MITIGATING THE IMPACT OF FOOD EFFECT: BIOLOGICAL CONSIDERATIONS & FORMULATION APPROACHES

VIEW POINT

Food Effect: Food effect on drug absorption mainly occurs when the bioavailability of drug alters upon administration of a drug product orally in fed state in contrast to fasting state. Clinically assessed by the following parameters namely maximum serum concentration (Cmax), time to reach maximum serum concentration (Tmax) and area under the concentration time curve (AUC0-∞ to AUC0-t), lag time for modified release products (Tlag), Terminal elimination half-life (t1/2) and other relevant pharmacokinetic parameters.

As per the FDA guidance food-effect is established if the 90% confidence intervals for the ratio of population geometric means, based on log-transformed data, for either AUC0∞ or Cmax fall outside the 80-125% bioequivalence limits relative to the reference, i.e. the same formulation administered in the fasting stated1. The fed state represents dosing post ingestion of a high fat, FDA standard breakfast, containing 800 – 1000 kcal with approximately 50% of total calories coming from fat, to maximize potential for demonstrating a food effect.1

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Biological changes during fed state2

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Stomach

Fasting State:1. pH usually ranges between 0.8 to 2 and maintains acidic environment3

2. Gastric retention and emptying is under the control of migrating myoelectric complex (MMC) in the distal antrum and pyloric sphincter4

3. Less fluid volume, enzymatic secretion because it is voluntary due to food ingestionFed State:1. Intraluminal environment changes up to pH 5 leads to increase bu�er capacity2. Gastric transit time of drug to small intestine delays since MMC get disrupted and get replaced by fed state contractions3. Fluid volume increases due to dietary lipids and digestion products4. Pepsin and other stomach enzymes increases leading to high viscous environment5. Acid secretion increases due to voluntary action

Gallbladder

Fasting State:1. Low bile secretionFed State:1. During the digestive phase gall bladder contracts and bile secretion increases which contain bile salts like sodium

taurocholate etc.

Liver

Fasting State:1. Liver enzymes are available to cause �rst pass metabolismFed State:1. Splanchnic blood �ow causes saturation of liver enzymes and avoidance of �rst pass metabolism occurs5

Fasting State:1. No digestive enzymes present.2. Less viscous walls and increased surface tensionFed State:1. Increased fatty acid content and bile salts since the intestinal chyme reaches large intestine2. Increased bu�er capacity3. Decreased surface tension

Small Intestine

Large Intestine

Pancreas

Fasting State:1. Secretion of enzymes is not induced since cell signaling secretions doesn’t take place Fed State:1. Digestive enzyme secretion induced when food is in duodenum (proteases, lipases, nucleases and amyloytic enzymes)

since acetylcholine/cholecystokinin act as secretogogues act as a signaling function

Fasting State:1. Transit time is independent of fed/fasting conditions2. Minimal �uid volume, enzyme secretion and bile salts Fed State:1. Intestinal enzymes increase and bile salts2. Increased �uid volume3. Increased motility4. Increased digestion products5. Increased osmolality6. Potential inhibition of transporters and CYP7. Potential decrease in permeability

Positive food effects Negative food effects

1. Increase in solubilisation and dissolution of poorly water soluble drugs.

2. Bile salts in presence of ingested lipids and its digestive products lead to solubilisation capacity of GIT fluid where the gastric residence time of the drug product increases.

3. Rise in pH increases the drug solubility of weak acids.

4. Inhibition of intestinal transporters can play a role in enhancing bioavailability of BCS class II compounds since transporters predominate to compounds.

5. Reduction in first pass metabolism through several mechanisms like deviated blood flow, increased lymphatic uptake and reduce enteric metabolisms can increase bioavailability.

6. Intake of food increases splanchnic blood flow and increases hepatic blood flow and reduces drug clearance.

7. Co-administration of lipidic food with lipophilic drugs can increase bioavailability by increasing systemic absorption and reducing fractions escaping GIT and limit first pass effect.

8. Dietary monoglycerides and bile salts reduces inhibitory effect of enzymes like CYP3A4, CYP3A and hence reduces metabolism of drugs.6

1. Supports reduced and delayed drug absorption.

2. Delay in transit time manifests prolonged Tmax and may affect

reduction in lag time for Chrono-therapeutic formulations.

3. Similarly decrease in absorption could lead to sub-therapeutic plasma levels (AUC) and Cmax result in inefficacy of

dosage form.

4. For drugs with narrow window increased viscosity in the upper GIT upon fed state can delay disintegration/drug release and hinders diffusion of drugs through absorptive GIT membranes.

5. Food can also hinder drug absorption altering passive permeability and active transport.

6. Increased lipids and bile salts can cause micellar entrapment of drugs and cause reduction in free drug hence reduces permeability which effects drug absorption having low permeability.

7. Inhibition of efflux transporters like OATP, PAT1 which acts as a substrate of various components leads to decrease in bioavailability.6

Food effects: Positive and negative aspects

Based on the different physiological effects as described above, the presence or absence of food in the gastro intestinal system can have

a very BIG say on the pharmacokinetics of ingested drugs. The effect of food on the bioavailability can be either positive or negative. The

effects are illustrated below. The probable reasons behind the positive and negative effect on the drug pharmacokinectics is tabulated below.

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fasting

after meal

fasting

after meal

fasting

after meal

no food e�ect negative food e�ect positive food e�ect

Physico-chemical properties of drug which affect food effect

The absorption of drugs from the gastrointestinal (GI) tract is often limited by dissolution from the dosage form. As per the Noyes-Whitney

dissolution model, the following are the major factors affecting drug dissolution:

• drug diffusivity

• solubility in the gastrointestinal contents

• the surface area of the solid wetted by the lumenal fluids

• Gastro -intestinal hydrodynamics play a role in determining the in vivo dissolution rate.

Solubility in the GI contents is determined by aqueous solubility, crystalline form, drug lipophilicity, solubilization by native surfactants and

co-ingested foodstuffs, and pKa in relation to the GI pH profile.

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Formulation approaches to mitigate food effect

We now know that food intake induces

dynamic changes in the composition and

volumes of luminal fluids as well as the

patterns of GI motility which ultimately

affect the behavior of orally administered

drug products. The changes induced

by food consumption have been briefly

described in the earlier sections of this

blog, however, the formulation strategies

to overcome food effects will be discussed

in this section. The general approaches

that drug development scientists can

implement to mitigate against a food effect

include:

1. Consider an alternative lead drug molecule that will not display food effect, however, this method is complicated, expensive and can delay the drug development process;

2. Apply specific instruction for how a drug is taken with regards to food, although this is restrictive and may interfere with the patient’s daily life orto;

3. Design a formulation which overcomes the overall food effect. When compared with the other available strategies, the latter is considered to be the most practical solution to circumvent potential food effects.

4. Food-drug interactions can lead to a positive food effect whereby food consumption increases drug bioavailability such as for poorly soluble drugs that are presented as immediate release formulations. In addition, food can delay the disintegration of immediate release products in the stomach. The principal cause of positive food effects is the increase in dissolution and solubilization of poorly water-soluble drugs in the fed state. The release of bile salts and the presence of exogenous solubilizing species such as ingested lipids and their digestion products, serve to enhance solubilising capacity of

gastro-intestinal fluid. In order to mitigate positive effects, formulation strategies can be implemented to boost drug bioavailability in the fasting state in order to match that of the fed state, thereby eradicating a food effect. Such approaches include amorphous and solid dispersions, lipid-based formulations and nano-sized preparations.

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Several formulation approaches have

been utilized to overcome food effect

and depends on factors like the drug

physiochemical properties and the

intended therapeutic profile. Some

approaches are discussed below:

a. Nanonized/Micronized preparations: Nanosizing/Microsizing generally refers to reduction of API particle size ranging from 100µm to 500nm. Several techniques even reduce particle size to less than 150nm scale. The approach behind the strategy is that the reduction in particle size leads to increase in surface area available for solvation and increase the rate of dissolution. Nanocrystals a carrier free colloidal delivery system in Nano-sized range is an interesting approach for poorly water soluble drugs providing saturation solubility, dissolution velocity and adhesiveness to surface cell membranes. This polymorphic modification leads to highest energy and lowest melting point which leads to best solubility. Marketed formulation Lipantil Supra® contains fenofibrate in micronized form and the leaflets states that can be taken with or without food.7

b. Amorphous solid dispersions: Amorphous solid dispersions are commonly used for improving dissolution and oral absorption of poorly soluble compounds because they exhibit higher apparent solubility values and faster dissolution rates compared with crystalline materials. Amorphous solid dispersions key components are an amorphous API mixed with a carrier polymer or mixtures of polymer and surfactants8. Common methods of preparation of solid dispersion are hot melt extrusion and spray drying method, even fluid bed granulation has also been used for certain drugs. Melt extrusion forms a dispersion by melting the API/polymer mixture

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followed by rapid cooling to solidify the components and prevent API crystallization. A variety of polymers can be used for this process and the most common polymers include copovidone, povidone, HPMCAS, polyethylene oxide, polyethylene glycol (PEG), HPMC-E5 and methacrylate’s. Plasticizers such as PEGs, poloxamers, and triethyl citrate, may be added to lower thermal transitions of the individual components or the extruded dispersion. Additives to alter dissolution, dissolution, such as surfactants, may be included to extend the duration of supersaturation or delay drug release. Extruders usually run in a continuous mode. Key process parameters include extruder screw design, feed rate, and temperature. It is critical that API and excipients do not degrade at the processing temperature. The extrudate undergoes downstream processing to tailor the physical form for the final dosage form. Downstream processing can include palletization or milling. Spray drying is a solvent-based method commonly used to produce amorphous solid dispersions where droplets are produced and the solvent is removed within milliseconds. The spary-drying process consists of four stages: atomization of the liquid, mixing of the liquid with drying gas, evaporation of the liquid and separation of the dried particles from the gas. Amorphous dispersions can also be produced using conventional manufacturing equipment, such as a fluid bed dryer/granulator or high-shear mixer by spraying an API/polymer solution onto an inert substrate. Marketed formulation Certican®/Zortress® contains everolimus as solid dispersion form and the leaflets states that can be taken with or without food.7

c. Lipid-based formulations: Case studies have shown that

administration of lipidic foods along with formulation have shown positive food effects. Utilizing this as rationale and formulating with lipid itself would enhance the bioavailability of the formulation. Several approaches using SEDDS, SMEDDS owing principally to its elimination of food effects and reducing intersubject variability. Marketed formulation Avodart® contains dutasteride with lipid excipient lecithin and the leaflets states that can be administered with or without food.7

d. Cyclodextrins: Cyclodextrins have been widely used to enhance the oral bioavailability of lipophilic and poorly water soluble drugs. The bioavailability enhancing effects are mainly due to enhanced dissolution kinetics, increased solubility and potential reduction in degradation as well as increased permeability.

© 2019 Syngene International Limited, Bengaluru, India. All Rights Reserved. Syngene believes the information in this document is accurate as of its publication date; such information is subject to change without notice. Syngene acknowledges the proprietary rights of other companies to the trademarks, product names and such other intellectual property rights mentioned in this document. Except as expressly permitted, neither this documentation nor any part of it may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, printing, photocopying, recording or otherwise, without the prior permission of Syngene International Limited and/ or any named intellectual property rights holders under this document.

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About the author

Vivek Kumaravel

Group Leader – Pharmaceutical Development

Vivek Kumaravel is a Group Leader at the Formulations Center at Syngene. He holds a Ph.D. in Pharmaceutical

Sciences from the Maharaja Sayirao University, Vadodara with over 14 years of industrial experience in

formulation development of various dosage forms, including solid orals, liquids and parenterals.

Prior to joining Syngene in 2016, Vivek worked with Sun Pharma Advanced Research Center (SPARC),

Ranbaxy Laboratories Limited and Novartis. During this tenure, he has experience working on various

generics, 505 b(2) applications and late phase programs.

References1. Food-effect bioavailability and fed bioequivalence studies: guidance for industry. Food effect bioavailability and fed bioequivalence

studies: guidance for industry 2002.

2. Varum FJO et al. Food, physiology and drug delivery. Int J Pharm 2013; 2: 446-460.

3. J. Fallingborg et al. pH‐Profile and regional transit times of the normal gut measured by a radiotelemetry device. Alimentary pharmacology and therapeutics 1989; 3: 605-614.

4. Kellow et al. Human inter-digestive motility: variations in patterns from esophagus to colon. Gastroenterology 1986; 91, 386-395.

5. Marasanapalle VP et al. Correlation between the systemic clearance of drugs and their food effects in humans. Drug Development andIndustrial Pharmacy 2011; 11: 1311-1317.

6. Lawless et al. Exploring the Impact of Drug Properties on the Extent of Intestinal Lymphatic Transport - In Vitro and In Vivo Studies.Pharmaceutical Research 2015; 5: 1817-1829.

7. European Summary of Pharmaceutical Characteristics (SPC).

8. A. Newman. Rationale Design for amorphous solid dispersions. Developing solid oral dosage forms. Elsevier Inc. 2017; 497-518.