BCS Hitesh

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Biopharmaceutics Classification System:

Biopharmaceutics Classification System PREPARED BY : HITESH CHIHLA M.PHARM SEM-1 PHARMACEUTICS

OUTLINE TOPICS:

OUTLINE TOPICS BIOPHARMCEUTICS CLASSIFICATION SYSTEM (BCS) BCS SIGNIFICANCE ON DISSOLUTION STUDY BCS APPLICATION IN DOSAGE FORM DEVELOPMENT 2

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Introduction Aim of BCS Guidance Classification of D rugs as per BCS Class description Key Parameters Basic Requirements of BCS Industrial Implementation Application Conclusion Questions References LIST OF CONTENT 3

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The BCS is a scientific framework for classifying drug substances based on their aqueous solubility & intestinal permeability. When combined with the dissolution of the drug product, the BCS takes into account three major factors that govern the rate & extant of drug absorption from IR (Immediate Release) solid oral dosage forms: Dissolution, Solubility & Intestinal permeability. Thus, it is a theoretical basis for correlating in-vitro drug dissolution with in-vivo bioavailability. INTRODUCTION 4

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The drug in the dosage form is released and dissolves in the surrounding gastrointestinal fluid to form a solution. This process is solubility limited. Once the drug is in the solution form, it passes across the membranes of the cells lining the Gastro-Intestinal tract. This process is permeability limited. Then onwards the drug is absorbed into systemic circulation. In short, the oral absorption and hence bioavailability of drug is determined by the extent of drug solubility and permeability. 5

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The oral route of drug administration is the route of choice for the formulators and continues to dominate the area of drug delivery technologies. This route is not free from limitations of absorption and bioavailability . BCS takes into account three major factors that govern the rate and extent of drug absorption. Solubility Dissolution Intestinal permeability 6

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To improve the efficiency of drug development and the review process by recommending a strategy for identifying expendable clinical BE tests. Expands the regulatory application of the BCS and recommends methods for classifying drugs. To provide guidance for industry. To provide regulatory tool for replacing certain bioequivalence studies by accurate in-vitro dissolution tests. This will reduce the cost in drug development process ,also reduce unnecessary drug exposure in healthy objects. AIM OF BCS GUIDANCE 8

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CLASSIFICATION OF DRUGS AS PER BCS 9 Class 1: High Solubility - High Permeability Class 2: Low Solubility - High Permeability Class 3: High Solubility - Low Permeability Class 4: Low Solubility - Low Permeability

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BCS and IVIVC: :

BCS and IVIVC: 11 The BCS is a fundamental guideline for determining the condition under which in-vitro in-vivo correlation are expected. For the Class I drugs IVIVC expected, if dissolution rate is slower than gastric emptying rate. For Class II drugs IVIVC expected, if in vitro dissolution rate similar to in vivo dissolution rate, unless dose is high. For Class III & IV IVIVC is not expected with dissolution because absorption is rate limiting step.

KEY PARAMETERS:

KEY PARAMETERS This classification is associated with drug dissolution and absorption model, which identifies the key parameters controlling drug absorption as a set of dimensionless numbers. ABSORPTION NUMBER, defined as the ratio of the mean residence time to mean absorption time. DISSOLUTION NUMBER, defined as the ratio of mean residence time to mean dissolution time. DOSE NUMBER, defined as the mass divided by the product of uptake volume (250 ml) and solubility of drug. 12

Solubility:

Solubility The solubility class boundary is based on the highest dose strength of an IR product that is the subject of a biowaiver request. A drug substance is considered highly soluble when the highest dose strength is soluble in 250 ml or less of aqueous media over the pH range of 1-7.5. The volume estimate of 250 ml is derived from typical BE study protocols that prescribe administration of a drug product to fasting human volunteers with a glass (about 8 ounces) of water. 13

Permeability:

Permeability The permeability class boundary is based indirectly on the extent of absorption (fraction of dose absorbed, not systemic BA) of a drug substance in humans and directly on measurements of the rate of mass transfer across human intestinal membrane Alternatively, nonhuman systems capable of predicting the extent of drug absorption in human can be used. In the absence of evidence suggesting instability in the gastrointestinal tract, a drug substance is considered to be highly permeable when the extent of absorption in humans is determined to be 90% or more of an administered dose based on a mass balance determination or in comparison to an intravenous reference dose . 14

Dissolution:

Dissolution In this guidance, an IR drug product is considered rapidly dissolving when no less than 85% of the labeled amount of the drug substance dissolves within 30 minutes, using U.S. Pharmacopeia (USP) Apparatus I at 100 rpm (or Apparatus II at 50 rpm) in a volume of 900 ml or less in each of the following media: (1) 0.1 N HCl or Simulated Gastric Fluid USP without enzymes; (2) a pH 4.5 buffer; and (3) a pH 6.8 buffer or Simulated Intestinal Fluid USP without enzymes . 15

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CLASS I 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. Rate of absorption is higher than rate of excretion. e.g. Metoprolol, Diltiazem, Verapamil, Propranolol. No major challenges for immediate release forms but CR forms need to limit drug release or dissolution since absorption of release drug is rapid. 16

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17 CLASS II drugs 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. The absorption for class II drugs is usually slower than class I and occurs over a longer period of time. In vitro- In vivo correlation (IVIVC) is usually excepted for class I and class II drugs. e.g. Phenytoin, Nifedipine . Formulation are designed to overcome solubility or dissolution problems by several approaches like, Microionization Supercritical fluid recrystallization Salt form

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18 Solvent Deposition Evaporation Precipitation into Aqueous Solution CLASS III 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. e.g. Cimetidine, Acyclovir, Neomycin B, Captopril . Approaches are employed to enhance permeability.

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Lipid technologies- Ion pairing- Penetration enhancer CLASS IV drugs exhibit a lot of problems for effective oral administration. Fortunately, extreme examples of class IV compounds are the exception rather than the rule and are rarely developed and reach the market. Nevertheless a number of class IV drugs do exist. e.g. Taxol, Griseofulvin Combition of strategies used for Class II & Class III drugs are employed to improve both dissolution and permeability. 19

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Absorption enhancing excipient, Lipid filled capsule, GI motility consideration Lipid solution ,Solid lipid nano particle, Salt form, Cosolvent, Solubilization by Surfactants, Micro-particles, Penetration enhencer, Liposome . Particle size reduction, Soluble salts, Self emulsifying system, Solid dispersion, SFR , Nanoparticles, Cyclodextrine complex, pH adjustment, Salting out I III II IV 20

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pH-solubility profile of test drug in aqueous media with a pH range of 1 to 7.5 . The pH-solubility profile of the test drug substance should be determined at 37 ± 1ºC in aqueous media with a pH in the range of 1-7.5. The number of pH conditions for a solubility determination can be based on the ionization characteristics of the test drug substance. solubility should be determined at pH = p Ka, pH = p Ka +1, pH = pKa-1, and at pH = 1 and 7.5. 21 SOLUBILITY DETERMINATION

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A minimum of three replicate determinations of solubility in each pH condition is recommended . Standard buffer solutions described in the USP are considered appropriate for use in solubility studies . Acid or Base titration methods , can also be used with justification to support the ability of such methods to predict equilibrium solubility of the test drug substance. 22

Shake-flask method:

Shake-flask method The classical and most reliable method of log P determination is the shake-flask method 23

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which consists of dissolving some of the solute in question in a volume of octanol and water, then measuring the concentration of the solute in each solvent. The most common method of measuring the distribution of the solute is by UV/VIS spectroscopy. 24

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Pharmacokinetic Studies in Humans- Mass Balance Studies Absolute Bioavailability Studies Intestinal Permeability Methods- In vivo intestinal perfusions studies in humans. In vivo intestinal perfusions studies in animals . In vitro permeation experiments with excised human or animal intestinal tissue. In vitro permeation experiments across epithelial cell monolayers. PERMEABILITY DETERMINATION 25

Pharmacokinetic Studies in Humans :

Pharmacokinetic Studies in Humans 26 Mass balance studies:- Pharmacokinetic mass balance studies using labeled, stable isotopes or a radiolabeled drug substance can be used to document the extent of absorption of a drug. Because this method can provide highly variable estimates of drug absorption for many drugs, other methods described below may be preferable.

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27 Absolute Bioavailability Studies:- Oral BA determination using intravenous administration as a reference can be used . Depending on the variability of the studies, a sufficient number of subjects should be enrolled in a study to provide a reliable estimate of the extent of absorption. When the absolute BA of a drug is shown to be 90% or more, additional data to document drug stability in the gastrointestinal fluid is not necessary.

Intestinal permeability methods :

Intestinal permeability methods In vivo intestinal perfusions studies in humans . In vivo intestinal perfusions studies in animals. In vitro permeation experiments with excised human or animal intestinal tissue. In vitro permeation experiments across epithelial cell monolayers . 28

Instability in the Gastrointestinal Tract:

Instability in the Gastrointestinal Tract 29 Drug solutions in these fluids should be incubated at 37 o C for a period that is representative of in vivo drug contact with these fluids; for example, 1 hour in gastric fluid and 3 hours in intestinal fluid. Obtaining gastrointestinal fluids from human subjects requires intubation and may be difficult in some cases. Use of gastrointestinal fluids from suitable animal models and/or simulated fluids such as Gastric and Intestinal Fluids USP can be substituted .

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For capsules and tablets with gelatin coating, Simulated Gastric and Intestinal Fluids USP (with enzymes) can be used. The USP Apparatus I ( basket method ) is generally preferred for capsules and products that tend to float, and USP Apparatus II ( paddle method ) is generally preferred for tablets. such modifications can be justified by comparing in vitro dissolution with in vivo absorption data (e.g., a relative BA study using a simple aqueous solution as the reference product. DISSOLUTION PROFILE 30

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When comparing the test and reference products, dissolution profiles should be compared using a similarity factor (f 2 ). SIMMILARITY FACTOR F 2 31

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The similarity factor is a logarithmic reciprocal square root transformation of the sum of squared error and is a measurement of the similarity in the percent (%) of dissolution between the two curves. Two dissolution profiles are considered similar when the f 2 value is > 50. To allow the use of mean data, the coefficient of variation should not be more than 20% at the earlier time points (e.g., 10 minutes), and should not be more than 10% at other time points. 32

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Bio waivers:- Bio waivers means to get a waive off for doing bioavailability and bioequivalence studies. BCS gives bio waivers only for class -1 drugs for pre (IND/NDA and ANDA) and post approval phase. Criteria for bio waivers The drug substance should be highly soluble and highly permeable( class-1) An immediate release(IR) drug product The drug should not be a narrow therapeutic index . Drug should be stable in GI tract. BIOWAIVERS 33

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F or waiver of an in-vivo relative bio-availability study, dissolution should be greater than 85% in 30 minutes in the 3 recommended dissolution media. Two dissolution profile may be considered similar when compared using f2 metric (f2>50) as described in the guidance for industry on dissolution testing. 34

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Limits for permeability and solubility must be balanced. -vitro methods should be sufficiently robust for correct classification. It must predict the in-vivo dissolution system well. Rate limiting step for in-vivo absorption must be well defined. BASIC REQUIRMENTS OF BCS 35

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Potential Cost Savings- The potential saving is a function of the potential number and likely cost of bioequivalence studies saved (not performed). To examine the potential saving, the number of bioequivalence studies performed by the pharmaceutical industry per year was examined. INDUSTRIAL IMPLEMENTATION 36

REGULATORY APPLICATIONS:

REGULATORY APPLICATIONS NDAs- This approach is useful only when the drug substance is highly soluble and highly permeable (BCS Class I) They do not apply to food effect bioavailability (BA) studies. ANDAs can be requested for rapidly dissolving immediate release (IR) test products containing highly soluble and highly permeable drug substances 37

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This approach is useful when the test and reference dosage forms are pharmaceutical equivalents. Post approval Changes- it can be requested for significant post approval changes to a rapidly dissolving immediate release (IR) product containing a highly soluble, highly permeable drug substance. 38

Conclusion:

Conclusion 39 The in vivo performance of the drug depends upon its solubility and permeability. The biopharmaceutical classification system is the guiding tool for the prediction of in vivo performance of the drug substance and development of drug delivery system to suit that performance. The knowledge of the biopharmaceutical class of the drug substance is also essential for bio waivers thereby reducing the cost both in terms of money and time.

Asked questions :

Asked questions Describe BCS & its significance. Give idea regarding to BCS classification & its application in development of new drug formulation. 40

References:

References 41 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: 413-42(1995 ) Remington’s pharmaceutical sciences www.pharmainfo.ne t Journal of Pharmaceutical science vol.96(3),March 2007 BCS classification system. Highlight of the FDA’s draft guidance Brahmandkar D.M., Jaiswal S. B. Biopharmaceutics and Pharmacokinetics, page no-315

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