changes in the appearance, Shift of melting endotherms and exotherms, and/or variations in the corresponding enthalpies of reaction DSC thermograms of pure drug (PDS), HPMC K-4M and HPMC K-100M, Ethyl cellulose, Starch were taken for their identical endothermic reaction. Finally physical mixture of all above ingredients was scanned for DSC. The thermal analysis was performed in a nitrogen atmosphere at a heating rate of 10°C/min over a temperature range of 50°C to 300°C.
2) Preparation of tablets
The tablets were prepared by wet granulation technique. Drug, polymers and diluent were passed through 60 # sieve and then dry blend of drug, polymer and diluent were granulated with starch paste. The mass was dried at 50°C for about 30 min and sized through 22 # sieve. Finally, weighed quantity of magnesium stearate, aerosil and talc were mixed glidant and lubricant and then tablet blend was compressed on Rotary tablet compression machine (CMB4 -12 stations).
3) Full factorial design
A 32 randomized full factorial design was used in this study. In this design 2 factors were evaluated, each at 3 levels, and experimental trials were performed at all 9 possible combinations. The amounts of HPMC K-4M (X1) and EC (X2) were selected as independent variables. Percentage release of drug for 1st hour (Q1) and 8th hour (Q8) were selected as dependent variables.
4) Evaluation of tablet blends
4.1 Angle of Repose
The fixed funnel and free-standing cone methods employ a funnel that is secured with its tip at given height, H, which was kept 2 cm, above graph paper that is placed on a flat horizontal surface. With R, being the radius of base of conical pile, angle of repose can be determined using following equation:


                & nbsp;                 ;          …………………. (1)

4.2 Bulk density and Tapped density

Density is a term obtained by dividing weight of powder by volume of powder. It is given as g/cm3. Bulk density (ρB) is determined by the bulk volume and the weight of dry powder in a graduated cylinder. Bulk volume of powder is sum of tapped volume plus void volume. Void volume is eliminated by tapping the graduated cylinder on flat horizontal surface from constant height and by constant force for 4000 times. This tapped volume gives the tapped density (ρT).The equations are as following:

                & nbsp;                 ;            ……………….. (2)

                & nbsp;                 ;            .………………. (3)

Where W is the weight of dry blend, VB is the bulk or untapped volume, VT is the tapped volume.

4.3 Compressibility Index

Compressibility index (Carr’s index) gives the important property of granules. It can be calculated by following equation:

                                              ………………. (4)

5) Evaluation of tablets

Prepared tablets were evaluated for certain physical properties like uniformity of weight, hardness, friability and dissolution study etc.

5.1 Uniformity of weight

Every individual tablet in a batch should be in uniform weight and weight variation in within permissible limits. The weights were determined to within ±1mg by using Sartorious balance (BT 124 S). Weight control is based on a sample of 20 tablets.

5.2 Dimensions

The dimensions (diameter and thickness) were then determined to within ± 0.01 mm by using digital vernier calipers.

5.3 Hardness

The hardness of the tablets was determined by diametric compression using a Hardness testing apparatus (Monsanto Type). A tablet hardness of about 4-5 kg is considered adequate for mechanical stability. Determinations were made in triplicate.

5.4 Friability

The friability of the tablets was measured in a Roche friabilator (Camp-bell Electronics, Mumbai). Tablets of a known weight (W0) or a sample of 400 tablets are dedusted in a drum for a fixed time (4000 revolutions) and weighed (W) again. Percentage friability was calculated from the loss in weight as given in equation as below. The weight loss should not be more than 1 %.

                & nbsp;                            ..……………… (5)

5.5 In-vitro dissolution study
The release rate of PDS matrix tablet was determined using United State Pharmacopoeia (USP) XXIV dissolution testing apparatus II (paddle method). The dissolution test was performed using 900 ml of phosphate buffer (PH=7.2), at 37 ± 0.5 °C and 100 rpm. A sample (10 ml) of the solution was withdrawn from the dissolution apparatus at 1, 2, 4, and 8 hour. The samples were replaced with fresh dissolution medium of same quantity. The samples were filtered through a 0.45 um membrane filter. Absorbance of these solutions was measured at 246 nm using a UV – 1800; M/s Shimadzu UV/V is double beam spectrophotometer.
5.6 Accelerated stability studies
Optimized formulation were packed in blister and stored in ICH certified stability chambers maintained at 40°C and 75% RH for three months. The tablets were withdrawn periodically and evaluated for drug content and release studies.
6. Preparation of Eudragit coating solutions
Coating of PDS sustained release matrix tablet was done with Eudragit RS100 solution and Eudragit FS 30D solution. Eudragit RS100 solution was prepared by dissolving Eudragit RS100 powder in isopropyl alcohol solution, diluted up to concentration of 12.5 % and finally PEG-400 (1.25%) was added as a plasticizer. Eudragit FS 30D solution is available as aqueous dispersion and PEG-400 (1.25%) was used as plasticizer. About 1000 tablets of PDS sustained release matrix tablet were taken and allow to coating in pan coater at 50 rpm and 50oC temperature. Coating was carried out with spraying method and dried with same.


Results


a) Differential Scanning Calorimetry (DSC) Analysis
DSC curves obtained for pure PDS, HPMC K-100M, ethyl cellulose, ctarch, pectin and their physical mixtures are shown in Figure 1 (a) & (b). Pure powdered PDS showed a melting endotherm at 241.98°C. DSC scan of PDS with HPMC K-100M showed single broad endotherm at 241.23°C, while PDS and pectin shows peak at 238.15oC and 160.66oC. DSC thermo grams of physical mixture of drug and excipients showed the melting peak of the drug at 239.75°C and broad endothermic peak at 160.11°C due to melting of HPMC. Physical mixture of all above ingredients showed their identical peaks at defined temperature range. Presence of all peaks indicates that all ingredients are compatible with each other.
b) Full factorial design
i) Factorial equation for Q1
Concerning Q1, the results of multiple linear regression analysis showed that both the coefficients b1 and b2 bear a negative sign. It is possible that at higher polymers concentration, PDS is trapped in smaller polymer cells and it is structured by its close proximity to the polymer molecules. So, increasing the amount of the polymer in the formulations increased the time it took for the drug to leave the formulation and retard release of drug into the medium.
Q1 = 18.45-6.447 X1 -1.281X2 + 0.949 X1X2 +0.537X12 – 0.123X22 (R2= 0.9965) …..(6)
The Q1 for all the batches F1 to F9 varied from 24.12 % to 6.12 % showed good correlation coefficient as 0.9965. Results of the equation (2) indicated that both the concentration of the X1 and X2 were responsible for the Q1.
ii) Factorial equation for Q8
The amount of drug released after 8 hrs is also important parameters for prominent drug release from sustained release matrix formulation. The Q8 for all the batches F1 to F9 varied from 97.23% to 76.38 %. Concerning drug release at 8 hrs (Q8), the results of multiple linear regression analysis showed that both the coefficients b1 and b2 bear a negative sign. Therefore, increasing the concentration of either HPMC K4M or EC is expected to decrease the drug release. Such delay in drug release may be because of the release rate is conditioned by the concentration of the polymer. The fitted equation relating the response Q8Hrs (Y) to the transformed factor is shown in following equation,
Q8 = 68.98- 10.21X1 -5.67X2 +1.167 X1X2+0.0145 X12+ 2.389 X22 (R2= 0.987) ……. (7)
From the results of the equation (3) it was concluded that the effect of the concentration of HPMC K4M (X1) was very high and in minus sign while the effect of the concentration of EC (X2) was also in minus sign but it was lesser than X1.
c) Evaluation of tablet blends
Evaluation of prepared blend shows bulk density is between 0.39 to 0.47 gm/cm3, tapped density is 0.49 to 0.59 gm/cm3, Carr’s Index is 16.07 to 23.72 % and Angle of Repose is 28.56 to 30.62 (F).
d) Evaluation of tablets
Evaluation of prepared tablet shows hardness is 4.2 ± 0.60 to 5.0 ± 0.55 kg/cm2, thickness is 2.84 ± 0.05 to 2.98 ± 0.07 mm, friability is 0.30± 0.11 to 0.63± 0.19 % and Weight variation is 100±1.15 to 100±3.50 mg. Batch F9 shows hardness is 4.7 ± 1.50 kg/cm2, thickness is 2.92 ± 0.18 mm, friability is 0.30± 0.11 % and weight variation is 100±1.20 mg.
e) In vitro dissolution studies
Dissolution profiles of PDS sustained release matrix tablets of preliminary trials and factorial batches are shown in Figure 2, 3 & 4, respectively. From the release profile we can see that batches F1 to F8 shows release of drug in between 10.23-24.12 % at 1st hour. Whereas, batch F9 shows that release of drug at 1st hours between 6 .12 %. Batches F1-F8 shows that release of drug at 8th hour is between 82.12 - 95.12 %. Whereas, batch F9 shows release of drug at 8th hour is 76.38 %.
f) Accelerated stability study of best batch (F­7)
Sample withdraws at the interval of one month for three months t showed no change in in-vitro drug release profile (Figure 5). Results of stability study do not show any remarkable change in the release profile of the PDS SR matrix tablet after the stability.
g) Evaluation of Eudragit coated tablet
i) Physical Evaluation
Physical evaluation is based upon color, roughness and uniformity of coating materials.
ii) Disintegration study (Swelling study)
Disintegration study was performed at various pH solutions like 5.0, 6.0 and 7.0 in glass beaker and study was based on removing of coating layer. A shown in Table 8, Coated tablet do not disintegrate in pH 5.0 and 6.0 where as in pH 7.0 breaking of layer start progressively.
iii) The in-vitro dissolution study of PDS SR matrix enteric coated tablet
As shown in Figure 6, Eudragit polymers are works effectively for colon targeted delivery of prednisolone tablet. Both grades like Eudragit RS100 and Eudragit FS30D are soluble at pH >7.0 or colonic pH. PEG-400 is used as plasticizer with both coating agents. Eudragit RS100 will give drug release some faster than Eudragit FS30D in stimulated colonic fluid. Perfect drug release profiles was obtained by Eudragit FS30D coating with PEG-400 as a plasticizer and pan coating will give sufficient coating efficiency with spraying method. Eudragit FS30D coated prednisolone sustained release matrix tablet will does not give release in 0.1M HCL and 2% release in 4.5 pH phosphate buffer and will dissolve uniformly at 7.2 pH stimulated colonic fluid.


Conclusion(s)


In formulation PDS Sustained Release Matrix Tablet, a 32 full factorial design was employed for preparation of tablets possessing optimized characteristics (batches F1 to F9). The amount of HPMC K-4M (X1) and EC (X2) were selected as independent variables. Cumulative % drug release selected as dependent variable (response; Y). Based on result of multiple linear regression analysis, it was concluded that dissolution of tablet could be retarded for 8th hour when X2 is kept at high level. So role of polymer concentration is very important in this formulation. From DSC study, we can show that there is no change in drug’s melting peak (241.98°C) after the preparation of tablet. So we can conclude that drug and other excipients are compatible which each other. While studying IR spectrum, we can conclude that there is no interaction between drug and other excipients. Stability study of batch F­9 after three month showed no change in in-vitro drug release profile. It was concluded that by adopting a systematic formulation approach, an optimum point could be reached in the shortest time with minimum efforts.

References


1. Abdul B, John B. Perspective on colonic drug delivery. Drug Delivery. 2003; 185.
2. Chien Y. Novel drug delivery systems. 2nd Ed.; Marcel Dekker Inc: New York: 1992; 139-40.
3. Gayton A, Hall J. Introduction and treatment to bowel diseases. 11th Ed. Textbook of medical physiology, 2006: 455.
4. Rang HP and Dale MM. Drugs affecting gastrointestinal systems, 6th Ed; Churchill and livingstone publisher, 2006; 342.
5. Sarasija S and Hota A. Colon- specific drug delivery systems. Ind. J. Pharm. Sci. 2002; 62(1): 1-8.
6. www.wikipedia.com
7. Ford J, Rubinstain MH, Hogan JE and Edgar AJ. Importance of drug type, tablet shape, added diluents on drug release from hydropropylmethylcellulose matrix tablets. Int. J. Pharm. 1987; 40: 223-234.
8. Shah NH, Railkar AS, Phuapradit W, Zeng FW, Chen A, Infeld MH and Malick AW. Effect of processing techniques in controlling the release rate and mechanical strengh of hydroxypropyl methylcellulose based hydrogel matrices. Eur. J. Pharm. Biopharm. 1996; 42:183-187.
9. Reynolds TD, Gehrke SH, Hussain AS and Shenoouda LS. Polymer erosion and drug release characterization of hydroxypropyl methylcellulose matrices. J. Pharm. Sci. 1988; 87:1115-1123.
10. Ceballos A, Cirri M, Maestrelli F, Corti G and Mura P. Influence of formulation and process variables on in vitro release of theophylline from directly-compressed Eudragit matrix tablets. IL Farmaco. 2005; 60: 913-918.
11. Martin A. Micromeritics, In: Physical Pharmacy. 4th ed. Philadelphia: Lippincott Williams & Wilkins; 2001; 423-52.
12. Banker GS, Anderson NR. Tablets. In: Lachman L, Lieberman HA, Kanig JL. The Theory and Practice of Industrial Pharmacy. 3rd ed. Philadelphia: PA: Lea & Febiger; 1986; 293-345.
13. Gupta V, Beckert T, Deusch N and Hariharan M. Investigation of Potential Ionic Interactions Between Anionic and Cationic Polymethacrylates of Multiple Coatings of Novel Colonic Delivery System; Drug Dev. and Ind. Pharm. 2002; 28(2): 207–215.
14. Khan M, Prebeg Z and Kurjakovic N. A pH-dependent colon targeted oral drug delivery system using methacrylic acid copolymers; Journal of Controlled Release 1999; 58: 215–222.

Source(s) of Funding


Not applicable

Competing Interests


None

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