Bcs classification system
Download as PPT, PDF104 likes34,539 views
The Biopharmaceutics Classification System (BCS) classifies drug substances based on their aqueous solubility and intestinal permeability. The BCS defines four classes of drugs based on whether a drug is highly soluble/highly permeable (Class I), low solubility/high permeability (Class II), high solubility/low permeability (Class III), or low solubility/low permeability (Class IV). The classification system provides a scientific framework for predicting a drug's absorption based on its solubility and permeability characteristics. It is used to guide drug development and determine if in vitro dissolution testing can substitute for in vivo bioequivalence studies.
Bcs classification system
- 1. BIOPHARMACEUTICS CLASSIFICATION SYSTEM
- 2. Contents • Introduction • Overview of the Classification system • Applications • Conclusion • References
- 3. Introduction ۞Biopharmaceutics Classification System (BCS) ♥ Scientific framework for classifying drug substances based on their aqueous solubility and intestinal permeability What is the need for a classification based on biopharmaceutics of the drug ? • Ans. Its importance in determining bioavailability
- 4. ORAL ROUTE ♠ Route of choice for the formulators Continues to dominate the area of drug delivery technologies. LIMITATIONS Absorption and Bioavailability in the milieu of gastrointestinal tract. Limitations more prominent with the advent of protein and peptide drugs compounds emerging as a result of combinatorial chemistry and the technique of high throughput screening
- 5. API structure salt form and excipients Bioavailability of drug is determined by extent of drug solubility and permeability drug solubility drug product quality attributes
- 6. Biopharmaceutics Classification System Guidance provided by the U.S. Food and Drug Administration for predicting the intestinal drug absorption The fundamental basis established by Dr. Gordon Amidon Distinguished Science Award (Aug ’06 ,FIP) First introduced into regulatory decision-making process in the guidance document on Immediate Release Solid Oral Dosage Forms: Scale Up And Post Approval Changes
- 7. Drug development tool that allows estimation of the contributions of 3 major factors, that affect oral drug absorption from immediate release solid oral dosage forms Dissolution Solubility Intestinal permeability.
- 8. The Biopharmaceutics Classification System (BCS) (as defined by the FDA after Amidon)
- 9. Basis of BCS Dissolution of drug in vivo SIMILAR IN VIVO DISSOLUTION determines Drug Concentration in SIMILAR IN VIVO ABSORPTION the Membrane Domain proportional SIMILAR SYSTEMIC Intestinal Absorption AVAILABILITY
- 10. SOLUBILITY DETERMINATION (37±100C in aqueous medium with pH range of 1-7.5.) A sufficient number of pH conditions ionization characteristics of the test drug substance A minimum of three replicate determinations of solubility in each pH condition Standard buffer solutions described in pharmacopoeias Methods other than shake flask method (with Justification). e g. acid or base titration methods
- 11. Determination of permeability ♣ Not just based on lipophilicity (encompass in vivo effects of efflux and uptake transporters) A. Human studies Mass balance studies Absolute bioavailability studies Intestinal perfusion methods B.In vivo or in situ intestinal perfusion in a suitable animal model C.In vitro permeability methods using excised intestinal tissues D. In vitro permeation studies across a monolayer of cultured epithelial cells.e.g. Caco-2 cells or TC-7 cells
- 12. 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). 0
- 13. CLASS BOUNDARIES HIGHLY SOLUBLE the highest dose strength is soluble in < 250 ml water over a pH range of 1 to 7.5. The volume estimate-a glassful (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.
- 14. BCS Class Boundaries: Objectives Dissolution Rapid dissolution - ensure that in vivo (Product) dissolution is not likely to be the “rate determining” step Solubility High solubility- ensure that solubility (Drug) is not likely to limit dissolution and, therefore, absorption Permeabilit High permeability - ensure that drug y is completely absorbed during the limited (Drug) transit time through the small intestine
- 16. BCS -Implications for drug development Ж Application in early drug development and then in the management of product change through its life cycle Ж Aids fundamental understanding of the biopharmaceutical and physical properties of the drug Ж Aids discriminatory dissolution method development Ж Can help guide the development of in-vitro/in-vivo correlations Ж Can be used to obtain a biowaiver Ж Development of poorly soluble drugs
- 17. This classification is associated with drug dissolution and absorption model, which identifies the key parameters controlling drug absorption as a set of dimensionless numbers viz BCS defines 3 numbers (no units) An ~ absorption number Do ~ dose number Dn ~ dissolution number
- 18. Absorption Number A function of GI Permeability to Drug Substance Effective permeability Residence time in GI P T An = ( T ) = eff GI R T GI ABS Radius of GI Time required for complete absorption
- 19. Dose Number A function of solubility of drug substance Highest Dose Unit D 250 mL V Do = Water C Solubility S
- 20. Dissolution Number A function of drug release from formulation Solubility mg/mL Residence time in GI Diffusivity 180 min 5x10-6 cm2/s 3D C ( T ) = T Dn = S GI r ρ T 2 GI DISS Particle Radius 25 µm Density Time required for 1.2 mg/cm3 complete dissolution
- 22. IVIVC expectations for immediate release products based on BCS Class Solubility Permeability Absorption IVIVC expectations for rate control Immediate release product I High High Gastric IVIVC expected, if dissolution rate is emptying 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 Limited or no IVIVC is expected. case
- 23. High Solubility Low Solubility Class 1 ImipramineI Class 2 Ketorolac Itraconazole S,I Abacavir Ketoprofen Amiodarone I Acetaminophen AtorvastatinS, I Ketoconazole I Labetolol LansoprazoleI Acyclovirb LevodopaS AzithromycinS ,I AmilorideS,I Carbamazepine S,I Lovastatin S,I Levofloxacin S Mebendazole Amitryptyline S,I LidocaineI Carvedilol Antipyrine Chlorpromazine I Naproxen Lomefloxacin Nelfinavir S,I Atropine Meperidine CisaprideS High Permeability Buspironec Ciprofloxacin S Ofloxacin Metoprolol Oxaprozin Caffeine Metronidazole Cyclosporine S, I Captopril Danazol Phenazopyridine MidazolamS,I PhenytoinS ChloroquineS,I Minocycline Dapsone Chlorpheniramine Diclofenac Piroxicam Misoprostol Raloxifene S Cyclophosphamide Nifedipine S Diflunisal Desipramine Digoxin S Ritonavir S,I Phenobarbital Saquinavir S,I Diazepam Phenylalanine Erythromycin S,I Diltiazem S,I Flurbiprofen Sirolimus S Prednisolone Spironolactone I Diphenhydramine PrimaquineS Glipizide Disopyramide GlyburideS,I Tacrolimus S,I Promazine TalinololS Doxepin Propranolol I Griseofulvin Doxycycline Ibuprofen Tamoxifen I QuinidineS,I Terfenadine I Enalapril Rosiglitazone Indinavir S Ephedrine Indomethacin Warfarin Salicylic acid Ergonovine Theophylline Ethambutol Valproic acid Ethinyl Estradiol Verapamil I FluoxetineI Zidovudine Glucose
- 24. High Solubility Low Solubility Class 3 Class 4 Acyclovir Fexofenadine S Amphotericin B Amiloride S,I Folinic acid Chlorthalidone Amoxicillin S,I Furosemide Chlorothiazide Atenolol Ganciclovir Colistin Atropine Hydrochlorothiazide Ciprofloxacin S Low Permeability Bisphosphonates Lisinopril Furosemide Bidisomide Metformin Hydrochlorothiazide Captopril Methotrexate Mebendazole Cefazolin Nadolol Methotrexate Cetirizine Pravastatin S Neomycin Cimetidine S Penicillins Ciprofloxacin S Ranitidine S Cloxacillin Tetracycline Dicloxacillin S Trimethoprim S Erythromycin S,I Valsartan Famotidine Zalcitabine
- 25. Applications of BCS in oral drug delivery technology Class I - High Permeability, High Solubility Achieve a target release profile associated with a particular pharmacokinetic and/or pharmacodynamic profile. Formulation approaches include both control of release rate and certain physicochemical properties of drugs like pH-solubility profile of drug.
- 26. Class II - High Permeability, Low Solubility Micronisation, Addition of surfactants, Formulation as emulsions and microemulsions systems, Use of complexing agents like cyclodextrins
- 27. Class III - Low Permeability, High Solubility Require the technologies that address to fundamental limitations of absolute or regional permeability. Peptides and proteins constitute the part of class III and the technologies handling such materials are on rise now days
- 28. Class IV - Low Permeability, Low Solubility ♫Major challenge for development of drug delivery system and the route of choice for administering such drugs is parenteral (solubility enhancers.) ♫Fortunately, extreme examples are the exception rather than the rule and are rarely developed and reach the market
- 29. Biowaiver A biowaiver is an exemption from conducting human bioequivalence studies when the active ingredient(s) meet certain solubility and permeability criteria in vitro and when the dissolution profile of the dosage form meets the requirements for an "immediate" release dosage form.
- 30. Waiver of In Vivo Bioequivalence Study based on Pharmaceutical Dosage Form (Solutions) Biopharmaceutics Classification System Dose. (Highest Strength should be tested)
- 31. BCS BIOWAIVER Biowaiver for Rapid and similar dissolution. High solubility &High permeability. Wide therapeutic window. Excipients used in dosage form used previously in approved IR solid dosage forms.
- 32. REQUEST FOR BIOWAIVERS Data Supporting :- Rapid and Similar Dissolution High Permeability High Solubility
- 33. Limitations of BCS as a Predictor of Drug Disposition Ω Permeability (90% absorption) is difficult to determine, and difficult to convince the regulatory agency . Ω There is little predictability for BCS classification drugs beyond Class 1 primarily due to the difficulty of determining and proving 90% absorption. many drugs are misclassified (e.g. HIV protease inhibitors as Class 4 compounds)).
- 34. Conclusion BCS aims to provide a regulatory tool for replacing certain BE studies by accurate in- vitro dissolution tests.. This increased awareness of a proper biopharmaceutical characterization of new drugs may in the future result in drug molecules with a sufficiently high permeability, solubility and dissolution rate , and that will automatically increase the importance of the BCS as a regulatory tool over time
- 35. References: 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 biopharmaceutic classification system, february 1999, CDER/FDA. Amidon G.L., Lennernas H., Shah V.P., Crison J.R.A., A theoretical basis for a biopharmaceutic 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/.
- 36. 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
- 37. Thank you..