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Biopharmaceutical classification system.

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Biopharmaceutical classification system.

  1. 1. Biopharmaceutical Classification System By- Smrati Bhardwaj M. Pharma (Pharmaceutics) Swift, School of pharmacy Smrati Bhardwaj M. Pharma (Pharmaceutics) Swift, School of pharmacy
  2. 2. Content  Introduction  Goals of the BSC guidance  Principle  Biopharmaceutical Classification System  Factors affecting on BCS  Class Boundaries used in BCS  Applications of biopharmaceutics classification system  Biowaivers  Advantages of biowaivers  Limitation of BCS 2
  3. 3. Introduction  The biopharmaceutical classification system (BCS) is a new concept in the field of pharmaceutical science and technology  The BCS was first devised in 1995, by Amidon et al. and since then it has become a benchmark in the regulation of bioequivalence of oral drug products  The Biopharmaceutics Classification System (BCS) is a scientific framework for classifying drug substances based on their aqueous solubility and intestinal permeability  It reduce the need for in vivo bioequivalence studies, utilization of in vitro dissolution tests as a surrogate for in vivo bioequivalence studies 3
  4. 4.  The BCS serves as a guiding tool for formulation scientists, for recommending a strategy to improve the efficiency of drug development by proper selection of dosage form and bioequivalence tests, to recommend a class of immediate release (IR) solid dosage  The concept of BCS provides a better understanding of the relationship between drug release from the product and the absorption process  The BCS has also got a place in various guidance documents of regulatory importance 4
  5. 5. Goals of the BSC guidance  To improve the efficiency of drug development and the review process by recommending a strategy for identifying expendable clinical bioequivalence tests  To recommend a class of immediate-release (IR) solid oral dosage forms for which bioequivalence may be assessed based on in vitro dissolution tests  To recommend methods for classification according to dosage form dissolution, along with the solubility and permeability characteristics of the drug substance 5
  6. 6. Principle  The principles of the BCS classification system can be applied to NDA and ANDA approvals as well as to scaleup and post approval changes in drug manufacturing  Therefore, can save significant amount of product development time of pharmaceutical companies and reduces it costs  BCS is a drug development tool that allows estimation of the contributions of three major factors, dissolution, solubility, and intestinal permeability, which affect oral drug absorption from immediate release (IR) solid oral products  Knowledge of BCS helps to the formulation scientist to develop a suitable dosage forms based on mechanistic rather than empirical approaches 6
  7. 7. Principle concept behind BCS  Principle concept behind BCS is that if two drugs products yield the same concentration profile along the gastrointestinal (GI) tract, they will result in the same plasma profile after oral administration. This concept can be summarized by application of Fick’s first in the following equation  J = Pw Cw  Where J is the flux across the gut wall, Pw is the permeability of the gut wall to the drug, and Cw is the concentration profile at the gut wall  In terms of bioequivalence, it is assumed that highly permeable, highly soluble drugs housed in rapidly dissolving drug products will be bioequivalent 7
  8. 8. Biopharmaceutical Classification System  The BCS categorizes drug substances into one of four BCS classes as follows:  Class I: high solubility, high permeability  Class II: low solubility, high permeability  Class III: high solubility, low permeability  Class IV: low solubility, low permeability 8
  9. 9. BCS 9
  10. 10. Factors affecting on BCS  The BCS guidance takes into account three major factors, which govern the rate and extent of drug absorption from immediate release (IR) solid dosage forms  Solubility  Intestinal Permeability  Dissolution 10
  11. 11. Solubility  The solubility is a property of substance by virtue of which it forms mixtures with other substances, which are chemically and physically homogeneous throughout  The degree of solubility is the concentration of the solute in a saturated solution (in equilibrium with solid/drug) at any given temperature  The rate of dissolution and solubility are not the same  The higher single unit dose is completely soluble in 250 ml at pH 1- 6.8 ( 37˚C 11
  12. 12. Determination of solubility  The solubilities are determined by exposing an excess of solid (drug) to the liquid in water/buffer and assaying after equilibrium has been established  It usually takes 60 to 72 hours to establish equilibrium; sampling at earlier points is necessary  The pH solubility profile of the drug is determined at 37 ± 10°C in the aqueous medium, with pH in the range of 1-7.5  A sufficient number of samples should be evaluated, to accurately define the pH solubility profile  A minimum of three replicate determinations of solubility in each pH condition should be carried out  The conc. of the drug substance in the selected buffer or pH condition should be determined using a validated solubility-indicating assay that can distinguish the drug substances from their degradation products 12
  13. 13. Permeability  Permeability along with solubility forms the backbone of BCS that helps in accessing oral absorption of drug molecules  Permeability of the drug to pass the biological membrane which is the lipophilic  Permeability is indirectly based on the extent of absorption of a drug substance  Drug substance is considered to be highly permeable, when the extent of absorption in human determined to be 90% or more of administered drug or compare to in vivo reference dose 13
  14. 14. Determination of permeability  The various methods used for permeability screening are as mentioned below:  Determination of o/w pH partition profile of the drug  Studies of the extent of absorption inhumans - Pharmacokinetic mass balance and absolute bioavailability studies  In vitro permeation studies using excised human or animal intestinal tissue  Intestinal permeability studies - The following tissues can be used: i) In-vivo intestinal perfusion studies in human ii) In-vivo or in-situ perfusion studies in animals 14
  15. 15. Dissolution  It is process in which solid substance solubilises in given solvent i.e mass transfer from solid surface to liquid phase  Using USP apparatus I at 100 rpm or USP apparatus II at 50 rpm  Dissolution Media [900 ml]  0.1 N HCl or simulated gastric fluid (pH 1.2) without enzyme  pH 4.5 buffer & pH 6.8 buffer  Simulated intestinal fluid without enzyme 15
  16. 16. Class Boundaries used in BCS  A drug substance is considered highly soluble when the highest dose strength is soluble in < 250 ml water over a pH range 1 to 7.5  A drug is considered highly permeable when the extent of absorption in humans is determined to be 90% of an administered dose, based on the mass balance or in comparison to an intravenous dose  A drug product is considered to dissolve rapidly when 85% of the labeled amount of drug substance dissolves within 30 minutes, using USP apparatus I or II in a volume of < 900 ml buffer solution 16
  17. 17. IVIVC expectations for IR products based on BCS 17
  18. 18. Class I Drugs These exhibit a high absorption number and a high dissolution number  The rate limiting step is drug dissolution and if dissolution is very rapid then gastric emptying rate becomes the rate determining step  Bioavailability and dissolution is very rapid so bioavailability and bio- equivalency studies are unnecessary for such product.  In vitro- In vivo correlation (IVIVC) cannot be expected  These compounds are highly suitable for design the SR and CR formulations  Examples include Ketoprofen, Propanolol, Metoprolol, Verapamil etc 18
  19. 19. Class II drugs  These have a high absorption number but a low dissolution number  In vivo drug dissolution is then a rate limiting step for absorption except at a very high dose number  These drug exhibited variable bioavailability and need the enhancement in dissolution for increasing the bioavailability  These compounds are suitable for design the SR and CR formulations  In vitro- In vivo correlation (IVIVC) is usually expected for class II drugs  Examples: Phenytoin, Ketoconazole, Mefenamic acid 19
  20. 20. Method of enhancing the dissolution  Micronization (reduced the particle size to increase the surface)  Solvent deposition (deposition of poorly soluble drugs on inert material)  Solid dispersions (dispersion of poorly soluble drugs in a solid matrix of the water soluble carrier)  Use of the surfactants(to increasing the surface area by facilitating proper wetting) 20
  21. 21. Class III drugs  In these drugs permeability is rate limiting step for drug absorption  These drugs exhibit a high variation in the rate and extent of drug absorption  Since the dissolution is rapid, the variation is attributable to alteration of physiology and membrane permeability rather than the dosage form factors  These drugs are problematic for controlled release development  These drugs showed the low bioavailability and need enhancement in permeability  Examples include Acyclovir, Alendronate, Captopril, Neomycin B etc 21
  22. 22. Following permeation enhancers can be used  Synthetics surfactants : SLS, Polysorbate 20 & 80, Sorbitan laurate  Bile Salts: Sodium deoxycholate, Sodium glycocholate, Sodium fusidate  Fatty acids and derivatives: Oleic acid, Caprylic acid, Lauric acid  Chelators: Sod EDTA, Citric acid, Salicylates  Inclusion complexes: Cyclodextrins and derivatives  Mucoadhesive polymers: Chitosan, Polycarbophil 22
  23. 23. Class IV drugs  These exhibit poor and variable bioavailability  Several factors such as dissolution rate, permeability and gastric emptying form the rate limiting steps for the drug absorption  These are unsuitable for controlled release  Examples: Furosemide, Cefuroxime etc 23
  24. 24. Applications of biopharmaceutics classification system  Drug delivery technologies (Class I systems) : The Class I drugs are not those in which either solubility or permeability is limiting within the target regions of the GI tract  The drug release in such cases can be modulated using controlled release technology. Controlled release technologies for Class I drugs includes number of products such as -  Microsphere, MODAS (Multiporous oral drug absorption system)  SCOT (Single composition osmotic tablet system)  CONSURF (constant surface area drug delivery shuttle)  Diamatrix (Diffusion controlled matrix system)  DPHS (Delayed pulsatile hydrogel system) 24
  25. 25.  DUREDAS (Dual release drug absorption system)  GMHS (Granulated modulating hydrogel system)  IPDAS (Intestinal protective drug absorption system)  Multipor, Pharmazone (Microparticle Drug Delivery Technology)  PPDS (Pelletized pulsatile delivery system)  BEODAS (Bioerodible enhanced oral drug absorption system)  PRODAS (Programmable oral drug absorption system)  SODAS (Spheroidal oral drug absorption system)  SMHS (Solubility modulating hydrogel system) and SPDS (Stabilized pellet delivery system) 25
  26. 26. Class II systems:  This class relates to the cases in which solubility or dissolution rate is limiting, and thus significantly affects absorption and BA  The technologies under this class include the approaches such as classical micronization, stabilization of high-energy states (including lyophilized fast- melt systems), use of surfactants, emulsion or microemulsion systems, solid dispersion and use of complexing agent such as cyclodextrins  The technologies under this class include:  SoftGel (soft gelatin capsule formulation)  Zer-Os tablet technology (osmotic system)  Triglas and nanosized carriers such as nanoemulsion, nanosuspension and nanocrystals are treated as hopeful means of increasing solubility and BA of poorly water-soluble active ingredients 26
  27. 27. Class III systems:  Manipulating the site or rate of exposure or perhaps by incorporating functional agents into the dosage form to modify the metabolic activity of the enzyme systems are included in Class III technologies  The technologies under this class include Oral vaccine system, Gastric retention system, High-Frequency Capsule and Telemetric Capsule 27
  28. 28. Class IV systems:  Extreme examples of Class IV compounds are exceptions rather than the rule and are rarely developed to reach the market  But a number of examples of Class IV drugs do exist, for example, Cyclosporin A, Furosemide, Ritonavir, Saquinavir and Taxol 28
  29. 29. Biowaivers  Biowaiver means to obtain waive off for carrying out expensive and time- consuming BA and BE studies  BCS provides biowaivers for Class I and III drug with some specifications  This waiver is for both pre- and post approval phases  BCS-based biowaivers are applicable for immediate-release solid oral dosage formulations containing one or more of the API(s), identified by WHO prequalification of medicines programme (PQP) to be eligible 29
  30. 30. Advantages of biowaivers  Circumvent expensive and sometimes unethically questionable human testing  Reducing time in bringing product to the market  Reduce product cost 30
  31. 31. The criteria recommended by USFDA BCS guidance for Biowaiver  The drug substance should be highly soluble and highly permeable (Class I drugs)  An immediate release drug product  For waiver of an in vivo relative BA study, dissolution should be greater than 85% in 30 minutes in the 3 recommended dissolution media  The drug should not be a narrow therapeutic index drug  Excipients used in the dosage form should have been previously used in a FDA approved IR solid dosage forms  The drug must be stable in gastrointestinal tract and the product is designed not to be absorbed in oral cavity 31
  32. 32. BCS Based Biowaiver Approach  BCS framework – Drug substance categorized into 4 classes 32
  33. 33. For BCS class 1 drug products The following should be demonstrated:  The drug substance should be highly soluble (pH 1- 6.8)  The drug substance should be highly permeable  The drug product (test and reference) should be rapidly dissolving (≥ 85% in 30 min)  The product does not contain any excipients that will affect the rate or extent of absorption of the drug 33
  34. 34. For BCS class 3 drug products The following should be demonstrated:  The drug substance should be highly soluble (pH 1- 6.8)  The drug product (test and reference) should be rapidly dissolving (≥ 85% in 30 min)  The test product formulation is qualitatively the same and quantitatively very similar 34
  35. 35. Limitation of BCS BCS based biowaiver are not applicable for the following:  Narrow therapeutic range drug products  BCS based biowaivers have limited application for the class II drugs  Dosage form meant for absorption in the oral cavity e.g. sublingual or buccal tablets  Effects of food, absorptive transporters, efflux transporters, and routes of elimination (renal/biliary) were important determinants of overall drug absorption and bioavailability for immediate release oral dosage forms, which are not considered in BCS 35
  36. 36. 36

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