Oral Absorption Promoters: Opportunities, Issues, and Challenges,

Critical Reviews™ in Therapeutic Drug Carrier Systems, 32(5), 363–387 (2015)

0743-4863/15/$35.00 ©2015 Begell House, Inc. www.begellhouse.com 363

Oral Absorption Promoters: Opportunities, Issues, and ChallengesChetan Yewale, Sushilkumar Patil, Atul Kolate, Girish Kore, & Ambikanandan Misra*

Pharmacy Department, Faculty of Technology & Engineering, The Maharaja Sayajirao University of Baroda, Kalabhavan, Vadodara - 390 001, Gujarat State, India

*Address all correspondence to: Ambikanandan Misra, Professor in Pharmacy and Dean, Faculty of Technology & Engi-neering, The Maharaja Sayajirao University of Baroda, Post Box No.: 51, Kalabhavan, Vadodara - 390 001, Gujarat state, India; Tel.: +91-265-2419231 (Direct -O), +91-9426074870 (M), Fax: +91-265-2418927; Email: [email protected] or [email protected].

ABSTRACT: Transport of a drug across the biological membrane of the gastrointestinal tract has turned out to be a critical barrier against the success of any oral drug delivery technology. The unique advantages of the oral route, along with need for an oral substitute of invasive parenteral formulations and the reduction of intersubject variability in plasma profiles, has been an incentive for the use of excipients with absorption-enhancing properties to boost the bioavailability of poorly absorbed drugs. The development of such excipients is not a simple task, so understanding enhancement mechanisms in relation to physiology can facilitate the identification of structure–function relationships as well as the development of newer agents for customary applications. The literature is replete with reports of absorption promoters, the selection of which is influenced by the mechanisms, safety, pharmacological inertness, rapidity of action, reversibility of induced membrane alterations and excipient compatibility. Despite promising results in preliminary screenings, the development process is hindered by low re-producible efficacy and pharmacologically driven safety issues. In this review, we elaborate on the importance of permeation enhancers in oral drug delivery, their current status, and issues at the forefront of the development of formulations using absorption promoter technologies.

KEY WORDS: Absorption, bioavailability, membrane, oral delivery, permeation, protein.

I. INTRODUCTION

The oral route is generally considered the most convenient and patient-friendly route for drug administration. However, inadequate oral bioavailability of many pharmacologically active com-pounds curtails the usefulness of the oral route. Poor aqueous solubility, poor membrane perme-ability,1 presystemic metabolism, or degradation within the gastrointestinal tract (GIT) are the major factors responsible for the poor oral bioavailability of drugs. Improvements in solubility can solve bioavailability issues with poorly soluble drugs, but they may not be useful if poor membrane permeation is rate limiting, as in the case of Biopharmaceutics Classification System (BCS) class III and IV drugs.2 Poor membrane permeation is frequently encountered due to higher molecular weight (e.g., in proteins and peptides) and insufficient lipophilicity to partition into biological membranes (e.g., of hydrophilic and low-molecular-weight compounds).

Therefore, new approaches are needed to promote the absorption of drugs either by increas-ing partioning of the drug into a biological membrane or by facilitating the transport of the drug through the membrane or tight junctions within membrane. The partitioning of the drug can

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364 Yewale et al.

be improved by the chemical modification3 of an active compound, i.e., prodrug preparation. However, complete clinical evaluation is needed, similar to that of a new chemical entity (NCE), which incurs substantial costs. Therefore, the use of an absorption promoter is a very good alter-native because it includes the addition of specific excipients into the formulation that can facili-tate the drugs across biological membranes.

Technologies employing an absorption promoter can enable the noninjection delivery of poorly membrane-permeable compounds like proteins and peptides, which are currently administered only by injection, as well as new chemical entities (NCEs) with poor absorption profiles that otherwise would not be developed into drugs. Companies are rushing to the market with a battery of compounds in clinical trials, and many others are being protected by intellectual property rights. Examples include steroids, calcitonin, viatmin B12, glucagon-like peptide-1 (GLP-1) analogues, insulin, etc. For insulin, Diabetology, Ltd. (Saint Helier, Jersey, UK), has performed a phase 2a study with oral insulin, offer-ing hope of relief from daily injections for millions of diabetes patients.4

The widespread application of this technology demands that formulators have a thorough understanding of the basic mechanism of action of absorption enhancers, the options available while designing formulations, criteria of selection and potential complications, and regulatory issues with the use of such excipients. Therefore, in the present review, we describe the funda-mentals for application of absorption enhancers and mechanisms of absorption enhancement. The review further focuses on currently used absorption enhancers, delivery system designs, products under development, and challenges in the development of absorption enhancers.

II. DRUG ABSORPTION AND ORAL DELIVERY

After oral administration, absorption plays a major role in controlling the pharmacokinetic profile of drug because the balance between the rate of absorption and the rate of elimination governs the plasma concentration curve of the drug. The use of absorption promoters can favorably modify the profile of a drug after oral administration. Several advantages of oral delivery and absorp-tion promoters5 have been recognized: (1) Needle-free delivery is generally better accepted for medications in chronic conditions than injectable drugs, resulting in improved patient compli-ance over the long term. (2) Elimination of permeability limitation of BCS class III and IV drugs can reduce intra- and intersubject variability observed in these drugs and might be useful in supporting biowaivers in the future due to better in vitro and in vivo correlations for this cat-egory of drugs in the presence of absorption promoters. (3) Absorption enhancement reduces the amount of drug wasted and thus provides an economic advantage for costly drug substances. A large number of compounds on the market could benefit from absorption promoters or from absorption-enhancing technologies.

A. Hydrophilic Small Molecules

Hydrophilic drugs are often poorly absorbed when administered orally. Aminoglycoside anti-biotics6 and bisphosphonates7 are examples of small hydrophilic molecules with one or more hydrophilic functional groups as part of the pharmacophore, which results in poor membrane permeability. BCS class III drugs like voglibose, rosuvastatin, although categorized as small molecules, are too hydrophilic to be absorbed transcellularly, so absorption occurs only through paracellular tight junctions.8 This category also includes some promising pharmacologically active compounds, such as DMP728, a cyclic peptide antagonist of the glycoprotein IIb/ IIIa receptor, which have yet to be developed as injectable products. Meanwhile, inadequate bioavail-ability is preventing their development into noninjectable products as well.9

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365Oral Absorption Promoters: Opportunities, Issues, and Challenges

B. Proteins and Peptides

Of several therapeutic agents, proteins10 and peptides have shown highly potent and selective action, and they are providing new opportunities for future therapeutics that will treat serious illnesses. However, most proteins and peptides simply do not make good drugs due to their oral bioavailability issues. Currently, most protein and peptide products are available as injectable products and the need to develop the non-injectable alternatives is obvious. Hormones like insu-lin and calcitonin, growth factors like erythropoietin, and engineered antibodies or recombinant proteins are among the most advanced prescription drugs, known as ‘biologicals,’ which have been continuously researched to develop noninjectable dosage forms. Along with patient con-venience and compliance, an oral route of insulin delivery can offer pharmacological benefits; absorption of orally administered insulin from intestine can mimic insulin secretion from the pancreas via portal circulation to the liver.4 Clinical benefits such as improved weight control, reduced hyperinsulinemia, and risk of hypoglycemia can be achieved by liver targeting and con-trolled release of insulin via oral delivery.4

Calcitonin, a peptide used in the treatment of postmenopausal osteoporosis, is already avail-able in alternative delivery options such as nasal spray,11 but the bioavailability of the drug by the nasal route is very low (~3–5%) and the nasal route is more is inconvenient than the oral route.

C. Nonpeptide Macromolecules

Drugs belonging to BCS class IV, such as cyclosporine and lovastatin, have a desirable log P value required for absorption through transcellular route (log P 3.64 and log P 3.9, respectively), but they still fail to utilize the transcellular absorption pathway due to their large molecular weights. A log P value greater than that of metoprolol (1.72) is expected to yield high permeabil-ity. Similarly, heparin, low-molecular-weight heparins, unfractionated heparin, and antisense oli-gonucleotide are typically categorized as nonpeptide macromolecules (MW>1,000). Commonly, antithrombotic and thromboprophylactic agents (e.g., low-molecular-weight heparin and unfrac-tionated heparin) administered via the parenteral route could be a good candidates for absorption enhancement technologies.12 Antisense oligonucleotides emerged as potential gene-specific ther-apeutic agents long ago; still, clinical applications are scarce, mainly due to inefficient delivery systems. Oral administration of antisense oligonucleotides results in poor bioavailability due to poor permeability owing to high molecular weight and rapid degradation by the acidic environ-ment of the stomach and by intestinal enzymatic activity.13

Therefore, to extend future applications of the aforementioned therapeutic categories and in some cases to exploit specific pharmacological advantages (e.g., insulin by the oral route) as well as to improve the efficacy and patient compliance of currently available drugs, there is urgent need to solve associated bioavailability issues. An understanding of barriers in the absorption of therapeutic agents can help identify possible modes of absorption enhancement.

III. BARRIERS TO DRUG ABSORPTION

There are many barriers to the absorption of small hydrophilic, proteins/peptides, and nonpep-tide macromolecules in the GIT. These barriers include conditions responsible for degradation of an active compound (e.g., low pH in the stomach, enzymes) before it reaches the wall of the GI tract as well as those limiting diffusion and permeability across the intestinal membrane. The intestinal epithelial membrane is composed of a layer of columnar cells interconnected via tight junctions. In addition, a layer of unstirred water acts as another barrier between the luminal sur-


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faces of the intestinal membrane and the epithelial cell surface (Fig. 1). The minimal thickness of the unstirred water layer is approximately 50–100 µm, which is similar to that of the mucous layer due to its compositional similarity. Glycocalyx, a 500-nm-thick glycoprotein polysaccha-ride sheath present on membranes of brush border cells, binds this layer to the apical surface.

The different barriers to absorption are shown in Figure 1. The drugs with large partition coefficients in the biological membrane, although absorbed rapidly by passive diffusion through apical membrane, diffuse slowly through the aqueous unstirred water layer. The case is reversed in hydrophilic drugs, which may diffuse rapidly through the water layer. Proteins and peptides face challenges of degradation in the GIT and slow diffusion through the unstirred water layer; the transcellular route is unusable due to their large size.

After diffusing through the unstirred water layer, an active compound reaches the lipid bilayer composed of the apical cell membrane through which most drugs are mainly absorbed transcellularly. The apical cell membrane bears a 10-nm-thick lipid bilayer composed of hydro-phobic and hydrophilic molecules, the surface area of which is greatly increased by the presence of a 1-µm-thick brush border. There, a dynamic, regenerating type of epithelial cell encom-passes absorptive cells/enterocytes, secretory, and endocrine cells. The entire epithelial lining is replaced every 3–5 days. Drug molecules can also utilize transporters present on the apical and basolateral cell membranes to enter systemic circulation, but this is limited to certain category of drugs that have structural similarity to the natural substrates of these transporters, e.g., sugars, amino acids, vitamins, organic anions and cations, etc. In addition, drugs can also be absorbed

FIG. 1: Barriers in drug absorption.



via a paracellular mechanism in addition to transcellular permeation wherein the state of tight junctions governs the permeability of the drug, especially those categorized as small molecules. The ‘leakiness’ of the epithelium depends on the network of strands forming the tight junction; therefore, decreasing the number of strands can increase permeability. Passive ion permeation of small-sized solutes, such as sugars, ions, and water, takes place via this route. However, the tight junctions are selective for cations and are impermeable to cations with diameters >0.8 nm.

Absorption of a drug into the blood is generally not restricted once a drug has passed through to the basolateral side of the intestinal epithelium. Before reaching the intestinal epithelium or during permeation through intestinal membrane the peptides, polypeptides and proteins may be subjected to metabolism.

IV. MECHANISMS OF ABSORPTION ENHANCEMENT

Mechanisms by which absorption of the compound can be improved are needed to formulate a solution to the absorption problem. Different absorption enhancers act via mechanisms that might be dependent on the specific physicochemical features of a drug. Moreover, even with the same underlying mechanism, the degree of permeation enhancement may differ depending on parameters like lipophilicity, charge, molecular weight, etc.; drugs with lower lipophilicity may a need higher amount of permeation enhancement. Absorption enhancers act either by preventing degradation/metabolism, or by enhancing membrane permeability (Figure 2).

FIG. 2: (a) Normal epithelial membrane with tight junction restricting absorption of drug. (b) Absorption enhancer acting through different mechanisms.


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A. Preventing Degradation/Metabolism

Encapsulation of a drug, addition of a protease-inhibitor and control of the pH of the drug-releas-ing environment (e.g., chitosan, poly (lactic-co-glycolic acid), alginate, polyethylene glycol, pro-tease inhibitor cocktail, etc.) is necessary to prevent the degradation or metabolism of the drug.14

B. Enhancing Membrane Permeability

Membrane permeability modulation excipients can also be considered true absorption promoters due to their ability to directly alter the permeability coefficient of a drug across the biological membrane. The mechanism by which increased permeability is accomplished is likely to deter-mine whether the increase in permeability is transient and non-cytotoxic.

1. Transient Opening of Tight Junctions

Opening and closing of tight junctions in response to physiological stimuli regulates the permeabil-ity of low-molecular-weight compounds. This mechanism might afford a relatively safe and revers-ible means of permeation enhancement. Any substance that can modulate these tight junctions can act as permeation enhancers, such as cytochalasins B or D, protein kinase C activators, calcium che-lators, and Clostridium difficile toxin, listed by Hochman and Artursson.15 Salama et al. observed increased intestinal absorption of several poorly absorbed compounds through a mechanism of tight junction modulation in rats by a toxin called zonula occludens and its peptide fragments.16

2. Disruption of Lipid Bilayer Packing and Lipid Packing in Intercellular Spaces

The alternative mechanism of permeation enhancement occurs through the promotion of trans-cellular permeation by disrupting lipid bilayer packing and lipid packing in intercellular spaces. Swenson and Curatolo observed that surfactants act as permeability enhancers by epithelial cell membrane partitioning and by disrupting membrane lipid packing, which forms structural defects that reduce membrane integrity. Simultaneously, a surfactant’s ability to extract proteins from the cellular membrane alters membrane permeability in a way that might disrupt the normal extra-cellular–intracellular ion gradients responsible for cellular functions, resulting in cytotoxicity.17

The lipid protein partitioning concept proposes that absorption enhancers commonly work via three different mechanisms: (1) by altering lipids or proteins, (2) by increasing partitioning of the drug, or (3) via another applied excipient. Lipids packed into well-organized structures that constitute the intercellular spaces and disruption of lipid packing in intercellular spaces are also mechanisms for permeability enhancement.

3. Complexation, Carriers, and Ion pairing

Formation of a membrane permeable complex (ion pairing) is another mechanism that works by altering physicochemical drug properties rather than cell membrane properties. Physicochemi-cal properties are altered by forming a complex (ion pair) that is nonpolar or lipophilic in nature (compared to a free drug) and easily partitions in a membrane. There is a difference between complexation to increase aqueous solubility and complexation to increase membrane perme-ability. Miller et al. enhanced intestinal absorption of the highly polar antiviral agent zanamivir heptyl ester and guanidine oseltamivir by including 1-hydroxy-2-naphthoic acid as a counter-ion to facilitate membrane permeation.18 Several recent publications have provided evidence that



sodium N-(8-(2-hydroxybenzoyl) amino) caprylate acts by forming an association with the drug in a way that increases the membrane permeation of the drug.

4. Solvent Drag

Aungst et al. reported solvent drag to be a process that involves increased penetration of the vehicle through the membrane accompanied by increased drug permeation.19 The basic mecha-nism involves the transport of sodium-coupled organic solutes from lumen to cells, wherein the accumulation of sodium generates osmotic pressure forcing fluid absorption through widened intercellular junctions, accompanied by drug absorption. Pappenheimer et al. reported that this drag is primarily involved in the intestinal transport of glucose and amino acids in normal physi-ologic states of ion movement and concentrations.20

V. EVALUATING INTESTINAL ABSORPTION OF THERAPEUTICS

The oral route is favored for the administration of therapeutics; therefore, it is imperative to be aware of the intestinal absorption mechanics of therapeutics before the development process begins. Obviously, sole dependence on costly animal experimentation cannot be used at an early stage; therefore, in vitro absorption models play an important role at early stages of development. The typical features of some of these models, along with advantages and disadvantages, have been summarized in Table 1.21–26 Although Caco 2 cell lines are used most predominantly in other cell lines [e.g., Madin-Darby canine kidney (MDCK) cells], pig kidney epithelial cells (LLC-PK1), rat fetal intestinal epithelial cells (2/4/A1), Caco-2 subclone (TC7), and human colon cells (HT29) are also used to predict intestinal absorption of new compounds.27

VI. ABSORPTION ENHANCERS CURRENTLY IN USE

Various permeation enhancers like bile salts, surfactants, cosolvents, fatty acids, and chelators have been used successfully to improve the bioavailability of BCS class III and class IV drugs. Different absorption enhancers with their corresponding mechanisms of action are listed in Table 2.

A. Bile Salts

Bile salts are amphiphilic; they are surface-active, cholesterol-based, hepatobiliary steroids impor-tant for digestion. Bile salts show membrane permeation enhancing effects through extraction, and solubilization of phospholipids of bilayer membrane and proteins, resulting in improved transcel-lular as well as tight-junction passage and inhibition of mucosal membrane peptidase.28,29 Various dihydroxy salts (e.g., sodium deoxycholate, sodium glycodeoxycholate, and sodium taurodeoxy-cholate) and trihydroxy salts (e.g., sodium cholates, sodium glycocholate, and sodium taurocholate) have been reported to possess permeation enhancement properties.30,31 Dihydroxy salts were found to enhance permeation more effectively than trihydroxy salts due to their higher lipophilicity.32 The efficacy of a permeation-enhancing effect maximum for deoxycholate followed by glycocholate and taurocholate has been attributed to their varying lipophilicity. Chenodeoxycholate was used to enhance the absorption of the octreotide, a somatostatin analog. It has been reported that 1% cheno-deoxycholate increases the Caco-2 permeation of octreotide 3-fold. In rats, 1% chenodeoxycholate increased the absorption of octreotide approximately 75-fold after intrajejunal administration. Fur-ther, 1.26% oral bioavailability of octreotide in humans was achieved at 100-mg doses of chenode-oxycholate. However, studies on insulin absorption in a rat model using glycocholate proved that


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Absorption model Advantages DisadvantagesIn silico • Quick and inexpensive

• No animals required• Difficult to model active

processes and complex interactions of multiple factors

• Not as reliable as real experiment

In vitro Caco-2 cell system

• Good screening model• Less labor, inexpensive• No animals required• Transport mechanisms

and absorp-tion enhancing strategies can be evaluated on a mechanistic basis

• Better for evaluation of toxicity of compounds

• Provides better correlation

• Absence of a mucus layer due to lack of mucus secreting cells.

• Effect of physiological factors cannot be incorporated

• Presence of a thicker unstirred water layer compared to human small Cancer cells.

• “Tighter” monolayer compared to human small intestine

• Inter- and intralaboratory variability

• Long differentiation period

Physicochemical methods (e.g., log P, log D)

• No animals required• Easy, fast, and inexpensive

• Predictive only for transcellular pathway

• Low extrapolative valueEverted intestinal rings/sacs • Easy and inexpensive

• Both animal and human tissue can be used

• Useful for mechanistic studies

• Nonspecific binding• Viability of tissue

(<30 min)• Suboptimal stirring

ConditionsIn situ intestinal perfusion • Contiguous model to in

vivo situation• Evaluation of intestinal

absorption without influence of hepatic first pass

• Implies anesthesia and surgery

• No screening tool• Large number of animals

required for statistically valid data

• High amounts of test compounds

• Difficult analysis due to biological media (e.g., blood)

TABLE 1: Absorption models used for screening of intestinal absorption of drugs.21–26



Absorption model Advantages DisadvantagesIn vivo methods (Rat, Monkey, Dog, Pig)

• Good correlation for compounds without dissolution problems

• Most similar to humans in terms of physiology and biochemistry of the gastrointestinal tract

• Required whole animals • Time-consuming and

labor-intensive • Ethical issues• Difficult to separate

individual variables • Isolated mechanisms

of transport cannot be studied

Ex vivo using chambers (Diffusion chambers)

• Good screening model• Good correlation with in

vivo per-meability data• Uses simple salt buffer

solutions• Different regions of GI

tract can be evaluated• Transport mechanisms

and absorp-tion enhancing strategies can be evaluated on a mechanistic basis

• Tissue viability• Under-estimation of the

permeability• Difficulties with unstirred

water layer• Tissue availability

(human)

Artificial membranes (PAMPA technique)

• Different lipid compositions avail-able

• High throughput• Good predictability

• Only part of absorption process can be predicted

• Membrane retention of lipophilic com-pounds

• Dependent on lipid composition and pH

Brush border membrane vesicles IAM

• Both animal and human tissue can be used

• Useful for mechanistic studies

• Nonspecific binding • Only part of absorption

process can be predicted

TABLE 1: Continued

the colon responds better to the absorption enhancer than does the small intestine.33 Uchiyama et al. used sodium glycocholate and sodium deoxycholate to enhance insulin permeability across the small intestine.34 Moreover, synthetic glycosylated bile acid has been found to be more effective in enhancing the intestinal absorption of gentamicin, vancomycin, and calcitonin in rats.35,36 Apart from drugs, sodium taurodeoxycholate was also used to enhance absorption of peptides like salmon calcitonin (sCT), which, when administered duodenally to rats as proliposomes, resulted in 10.8-fold and 7.1-fold increases in the bioavailability of sCT.37

B. Fatty Acids

The medium-chain fatty acids [e.g., lauric acid (C12) and capric acid (C10)] and long-chain fatty acids [e.g., oleic acid (C18)] can increase permeability by widening epithelial tight junc-


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TABLE 2: Absorption enhancers with mechanisms of action.

Absorption enhancer Mechanism of action ReferencesClass Example

Fatty acids

Long-chain fatty acids (e.g., sodium caprate, sodium N-[8-(2-hydroxylbenzoyl)amino] caprylate (SNAC), 8-(N-2-hydroxy-5-chloro-benzoyl)-amino-caprylic acid (5-CNAC)

Opening of tight junctions Disruption of lipid bilayer packing Formation of membrane permeable complex (Ion Pair)

91, 92, 93

Medium chain glycerides (e.g., Monocaprin)

6Long chain fatty acid ethers (e.g., palmitoylcarnitine)Omega 3 fatty acid 68Fatty acids derivatives (e.g., oleic acid, caprylic acid, lauric acid)

Phospholipid acylchain disruption 38, 39

Bile salts

Sodium taurocholate, Sodium taurodeoxycholate, Sodium Taurodihydrofusidate

Disruption of membrane integrity by phospholipids solubilisation and cytolic effects

30, 31Sodium cholate, sodium deoxycholate, Sodium glycocholate, sodium fusidate Sodium taurodihydrofusidate

Protein denaturation Decreasing mucus viscosity and peptidase activity Solubilizing peptides Forming reverse micelles

Surfactants

Sodium lauryl sulphate, polyoxyethylene, sodium dioctyl sulfosuccinate, laureth-9, polysorbate 20 and 80, PEG-8 laurate, Sorbitan laurate, Glyceryl monolaurate, Quillaja saponins

Extraction of membrane proteins or lipids Solubilization of peptides

27, 48, 49, 50

Chelating agents

EDTA (ethylene-diamine-tetraacetic acid), EGTA (ethylene-glycol-tetraacetic acid), Citric acid

Modulation of tight junction by complexation with calcium and magnesium.

28, 69, 71, 72

Salicylates Sodium salicylate

Increases cell membrane fluidity and complexation with calcium influencing tight junctions



tions, which is appropriate for hydrophilic drugs without prominent cytotoxicity.38,39 Although various fatty acids have been reported to be useful as absorption enhancers, C10 (sodium caprate) has emerged as the primary prototype and has been studied extensively. Sodium cap-rate at 10–13 mM is used to enhance permeability of mannitol, PEGs, arg-vasopressin, and FITC-dextrans across Caco-2.40 Sodium caprate, sodium caprylate, and sodium laurate suc-cessfully enhanced the in situ absorption of cefmetazole in rat colon by 10-, 2-, and 7-fold, respectively.41 However, at similar experimental conditions, sodium caproate increased in situ jejunal absorption of cefmetazole only 6-fold, confirming that the colon responds more than the jejunum to its absorption-enhancing effect.42 The findings of Yamamoto et al. cor-roborated the greater permeation of peptide by sodium caprate in rat colon than jejunum.43 Recently, sodium caprate has been used as the principal constituent of gastrointestinal perme-ation enhancement technology (GIPETTM) by Merrion Pharmaceuticals (Ireland). Using this technology, sodium caprate was developed as an enteric-coated formulation to enhance the absorption of low molecular weight heparins, bisphosphonates and acyline.44 Currently, Novo Nordisk (Denmark) is utilizing GIPETTM technology for oral insulin and GLP-1 analogue delivery. Isis Pharma (Carlsbad, CA, USA) has also developed an enteric-coated formulation of antisense oligonucleotides using C10 fatty acid, which showed enhanced bioavailability in dogs, in pigs, and in preliminary clinical studies.45

Absorption enhancer Mechanism of action ReferencesClass Example

Inclusion complexes Cyclodextrins and derivatives

Increasing solubility and stability of peptide by enzyme inhibition

52

Toxins and venom extracts

Zonula occludens toxin

Induction of actin polymerization and tight junction opening by interaction with zonnulin surface receptor 21, 22

MelittinBilayer micellisation, α-helix channel formation and fusion

Anionic pol-ymers Poly(acrylic acid) derivatives

Enzyme inhibition and extracellular calcium depletion

20

Cationic polymers

Chitosan salts and N-trimethyl chitosan chloride Mucoadhesion and ionic

interaction with cell membrane

55–61Swellable polymers

Polycarbophil and chitosan

Miscella-neous

Azone Disruption of lipid structure20

Protease inhibitor Inhibiting protease enzyme

Table 2: Absorption enhancers with mechanisms of action.


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C. Surfactants

Surfactants are the water-soluble amphiphillic molecules that form micelles in aqueous solution. Based on their charge, nonionic, anionic, and cationic surfactants have been evaluated for their absorption-enhancing effects.27 For nonionic surfactants, along with the type of polar hydrophilic group, the structure and size of the alkyl chain affects permeation enhancement through its ability to solubilize the membrane components. A correlation has been identified between the colonic absorption of drugs and lactate dehydrogenase (LDH) release as an injury marker in the intestine of polyoxyethylene (POE) ethers, POE esters, and POE sorbitan esters.46 A similar effect was found in nonylphenoxy-polyoxy-ethylene surfactants, which led to increase in LDH release or phospholipid release in a rat model, indicating intestinal damage.23 However, the underlying intestinal damage was rapidly revers-ible. On the other hand, dodecylmaltoside (DDM), when used as an absorption enhancer for phenol red, showed no such effect on membrane protein and phospholipid release in rats.47 However, when used for absorption enhancement of adrenocorticotropic hormone (ACTH) in vitro through rat jeju-num and colon, it showed significant protein and phospholipid release at the same concentration.44 Furthermore, the use of DDM in combination with citric acid in an enteric-coated capsule formulation improved azetirelin absorption through the colon by 8.7-fold in rats and 3-fold in dogs.48 Recently, these alkylmaltosides (Intravail) have been used as an absorption enhancer by Aegis Therapeutics (San Diego, CA, USA) for nasal delivery of macromolecules.49 These alkylmaltosides include amphi-philic surfactants, tetradecyl-maltoside (TDM) and dodecylmaltoside (DDM). TDM has been studied with nasal delivery, whereas DDM has been studied for oral delivery of octreotide in rodents.50 Intra-vail showed improved absorption of the synthetic peptide (D-Leu-4)-OB3 in mice resulting in oral bioavailability of 47% compared to subcutaneous administration.51 Improved absorption of intravail was observed; transcellular enhancement and mild morphological change was confirmed through its effect on improved insulin bioavailability through the nasal route.52

D. Chitosan Derivatives

Chitosan is a non-toxic, biocompatible, linear chain polysaccharide made up of glucosamine and N-acetylglucosamine monomers. Continued research has proven its potential as an absorption enhancer for hydrophilic macromolecular drugs through intestinal, buccal, and nasal routes.53,54 The mechanism of absorption enhancement is due to the interaction of a positively charged poly-mer with a negatively charged cell membrane, which promotes the structural reorganization of the membrane proteins and opens the tight junction to facilitate the paracellular transport of hydrophilic macromolecules.55 Chitosan has pKa in the physiologic range (i.e., 6.7) and therefore showed pH-dependent improvement of Caco-2 permeability with the change in degree of ioniza-tion. Acidic pH, where chitosan is largely ionized, increased Caco-2 permeability of mannitol56 and peptide DGAVP.57 While at neutral pH, where chitosan is essentially un-ionized as well as insoluble in water, had no effect on TEER, or on mannitol absorption across Caco-2.58 However, at pH 6.7, a vehicle with 1.5% chitosan improved the bioavailability of buserelin from 0.1% to 5.1% when administered intraduodenally in rats.59 To improve its solubility and effectiveness at neutral pH of the GIT, various chitosan derivatives are being developed. N-trimethyl chito-san chloride (TMC) is a cationic derivative of chitosan with high aqueous solubility at neutral and alkaline pH.60 TMC can act as a carrier for neutral and cationic peptide analogues and can improve their intestinal permeability. Monocarboxymethylated chitosan (MCC) is a chitosan derivative with polyampholytic properties that shows a viscoelastic gel formation tendency with anionic macromolecules (e.g., low-molecular-weight heparin) at neutral pH as well as in aqueous solution and improves their absorption across the intestine.61



E. Cyclodextrins

Cyclodextrins (CDs) have a bowl-shaped arrangement of oligosaccharides of d (+) glucopyra-nose units attached by (1, 4) glucosidic bonds. Their unique structure (i.e., hydrophobic bowl cavity and external hydrophilic surface) endows them with the ability to form inclusion com-plexes with hydrophobic molecules.52 Cyclodextrins, due to their hydrophilicity and large size, lack absorption through intestinal tract and are absorbed mainly from the colon after hydrolysis by anaerobic microflora.62 Complexation with CD can enhance bioavailability of lipophilic drugs through enhanced solubility and dissolution. However, cyclodextrins can also improve bioavail-ability through the enhanced permeability of drugs through improvement in diffusion of a lipo-philic drug across a rate-limiting aqueous water layer by increasing the concentration gradient. Burcin et al. demonstrated that CD forms an inclusion complex with exemestane; the resulting inclusion complex showed improved solubility and, thus, enhanced the intestinal permeability of exemestane.63 Recently, Zang et al. utilized CD to enhance the intestinal absorption of genipin, a P-glycoprotein substrate, through formation of a genipin/hydroxypropyl-β-cyclodextrin (HP-β-CD) inclusion complex.64 Similar results were observed with berberine hydrochloride, a P-glycoprotein substrate complexed with CD.65 In another study, Zang et al. evaluated the effect of the CD complexation using β-CD and HP-β-CD on the intestinal absorption of the Icariin, a bioactive herbal molecule used to treat osteoporosis and male sexual dysfunction.66 The icariin/HP-β-CD inclusion complex showed higher intestinal absorption in a rat model of single-pass intestinal perfusion than the icariin/β-CD inclusion complex, due to HP-β-CD–mediated Pgp inhibition. Compared to free drugs, a thalidomide–hydroxypropyl-β-cyclodextrin complex showed significantly improved aqueous solubility, after which thalidomide dissociated from the complex and easily permeated the intestinal epithelial Caco-2 cells.67

F. Chelators

Different chelators like EDTA and sodium citrate have been appreciated for their absorption-enhancing effects.28 Salts of EDTA are used for the enhancing absorption of the BCS class III drugs. They are characterized by semitransient improvement with slower recovery of the mem-brane.68 Sodium EDTA is nontoxic and is a nonirritant when used in formulations at concentra-tions of 0.01–0.1% (w/v). It improves paracellular permeability by interacting with membrane calcium ions, thus enhancing the membrane fluidity.69 This property of chelators has been utilized for successful delivery of various therapeutics. Oral and rectal delivery of insulin [(ORMD-0801) and GLP-1 analogues (ORMD-0901), Oramed Pharmaceuticals (Jerusalem, Israel)] is based on the use of chelators and has shown promising results.70–72 Another formulation by Oramed con-taining omega-3 fatty acid and sodium EDTA in enteric-coated oral formulas showed only mild gastrointestinal discomfort.68 Oral formulations of salmon calcitonin (sCT) (Oracal) have been developed by Tarsa Therapeutics (Philadelphia, PA, USA) for treating osteoporosis, which con-sists of enteric-coated vesicles of eudragit containing citric acid, which protects sCT and pro-motes its absorption via an EDTA-like mechanism.73–75 The formulation showed a significant positive effect on bone mass density at the lumbar spine of 565 postmenopausal women with osteoporosis in phase II studies and is claimed to be an advanced oral peptide formulation.76

G. Vehicles

Various cosolvents, such as ethanol and polyethylene glycol, have been used in combination with other absorption enhancers to enhance the absorption of macromolecules. These solvents change


376 Yewale et al.

the thermodynamic activity of the drug in solution; thereby increasing its concentration in solu-tion, which facilitates drug partition across the membrane and promotes passive diffusion of the drug.77 Ethanol also causes morphological and functional damage to the gastrointestinal mucosal surface; thereby enhancing vascular permeability. Thomas et al. studied the effects of ethanol on the intestinal epithelial tight junction barrier function using Caco-2 intestinal epithelial cells.78 They observed that ethanol produces a dose-dependent drop in Caco-2 epithelial resistance and facilitates paracellular permeability but did not cause cytotoxicity to the Caco-2 cells. Ethanol also disrupts tight junction proteins, separates them from the cellular junctions, and forms large gaps between the adjacent cells. Hydrophilic aromatic alcohols such as phenoxyethanol, phenyl ethanol, and benzyl alcohol, which are generally used as preservatives and solvents in pharmaceu-ticals, have been used to enhance bioavailability of macromolecules such as insulin, calcitonin, and heparin through enhanced intestinal permeation.79 Capsulin (150–300 IU) is an oral format of insulin containing enhancers that was very effective in a study using the glucose clamp tech-nique.80 Recently, Zang et al. showed that polyethylene glycol 1500 significantly increases the absorption kinetics of paclitaxel in intestinal membranes of mice.81 The effect on absorption char-acteristics of paclitaxel in the intestinal mucosa was attributed to the change in membrane fluid.

H. Other Absorption Enhancers

Apart from the aforementioned absorption enhancers azones, volatile oils, gums, and surfactants can also be used for the same purpose. Kurosaki Yuji et al. investigated the effect of 1-dodecy-lazacycloheptan-2-one (Azone) on the permeability of salicylic acid on keratinized oral mucosa using a mucosal hamster cheek pouch model. Azone resulted in an increase in membrane fluidity by lipid extraction.82 The permeation was significant with 4 h pretreatment with azone irrespec-tive of pH conditions influencing ionization of the drug, resulting in apparent disappearance rate constant 2.7 times larger than that in a non-pretreated control.83 In another experiment, they studied the effect of 1-h pretreatment of 1-dodecylazacycloheptan-2-one (Azone) as 5% emul-sion on permeation of propranolol across keratinized oral mucosa, which resulted in bioavail-ability of 97.1% for propranolol.84 Various surfactants, such as sodium lauryl sulfate (SLS), cetyl pyridinium chloride (CPC), polysorbate 80 (PS-80) and sodium taurocholate (STC), have also been evaluated similarly.85 Surfactant such as PS-80 showed decreased bioavailability at lower pH due to a loss of free fraction of salicylic acid and interaction between drug and surfactant. On the other hand, ionic surfactants, SLS or CPC pretreatment resulted in increased salicylic acid absorption at all pH conditions, with efficacy being proportional to the surfactant concentration. Gum arabic (GA) was used to promote the absorption of sodium.86 The sodium removal rate after perfusing the intestinal lumen with an oral rehydration unit increased with the addition of 5 and 10 g/L of GA. Although GA may induce bidirectional transport, the net water flux was unaf-fected. The selective effect of GA on solute transport was due to the widening of the basolateral intercellular spaces. In another study, the effect of GA on zinc absorption after administration of isotonic solutions showed a higher serum zinc level than without GA.87 Volatile oils have also proven beneficial to improving oral absorption of drugs. Qi et al. studied the bioavailability of hydroxysafflor yellow A in rats after co-administration of 100 and 25 mg/kg of Ligusticum chuanxiong volatile oil, and bioavailability increased 6.48-fold and 4.91-fold, respectively.87

VII. DELIVERY SYSTEM DESIGN AND PRODUCTS UNDER DEVELOPMENT

Absorption-enhancing technologies used for different products are revealed in this section. We were unable to include all of the recent technologies because many products under develop-



ment are not disclosed by the companies before they acquire intellectual property protection. The absorption enhancer cyclopentadecalactone (also known as pentadecalactone) is the intellectual property of Bentley Pharmaceuticals (Exeter, NH, USA); it was used for absorption enhance-ment of the testosterone product Testim. Ethanol, used previously as an absorption enhancer in gel formulation, was replaced by 8% pentadecalactone. This formula is promoted by the trade name CPE-215 and is being used in the development of a nasal insulin delivery product that is in early clinical trials. In comparison to subcutaneous injection, nasal bioavailability of insulin was improved by 10–20%.88 Although the oral mucosa is the optimal route for the administration of peptide drugs, its low permeability limits its application.89 α-Interferon is an antiviral peptide administered via the buccal route to avoid gastrointestinal degradation and first-pass metabolism. Stewart et al. reported enhanced bioavailability using sodium taurocholate in rats.90

Emisphere Technologies (Roseland, NJ, USA) formulated a library of compounds with absorption-enhancing properties of which sodium N-[8-(2-hydroxybenzoyl) amino] caprylate, also known as SNAC or salcaprozate sodium, has the greatest potential. SNAC acts by forming a noncovalent complex with the active agent to propel it through the transcellular route without affecting the tight junction.91 Further, it has the ability to increase membrane fluidity and perme-ability and to induce reversible changes in protein conformation, which reduce its susceptibility to enzymatic degradation.92 Toxicity attributes are not yet conclusive due to variability in results. In a subchronic toxicity study in rats, no adverse effect was observed at a dosage of 1,000 mg/kg/day or greater; however, in vitro toxicity study on Caco-2 cells line showed cell damage.93 Despite this result, a phase 3 clinical trial is being conducted for calcitonin formulation using SNAC as an absorption enhancer. In addition to calcitonin, it has also been used to deliver glu-cagon-like peptide-1 and peptide Y via the oral route. However, its use in the oral delivery of heparin and insulin has failed thus far.

Another absorption enhancer, the Emisphere series, is an 8-(N-2-hydroxy-5-chloro-benzyl)-aminocaprylic acid, known as 5-CNAC. It is used in development of oral calcitonin tablet. A 200-mg 5-CNAC for an 0.8 mg dose of calcitonin showed positive results of calcitonin absorp-tion and biomarker level involved in bone resorption compared with nasal calcitonin, but the sensitivity of absorption to a fed state and the volume of water taken with the tablet is of greater concern for oral tablets than for nasal calcitonin.94

In the conventional technology the bioavailability of peptides has been enhanced by enteric-coated dosage forms. To improve the oral delivery of existing drugs, Errion Pharmaceuticals (Dublin, Ireland) developed a gastrointestinal permeation enhancement technology (GIPET). Medium-chain fatty acids and salts and their derivatives are the mainstay of this technol-ogy, which has shown success in clinical phase 1 and 2 studies. The developmental pipeline includes bisphosphonates, alendronate, and newer agents like zoledroni acid and fondaparinux (a gonadotropin-releasing hormone antagonist) and a pentasaccharide factor Xa antagonist. GIPET formulations have yielded 5–9% oral bioavailability in low-molecular-weight heparin and 7% in alendronate (12-fold), compared with the existing marketed product.38 Sodium cap-rate, a medium-chain fatty acid salt, has the ‘generally recognized as safe’ (GRAS) label for oral administration. Sodium caprate has been used for oral delivery of high-molecular-weight (7701 Da) antisense oligonucleotide (ISIS 104838) and has been tested in preclinical and clinical studies. The preclinical studies of ISIS 104838 in rats, dogs, and pigs showed imperceptible oral bioavailability. On the other hand, an enteric-coated tablet of ISIS 104838 containing sodium caprate showed typical oral bioavailability of 1.4%.95 Sodium caprate was found to be safe in a once-daily dose; studies with tablets containing approximately 1 g of sodium caprate for 7 con-secutive days did not induce any histological changes in small or large intestines. ISIS 104838


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in immediate-release and delayed-release enteric-coated capsule formulation containing sodium caprate (660 mg) have been evaluated in humans.96 The modified-release formulation prolonged the duration of exposure of the intestinal membrane to sodium caprate and increased the overall exposed surface area. Chiasma developed another proprietary technology, based on the use of a system based on medium-chain fatty acid salt, known as a transient permeability enhancer (TPE) system, which successfully reached clinical trial with an oral form of octreotide acetate.97 The limited information available indicates that this formulation is a suspension of a medium-chain fatty acid salt, such as sodium caprylate, and a matrix-forming polymer in a hydropho-bic medium, such as glyceryl triglyceride. The technology claims to extend its application for increasing the oral bioavailability of octreoride, exenatide, and other macromolecules.

Oral delivery of insulin has been a challenging topic for scientists in industry as well in academics. Insulin, in addition to its limited permeation across the intestinal membrane, becomes degraded in the stomach and intestinal lumens. An oral insulin produced by Oramed Pharmaceuticals has displayed positive results and is well tolerated, but the extent of the increase of insulin bioavailability with this product is unknown.72 The patent literature, with unrevealed working composition, claims that the formulation may contain one or more protease inhibitors: bile salt as a permeation enhancer and an omega-3 fatty acid in an enteric-coated formulation.70 Another oral insulin formulation, capsulin (Diabetology) has shown good clinical results; oral doses of 150 and 300 U were sufficient to achieve hypoglycemic effects with gentle increases in plasma insulin levels.80 In addition, absorption enhancers have also been investigated for buc-cal delivery of insulin. This new technology developed by Generex Biotechnology, consists of sodium lauryl sulfate, fatty acids, bile acids, and other excipients in a liquid mixed-micellar spray for buccal delivery that results in the maximum systemic exposure of insulin.98 The excipi-ents used for absorption-enhancement are claimed to be GRAS, and the system can yield 10% bioavailability.99

Unigene developed an enteric-coated salmon calcitonin formulation based on the concept of protein/peptide protection from protease degradation in the small intestine. The technology con-sists of an absorption-enhancer, preferably lauryl L-carnitine with an acidifier to decrease the local pH of the intestinal fluids to reduce protease activity.100 The product is in late-stage clinical trials.

Peptide protection was also achieved by encapsulating of peptide inside the inner core of a micelle composed of a lipid polymer with absorption enhancing property. It is assumed that Solgenix (Princeton, NJ, USA) used this technology for leuprolide delivery, which is in clinical trials. This micellar technology based on peptide protection as well as permeation enhancement increased oral bioavailability in rats and dogs from 2.2% to 20–40%.

Archimedes Pharma (Reading, UK) developed a product using a chitosan derivative with an absorption-enhancing property to deliver morphine, granisetron, and vaccines.101 The success of every technology in humans depends upon its preclinical development process.

VIII. IMPACT OF ENHANCERS ON DOSAGE FORM

Different classes of enhancers have proven to improve the drug permeation. However, perme-ation enhancer alone is not sufficient to optimize the permeation of all types of drug. An effective permeation technique is a combination of a suitable dosage form and a permeation enhancer. The enhancer acts effectively if it successfully surrounds the drug until its absorption. In oro-dispersible tablets, fast-dissolving tablets, and chewing gum; the drug is absorbed through the buccal mucosa and through the GI mucosa. In these dosage forms, the drug dissolves within a short period of time when placed in the oral cavity. Hence, the time required for the enhancer to



act is shorter. Oral absorption enhancers may play a role in buccoadhesive tablets or gastroreten-tive tablets because they help the drug and permeation enhancer to remain in contact with the tissue for a longer period. In drugs that are degraded by the first-pass metabolism, enzymatic degradation, or acid degradation after oral administration, the aim of using buccal or gastroreten-tive delivery systems is to boost the permeation of a drug across the buccal and gastric mucosa, respectively. In the colon, a drug carrier remains up to 5 days and is influenced by physicochemi-cal properties of the drug and of the absorption enhancer selected.102 Rebamipide absorption was improved considerably by formulating it as a chitosan capsule across the colon tissue.103

IX. FUTURE PERSPECTIVE AND CHALLENGES

Most of the absorption promoters effective in increasing permeation of the drug through the membrane undergo preliminary screening on cell culture models or excised tissue membranes in vitro. These preliminary screenings should be reported with the effective concentration range of the enhancer and the safety margin. With oral delivery, it is also necessary to recognize the variables capable of affecting the efficacy in different locations of the intestinal tract. Moreover, in vitro studies can also provide useful information regarding the permeation mechanism. There-fore, customary protocols for preliminary screening of absorption enhancers should be in place to increase the likelihood of developing safe and effective agents.

Establishing correlations among in vitro diffusion experiments and maintaining a precisely controlled milieu in in vivo animal studies are difficult tasks hindered by many variables such as intestinal transit time, type of food, dilution by fluid, and related drug interactions. Variable transit time in the small intestine is a result of variable peristaltic flow rates, which affect the effective contact duration of the enhancer and the drug with the stomach or intestinal wall.104 Although contact time may be increased by mucoadhesive polymers, rapid mucous turnover could be limiting.105 Thus, there is a need to understand this relationship using selective inhibi-tors to facilitate future developments.106 The dilution effect in the small intestine is approximately 45–320 ml (fasted) to 20–150 ml (fed),107 which can impede the attainment of effective concen-tration of absorption enhancer and its transfer to the membrane surface. Therefore, novel tech-nologies modulating the release of the drug and the enhancer to specific absorption sites could help mitigate such problems.108 Dilution with a volume of fluid ingested with the formulation also influences absorption; a 50 ml volume of water was more effective than 200 ml for N-(5-chlorosalicyloyl)-8-aminocaprylic acid/salmon calcitonin.109 Therefore, future studies need to investigate the effect of these two variables. Moreover, use of site-specific release technologies, such as colon targeting, have been useful with agents, such as fatty acids and DDM, due to their greater sensitivity to absorption enhancers.110 However, safety issues originating from bystander absorption must be solved to exploit this approach.

Despite their potential, major concerns associated with enhancers include the association between potency and toxicity. To avoid toxicological risk, the US Food and Drug Administration (FDA) enforces full toxicological assessment of pharmacologically active excipients in preclini-cal and clinical stages, which represents a huge cost burden. For example, paracellular enhanc-ers like cytochalasin D have been reported to cause hepatotoxicity.111 The issues identified with first-generation paracellular modulators have led to safe and selective second-generation paracel-lular enhancers.112,113 Therefore, formulators must stick to absorption promoters with established safety or food-additive classifications.

In addition to the general safety level, specific attention should be given to potential local surface damage of membrane or tissue by the absorption enhancer. However, the high turnover


380 Yewale et al.

rate of enterocytes combined with dilution and absorption of the enhancer itself could defer such effects.114 Furthermore, this damaging action may result from systemic effects leading to interfer-ence with mucosal repair.115 Fortunately, no such reports are associated with enhancers apart from repeat-exposure superficial mucosal damage, which can be controlled through the adjustment of the daily dosage regimen.

Another challenge with absorption enhancers is the opportunity for bystander absorption. But the precise conditions of absorption, such as large-molecular-weight difference between a drug (<10 kDa) and precarious luminal bystanders (<100 kDa) might prevent such an effect. In addition, permeability changes have been reported to occur transiently for the first 20 min and are far less than those observed in disease cases.116 Further research will help eliminate these concerns.

Efforts should be made to establish the duration of permeability enhancement, which should be transient to allow fast and complete tissue recovery. Further, if absorbed, evaluation of phar-macokinetic and pharmacodynamics consequences is required that consider the enhancers as a foreign substance. Further, successful permeation-enhancing formulation may not always make the drug completely available, which may not permit a biowaiver due to inherent inter-subject variability in partially absorbed drugs.

Thus, limiting the toxicity while maintaining the enhancing effect produced by optimizing the concentration of enhancer is a primary challenge for future drug developers. Advances in understanding permeability enhancement mechanisms and the advent of nanotechnology-based formulations containing enhancers can help solve drug permeability issues.

X. CONCLUSION

Poor permeability of orally administered drugs is the major factor limiting the bioavailability of orally administered drugs. The unique barrier properties imposed by the intestinal membrane are contributors to poor permeability, which further contributes to intersubject variability in bioavail-ability. Permeation enhancers can benefit the drugs with this problem, especially BCS class III and class IV drugs. Different mechanisms have been established to underlie permeation enhance-ment effect of different permeation enhancers; this understanding can facilitate the selection of suitable absorption promoters for drugs having specific physicochemical properties. However, certain issues with development of absorption promoter technology remain due to lack of in vitro and in vivo correlation of efficacy, reproducibility, and safety issues. Therefore, the ideal permeation enhancer should be free from any pharmacological effects, should have acceptable safety profile, and should act transiently to result in reproducible bioavailability free from any bystander absorption.

ACKNOWLEDGMENT

The authors (Chetan Yewale, Atul Kolate and Girish Kore) sincere acknowledge the Indian Council of Medical Research, New Delhi for providing ‘‘Senior Research Fellowship’’.

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