I= PHARMACOKINETIC AND PHYSICO-CHEMICAL STUDIES ON ORAL CEPHRADINE PREPARATIONS
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Title of Thesis
PHARMACOKINETIC AND PHYSICO-CHEMICAL STUDIES ON ORAL CEPHRADINE PREPARATIONS

Author(s)
Muhammad Harris Shoaib
Institute/University/Department Details
University of Karachi/ Department of Pharmaceutics
Session
2004
Subject
Pharmaceutics
Number of Pages
391
Keywords (Extracted from title, table of contents and abstract of thesis)
cephradine, antibiotics, hplc, antimicrobial activity, cephalosporins

Abstract
Society has rightly come to expect that any medicine used in the treatment of its ailment is both efficacious and safe. A number of developing countries are producing high quality Pharmaceutical product for their own country and sometimes for export. But this is always recognized that careless and rogue manufacturer also exist in these countries. Pakistan as a developing country offers a growing market for antibiotics which constitute

27 percent of the total market for pharmaceuticals. The leading suppliers, with combined market share of 79 percent are the United States, Singapore, Italy, China, the U.K, Switzerland, Japan, and Germany. The U.S. share of the import market has averaged about 14 percent during the last three years. There are approximately 230 licensed manufacturers of pharmaceutical products in Pakistan, including 23 multinational companies (MNCs) from the United States, the U.K, Europe and Japan. The average annual production of pharmaceuticals in Pakistan during the last three years is estimated at USD 600 million each year of which antibiotics accounts for USD 140 million. Some antibiotics namufactured locally include Penicillin’s, Cephalosporin’s, Trimethoprim, Ibuprofen and Macrolides, Nearly all Pharmaceutical agents which are manufactured and marketed in Pakistan was the research product of developed countries. All necessary test and trials which are it was originally developed. In Pakistan both Local and multinational Pharmaceutical companies manufactured drugs and now there are several brands available for the single generic. These brands of a single generic have variable price ranges, some of them are very costly usually manufactured by multinational firm while the brands manufactured by Local firm was very cheap. Moreover these agents were marketed without having the necessary tests and trials for example the Pharmacokinetic study performed on this part of the world, as there racial and formulation factor which effect the concentration of the drug in blood

Cephradine capsule 250mg which was originally a research product of Bristol Myers & Squibb was also manufactured by more than 15 Local manufacturers having different price range. The Pharmacokinetics including its bioavailability and bioequivalency test was not performed on a single brand marketed in Pakistan. The only data available for Cephradine Pharmacokinetics was of different ethnic origin.

In present study 16 different brands of Cephradine capsule 250mg which was manufactured both by multinational and local Pharmaceutical companies was collected from the local market. Physico-chemical test such as the dissolution test and the Pharmaceutical Assay was performed on these brands. Nearly all brands passes the dissolution test except Ceph-test 15 and 7 similarly all brands passes the Assay procedure except Ceph-test 3,7,11 and 15

One the basis of these Physico-chemical studies three different brands was selected for Pharmacokinetic studies. One of brand Ceph-std was taken as a reference or standard brand, which was manufactured by a multinational firm while the second brand Ceph-test 14 was selected on the basis that it was manufactured by a Local Pharmaceutical company having price considerably lower than the multinational firm and it also passes the necessary Pharmacopeial analytical test. The another brand Ceph-test 15 which was also manufactured by a Local Pharmaceutical firm was selected on the basis that although it was a low cost brand but it does not passes the physico-chemical test. Parallel group design was used in which eighteen different healthy volunteer was selected and divided into three groups and each group received only one brand. Blood samples were collected from different volunteer at 0, 0.5, 1, 1.5, 2, 3, 4, 5, 6, and 7 hrs. Plasma was separated and concentration of drug was determined using HPLC technique. These concentration was then Pharmacokinetically analyzed

This Pharmacokinetic study will be helpful in many useful findings, such as, (a) We have a complete Pharmacokinetic profile of Pakistan population taking Cephradine (b) There is a mushroom growth of Local Pharmaceutical manufacturer. So this study will determine the over all condition of the market and whether the quality will be correlated with the cost of the brand

Present study showed that the Cmax of Ceph-std, Ceph-test14 and Ceph-test15 was 9.48, 9.58 and 6.42μg/ml at Tmax of 1hr. The AUC0-4 and AUC0-α of Ceph-std was found to be 16.95 ±0.35 and 26.957±3.56 μg hr/ml. The AUC 0-4 and AUC0-α of Ceph-test14 was 18.53±1.82 and 24.56±3.06μg hr/ml. The AUC 0-4 and AUC0-α of Ceph-test15 was 11.74±2.27 and 16.67±3.58μg hr/ml. These results of locally manufactured brand Ceph-test14 and Ceph-test15 was then statistically compared with multinational brand Ceph-std, which was taken as a reference standard or standard formulation. Independent group / test one way ANOVA and Confidence interval was used to compared these brands. FDA requires Cmax Tmax and AUC as a necessary bioavailability and bioequivalence parameter to be monitored for the registration of a new formulation. The statistical test showed that Ceph-std and Ceph-test14 are statistically similar while Ceph-test15 failed to pass the test

The other Pharmacokinetics parameter such as Volume of distribution, Mean residence time, rate constants and clearance was also monitored and compared. One was ANOVA and independent group / test was used to compared the results. There was no legal requirement either from the FDA or the health regulating agency in Pakistan to compare two different brands on these parameters for registration of the drug. In present study these parameters was also compared statistically. The rate constant Kα, Kd and Kel of Ceph-std was 5.29, 2.71 and 0.431 ht-1. The rate constant Kα, Kd, and Kel of Ceph-test14 was 3.868, 1.962 and 0.51hr-1 and for Ceph-test14 was 3.82, 1.392 and 0.3598hr-1. One way ANOVA passes Ceph-test14 while failed to pass Ceph-test15. Independent group / test failed to pass the Kα, and K,1 of Ceph-test 14 while all result of Ceph-test 15 faild to lie in the acceptance limit. The microconstant K12, K21 and K13 of Ceph-std was o.445, 0.589 and 2.724hr-1 while that the Ceph-test14 was 0.45,0.87 and 1.628ht-1, for Ceph-test15 it was 0.304, 0.573, and 1.134hr-1. The one region except that of K12. The t test for Kel and K12 lies in the acceptance limit. The microceonstant K12, K21 and K13 of Ceph-std was 0.445, 0.589 and 2.724hr-1 While that of 1.134hr-1. The one way ANOVA for rate constant and microconstant of Ceph-test14 lies in the critical region except that of K12. the t test for Kel and K12 lies in the acceptance limit while other rate constant and microconstant of Ceph-test14 lies in the critical region except that of K12. The t test for kel and K12 lies in the acceptance limit while other rate constant and .microconstant of Ceph-test14 lies in the critical region. Only Kel and K21 passes the one way ANOVA test of Ceph-std was 6.818L and 35.51L. The Vc and Vdb of Ceph-test14 was 11.324 and 36.148L and for Ceph-test15. it was 19.53 and 61.554L The clearance (Cltot) of Ceph-std was 9.29.66ml/min. The clearance of test brands i.e Ceph-test14 was 10.36.535ml/min and Ceph-test15 was 1283.194ml/min. The mean residence time of the central compartment of Ceph-std was 0.335hr. The MRTc of Ceph-test14 and Ceph-test15 was 0.614hr and 0.882hr. One way ANOVA for Vc of Ceph-test14 and Ceph-test15 failed to pass the test when compared with Ceph-std. The Vdb of Ceph-test14 falls in the acceptance limit while Ceph-test15 lies in the critical region. The independent group t test for Vc and Vdb passes Ceph-test14 but the results was not in the limit for Ceph-test15. The one way ANOVA (f distribution) and t test for Ceph-test14 was within the limit but f distribution for Ceph-test15 was in the critical region. Values of total clearance of Ceph-test14 was within the statistical limit for both the test used but the values of clearance of Ceph-test15 was not statistically equivalent to Ceph-std

These statistical tests clearly shows that Ceph-test14 passes all test for those Pharmacokinetic parameter (Cmax AUC, AUCo-oo and Tmax) required for the registration of the product. There is no official requirement of these statistical test for other Pharmacokinetic parameters, but in present study these test was also performed and it showed that Ceph-test14 nearly passes all Pharmacokinetic parameter as compared with that of Ceph-std. The other brand Ceph-test15, although a marketed brand failed to pass the bioavailability and bioequivalence test. Nearly all other Pharmacokinetic parameter showed dissimilarity with standard brand

Serum inhibitory and bactericidal test was also performed on both of the test and the standard brand. Similar result was observed for Ceph-std and Ceph-test14 in which inhibitory activity was observed in two fold dilution of the sample taken at Cmax Ceph-test15 showed inhibitory activity only in the Cmax sample

There is no major difference in the Cmax and Tmax of Pakistani population and the other areas of the world. But there is variation observed in other Pharmacokinetic parameters between Pakistani and the other regions

Finally these studies concluded that a strict monitoring of the health regulating agencies was required on these substandard brands and there must be a proper protocol for conducting physico-chemical and Pharmacokinetics test for every product to be marketed in Pakistan. Moreover because of racial difference, every new product which was launched in Pakistan must be subjected to these Pharmacokinetic test

Download Full Thesis
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S. No. Chapter Title of the Chapters Page Size (KB)
1 0 Contents 0
190.67 KB
2 1 Introduction 1
280.99 KB
  1.1 Pharmacokinetic Studies Of Sodage Form 4
  1.2 Dissolution Testing 6
  1.3 Assay Of Drugs In Dosage Forms 9
  1.4 Analysis Of Antibiotic Using Hplc 11
  1.5 History And Source Of Cephalosporins 12
  1.6 Chemistry 12
  1.7 Mechanism Of Action 13
  1.8 Classification 15
  1.9 Antimicrobial Activity 16
  1.10 Pharmacokinetics Of Cephalosporins 18
  1.11 Cephradine 18
3 2 Objective Of Study 22
899.94 KB
  2.1 Literature Survey 23
  2.2 Experimental 70
  2.3 Assay Of Cephradine Capsule 250mg 70
  2.4 Dissolution Test 72
  2.5 Pharmacokinetic Studies 74
  2.6 Statistical Analysis Of The Data 85
  2.7 Plasma Bactericidal Test 89
4 3 Results 91
3122.72 KB
5 4 Statistical Analysis 216
721.57 KB
6 5 Discussion 322
861.47 KB
  5.1 References 353