CHAPTER 1 INTRODUCTION

CHAPTER 1 INTRODUCTION

1.1 Intrductin t tpic Biavailability is cnsidered t be ne f the mst imprtant pharmackinetic parameters f any drug develped fr extra vascular administratin. Oral biavailability is a relative term used t describe the rate and extent f absrptin after ral administratin f a drug cmpared t that after its administratin via a reference rute, usually blus injectin. Biavailability has n unit ften it is expressed as percentage. Fr any drug t elicit its pharmaclgical respnse, it s very necessary t becme available t bdy that is it has t reach in the bld.oral dsing is the mst cmmn rute fr the administratin f drugs and mst f the drugs given rally are generally designed t shw systemic pharmaclgical efficiency rather than lcal effects in the gastrintestinal tract. Fr drugs rally dsed in slid dsage frms such as tablets r capsules, there are tw distinctive prcesses during absrptin: disslutin f slid drug particles t drug mlecules in the GI fluid and permeatin f the drug mlecules acrss intestinal membranes. Depending n the relative magnitude f the rates f theses tw prcesses, ne f them can be rate-limiting in verall drug absrptin. 1-3 Rate limiting steps in ral drug absrptin Disslutin rate limited absrptin Permeatin rate limited absrptin Figure 1.1 Rate limiting steps in ral absrptin 1.2 Bipharmaceutics Classificatin System Drug absrptin in the gastrintestinal tract is influenced by a variety f physicchemical, prduct related and physilgical factrs. SPTM, SVKM S, NMIMS, MUMBAI 1

The bipharmaceutics classificatin system (BCS) is a drug develpment tl fr the estimatin f the cntributins f three majr factrs, slubility, disslutin and intestinal permeability, affecting ral drug absrptin frm immediate release (IR) slid ral prducts. The system was develped t prvide a scientific apprach t predict in viv drug prduct perfrmance frm in vitr assays f ral IR prducts by classifying drugs based n their dse related slubility and intestinal permeability in cmbinatin with disslutin prperties f the dsage frm. 4,5,6,7 Accrding t the Bipharmaceutics Classificatin System, drug substances are classified as fllws: Class I High permeability, High Slubility Example: Metprll Thse cmpunds are well absrbed and their absrptin rate is usually higher than excretin. Class II High Permeability, Lw Slubility Example: Gibenclamide The biavailability f thse prducts is limited by their slvatin rate. A crrelatin between the in viv bivailability and the in vitr slvatin can be fund. Class III Lw Permeability, High Slubility Example: Cimetidine The absrptin is limited by the permeatin rate but the drug is slvated very fast. If the frmulatin des nt change the permeability r gastr-intestinal duratin time, then class I criteria can be applied. Class IV Lw Permeability, Lw Slubility Example: Hydrchlrthiazide Thse cmpunds have a pr biavailability. The drugs are classified in BCS n the basis f fllwing parameters 1. Slubility 2. Permeability 3. Disslutin SPTM, SVKM S, NMIMS, MUMBAI 2

The class bundaries fr these parameters are 1. Slubility class bundaries- It is based n the highest dse strength f an immediate release prduct. A drug is cnsidered highly sluble when the highest dse strength is sluble in 250 ml r less f aqueus media ver the ph range f 1 t 7.5. The vlume estimate f 250 ml is derived frm typical biequivalence study prtcls that prescribe administratin f a drug prduct t fasting human vlunteers with a glass f water. 2. Permeability class bundaries- It is based indirectly n the extent f absrptin f a drug substance in humans and directly n the measurement f rates f mass transfer acrss human intestinal membrane. Alternatively nn-human systems capable f predictin the drug absrptin systems capable f predicting the drug absrptin in humans can be used (such as in-vitr culture methds). A drug substance is cnsidered highly permeable when the extent f absrptin in humans is determined t be 90 % r mre f the administered dse based n a mass-balance determinatin r in cmparisn t intravenus dse. 3. Disslutin class bundaries- An immediate release prducts is cnsidered rapidly disslving when n less than 85% f the labeled amunt f the drug substance disslve within 30 minutes using USP Disslutin Apparatus 1 at 100 RPM r Apparatus 2 at 50 RPM in a vlume f 900ml r less in fllwing media s such as 0.1 N HCl r simulated gastric fluid r ph 4.5 buffer and ph 6.8 buffer r simulated intestinal fluid. 8,9 Figure 1.2 Bipharmaceutical Classificatin System f drugs (Surce Wikipedia) SPTM, SVKM S, NMIMS, MUMBAI 3

1.3 Imprtance f biavailability It is imprtant fr any drug t reach systemic circulatin fr eliciting desired pharmaclgical respnse, s sufficient biavailability is imprtant fr getting desired therapeutic actin frm the drug. Figure 1.3 ADME pattern f drugs (Surce Wikipedia) 1.4 Basics abut Biavailability and absrptin 1.4.1 Types f biavailability 10 Abslute biavailability Abslute biavailability cmpares the biavailability f the active drug in systemic circulatin fllwing nn-intravenus administratin (i.e., after ral, rectal, transdermal, subcutaneus, r sublingual administratin), with the biavailability f the same drug fllwing intravenus administratin. It is the fractin f the drug absrbed thrugh nn-intravenus administratin cmpared with the crrespnding intravenus administratin f the same drug. The cmparisn must be dse nrmalized (e.g. accunt fr different dses r varying weights f the subjects); cnsequently, the amunt absrbed is crrected by dividing the crrespnding dse administered. In pharmaclgy, in rder t determine abslute biavailability f a drug, a pharmackinetic study must be dne t btain a plasma drug cncentratin vs time plt fr the drug after bth intravenus (IV) and nn-intravenus administratin. The abslute biavailability is the dse-crrected area under curve (AUC) nn-intravenus SPTM, SVKM S, NMIMS, MUMBAI 4

divided by AUC intravenus. Fr example, the frmula fr calculating F fr a drug administered by the ral rute (p) is given belw. 1.1 Relative biavailability In pharmaclgy, relative biavailability measures the biavailability (estimated as the AUC) f a certain drug when cmpared with anther frmulatin f the same drug, usually an established standard, r thrugh administratin via a different rute. When the standard cnsists f intravenusly administered drug, this is knwn as relative biavailability. 1.2 1.4.2 Factrs affecting biavailability Biavailability Pharmaceutical factrs Patient related factrs Physicchemical prperties f drug substance Dsage frm characteristics and pharmaceutical ingredients Figure 1.4 Factrs affecting biavailability SPTM, SVKM S, NMIMS, MUMBAI 5

A. Phamaceutical factrs Includes factrs relating t the physicchemical prperties f the drug and dsage frm characteristics and pharmaceutical ingredients I. Physicchemical prperties f drug substances 1. Drug slubility and disslutin rate 2. Particle size and effective surface area 3. Plymrphism and amrphism 4. Pseud plymrphism(hydrates/slvates) 5. Salt frm f the drug 6. Lipphilicity f the drug 7. pka f the drug and ph 8. Drug stability II. Dsage frm characteristics and pharmaceutical ingredients 1. Disintegratin time 2. Disslutin time 3. Manufacturing variables 4. Pharmaceutical ingredients 5. Nature and type f dsage frm 6. Prduct age and strage cnditins B. Patient related factrs Includes factrs relating t the anatmical, physilgical and pathlgical characteristics f the patient 1. Age 2. Gastric emptying time 3. Intestinal transit time 4. Gastrintestinal ph 5. Disease states 6. Bld flw thrugh the GIT SPTM, SVKM S, NMIMS, MUMBAI 6

7. Gastrintestinal cntents: ther drugs, fd, fluids, ther GIT cntents 8. Presystemic metablism: By lumenal enzymes, gut wall enzymes, bacterial enzymes, hepatic enzymes 11 1.5 Prblems due t lw biavailability Majr prblems due t lw biavailability are High dse requirement fr getting desired level f drug in the bdy Increased cst Increased side effects Increased dsing frequency Lw patient cmpliance Enhancement f biavailability leads t Imprved clinical prfiles and patient cmpliance Prducts with a mre rapid nset f actin Imprved dse prprtinality Minimized fd effect and/r gastric irritatin Reduced intra- and inter-subject variability Significant reductin in dse while maintaining therapeutic efficacy Imprved safety prfiles SPTM, SVKM S, NMIMS, MUMBAI 7

1.4.3 GI physilgy and drug absrptin Table 1.1 GI Physilgy and Drug Absrptin 12 ph Membrane Bld Supply Surface Area Transit Time By-pass liver BUCCAL Gd, fast apprx 6 thin absrptin with lw small Shrt unless cntrlled yes dse ESOPHAGUS Very thick, 6 n - small shrt - absrptin STOMACH 1-3 30-40 decmpsitin, weak acid nrmal gd small minutes, reduced n uninized absrptin DUODENUM 5-7 very shrt bile duct, surfactant nrmal gd very large (6" lng), windw n prperties effect SMALL very INTESTINE 6-7 nrmal gd large 10-14 ft, 80 abut 3 hurs n cm 2 /cm LARGE INTESTINE 6.8 7 - gd nt very large 4-5 ft lng, up t 24 hr lwer cln, rectum yes SPTM, SVKM S, NMIMS, MUMBAI 8

1.6 Methds fr enhancing biavailability There are varius barriers fr the absrptin f lipphilic drugs such as 13 1. Disslutin and slubilizatin in stmach and intestine 2. Narrw absrptin windw 3. Unstirred water layer 4. Efflux pumps 5. Intrentercyte metablism 6. First pass hepatic metablism Figure 1.5 Barriers fr the mdificatin f lipphilic drugs Biavailability f the lipphilic drugs can be imprved majrly by 1. Enhancing permeability f the drug 2. Enhancing slubility f the drug 3. Bypassing hepatic first pass SPTM, SVKM S, NMIMS, MUMBAI 9

1.7 Aim and bjectives The aim f present research was t enhance the biavailability f a prly sluble antihypertensive drug. Objectives f the present research were 1. Enhancing slubility and disslutin f a prly sluble antihypertensive drug by different appraches 2. In vitr evaluatin f prepared systems 3. Optimizatin f selected systems 4. Accelerated stability testing f ptimized frmulatins 5. In viv evaluatin f ptimized frmulatins SPTM, SVKM S, NMIMS, MUMBAI 10