{"id":895,"date":"2015-02-16T07:20:29","date_gmt":"2015-02-16T07:20:29","guid":{"rendered":"http:\/\/biomedpharmajournal.org\/?p=895"},"modified":"2020-04-25T08:28:42","modified_gmt":"2020-04-25T08:28:42","slug":"pharmcokinetic-evaluation-of-prednisolone-sr-formulations-designed","status":"publish","type":"post","link":"https:\/\/biomedpharmajournal.org\/staging\/vol2no2\/pharmcokinetic-evaluation-of-prednisolone-sr-formulations-designed\/","title":{"rendered":"Pharmcokinetic Evaluation of Prednisolone SR Formulations Designed"},"content":{"rendered":"

Introduction<\/strong><\/p>\n

Prednisolone is a corticosteroid anti-inflammatory, analgesic agent used in treatment of inflammatory diseases1<\/sup>. It is indicated for the treatment of primary or secondary adrenocortical insufficiency such as congenital adrenal hyperplasia and thyroiditis2<\/sup>. Prednisolone is a poorly water soluble drug. There are several reports 3-6 <\/sup>on the development of oral sustained release formulations of prednisolone.<\/p>\n

The design of sustained release formulations of water in
\nsoluble drugs is always difficult because in the absence of rapid dissolution of the drug, \u00a0the release of the drug from the formulated product such as a matrix tablet is controlled more by the dissolution of the drug than by the nature of the polymer employed. It is common with oral sustained release formulations of poorly water soluble drugs that they show incomplete release from hydrophilic polymeric matrix systems.\u00a0 In a previously published research paper7<\/sup>, we reported the development of a sustained release matrix tablets of prednisolone. \u00a0In\u00a0 that work, \u00a0the dissolution rate of the drug was enhanced by solid dispersion and this dispersion was employed in the designing of matrix tablets to get faster release compared to that of matrix tablet which contained only the pure drug.<\/p>\n

In this present study, the developed matrix tablet was subjected to in vivo pharmacokinetic evaluation in rabbits in comparison with that of pure drug and the drug solutionis \u00a0employed as reference standard.<\/p>\n

Materials and Methods<\/strong><\/p>\n

Materials <\/strong><\/p>\n

Prednisolone pure drug\u00a0 was obtained as a gift sample from M\/s. Cipla Ltd. , Mumbai ; Ethyl acetate, Isoamyl alcohol, Hexane, Perchloric acid, Tetrahydrofuran and Water \u2013 all the chemicals are of HPLC grade.<\/p>\n

The pharmacokinetic evaluation was done on the following products.<\/p>\n

Prednisolone solution ( a solution of prednisolone in alcohol at 2 mg \/ ml concentration) Prednisolone pure drug Prednisolone SR formulation containing the more dissolving dispersion ( Pr : PVP at 1: 3 ratio )<\/p>\n

The in vivo experiments were carried out in healthy rabbits as per the following experimental design and protocol. The protocol was approved by the IAEC.<\/p>\n

Experimental Design<\/strong><\/p>\n

A crossover randomized block design ( RBD ) in which four rabbits each weighing 3.5 \u2013 4.0 kg \u00a0received one treatment ( product ) each every 15 days such that all the product are tested in all the four rabbits during the study. Thus, each treatment is replicated four times.<\/p>\n

In Vivo Study Protocol<\/strong><\/p>\n

Rabbits weighing between 3.5-4.0 \u00a0kg of either sex were used. They were fed on uniform diet. In the experiments, 18 hours fasted rabbits were used. The rabbits were not given food during the experiment, however they had free access to water.<\/p>\n

After collecting the zero hour blood sample (blank), the product involved in the study was administered orally employing Ryle\u2019s tube ( intubation tube )\u00a0 at a dose equivalent to 2.0 mg of prednisolone. After administration 2 ml blood samples were collected from the marginal ear vein at 0.5, 1.0. 2.0, 3.0, 4.0 , 6.0, 8.0, 10.0 12.0, 18.0, and 24.0 hrs after administration of the product. The blood samples were centrifuged at 5,000 rpm and the serum separated was collected into dry tubes and stored under refrigerated conditions till assayed. Prednisolone content of the serum samples was determined by a known HPLC reported previously8<\/sup>. The serum prednisolone concentrations were calculated from a standard calibration graph. \u00a0From the time versus serum concentrations data, various pharmacokinetic parameters such as peak concentration ( Cmax<\/sub> ), time at which peak concentration resulted ( Tmax<\/sub>\u00a0\u00a0 ), area under curve ( AUC ), elimination rate constant ( Kel<\/sub> ), biological half life (\u00a0 t1\/2<\/sub> ), percent absorbed to various times, the absorption rate constant ( Ka<\/sub> ), and mean residence time ( MRT ) were calculated in each case.<\/p>\n

Estimation of Prednisolone in serum samples<\/strong><\/p>\n

Chromatographic Conditions<\/strong><\/p>\n

\u00a0<\/strong>The chromatographic system consisted of a Model Agilent 1120 compact LC; samples were chromatographed at room temperature on a reversed phase C18 <\/sub>column (\u00a0\u00a0\u00a0 Qualisil BDS CB, 150 X 4.6 mm, 5 \u00b5m \u00a0). The mobile phase consisting of (20: 80 v\/v) tetrahydrofuran and water was used at a flow rate of 1.0 ml \/ min and the pressure was approximately 240 kg \/ sq.cm. Ultraviolet absorption was measured at 250 nm using\u00a0\u00a0\u00a0 Agilent variable wavelength detector.<\/p>\n

Procedure <\/strong><\/p>\n

Prednisolone was isolated from 1.0 ml of\u00a0 human serum via precipitation with perchloric acid ( 60%), followed by liquid \u2013 liquid extraction with 5.0 ml of ethyl acetate: hexane : isoamyl alchol ( 80:19:1 v\/v ). The samples were vortexed for 60 seconds and then centrifuged at 10,000 rpm for 10 minutes at room temperature. The supernant is then transferred to 16 mm x 150 mm test tune and mixed with 5.0 ml of ethyl acetate : hexane : isoamyl alcohol( 80:19:1 v\/v ). After shaking samples for 45 to 60 seconds and centrifuging at 3200 rpm for 10 minutes, the organic layer was transferred to a clean 13 m x 100 mm test tube and evaporated to dryness at 40 o<\/sup> C . The samples were then reconstituted with the mobile phase and 20 \u00b5l was injected into the HPLC column.<\/p>\n

\u00a0<\/strong>Results and Discussion<\/strong><\/p>\n

The elimination rate constant Kel<\/sub> for prednisolone was found to be\u00a0\u00a0\u00a0 0.29 hr -1<\/sup>\u00a0and the corresponding biological half life t1\/2<\/sub>\u00a0\u00a0 was found to be\u00a0\u00a0\u00a0\u00a0 2.41\u00a0\u00a0 hrs. following the administration of prednisolone as a solution. The t1\/2<\/sub>\u00a0\u00a0 value obtained in the present work is in good agreement with the earlier reported value of\u00a0\u00a0 2-4\u00a0 hours 9<\/sup> . The plasma concentration vs time profile obtained with different prednisolone products administered is shown in Fig.1 and the summary of the pharmacokinetic parameters is given in Table 1.<\/p>\n\n\n\n
\"Figure<\/td>\nFigure 1 : Serum Concentrations of prednisolone following its oral administration as solution (\u2666), SR formulation (\u25a0) and as pure drug (\u25b2).<\/strong><\/p>\n

 <\/p>\n

Click here to View figure<\/a><\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

 <\/p>\n\n\n\n
\u00a0\"Table<\/td>\n\n

Table 1: Summary of Pharmacokinetic Parameters of Prednisolone after administration as solution, SR formulation and as pure drug.<\/strong><\/p>\n

Click here to View table<\/a><\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

 <\/p>\n

Application\u00a0 of Wagner \u2013 Nelson method to the serum concentrations data indicated a very rapid absorption of prednisolone given orally in solution\u00a0 form. The absorption rate constant Ka<\/sub> is found to be\u00a0\u00a0 2.81 \u00b1 0.327\u00a0 hr-1<\/sup>\u00a0\u00a0 and in one hour\u00a0\u00a0 87.67 \u00a0\u00b1 0.425 \u00a0% was absorbed. Peak serum concentration of\u00a0 4.15 \u00b1 0.253 \u00b5g\/ml\u00a0 was observed at 1 hour after administration and latter the concentrations declined rapidly.<\/p>\n

Whereas when prednisolone was administered as pure drug there is found to be very low rate of absorption as evidenced \u00a0by the low Ka<\/sub> value (0.027 \u00b1 0.148\u00a0 hr-1<\/sup> ) and at the end of 4 hours, only\u00a0 37 \u00b1 0.661 % of drug was found to be absorbed. When prednisolone SR formulation was administered, serum concentrations were found to be intermediate between that of when solution form and the pure drug powder were given. For example, the peak prednisolone concentration was found to be\u00a0\u00a0 1.45\u00b1 0.897\u00a0\u00a0 \u00b5g\/ml. Application of Wagner \u2013 Nelson method to the serum concentration data indicated slow absorption of prednisolone from the SR products compared to that from the solution \u00a0but at the same time the absorption rate is found to be higher than that obtained with pure drug. From the SR formulation the absorption rate constant Ka<\/sub> is found to be 0.287 \u00b1 0.0.291 hr-1<\/sup> which is 10\u00a0 fold lower than the absorption rate constant observed with the solution form but it is found to be higher by\u00a0 10.6\u00a0 fold when compared to that \u00a0of pure drug. This goes to prove that the prednisolone bioavailability from the SR formulations employing the more dissolving solid dispersion form is higher that that of pure drug.<\/p>\n

Additionally it is also evident that the prednisolone concentrations were stabilized and maintained over a narrow range and for longer periods of time in the case SR products. For example the serum concentrations were maintained in the range of\u00a0 0.8 -1.0 \u00b5g\/ml during the period 1-11 hrs with the SR formulations. The mean residence time ( MRT ) was found to increase from\u00a0 4.66 \u00b1 0.345 hrs \u00a0 for prednisolone solution to\u00a0\u00a0 9.64 \u00b1 0.455\u00a0 hrs with \u00a0the SR formulation.\u00a0 SR formulation showed a relative bioavailability of 92.25% ( AUC \u2013 20.67 \u00b5g-hr\/ml ) when compared to prednisolone solution taken as 100% whereas when prednisolone pure drug was administered, the AUC value is found to be only 7.6 \u00b5g-hr\/ml.<\/p>\n

Conclusion<\/strong><\/p>\n

Thus the results of the pharmacokinetic studies carried out on the SR formulation of prednisolone developed by employing the solid dispersions of prednisolone indicated the drug was released and absorbed over longer periods of time which in turn maintained the serum concentrations within a narrow range for extended periods of time. \u00a0Thus the present in vivo\u00a0 study corroborates the usefulness of the approach of employing solid dispersions of prednisolone in designing formulations ( as reported in our previous communications ) for sustained release of prednisolone.<\/p>\n

Acknowledgement<\/strong><\/p>\n

The authors express their sincere gratitude to the management of Aditya Academy, Kakinada,\u00a0 for the facilities provided to carry out the research work<\/p>\n

Refrencess<\/strong><\/p>\n

    \n
  1. Paul-Clark, M.J., Mancini, L. and \u00a0Del Soldato P. \u201cPotent antiarthritic properties of a glucocorticoid derivative, NCX-1015, in an esperimental model of arthritis\u201d. Proc. Nat. Acad. Sci. USA, \u00a099<\/strong>,\u00a0 1677-1682,\u00a0 (2002)<\/li>\n
  2. Drug Bank – Drug Bank Category Browser. URL: redpoll.pharmacy.ualberta.ca\/drugbank\/cat_browse.htm. (2006)<\/li>\n
  3. Chen JH, \u00a0and Shagufta M, \u00a0\u00a0\u201cPreparation and characterization of prednisolone-poly (hydroxybutyrate-co-hydroxyvalerate) \u00a0nanoparticles\u201d. 37(6), <\/strong>473-6,\u00a0 2002<\/li>\n
  4. Shinya,\u00a0S, Teruko\u00a0.I and Masaki\u00a0O. (1994) \u201cThe Controlled Release of Prednisolone Using Alginate Gel.\u201d Pharmaceutical Research, 11<\/strong>, \u00a0272 \u2013 277, (1994)<\/li>\n
  5. Rao, VM, \u00a0Haslam J.L and Stella V.J. \u201c Controlled and complete release of a model poorly water-soluble drug, prednisolone, from hydroxypropyl methylcellulose matrix tablets using (SBE)(7m)-beta-cyclodextrin as a solubilizing agent\u201d. J Pharm Sci.; 90(7), <\/strong>807-16, (2001)<\/li>\n
  6. Di Colo G,, Baggiani A, and Zambito Y, \u201c A new hydrogel for the extended and complete prednisolone release in the GI tract.\u201d\u00a0 Int J Pharm., \u00a0310(1-2), <\/strong>\u00a0154-61. (2006.)<\/li>\n
  7. Ramesh K.V.R.N.S., Ravishankar,K and Bharathi A.\u00a0 \u201c<\/strong>Design and in vitro evaluation of controlled release matrix tablets of prednisolone,\u201d \u00a0Int.J.Chem.Sci., 5(3),<\/strong> 1053-1072,\u00a0 (2007)<\/li>\n
  8. Scott Penzak, R and \u00a0Elizabeth, <\/strong>T. \u201c<\/strong>Prednisolone pharmacokinetics in the presence and absence o fritonavir after oral prednisolone administration to healthy volunteer\u201d , J Acquir Immune Defic Syndr. ,40(5)<\/strong>,\u00a0 573-580.,(2005)<\/li>\n
  9. Med Safe \u2013 Information for health care professionals URL :http:\/\/www.medsafe.govt.nz\/profs\/Datasheet\/a\/Apoprednisonetab.htm, (2007)<\/li>\n<\/ol>\n

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    Introduction Prednisolone is a corticosteroid anti-inflammatory, analgesic agent used in […]<\/p>\n","protected":false},"author":2,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[7],"tags":[],"class_list":["post-895","post","type-post","status-publish","format-standard","hentry","category-vol2no2"],"_links":{"self":[{"href":"https:\/\/biomedpharmajournal.org\/staging\/wp-json\/wp\/v2\/posts\/895","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/biomedpharmajournal.org\/staging\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/biomedpharmajournal.org\/staging\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/biomedpharmajournal.org\/staging\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/biomedpharmajournal.org\/staging\/wp-json\/wp\/v2\/comments?post=895"}],"version-history":[{"count":5,"href":"https:\/\/biomedpharmajournal.org\/staging\/wp-json\/wp\/v2\/posts\/895\/revisions"}],"predecessor-version":[{"id":33029,"href":"https:\/\/biomedpharmajournal.org\/staging\/wp-json\/wp\/v2\/posts\/895\/revisions\/33029"}],"wp:attachment":[{"href":"https:\/\/biomedpharmajournal.org\/staging\/wp-json\/wp\/v2\/media?parent=895"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/biomedpharmajournal.org\/staging\/wp-json\/wp\/v2\/categories?post=895"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/biomedpharmajournal.org\/staging\/wp-json\/wp\/v2\/tags?post=895"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}