Bioavailability and Bioequivalence study

Bioavailability and Bioequivalence study

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  Bioavailability and Bioequivalence study Dr.V. S. Kashikar Asso. Prof., Head, Dept. of Pharmaceutics PES Modern College of Pharmacy (For Ladies), Moshi. 1
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  Biopharmaceutics Classification System BCS is a scientific framework for classifying drug substances based on their aqueous solubility and intestinal permeability.  It is a drug development tool that allows estimation of solubility, dissolution and intestinal permeability affect that oral drug absorption.  Key parameters are characterized in BCS classification are : 1. Absorption number (An) 2. Dissociation number (Dn) 3. Dose number (Do) 2
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   Absorption No.(An) :- It is the ratio of Residence time (Tres) to Mean absorbance time (Tabs) An ˃ 1 → indicate Complete absorption  Dissolution No. (Dn) :- The time required for drug dissolution which is the ratio of intestinal residence time to the dissolution time. Higher the Dn → Higher fraction dose absorbed.  Dose No. (Do):- It is the ratio of dose concentration to drug solubility. Do ≤ 1→ higher solubility. Do ˃ 1→ low solubility. 3
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  Class Boundaries  HIGHLYSOLUBLE:- The highest dose strength should be soluble in < 250 ml water over a pH range of 1 to 7.5. Acc. To BCS the highest dose strength volume in 250 ml, where the D/S ratio <250 refer to highly soluble But it s not true for pediatric patient  HIGHLY PERMEABLE:- When the extent of absorption in humans is determined to be > 90% of an administered dose. Based on mass balance or compared with an iv route.  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 This study is important for biological and in vivo-in vitro correalation.(IVIVC). 4
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  BCS CLASSIFICATION 5
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  Biowaiver  The termBiowaiver is applied to a regulatory drug approval process when the drug dossier (application) is approved based on the evidence of equivalence other than through in vivo equivalence testing.  In 1995 the American Department of Health & Human Service US Food & Drug Administration (HHS-FDA) instigated the Biopharmaceutics Classification System (BCS), with the aim of granting so-called biowaivers for SUPACs.  BCS provides biowaivers for Class I, II, III drugs with some specification.  As the BCS is only applicable to APIs which are absorbed from the small intestine. 6
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   A Biowaivermeans that in vivo bioavailability and/or bioequivalence studies may be waived (i.e. not considered necessary for product approval). Bioavailability :- It means the rate and extent to which the active drug substance is absorbed from a pharmaceutical dosage form and becomes available at the site of action. Bioequivalence :-It refers to the drug substance in two or more identical dosage forms, reaches in systemic circulation at the same rate and to the same relative extent. 7
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  Biowaiver for Bioequivalencestudy  If two product, containing the same , have the same concentration time profile at the intestinal membrane surface then they will have the same rate and extent of the absorption. 8 Generic Product Innovator Product / Std recommended by USFDA Ex. Paracetamol Tablet 650 mg DOLO-650 mg API - Paracetamol API - Paracetamol Tablet (oral) Tablet (oral) Bioavailability 80 % Bioavailability 80 %
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  Need & Objectivefor BE studies  If a new product is intended to be a substitute for an approved medicinal product as a pharmaceutical equivalent or alternative, the equivalence with this product should be shown or justified.  In order to ensure clinical performance of such drug products, bioequivalence studies should be performed. 9
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  10 Different Approaches for establishingBE Standard: in vivo BE study Clinical Study In vitro study
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  In vitro BEstudies  In vitro studies, i.e. dissolution studies can be used instead of in vivo bioequivalence under certain circumstances, called as biowaiver .  For waiver of in vivo, bioequivalence test and reference product should exhibit similar dissolution profile under the dissolution test condition defined for rapidly dissolving product.  Two dissolution profile may be considered similar. When both test and the reference products dissolve 85 % or more of the labeled amount in less than 15 minutes in all three dissolution media (at acidic i.e 01.N HCL, at pH 4.5 buffer and at 6.8 buffer ). A profile comparison is unnecessary. 11
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  Techniques For ImprovingBioavailability  One approach to improve the systemic availability of the drug is to deliver it by alternative routes of administration such as parenteral, nasal, vaginal, rectal or transdermal. However, improvement of the oral bioavailability of the drug is the most realistic approach, as it is the most preferred and convenient route of administration.  The techniques to improve oral bioavailability of the drugs are described as follows: 12
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  Enhancement Of DrugSolubility Or Dissolution Rate 1. Micronization 2. Nanonization 3. Supercritical Fluid Re-crystalization 4. Spray Freezing into Liquid (SFL) 5. Evaporative Precipitation into Aqueous Solution (EPSA) 6. Use of Surfactants 7. Use of Salt Forms 8. Use of Precipitation Inhibitors 9. Alteration of pH of the Drug Microenvironment 10. Use of Amorphous, Anhydrates, Solvates and Metastable polymorphs 13
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  11. Solvent Deposition 12.Precipitation 13. Selective Absorption on Insoluble Carriers 14. Solid Solutions 15. Eutetic Mixtures 16. Solid Dispersions 17. Molecular Encapsulation with Cyclodextrins 14
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   Micronization :- Theprocess involves reducing the size of the solid particles to 1 to 10 microns commonly by spray drying or by use of air attrition methods. This process is also called as mico-milling.  Nanonisation :- It is a process of the dry powder is converted to nanocrystals of sizes 200-600 nm . Eg. Amphotericin B. i. Pearl milling ii. Homogenisation in water iii. Homogenisation in non-aqueous media. 15
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   Spray Freezinginto Liquid (SFL) :- This technique involves an aqueous, organic, aqueous- organic cosolvent solution, aqueous organic emulsion and suspension containing drug and pharmaceutical excipients (CO2, helium, propane, ethane). The frozen particles are then lyophilized to obtain dry and free-flowing micronized powders. SFL powder containing amorphous nanostructured aggregates with high surface area and excellent wettability. 16
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   Solvent Deposition:- In this method, the poorly aqueous soluble drug such as nifedipine is dissolved in an organic solvent like alcohol and deposited on an inert, hydrophilic, solid matrix such as starch or MCC by evaporation of solvent. 17
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   Solid Dispersions:  These are generally prepared by Solvent or co- precipitation method whereby both the guest solute and the solid carrier solvent are dissolved in a common volatile liquid solvent such as alcohol.  The liquid solvent is removed by evaporation under reduced pressure or by freeze drying which results in amorphous precipitation of guest in a crystalline carrier.  These method is suitable for thermolabile substances. 18
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  Enhancement Of DrugPermeability Across Biomembrane 1. Lipid technology : With an increase in the number of emerging hydrophobic drugs, several lipid –based formulations have been designed to improve their bioavailability. 2. Ion pairing : The ion pairing approach involves co-administration of a hydrophilic or polar with a suitable lipophilic counterion, which consequently improves the partitioning of the resultant ion-pair into the intestinal membrane. These technique use to improve the oral BA of ionisable drugs. Eg ; Atenolol 19
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  3. Penetration Enhancers: Compound which facilitate the transport of drugs across the biomembrane are called penetration / permeation enhancer or promoters. This method is used mainly in cases of hydrophilic drugs which are expected to have difficulty in penetrating the lipid structure of the biomembrane. Eg. of Penetration enhancers :- Citric acid, SLS, EDTA, Salicylates and fatty acids such as oleic acid linoleic acid arachidonic acid. 20
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  Enhancement of DrugStability 1. Enteric coating : Enteric-coated systems utilize polymeric coatings that are insoluble in the gastric media and therefore, prevent or retard drug release in the stomach. Such systems release the drug in the alkaline media in intestine. Eg. Erythromycin, penicilin v, benzimidazole, omeprazol can be improved by enteric coating. 2. Complexation : It can be used to increase the stability of drug in GI media. Generally Beta- cyclodextrins are potential carriers for increasing the oral bioavailability of caffeiene, sodium salicylate, sodium benzoate. 21
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  3. Use ofMetabolic inhibiters : Co-administration of drug (with low BA) and its metabolism, which can selectively inhibit any of the contributing processes, would result in increased fractional absorption and hence increases bioavailability. 22
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  Significance of Biowaiver 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 bioequivalence 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. 23
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  Reference 1. Shekhawat P,Pokharkar V, Understanding peroral absorption: regulatory aspects and contemporary approaches to tackling solubility and permeability hurdles, Review Article, Acta Pharmaceutica Sinica B, 2017, Volume 7, Page no. 260-280. 2. Dahan A, Miller J, Amidon G , Prediction of Solubility and Permeability Class Membership: Provisional BCS Classification of the World’s Top Oral Drugs , Review Article , American Association of Pharmaceutical Scientists, 2009 , Volume 11, Page no.740 - 746. 3. Chavda H, Patel C, Anand I, Biopharmaceutics Classification System, Review Article , Sys Rev Pharm, 2010, Volume 1, Page no. 62-69. 24
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  4. Valsami G,Macheras P, Computational-Regulatory Developments in the Prediction of Oral Drug Absorption, Review Article , Wiley VCH Verlag GmbH & Co. KGaA, Weinheim , 2011, Page no. 112- 121. 5. Murakami T, Absorption sites of orally administered drugs in the small intestine, Review Article, Informa UK Limited, trading as Taylor & Francis Group, 2017 25
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