Biopharmaceutics classification system class 1
- 1. Biopharmaceutics Classification System (Class I Drugs) Name: Aloysia Cardoso Class: Fy Masters Of Pharmacy Specialisaton: Pharmaceutics Semester: One
- 2. INDEX DEFINATION OF BCS BIOPHARMACEUTICAL CLASSIFICATION SYSTEM CLASS I DRUGS PHYSIOCHEMICAL PARAMETERS ADVANTAGES DISADVANTAGES LIST OF DRUGS FORMULATION CONSIDERATION REFERENCES
- 3. What is BCS? The Biopharmaceutics Classification System or BCS(abbreviation) is a system which classifies bioactive molecules based on solubility and permeability which is widely used to guide new drug development and drug formulation, as well as predict pharmacokinetics under prescribed conditions. Established by Gordon Amidon et al The original purpose of the system was to aid in the regulation of post-approval changes and generics, providing approvals based solely on in vitro data when appropriate. Importantly, since the majority of drugs are orally dosed, the system was designed around oral drug delivery via passive diffusion process through the small intestine where major extent of oral absorption is largely influenced by drug’s membrane permeability and solubility. Currently it is used to predict the bioavailability of the drug. Used in in-vivo & in vitro correlations and bioavailability studies.
- 5. Biopharmaceutics Classification System CLASS SOLUBIIITY PERMEABILITY ABSORPTION PATTERN RATE LIMITING STEP IN ABSORPTION EXAMPLES 1 HIGH HIGH WELL ABSORBED GASTRIC EMPTYING DILTIAZEM 2 LOW HIGH VARIABLE DISSOLUTION NIFEDIPINE 3 HIGH LOW VARIABLE PERMEABILITY INSULIN 4 LOW LOW POORLY ABSORBED CASE BY CASE TAXOL According to the Biopharmaceutical Classification System (BCS) drug substances/APIs are classified to four classes Upon Their High/Low Solubility And Permeability:
- 6. Class I Drugs THE DRUGS BELONGING TO BCS CLASS I ARE HIGHLY SOLUBLE AND HIGHLY PERMEABLE, SO THEY CAN BE FORMULATED AS A SUITABLE CONVENTIONAL DOSAGE FORMS. WELL ABSORBED ORALLY. THEY EXHIBIT A HIGH ABSORPTION NUMBER AND A HIGH DISSOLUTION NUMBER. SINCE THEY DO NOT HAVE SOLUBILITY NOR PERMEABILITY LIMITATION THEREFORE THEY GENERALLY REPRESENT A LOW RISK GROUP OF COMPOUNDS IN TERMS OF THE POTENTIAL FOR EXCIPIENTS TO AFFECT ABSORPTION, COMPARED TO OTHER BCS CLASSES Example: Metoprolol, Paracetamol These Compounds Are Well Absorbed And Their Absorption Rate Is Usually Higher Than Excretion.
- 7. This system restricts the prediction using the physiochemical parameters Aqueous solubility and Intestinal permeability. The solubility classification is based on a United States Pharmacopoeia (USP) aperture . The intestinal permeability classification is based on a comparison to the intravenous injection. PHYSIOCHEMICAL PARAMETERS
- 8. 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 unecessory for such product. IVIVC cannot be expected. These compounds are highly suitable for design the SR and CR formulations
- 9. ADVANTAGES DRUG ABSORBED AND DISSOLVED RAPIDLY IN GASTRIC & INTESTINAL FLUID. READILY CROSS INTESTINAL WALL THROUGH PASSIVE DIFFUSION. RAPID THERAPEUTIC ACTION BIOAVAILIBILITY PROBLEM NOT EXPECTED FOR IMMEDIATE RELEASE DRUG PRODUCT IVIVC EXPECTED, IF DISSOLUTION RATE IS SLOWER THAN GASTRIC EMPTYING RATE, OTHERWISE LIMITED OR NO CORRELATIONS. UNLIKELY TO SHOW BIO-EQUIVALENCE ISSUES.HENCE INVITRO STUDIES ARE SUFFICIENT TO PROVIDE INFORMATION TO ENSURE INVIVO PRODUCT PERFORMANCE
- 10. DISADVANTAGE Although class I compounds are expected to have excellent oral absorption, given their high solubility and high permeability, additional absorption barriers may exist beyond the scope of the BCS For example, luminal complexation and degradation can significantly limit the amount of drug available for absorption. Even after the drug crosses the intestinal membrane, it may be metabolized within the enterocytes/hepatocytes and/or pumped out of the cells due to efflux mechanisms. High excretion rates, absorption window and toxicity due to burst release which may create a need to develop release modulated drug delivery systems
- 11. NAMES OF DRUGS UNDER 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
- 12. FORMULATION CONSIDERATION SOLUBILITY Solubility is defined as the maximum amount of solute dissolved in a given solvent under standard conditions of temperature, pressure and pH Ability of the drug to be solution after dissolution. HIGHLY SOLUBLE-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. At least three pHs within this range, including buffers at pH 1.2, 4.5 and 6.8, should be evaluated. Solubility is maintained over relevant timeframes to accommodate the expected duration of absorption. Solubility should be evaluated by a method appropriate to the properties of the drug substance.
- 13. EQUILIBRIUM SOLUBILITY experiments may be performed, using a shake-flask technique or an alternative method, if justified. Small volumes of solubility media may be employed if the available experimental apparatus will permit it. The pH for each test solution should be measured after the addition of the drug substance and at the end of the equilibrium solubility study to ensure the solubility measurement is conducted under the specified pH. The pH should be adjusted if necessary. The experiment should be conducted over a suitable timeframe to reach equilibrium. Solubility experiments where the highest therapeutic single dose is examined in a 250 ml volume, or a proportionally smaller amount examined in a proportionally smaller volume of buffer, can be considered. In addition, adequate STABILITY of the drug substance in the solubility media should be demonstrated. In cases where the drug substance is not stable with >10% degradation over the extent of the solubility assessment, solubility cannot be adequately determined and thus the drug substance cannot be classified
- 14. STABILITY Drug Substance Stability in the Gastrointestinal Tract Additional data to document the drug’s stability in the gastrointestinal tract should be provided if mass balance studies are used to demonstrate high permeability, unless ≥85% of the dose is recovered as unchanged drug in urine. Demonstration of stability in the gastrointestinal tract is required if in vitro Caco-2 studies are used to support high permeability. Stability in the gastrointestinal tract may be documented using compendial or simulated gastric and intestinal fluids. Drug solutions should be incubated at 37ºC for a period that is representative of the in vivo contact of the drug substance with these fluids, i.e., one hour in gastric fluid and three hours in intestinal fluid. Drug concentrations should then be determined using a suitably validated method. Significant degradation (>10%) of a drug precludes BCS high permeability classification.
- 15. PERMEABILITY HIGHLY PERMEABLE The assessment of permeability should preferentially be based on the extent of absorption derived from human pharmacokinetic studies, e.g., absolute bioavailability or mass balance High permeability can be concluded when the absolute bioavailability is ≥90%. High permeability can also be concluded if ≥85% of the administered dose is recovered in urine as unchanged (parent drug), or as the sum of parent drug, Phase 1 oxidative and Phase 2 conjugative metabolites Regarding metabolites in feaces, only oxidative and conjugative metabolites can be considered. Metabolites produced through reduction or hydrolysis should not be included, unless it can be demonstrated that they are not produced prior to absorption, e.g., by microbial action within the gastrointestinal tract. Permeability can be also assessed by validated and standardized in vitro methods using Caco-2 cells. If high permeability is not demonstrated, the drug substance is considered to have low permeability for BCS classification purposes.
- 16. When a single method fails to conclusively demonstrate a permeability classification, two different methods may be advisable. 1. Pharmacokinetic Studies in Humans a. Mass Balance Studies b. Absolute Bioavailability Studies 2. Intestinal Permeability Methods The following methods can be used to determine the permeability of a drug substance from the gastrointestinal tract: · In vivo intestinal perfusions studies in humans. · In vivo or in situ intestinal perfusion studies in animals. · In vitro permeation experiments with excised human or animal intestinal tissue. · In vitro permeation experiments across epithelial cell monolayer
- 17. Excipient effect Consideration of excipient effects for BCS Class I drug products should focus on potential changes in the rate or extent of absorption. For example, if it is known that the drug has high permeability due to active uptake, excipients that can inhibit uptake transporters are likely to be of concern. For BCS Class I drugs that exhibit slow absorption, the potential for a given excipient to increase absorption rate should also be considered. Where excipient differences exist, they should be assessed for their potential to affect in vivo absorption. Excipient differences should not affect the absorption profile of the drug substance under consideration, i.e., rate and extent of absorption, using a mechanistic and risk-based approach For BCS Class I drugs, qualitative and quantitative differences in excipients are permitted, except for excipients that may affect absorption, which should be qualitatively the same and quantitatively similar, i.e., within ± 10% of the amount of excipient in the reference product.
- 18. The possible effects of excipients on aspects of in vivo absorption such as solubility gastrointestinal motility, transit time and intestinal permeability including transporter mechanism. Excipients that may affect absorption include sugar-alcohols, e.g., mannitol, sorbitol, and surfactants, e.g., sodium lauryl sulfate.nisms, should be considered. The risk that a given excipient will affect the absorption of a drug substance should be assessed mechanistically by considering: • the amount of excipient used • the mechanism by which the excipient may affect absorption • absorption properties (rate, extent and mechanism of absorption) of the drug substance
- 19. DISSOLUTION An drug product is considered rapidly dissolving when a mean of 85 percent or more of the labelled amount of the drug substance dissolves within 30 minutes, using United States Pharmacopeia (USP) Apparatus 1 at 100 rpm or Apparatus 2 at 50 rpm (or at 75 rpm when appropriately justified in a volume of 500 mL or less (or 900 mL when appropriately justified) in each of the following media: (1) 0.1 N HCl or Simulated Gastric Fluid USP; (2) a pH 4.5 buffer; and (3) a pH 6.8 buffer or Simulated Intestinal Fluid USP without enzymes An IR(immediate release) product is considered very rapidly dissolving when a mean of 85 percent or more of the labelled amount of the drug substance dissolves within 15 minutes, using the above mentioned conditions.
- 20. Media For Class I Substances Substances that belong to class I possess good aqueous solubility and are transported through the GI mucosa. Their bioavailability after oral administration is usually close to 100 %, provided they are not decomposed in GIT and do not under go extensive first pass metabolism . After administration, the dosage form quickly passes into stomach and, usually disintegrates there, so it is logical to use a dissolution medium that reflects the gastric conditions. Simulated gastrointestinal fluid (SGF) without enzymes is suitable for many immediate release dosage forms of this class. In case of weak acidic drugs simulated intestinal fluid with out enzyme may be used For some capsules, an enzyme (pepsin) may have to be added to the medium to ensure the timely dissolution of the shell Water is less suitable medium than the aforementioned buffers, because it has a nominal buffer capacity zero; therefore, the pH may vary during the test
- 21. Method Of Enhancing The Dissolution Use of surfactants Complexation By making the prodrug Use of selected polymeric forms Use of solvates and hydrates Use of salt of weak acids and weak bases Buffering the pH of the microenvironment Method of enhancing the dissolution by increasing the surface area 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)
- 22. REFERENCES Biopharmaceutics and Pharmacokinetics –A treatise by D M Brahmankar & Sunil B Jaiswal Biopharmaceutical Classification System :An Account Mohd Yasir*1 , , Mohd Asif, Ashwani Kumar, Abhinav Aggarval ICH M9 guideline on biopharmaceutics classification system-based biowaivers Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate- Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System Guidance for IndustryU.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) www.fda.gov www.Wikipedia.com