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Session Topic:

Application of Biopharmaceutics, BCS, Biowaver to Assist FDA for Drug Approvals

Date & Time: 10:00am-12:00pm, Friday, 12/13/2019

Location: Room: 607 at Temple University Center City Campus

Address: 1515 Market Street, Philadelphia, PA 19102Presentation to Chinese Delegates

Reza Fassihi, Ph.D., HPA, AAPS FellowProfessor of Biopharmaceutics and Industrial Pharmacy

Temple University School of PharmacyPhiladelphia PA 19140

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What is Applied Biopharmacutics (AB)• AB comprehensively covers a complex and developing

scientific area, and interplay between the physicochemical properties of the drug, membrane transporters, permeability and GI physiological environment (mechanical and biochemical environments experienced by the luminal contents).

• It is relevant to preclinical, clinical, industrial pre-formulation and formulation development scientists, as well as those in regulatory affairs.

• It encompasses the field of characterizing, describing, evaluating, optimizing and predicting drug absorption, bioavailability and bioequivalency.

• It covers and considers IVIVC , Biowavers and methods applied in these fields.

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Prediction of Intestinal Absorption• For nearly half a century scientists have tried to develop theoretical

model capable of predicting oral drug absorption in humans. In recent years three models based on their dependence or independence on the spatial and temporal variables are proposed:

• Quasi-equilibrium models ( based on pH partition hypothesis and the absorption potential concept) provides basic guideline for absorption trends.

• Steady-state models (film model and the mass balance approaches) may provide estimate of the fraction of dose absorbed.

• Dynamic models ( dispersion,mixing tank and compartmental absorption and transit models-CAT) predicts the fraction of dose absorbed and is used to evaluate plasma concentration profiles.

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Center for Drug Evaluation and Research Biopharmaceutics Council Effective Date: 05/16/19

• Biopharmaceutics is a broad-based scientific discipline that studies the effect and interplay of the physicochemical properties of a drug, its dosage form, and the intended route of administration on the rate and extent of the drug’s absorption.

• Currently, CDER has multiple offices and multiple programs addressing various issues related to biopharmaceutics.

• Coordination is needed to foster collaboration and promote consistent and integrated biopharmaceutics-related activities throughout CDER.

• The formation of the CDER Biopharmaceutics Council (the Council) will help achieve these objectives.

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• POLICY:• The Council is a multidisciplinary and cross-organizational panel providing senior

management support to CDER on the development and application of policies, practices, and recommendations related to biopharmaceutics in drug review processes, as well as to other CDER programs, as appropriate.

• The Council will help ensure that biopharmaceutics-related policies, practices, and recommendations are implemented in a consistent manner throughout CDER.

• For the purposes of the Council, biopharmaceutics-related issues generally have implications for product quality (e.g., release testing) and/or clinical effectiveness or safety (e.g., formulation and physicochemical effects on drug absorption).

• Further issues relate to : IND, NDA 505(b)(1) of the FD&C Act, NDA 505(b)(2) of the FD&C Act, and ANDA 505(j) of the FD&C Act

Center for Drug Evaluation and Research Biopharmaceutics Council Effective Date: 05/16/19

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It takes ~ 10-13 years for a new molecular entities “NMEs” to reach market and about $800M---$1 B. In 2019 41 NMEs were approved by the FDA. In 2018, 59 and in 2017, 46 NMEs. (From: Applied clinical trials 2015)

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Various routes of drug administration, distribution, elimination and pharmacological effects

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Modified from Rang & Dale (1987).

Therapeutic Response or Toxicity

Oral

(MD, molecular dynamics; DFT, density functional theory computations; MC, Monte Carlo methods; CFD, computational fluid dynamics; DEM, discrete element method; FEM, finite element method; SPH, smoothed particle hydrodynamics; IVIVC, in vitro–in vivo correlations; PBPK). Common terms : PAT, QbD, QTPP (quality target product profile), CQAs (critical quality attributes), and CPP (critical process parameters). (From Rantanen and Khinast, J.Pharm.Sci.2015).

Formulation Sciences and Biopharmaceutics in drug delivery system design

Target & Response

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Especially Oral solids

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Types of Oral Drug Delivery Systems- FDA Approved

Bi-layer tablet

Tri-layer tablets

Enteric coated Minitablets and Pellets

Microporous CR mini-matrices

Push-pull Osmotic pump

Pellets in tablet

Tri-layer matrix caplet

Compression Coated

CR coated beads

From Fassihi (2017)12/16/2019 R.FASSIHI 9

Examples:EnzymesNifedipineOmeprazole

Fassihi (2017; 2019)

Poorly Soluble Compounds

Class I, 5%

Class II, 70%

Class III, 5%

Class IV, 20%Class I:High solubility, High permeability

Class II: Low solubility, High permeability

Class III: High solubility, Low permeability

Class IV:Low solubility, Low permeability

Benet, L. et al., Bulletin Technique Gattefosse Vol. 99, 2006

• About 90% of drugs are classified as poorly soluble• BCS Class II and BCS Class IV

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R2 = 0.340N= 184 compounds

Oral Bioavialbility: Human vs. AnimalDo they correlate?

A confidence interval (CI) is ideal for quantifying the degree of uncertainty around common parameters of interest such as the center of a sampled population, or its spread. PI =Prediction Interval

(Eur. J. Pharm Sci. 2014; 16;57, 280-291)

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Drug absorption and metabolism can vary between animal species and therefore it is not always possible to predict the influence of biological factors (e.g. pre-systemic metabolism) on drug uptake in humans from preclinical animal studies.

Physiological Constraints: GI environment and its impact on the dosage forms and drug release and absorption

Small Intestine SolutionVolume ~ 500mlpH ~ 4-7.5 HCO3

- ,MucusMaltase-Lactase-Sucrase-Lipase-NucleaseCarboxy and Amino peptidaseFats-Fatty Acids, LecithinBile saltsTransit time ~ 3-4 hrSurface tension lowPermeability highVariations in Cytochrome P450 3A4 levels*

Gastric SolutionVolume ~ 300mlpH = 1-3WaterHCl, Na+ ,K+

PO4-3 ,SO4

-2

HCO3- ,Mucus

Pepsin, ProteinResidence time- variable 0.25 - 5 hoursSurface tension < waterPermeability low

Complex Colonic Micro and Macro EnvironmentPermeability- Drug dependentTransit time 1 to >24 hRedox potential -400mvBacteria(cfu/g), 1x1012

pH ~ 7Fluid~ 187mL(total), 13mL(free)Length = 1.66 mSurface area = 3 m2

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*3-90 pmol/mg2-98

pmol/mg

2-38 nmol/mg

From Fassihi 2017

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Developability of new chemical entities (NCEs) and Hurdles: BCS and DCS tools

Developability Hurdles

BCS and DCS

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E. Sjögren et al. / European Journal of Pharmaceutical Sciences 49 (2013) 679–698

4 key factors:

Drug Delivery system Route of administration-Absorption Target-Drug Interaction-(response)

(PK / PD)

(Fassihi et.al. 2019 -Targeted Nanosystems for Therapeutic Applications: ACS Symposium Series; Washington, DC, 2019).

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Example:

Drug delivery systems and targeting:

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Most important barrier between the body proper and the external environment: A Single layer of cells

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In the GI tract, gastric acid and pancreatic and biliary juices take part in barrier function by degradation of bacteria and antigens; pathogenic bacteria are kept under control by the normal flora and secretion of chloride by enterocytes.

From: Johan D. Söderholm Physiology of the Gastrointestinal Tract, Two Volume Set. DOI: © 2012 Elsevier Inc. 10.1016/B978-0-12-382026-6.00074-9

Most important barrier between the body proper and the external environment: Molecular interplay in the GI tract

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Schematic of the villi covered by a monolayer of epithelial cells, separating the lumen from the blood capillary network , and the structure of epithelial cells, the tight junctions and the basement membrane.

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Lumen

Estimated dimensions of cells, and microenvironment

Physiological Constraints: Transit time in GI tract / PK A Scintigraphic analysis using labeled CR pellets (Tc-99m) and an Osmotic

Pump tablet (In-111) or Sm153 Neutron activated Microgranules

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Scintigraphic images for one volunteer, depicting the gastrointestinal transit of Sm153 Labelled microgranules.

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Drug absorption and transit time:Absorption Window Mapping of Drugs: Case Study 1

Compartmental absorption

Reza Fassihi (2017); Pharmaceutical Dosage Forms-Capsules; Chapter 12, pages: 317-344. “Taylor & Francis Group, LLC”.

Targeting in the GI tract

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• Four dimensionless parameters are fundamental variables for the estimation of the fraction dose absorbed (Fa) from the intestine: Initial saturation (Is), absorption number (An), dose number (Do), and dissolution number (Dn).

• Physicochemical properties of a drug and physiological factors of the intestine are incorporated into these parameters.

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- dMdt

=Q C0 -Cout( ) = 2pRPeff

C dz0

Lò

The small intestine is assumed to be a cylindrical tube with the surface area of 2πRL, where R is the radius and L is the length of the tube.

Q: volumetric flow rate. Peff: effective permeability

Macroscopic mass balance approach

( For more details see Yu et al. “Advanced Drug Delivery Reviews 19 (1996) 359-376”).

For insoluble drugs the microscopic and macroscopic approaches consider the dissolution of the particles and the absorption from solution of the drug from a set of differential equations which contain three dimensionless groups:dose number (Do),dissolution number (Dn) and absorption number (An).

D is the dose, Vo is the volume set to be 250 ml, S is physiological solubility, is particle density, r0 is the particle radius, R is tube radius, Di is diffusivity, L is the length, Q is volumetric flow rate.

Adv.Drug Del.Rev.19,359 (1996).

D/S >250ml GI condition is not optimal

Defined as the ratio of dissolution rate to flow rate

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An = < Tsi >R / Peff

=pRLPeff

Q

Absorption number: ratio of the mean small intestinal transit time <Tsi> to absorption time (R/Peff)

Prediction of intestinal absorption for drugs

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Permeability determination in humans: Loc-I-Gut Techniques: Through intestinal perfusion using the Loc-I-Gut instrument—a multichanneled tube with two or more balloons for insulation of different intestinal segments

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Loc-I-Gut is a perfusion technique for the intestinal regional absorption.

Hans Lennernas Mol. Pharmaceutics 2014, 11, 12−23

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Human in Vivo Regional Intestinal Permeability: Importance for Pharmaceutical Drug Development

Hans Lennernas Mol. Pharmaceu cs 2014, 11, 12−23

Summary of the in vivo effective permeability (Peff) of human jejunum and ileum to 11 drugs. The perfused small intestinal segment was 20, 30, or 80 cm long, and the single-pass perfusion rates were 5, 10, or 15 mL/min. The Peff was calculated using eq. 3.

Q in is the single-pass perfusion flow rate.

eq.3

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GastroPlus - uses Dimensionless Transport Parameters and formulation parameter based on BCS, CAT model

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( For more details see Yu et al. “Advanced Drug Delivery Reviews 19 (1996) 359-376”).

Adv.Drug Del.Rev.19,359 (1996).

Drugs S(mg/ml) (gm/ml) D(mg) Vo (ml) r₀ (m) Do Dn

Digoxin 0.024 1200 0.5 250 25 0.08 0.52

Griseofulvin 0.015 1200 500 250 25 133 0.32

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Estimated fraction of dose absorbed vs dissolution number (Dn), and dose number (Do).

Note: Digoxin is viewed as dissolution limited drug.

Griseofulvin has high dose is a solubility limited drug.

Examples:

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Mechanistic Approaches to Predicting Oral Drug Absorption1. Modeling and simulation of oral drug absorption have been widely used in drug

discovery, development, and regulation since the mid-1990s. 2. Predictive absorption models are used to determine the rate and extent of oral drug

absorption, facilitate lead drug candidate selection, establish formulation development strategy, and support the development of regulatory policies.

3. Common drug absorption models include- Dispersion and Compartmental models: The compartmental models include: The compartmental absorption and transit model (CAT model) Grass model; Gastrointestinal transit absorption model (GITA); Advanced compartmental absorption and transit model (ACAT); and Advanced dissolution, absorption, and metabolism model (ADAM).

-Currently predictive performance is improved by accounting for multiple factors such as drug degradation, gastric emptying, intestinal transit, first-pass metabolism, and intestinal transport.

For future model development, more heterogeneous features of the gastrointestinal tract (villous blood flow, metabolizing enzymes, and transporters), food effects, and drug-drug interactions should be fully characterized and taken into consideration. Moreover, predicting population inter- and intra-variability in oral drug absorption can be useful and important for the evaluation of clinical safety and efficacy of drugs.

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Physiologically Based Pharmacokinetic (PBPK); SimCyp; ADAM (advanced dissolution, absorption & metabolism).

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CR systems for Carbamazepine and QuetiapineBiopharmaceutical Considerations in development of CR dosage forms

IVIVC

Administration

Bioavailability Fasted vs. Fed

Number of subjects

Regional variations:pH, fluid volume, surface area, Gut wall enzymes, transporters, transit time.

Drug properties: Solubility Dissolution, MW & Shape, Lipophilicity, Ionization, Permeability

Quetiapine fumarate moderately soluble in water and Carbamazepine practically insoluble in water; Bioavailability of both drugs > 80%; Quetiapine is highly permeable while Carbamazepine is slowly and variably absorbed.

Formulation:

API dose, ExcipientsSpecial additives Stability, Unit dose IR vs MR

IVIVC

Seroquel-XR 50-400mg; Carbatrol-XR 100-300mg

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Multiparticulate systems: Nonpareil core pH-Modulation for sustained and complete drug release Carbamazepine case- Basic in character/solubility issue

Nonpareil Core

Eudragit RS/RL SR Coating

Drug, Succinic Acid, Wetting Agent

Succnic Acid

Permeable Coating Layer

0102030405060708090

100

0 5 10 15 20

% R

elea

sed

Time (hr)

pH = 7.0

Drug only

Drug+succinic acid

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Carbamazepine CR ;Patent # 5326570

Extended-Release Capsules: The three bead types are combined in a specific ratio to provide daily dose of (300mg). T ½ =12-17 hr on repeated doses.

y = 0.9037x + 4.9264R² = 0.8759

0102030405060708090

0 20 40 60 80%

rel

ease

d% absorbed

300mg; N=32

Relationship between carbamazepine release, plasma levels and IVIVR.12/16/2019 R.FASSIHI 31

Formulation-I : excipients Mg/tablet % of tablet

API (Quetiapine fumarate)LactoseMCCHPMC E50LV PremiumPurified waterMg.St.

460.51152.62

50.87120.00

q.s.16.00

57.6 19.1

6.315.0

-2.0

Formulation-II

APILactoseMCCHPMC E50LV PremiumHPMC E4M Premium CRPurified waterMg.St.

460.5181.7481.75

120.040.0

q.s.16.0

57.6 Quetiapine fumarate10.210.215.0

5.0-

2.0Formulation-II has slower release rate relative to the release rate from formulation-I

Quetiapine fumarateThe tablet formulation is 100% bioavailable relative to solution.

Table-1

Monolithic systems: SEROQUEL XR® (quetiapine fumarate)

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Figure- Shows dissolution profiles of IR tablet and formulations I and II using, USP apparatus 1; 750ml of 0.1N HCl for 2 hours at 100 rpm and then adding 250ml of 0.2 M sodium phosphate buffer to afford a pH of 6.2 for the remainder of dissolution.

0

20

40

60

80

100

120

0 5 10 15 20

IRCR-I

CR-II

Time (hr)

% R

elea

sed

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Formulations # AUC 0-24 (N=16) Cmax

I CRII CRIR

488656094818

505433563

Figure - Shows plasma levels of an IR twice a day and formulations I and II.

Patent# 5,948437

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Cyclosporine: a cyclic *undecapeptide used as an immunosuppressantlarge cyclic molecule (1202 Daltons) is a highly lipophilic molecule with water solubility <0.002%

Neoral® Soft Gelatin Capsules : Cyclosporine 25 or 100 mg ; alcohol,USP dehydrated; Corn oil-mono-di-triglycerides, polyoxyl 40 hydrogenated castor oil NF, DL-α-tocopherol USP, gelatin NF, glycerol, iron oxide black, propylene glycol USP, titanium dioxide USP, carmine .

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Blood profiles after administration of 180mg Self-Emulsifying microemulsion; and 300mg course dispersion formulation, to 24 fasted healthy volunteers (Novartis Pharma AG).

Note: inter-subject variability of the PK profiles

Performance of Two Lipid- Based Oral Drug Delivery Systems in Man Cyclosporine, a large cyclic molecule (1202 Daltons) is a highly lipophilic molecule with water solubility <0.002%. The disposition of cyclosporine from blood is biphasic with a terminal half-life of approximately 19 hours (range: 10 to 27 hours).

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Why it is important to maximize oral bioavailability: Five Reasons

1. To most effectively control plasma concentration, safety, and pharmacological effect

2. Low bioavailability increases variability*3. To avoid side effects due to products of first-pass

metabolism4. To predict the outcome of therapy

(e.g., oral vs. iv ; acute vs. chronic treatment)5. Most cost-efficient use of drug substance

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* variability in drug concentration and response may cause unexpected toxicities or drug-drug interactions.

12/16/2019R.Fassihi (2013);ACCP, September 23rd,Symposium VIII.

From: Hellriegel, E.T., Bjornsson, T.D. & Hauck, W.W. (1996) Interpatient variability in bioavailability is related to the extent of absorption: Implications for bioavailability and bioequivalence studies. Clinical Pharmacology and Therapeutics, 60, 601–607

Low bioavailability increases variability*

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Individual variability in addition to food effect Coated pellets in capsules

Sanctura XR-60mg

Indicated for urge incontinence (antispasmodic, antimuscarinic agent).

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F = 9.6 % (range 4.0 – 16.1%)

Administration of SANCTURA XR® capsules immediately after a high (50%) fat-content meal reduced the oral bioavailability of trospium chloride by 35% for AUC(0-Tlast) and by 60% for Cmax.

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In 2000, the U.S. Food and Drug Administration (FDA) released guidelines for the pharmaceutical industry, allowing for a “Biowaiver” that relied on the Biopharmaceutics Classification System (BCS-I) which classifies drugs according to the biopharmaceutical properties governing their absorption and the controlling factors, permeability, solubility and product dissolution.

The biowaiver extension for BCS class I drugs

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The biowaiver extension for BCS class III drugs will be discussed in Part –II of the presentation.

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Take home message:• Formulation design, Scale up operation and Dosage

form evaluation both “in-vitro / in-vivo” is not a straight forward process

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Thanks For Your Attention.

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I hope that I have shed some light on drug delivery technologies and relevancy of Biopharmaceutics in delivery system design.

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COMPARISON OF THE 3 DYNAMIC MODELS

Correlation between the fraction of dose absorbed and effective human intestinal permeability

• Single mixing tank model : underestimates Fa

• Complete Radial mixing model ( Dispersion model) : Assumes that drug will not leave the small intestine until mean intestinal transit time is reached .

• Mass balance approach : Assumes steady state and hence unable to estimate the rate of drug absorption

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