4. review article vikashdash


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4. review article vikashdash

  1. 1. Journal of Current Pharmaceutical Research 2011; 5 (1): 28-31JCPR 2011; 5 (1): 28-31© 2010 Medipoeia Role of Biopharmaceutical Classification System InReceived: 03-09-2011Revised: 04-09-2011 Drug Development ProgramAccepted: 6-09-2011 Vikash Dash* and Asha Kesari ABSTRACT Bioavailability (BA) and bioequivalence (BE) play a central role in pharmaceutical product development. The tenets of biopharmaceutics, solubility and permeability, are of pivotalVikash Dash* and Asha Kesari importance in new drug discovery and lead optimization due to the dependence of drug absorptionDepartment of Pharmaceutics and pharmacokinetics. Biopharmaceutical classification system (BCS) is based on solubility tests;Kanak Manjari Institute of for various drugs they correlate with their bioavailability in human body. It is widely used inPharmaceutical Sciences, Chhend,Rourkela: 769015, Orissa, design and development of innovation drugs, new dosage forms (permeability amplifiers), inIndia clinical pharmacology (drug-drug, drug-food interaction) and also by regulation agencies of several countries as the scientific approach, for testing of waiver on bioavailability. The present review considers the concept of biopharmaceutical classification system and its role in drug development program. It gives a brief idea on the future application of BCS in drug entity. Keywords: Bioavailability, biopharmaceutical classification system, solubility, permeability, drug development. 1. INTRODUCTION The Biopharmaceutical classification system (BCS) is a useful tool for decision making in the discovery and early development of new drug (Ku M. S., 2008).During the drug development process, the importance is given to its bioavailability and bioequivalence which determines the internal drug absorption provided by U. S. Food & Drug Administration(Waterbeemd H. V. and Testa B., 2009). BCS is based on scientific framework describing three rate limiting steps in oral absorption. The three necessary steps for a drug to be absorbed are (1) release of drug from dosage forms; (2) maintenance of dissolved state through Gastro-intestinal (G.I) tract; (3) permeation through G.I. membrane into hepatic circulation. The BCS became a benchmark in the regulation of bioequivalence of oral drug products (Meyer M.C et al, 1992) and it was first devised in 1995, (Amidon et al, 1995) . Since its inception in 1995, the BCS has become an increasingly important tool for regulation of drug products worldwide (FDA Guidelines, 1997). Until now, application of BCS has been partially hindered by the lack of a freely available and accurate database summarising solubility and permeability characteristics of drug substances. Thus the knowledge of BCS help the formulation scientist to develop a dosage form based on mechanistic rather than empirical approaches (FDA Guidelines, 2000). The aim of this review is to present the status of BCS and discuss its future application in pharmaceutical drug development. CONCEPT BEHIND BCSCorrespondence:Mr. Vikash Dash The in-vivo performance of orally administered drugs depends upon their solubility andDepartment of Pharmaceutics tissue permeability characteristics. The release rate or solubility of the drug substance will not be aKanak Manjari Institute of governing parameter if the absorption of the drug is permeation rate limited and in such cases the in-Pharmaceutical Sciences, Chhend,Rourkela: 769015, Orissa, India vitro dissolution study can be used to demonstrate the bioavailability (BA) or bioequivalence (BE) ofE-mail:-vikdash@gmail.com, the drug product through in vitro - in vivo correlation (IVIVC). On the other hand if absorption of the ashakeshri@yahoo.co.in drug is dissolution rate limited that means the drug in the gastrointestinal fluid passes freely through theMob: 09178140373, 09437502189 bio-membranes at a rate higher than it dissolves or is released from the dosage form. The specifically
  2. 2. Journal of Current Pharmaceutical Research 2011; 5 (1): 28-31designed in-vivo study will be required in such a case, to access the  Absorption number (An), defined as the ratio of the meanabsorption rate, and hence its bioavailability and to demonstrate the residence time to mean absorption time.bioequivalence ultimately. Such a drug substance is a good  Dissolution number (Dn), defined as the ratio of mean residence time to mean dissolution time.candidate for controlled delivery provided they qualify in terms of  Dose number (D0), defined as the mass divided by the producttheir pharmacokinetics and pharmacodynamics for controlled of uptake volume (250 ml) and solubility of drugrelease development. Also if a drug itself is having low solubilityand a slow dissolution rate, the release will automatically get Extension to BCS: (BCS Containing Six Classes)slower and the dosage form need not have an inbuilt release Bergstrom et al. in 2003 devised a modifiedretardation mechanism, rather the absorption will now be governed Biopharmaceutical Classification System, in which theyby the gastric emptying rate. Therefore, the dosage form must be categorized the drugs into six classes based on the solubility andable to restrain within the absorption window for a sufficient time permeability. The solubility was classified as "high" or "low" andso that absorption can take place. In such case, a hydrodynamically the permeability was allotted as "low", "intermediate," or "high".balanced (floating) system or a mucoadhesive dosage form will This new classification was developed based on the calculatedserve the purpose. Hence the BCS can work as a guiding tool for surface area descriptors on the one hand and solubility andthe development of various oral drug delivery technologies permeability on the other. Surface areas related to the nonpolar part(Johnson S.R.and Zheng Weifan, 2006). of the molecule resulted in good predictions of permeability. It was tentatively concluded that these models would be useful for earlyCLASSIFICATION OF BCS indication with regard to the absorption profiles of the compoundAccording to BCS, drug substances are classified as (Figure 1): during the early stages of drug discovery so that the necessary modifications can be made to optimize the pharmacokineticClass I drugs parameters (Bergstrom C. A et al, 2003).These exhibit a high absorption number and a high dissolution CLASS BOUNDARIES USED IN BCSnumber. The rate limiting step is drug dissolution and if dissolutionis very rapid then gastric emptying rate becomes the rate  A drug substance is considered HIGHLY SOLUBLE whendetermining step. e.g. Metoprolol, Diltiazem, Verapamil, the highest dose strength is soluble in ≤250 ml water over a pHPropranolol. range of 1 to 7.5.Class II drugs  A drug substance is considered HIGHLY PERMEABLE when the extent of absorption in humans is determined to be ≥These drugs have a high absorption number but a low dissolution 90% of an administered dose, based on mass-balance or innumber. In vivo drug dissolution is then a rate limiting step for comparison to an intravenous reference dose.absorption except at a very high dose number. The absorption for  A drug product is considered to be RAPIDLY DISSOLVINGclass II drugs is usually slower than class II and occurs over a when ≥ 85% of the labelled amount of drug substance dissolveslonger period of time. In vitro- In vivo correlation (IVIVC) is within 30 minutes using USP apparatus I or II in a volume of ≤usually excepted for class I and class II drugs. e.g. Phenytoin, 900 ml buffer solutions.Danazol, Ketoconazole, Mefenamic acid, Nifedinpine.For Class III drugs APPLICATION OF BCSHere permeability is rate limiting step for drug absorption. These BCS is widely used in design and development ofdrugs exhibit a high variation in the rate and extent of drug innovation drugs, new dosage forms (Permeability amplifiers), inabsorption. Since the dissolution is rapid, the variation is clinical pharmacology (drug-drug, drug-food interaction) and alsoattributable to alteration of physiology and membrane permeability by regulation agencies of several countries as the scientificrather than the dosage form factors. e.g. Cimetidine, Acyclovir, approach, for testing of waivers on bioavailability. Given belowNeomycin B, Captopril. the application of BCS in different fields:Class IV drugs 1. Application of BCS in Oral Drug Delivery TechnologyThese drugs exhibit a lot of problems for effective oral Once the solubility and permeability characteristics of theadministration. Fortunately, extreme examples of class IV drug are known it becomes an easy task for the research scientist tocompounds are the exception rather than the rule and are rarely decide upon which drug delivery technology to follow or develop.developed and reach the market. Nevertheless a number of class IV Class-I Drugsdrugs do exist e.g. Taxol.This classification is associated with drug dissolution and The major challenge in development of drug delivery system forabsorption model, which identifies the key parameters controlling class I drugs is to achieve a target release profile associated with adrug absorption as a set of dimensionless numbers viz. particular pharmacokinetic and/or pharmacodynamics profile.
  3. 3. Journal of Current Pharmaceutical Research 2011; 5 (1): 28-31Formulation approaches include both control of release rate and i. Selecting a route of experimentation.certain physicochemical properties of drugs like pH-solubility ii. Clinical development.profile of drug. iii.Improvement of Bioadhesive system if the drug is absorbed from the selective area of the intestine.Class-II Drugs According to Lipinski et al. (1997), ‘a rule of 5’ is widely adoptedThe systems that are developed for class II drugs are based on for screening of compounds that are likely to have poor absorptionmicronisation, lyophilization, and addition of surfactants, profiles. According to this rule the poor absorption or permeationformulation as emulsions and microemulsions systems and use of is more likely when: (Lipinski et al., 1997)complexing agents like cyclodextrins. • There are more than five H-bond donors (expressed as aClass-III Drugs sum of hydroxyl and N-H linkage).Class III drugs require the technologies that address to fundamental • The molecular weight of the drug moiety is more than 500limitations of absolute or regional permeability. Peptides and • The log P is over %proteins constitute the part of class III and the technologies • There are more than 10 H-bond acceptorshandling such materials are on rise now days. Compounds that are substrates for the biological transporters are anClass-IV Drugs exception to the rule.Class IV drugs present a major challenge for development of drug FUTURE PROSPECT OF BCSdelivery system and the route of choice for administering such The future application of the BCS is most likelydrugs is parenteral with the formulation containing solubility increasingly important when the present framework gainsenhancers. increased recognition, which will probably be the case if the BCS2. Application of BCS in New Drug Application (NDA) and borders for certain class II and III drugs are extended. The futureAbbreviated New Drug Application (ANDA) revision of the BCS guidelines by the regulatory agencies in communication with academic and industrial scientists is exciting The principles of the BCS classification system can be and will hopefully result in an increased applicability in drugapplied to NDA and ANDA approvals as well as to scale-up and development. Finally, we emphasize the great use of the BCS as apost approval changes in drug manufacturing. A waiver of In-vivo simple tool in early drug development to determine the rate-Bioavailability and Bioequivalence studies based on the BCS limiting step in the oral absorption process, which has facilitatedclassification can therefore save pharmaceutical companies a the information between different experts involved in the overallsignificant amount of development time and reduce development drug development process. This increased awareness of a propercosts biopharmaceutical characterization of new drugs may in the future(http://www.fda.gov/AboutFDA/CentersOffices/cder/ucm128219.h result in drug molecules with a sufficiently high permeability,tm). solubility and dissolution rate, and that will automatically increase3. Application of BCS in optimization of new chemical entity the importance of the BCS as a regulatory tool over time The pharmacokinetic idea of new chemical entity which is (Lennernäs H. et al, 2005).already synthesized or identified and has therapeutic value but still CONCLUSIONunder investigation for formulation development and final approval Poor solubility and poor permeability account for manycan be provided by BCS. The BCS provide an opportunity to the pharmacokinetic failures and about thirty percent of drugsynthetic chemist to manipulate in the chemical structure in the molecules are rejected due to pharmacokinetic failures. When poorchemical entity in order to optimize the physicochemical properties pharmaceutical properties are discovered in development, the costof lead molecule for desired delivery and targeting through High of bringing a potent, but poorly absorbable molecule to the productThroughput Pharmaceutics (HTP).( Jorgensen W. L. et al, 2002 stage by formulation can become very high. Fast and reliable inand Lobel L. M. et al, 2003) vitro prediction strategies are needed to filter out problematic4. Application of BCS for pharmacological screening molecules at the earliest stage of discovery. This communication Pharmaceutical drug discovery and delivery groups are will consider recent developments in physiochemical profiles used to identify molecules with physical properties related to good oralusing Human Drug Absorption (HDA) studies for understanding absorption. FDAs biopharmaceutical classification system (BCS)the biopharmaceutical properties of early drug candidates. is an attempt to rationalize the critical components related to oralHDA provides significant guidance to a pharmaceitcal formulation absorption and utilization of these principles for selection of ascientist in:- suitable technology to serve the interests of the early stages of drug discovery.
  4. 4. Journal of Current Pharmaceutical Research 2011; 5 (1): 28-31Figure-1: Biopharmaceutical Classification System of Drugs Class II Class I Low solubility High solubility High permeability High permeability e.g. Phenytoin, Danazol e.g. Metoprolol, Diltiazem Permeability Class IV Class III Low solubility High solubility Low permeability Low permeability e.g. Taxol e.g. cimetidine, neomycin SolubilityREFERENCES Lennernäs H., Abrahamsson B. The use of biopharmaceutical Amidon G.L., Lennernas H., Shah V.P., Crison J. R. A theoretical basis classification in drug discovery and development: current status and futurefor a biopharmaceutic drug classification: the correlation of in vitro drug product extension. J. Pharm. Pharmacol. 2005; 57(3): 273-85.dissolution and in vivo bioavailability. Pharm. Res. 1995; 12 (3): 413–20 Lipinsky C. A., Lombordo F., Dominy B. W., Feeney P. J. Experimental Bergstrom C. A., Strafford M., Lazorova L., Avdeef A., Luthman K., and computational approaches to estimate solubility and permeability in drugArtursson P. Absorption classification of oral drugs based on molecular surface discovery and development settings. Adv. Drug. Deliv. Rev. 1997; 23:3-26.properties. J. Med. Chem. 2003; 46:558-70. Lobel L. M., Sivrajah V. Silico prediction of aqueous solubility, human Center for drug evaluation, FDA "Guidance for Industry on Dissolution plasma protein binding and volume of distribution of compounds from calculatedTesting of Immediate Release Solid Oral Dosage forms" 1997. pKa and AlogP98 values. Mol. Divers 2003; 7:69-87. Center for drug evaluation, FDA "Guidance for Industry on the Waiver Meyer M.C., Straughn A.B., Jarvi E.J., Wood G.C., Pelsor F.R., Shahof in vivo Bioavailability and Bioequivalence for Immediate Release Solid Oral V.P., The bioinequivalence of carbamazepine tablets with a history of clinicalDosage forms based on Biopharmaceutical Classification system" 2000. failures. Pharm. Res. 1992; 9: 1612-1616. Johnson S.R., Zheng Weifan. Recent progress in computational NIa Golovenko and IIu Borisiuk. Biopharmaceutical classificationprediction of aqueous solubility and absorption. AAPS J. 2006; 8:E27-40. system--experimental model of the prediction of drug bioavailability. Biomed Jorgensen W. L., Duffy E. M.. Prediction of drug solubility from khim.2008; 54(4):392-407.structure. Adv. Drug Deliv. Rev. 2002; 54:355-66. Waterbeemd H. V. and Testa B. Drug Bioavailability: Estimation of Ku. M S. Use of the Biopharmaceutical Classification System in Early Solubility, Permeability, Absorption and Bioavailability. 2nd ed. Wiley-VCHDrug Development. The AAPS J. 2008; 10(1):208-12. publisher, Weinheim (2009).