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Biopharmaceutics classification system

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Biopharmaceutics classification system

  1. 1. BIOPHARMACEUTICAL CLASSIFICATION SYSTEM By: Md Shakeeb Ahmed Presented to: Dr. K. K. Jamia Hamdard Pillai
  2. 2. CONTENTS 1.INTRODUCTION 2.SIGNIFICANCE OF BCS 3.INFLUENCE OF BCS ON BIOAVAILABILITY
  3. 3. INTRODUCTION  Route of choice for the formulators  Continues to dominate the area of drug delivery technologies
  4. 4. DRUG DISSOLUTION AND ABSORPTION disintegration dissolution permeability formulated Drug product Kdd Kid Solubilized drug absorbed drug dispersed Drug particles Kp
  5. 5. BIOPHARMACEUTICAL CLASSIFICATION SYSTEM  A scientific framework for classifying drug substances based on their aqueous solubility and intestinal permeability  Established by Gordon Amidon et al.  BCS has gained importance worldwide as a drug product regulation tool For scale-up and post-approval changes  The aim of the BCS is to provide a regulatory tool for the replacement of certain BE studies by conducting accurate in vitro dissolution tests.
  6. 6. BIOPHARMACEUTICS CLASSIFICATION SYSTEM (as defined by the FDA after Amidon et al.)
  7. 7. BCS CLASS MEMBERSHIP Class I Propranolol Verapamil Metoprolol Class II Ketoprofen Naproxen Carbamazepine Low High Class IV Furosemide Hydrochlorothiazide Class III Ranitidine Cimetidine Atenolol Vancomycin High Low
  8. 8. Classification of a drug depends upon its three key parameters, that control absorption: Solubility Dissolution rate permeability that correlate with three respective dimensionless parameters Dose no. Dissolution no. Absorption no.
  9. 9. DOSE NUMBER A function of solubility of drug substance Should be less than 1. It is the dose concentration/solubility ratio            V Water C S D Highest Dose Unit Do 250 mL Solubility
  10. 10. DISSOLUTION NUMBER A function of drug release from formulation • Defined as the ratio of mean residence time to mean Should exceed 1 dissolution time Dn= [TGI/TCD] TGI = Residence time in GI (approx. 180 min) TCD= Time required for complete dissolution
  11. 11. ABSORPTION NUMBER “A function of GI Permeability to Drug Substance” • Absorption number (An) is the time required to absorb the • It is the ratio of the mean residence time to mean A T n GI T ABS administered dose absorption time. TGI = Residence time in GI (approx. 180 min) TABS Time required Should exceed = for complete 1 absorption
  12. 12. PERMEABILITY DETERMINATION A. Determination of extent of absorption in humans: • Mass balance P/K studies • Absolute bioavailability studies B. Intestinal permeability methods: • In vivo intestinal perfusion studies in humans • In vivo or in situ intestinal perfusion studies in animal • In vitro permeability methods using excised human/animal intestinal tissues • In vitro permeation studies across a monolayer of cultured epithelial cells. e.g. Caco-2 cells or TC-7 cells
  13. 13. DISSOLUTION DETERMINATION  USP apparatus I (basket) at 100 rpm or USP apparatus II (paddle) at 50 rpm.  Dissolution media (900 ml): 0.1 N HCl or simulated gastric fluid, pH 4.5 buffer, and pH 6.8 buffer or simulated intestinal fluid.  Compare dissolution profiles of test and reference products using a similarity factor (f2). If f2= 100 ; dissolution profiles are identical N= no. of dissolution time points Rt = dissolution value of the reference drug product at time t Tt = dissolution value of the test drug product at time t
  14. 14. SOLUBILITY DETERMINATION “Shake flask method” • pH- solubility profile of test drug in aqueous media within a pH range of 1.0-7.5 • A minimum of three replicate determinations of solubility in each pH condition • Methods other than shake flask method (with Justification). e g. acid or base titration methods
  15. 15. CLASS BOUNDARIES  HIGHLY SOLUBLE; the highest dose strength should be soluble in < 250 ml water over a pH range of 1 to 7.5. (The volume estimate-a glassful i.e. 8 ounce)  HIGHLY PERMEABLE when the extent of absorption in humans is determined to be > 90% of an administered dose  RAPIDLY DISSOLVING 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 solutions.
  16. 16. BCS CLASS BOUNDARIES: OBJECTIVES Dissolution (Product) Solubility (Drug) Permeability (Drug) Rapid dissolution - ensure that in vivo dissolution is not likely to be the “rate determining” step High solubility- ensure that solubility is not likely to limit dissolution and, therefore, absorption High permeability - ensure that drug is completely absorbed during the limited transit time through the small intestine
  17. 17. IVIVC EXPECTATIONS FOR IRP BASED ON BCS Class Solubil ity Perme ability Absorption rate control IVIVC expectations for Immediate release product I High High Gastric emptying IVIVC expected, if dissolution rate is slower than gastric emptying rate, otherwise limited or no correlations II Low High Dissolution IVIVC expected, if in vitro dissolution rate is similar to in vivo dissolution rate, unless dose is very high. III High Low Permeability Absorption (permeability) is rate determining and limited or no IVIVC with dissolution. IV Low Low Case by case Limited or no IVIVC is expected.
  18. 18. High Solubility Low Solubility High Permeability Class 1 Abacavir Acetaminophen Acyclovirb AmilorideS,I Amitryptyline S,I Antipyrine Atropine Buspironec Caffeine Captopril ChloroquineS,I Chlorpheniramine Cyclophosphamide Desipramine Diazepam Diltiazem S,I Diphenhydramine Disopyramide Doxepin Doxycycline Enalapril Ephedrine Ergonovine Ethambutol Ethinyl Estradiol FluoxetineI Glucose ImipramineI Ketorolac Ketoprofen Labetolol LevodopaS Levofloxacin S LidocaineI Lomefloxacin Meperidine Metoprolol Metronidazole MidazolamS,I Minocycline Misoprostol Nifedipine S Phenobarbital Phenylalanine Prednisolone PrimaquineS Promazine Propranolol I QuinidineS,I Rosiglitazone Salicylic acid Theophylline Valproic acid Verapamil I Zidovudine Class 2 Amiodarone I AtorvastatinS, I AzithromycinS ,I Carbamazepine S,I Carvedilol Chlorpromazine I CisaprideS Ciprofloxacin S Cyclosporine S, I Danazol Dapsone Diclofenac Diflunisal Digoxin S Erythromycin S,I Flurbiprofen Glipizide GlyburideS,I Griseofulvin Ibuprofen Indinavir S Indomethacin Itraconazole S,I Ketoconazole I LansoprazoleI Lovastatin S,I Mebendazole Naproxen Nelfinavir S,I Ofloxacin Oxaprozin Phenazopyridine PhenytoinS Piroxicam Raloxifene S Ritonavir S,I Saquinavir S,I Sirolimus S Spironolactone I Tacrolimus S,I TalinololS Tamoxifen I Terfenadine I Warfarin
  19. 19. High Solubility Low Solubility Low Permeability Class 3 Acyclovir Amiloride S,I Amoxicillin S,I Atenolol Atropine Bisphosphonates Bidisomide Captopril Cefazolin Cetirizine Cimetidine S Ciprofloxacin S Cloxacillin Dicloxacillin S Erythromycin S,I Famotidine Fexofenadine S Folinic acid Furosemide Ganciclovir Hydrochlorothiazide Lisinopril Metformin Methotrexate Nadolol Pravastatin S Penicillins Ranitidine S Tetracycline Trimethoprim S Valsartan Zalcitabine Class 4 Amphotericin B Chlorthalidone Chlorothiazide Colistin Ciprofloxacin S Furosemide Hydrochlorothiazide Mebendazole Methotrexate Neomycin
  20. 20. CLASS – I Class I - High Permeability, High Solubility • Drugs dissolved rapidly • Drugs absorbed rapidly • Rapid therapeutic action • Excellent property • Ideal for oral route • e.g. Metoprolol, Diltiazem, Verapamil, Propranolol,
  21. 21. CLASS – II • Drugs dissolve slowly • Drugs absorbed rapidly • Controlled released drugs • Oral / IV route for administration • Ex. Glibenclamide, Ezetimibe, Phenytoin, Nifedipine
  22. 22. CLASS – III • Dissolved rapidly • Absorbance is limited • Incomplete bioavailability • Oral / IV route for administration • Ex. Cimetidine, Acyclovir, Captopril
  23. 23. CLASS – IV • Low dissolution rate • Low permeability property • Slow or low therapeutic action • IV or other routes are required • Ex. Hydrochlorothiazide
  24. 24. Background: About biowaivers
  25. 25. BCS BASED BIOWAIVER A biowaiver is an exemption from conducting human bioequivalence studies Criteria for Biowaiver Immediate-release solid oral dosage form Rapid and similar dissolution. High solubility &High permeability. Wide therapeutic window. Excipients used in dosage form are same as those present in approved drug product • Companies can potentially save thousands of dollars in costs, and several months of time in development, if bioequivalence studies are avoided
  26. 26. REQUEST FOR BIOWAIVERS Data Supporting :- Rapid and Similar Dissolution High Permeability High Solubility Biowaiver: Class III compounds are eligible biowaiver if they dissolve within 15 minutes in buffer media pH 1.2 –6.8 (75 rpm) Biowaiver: Class II acids with D:S ratio < 250 ml at pH 6.8 and > 85 % dissolved within 30 minutes at pH 6.8 (75 rpm)
  27. 27. NO BIOWAIVER FOR: As the BCS is only applicable to APIs which are absorbed from the small intestine; drugs absorbed from other sites (e.g. from the oral cavity) are not eligible for a biowaiver non-oral immediate release forms with systemic action modified release products transdermal products
  28. 28. SURROGATE MARKERS Drug product Drug Possible surrogate marker for bioequivalence Topical steroid Hydrocortisone Skin blanching Anion exchange resin Cholestyramine Binding to bile acids Antacids Mg & Al hydroxide gel Neutralization of acid Topical antifungal Ketoconazole Drug uptake into stratum corneum
  29. 29. SIGNIFICANCE OF BCS Regulatory toll for replacement of certain BE studies. It can save both time and money—if the immediate -release, orally administered drug meets specific criteria, the FDA will grant a waiver for expensive and time-consuming bio-equivalence studies. Valuable tool for formulation scientist for selection of design of formulated drug substance. When integrated with other information provide a tremendous tool for efficient drug development. Reduces cost and time of approving Scale- up and post approval challenges. Applicable in both pre-clinical and clinical drug development process. Works as a guiding tool in development of various oral drug delivery systems.
  30. 30. BCS can be used as a key component to guide drug delivery system design for any route of administration
  31. 31. DRAWBACKS OF BCS BIOWAIVERS • Sponsors are sometimes reluctant to apply for biowaivers due to the perceived lack of certainty of acceptance by the regulatory agencies. • Industrial implementation of BCS may also be limited due to: – unnecessary barriers in existing guidelines – compartmentalization of company resources – or a general lack of knowledge about BCS or the biowaiver process.
  32. 32. ELIGIBLE APIs FOR WHO BCS-BASED BIOWAIVER APPLICATIONS: DRUG CATEGORY DRUGS ELIGIBLE FOR BIOWAIVER APPLICATIONS antiretroviral  Abacavir  Emtricitabine  Lamivudine  Stavudine  zidovudine anti-tuberculosis  Ethambutol  Isoniazid  Levofloxacin  Ofloxacin  Moxifloxacin  pyrazinamide
  33. 33. REFERNCES  Draft guidance for industry, waiver of in vivo bioavailability and bioequivalence studies for immediate release solid oral dosage forms containing certain active moieties/ active ingredients based on a biopharmaceutics classification system, February 1999, CDER/FDA.  Amidon G.L., Lennernas H., Shah V.P., Crison J.R.A., A theoretical basis for a biopharmaceutics drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm. Res. 12: 413-420 (1995).  Guidance for industry, immediate release solid oral dosage forms: scale up and post approval changes, November 1995, CDER/FDA.  Medicamento generico from website http://www.Anvisa.Go/.  Particle size; Drug development services; Technical Brief 2011 Volume 9
  34. 34. REFERNCES  Devane J., Oral drug delivery technology: addressing the solubility/ permeability paradigm, pharm. Technol. 68-74, November 1998  Amidon, G. L.,Lennernäs H., Shah V. P., And Crisonj. R., A theoretical basis for a biopharmaceutics drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability, Pharmaceutical research, 12: 413-420 (1995)  Guidance for Industry: Dissolution Testing of Immediate Release Solid Oral Dosage Forms, FDA CDER, 1997 http://www.fda.gov/cder/guidance/1713bp1.pdf  Guidance for Industry: Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System, FDA CDER, August 2000 http://www.fda.gov/cder/guidance/3618fnl.htm  WHO Prequalification of Medicines Programme; General notes on Biopharmaceutics Classification System (BCS)-based biowaiver applications; Guidance Document October 2012
  35. 35. REFERNCES  Chi-Yuan Wu and Leslie Z. Benet, (2005); “Predicting Drug Disposition via Application of BCS: Transport/Absorption/Elimination Interplay and Development of a Biopharmaceutics Drug Disposition Classification System” ; Pharmaceutical Research, Vol. 22, No. 1, January
  36. 36. If you’re not part of the solution….. © you’re part of the precipitate

Notes de l'éditeur

  • Whenever a new drug moiety is discovered, one of the 1st questions a pharmaceutical company asks is….whether or not the drug can be effectively administered by the oral route, for its intended use




    Biopharmaceutical Classification System (BCS) is a scientific framework for classifying drug substances based on their aqueous solubility and intestinal permeability


  • Biopharmaceutical Classification System (BCS) is a scientific framework for classifying drug substances based on their aqueous solubility and intestinal permeability
  • BCS was originally used to grant biowaivers for scale-up and post-approval changes for drug products, but was later extended to the approval of new generic products.

  • FDA suggests as a potential internal standard
  • (Determination in Caco II cells only applicable to passively absorbed substances)
  • A drug substance is considered “highly soluble” when the highest clinical dose strength is soluble in 250 mL or less of aqueous media over a pH range of 1–7.5 at 37 °C

  • when the dissolution rate is much greater than the gastric emptying, dissolution is not likely to be rate-limiting
  • BCS Can be used to obtain a biowaiver
  • It has been estimated that the application of BCS can result in annual savings of $35 million for
    the pharmaceutical industry
  • Reference: Particle size; Drug development services; Technical Brief 2011 Volume 9

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