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Novel phospholipid (PL)-cyclosporine conjugates were prepared and studied as potential prodrugs for inflammatory bowel disease (IBD). Our approach relies on phospholipase A2 (PLA2 ), which is overexpressed in the inflamed intestinal tissues, as the prodrug activator to potentially release cyclosporine at the site of inflammation. PL-cyclosporine prodrug conjugates with methylene linkers of various lengths between the sn-2 position of the PL and cyclosporine were synthesized and evaluated for in vitro activation. Surprisingly, despite previous work indicating that conjugates with six methylene linkers between the lipid and drug would suffer rapid enzymatic hydrolysis, with cyclosporine this was not observed. However, compounds with longer linkers (n=10, 12 methylene units) display complete release of the drug by PLA2 -catalyzed hydrolysis, thus demonstrating the importance and profound impact of structural fine-tuning. This study represents a proof-of-concept for our hypothesis and a first step towards a truly targeted IBD treatment with cyclosporine that could be administered throughout the GI tract.

The purpose of this work was to investigate the use of the dimethylaminoethyl methacrylate-copolymer Eudragit EPO (EPO) in oral solubility-enabling formulations for anionic lipophilic drugs, aiming to guide optional formulation design and maximize oral bioavailability. We have studied the solubility, the permeability, and their interplay, using the low-solubility nonsteroidal anti-inflammatory drug mefenamic acid as a model drug. Then, we studied the biorelevant solubility enhancement of mefenamic acid from EPO-based formulations throughout the gastrointestinal tract (GIT), using the pH-dilution dissolution method. EPO allowed a profound and linear solubility increase of mefenamic acid, from 10 μg/mL without EPO to 9.41 mg/mL in the presence of 7.5% EPO (∼940-fold; 37 °C); however, a concomitant decrease of the drug permeability was obtained, both in vitro and in vivo in rats, indicating a solubility-permeability trade-off. In the absence of an excipient, the unstirred water layer (UWL) adjacent to the GI membrane was found to hinder the permeability of the drug, accounting for this UWL effect and revealing that the true membrane permeability allowed good prediction of the solubility-permeability trade-off as a function of EPO level using a direct relationship between the increased solubility afforded by a given EPO level and the consequent decreased permeability. Biorelevant dissolution studies revealed that EPO levels of 0.05 and 0.1% were insufficient to dissolve mefenamic acid dose during the entire dissolution time course, whereas 0.5 and 1% EPO allowed complete solubility with no drug precipitation. In conclusion, EPO may serve as a potent solubility-enabling excipient for BCS class II/IV acidic drugs; however, it should be used carefully. It is prudent to use the minimal EPO amounts just sufficient to dissolve the drug dose throughout the GIT and not more than that. Excess amounts of EPO provide no solubility gain and cause further permeability loss, jeopardizing the overall success of the formulation. This work may help the formulator to hit the optimal solubility-permeability balance, maximizing the oral bioavailability afforded by the formulation.

Prodrugs are bioreversible, inactive drug derivatives, which have the ability to convert into a parent drug in the body. In the past, prodrugs were used as a last option; however, nowadays, prodrugs are considered already in the early stages of drug development. Optimal prodrug needs to have effective absorption, distribution, metabolism, and elimination (ADME) features to be chemically stable, to be selective towards the particular site in the body, and to have appropriate safety. Traditional prodrug approach aims to improve physicochemical/biopharmaceutical drug properties; modern prodrugs also include cellular and molecular parameters to accomplish desired drug effect and site-specificity. Here, we present recently investigated prodrugs, their pharmaceutical and clinical advantages, and challenges facing the overall prodrug development. Given examples illustrate that prodrugs can accomplish appropriate solubility, increase permeability, provide site-specific targeting (i.e., to organs, tissues, enzymes, or transporters), overcome rapid drug metabolism, decrease toxicity, or provide better patient compliance, all with the aim to provide optimal drug therapy and outcome. Overall, the prodrug approach is a powerful tool to decrease the time/costs of developing new drug entities and improve overall drug therapy.

Substantially altered gastrointestinal anatomy/physiology after bariatric surgery presents new challenges for the proper medication management of these patients; drug absorption and bioavailability may increase, decrease, or remain unchanged post surgery, depending on the specific drug in question and the type of bariatric procedure. In this article, we offer a concise overview of the various aspects of this clinically significant issue, aiming to provide readers with a clear understanding as well as practical tools to handle drug management post bariatric surgery. Realizing the potentially altered pharmacokinetics of various drugs after bariatric surgery is essential for providing optimal pharmacological therapy and overall patient care.

The aim of this work is to analyze relevant endogenous lipid processing pathways, in the context of the impact that lipids have on drug absorption, their therapeutic use, and utilization in drug delivery. Lipids may serve as biomarkers of some diseases, but they can also provide endogenous therapeutic effects for certain pathological conditions. Current uses and possible clinical benefits of various lipids (fatty acids, steroids, triglycerides, and phospholipids) in cancer, infectious, inflammatory, and neurodegenerative diseases are presented. Lipids can also be conjugated to a drug molecule, accomplishing numerous potential benefits, one being the improved treatment effect, due to joined influence of the lipid carrier and the drug moiety. In addition, such conjugates have increased lipophilicity relative to the parent drug. This leads to improved drug pharmacokinetics and bioavailability, the ability to join endogenous lipid pathways and achieve drug targeting to the lymphatics, inflamed tissues in certain autoimmune diseases, or enable overcoming different barriers in the body. Altogether, novel mechanisms of the lipid role in diseases are constantly discovered, and new ways to exploit these mechanisms for the optimal drug design that would advance different drug delivery/therapy aspects are continuously emerging.

The main factors influencing the absorption of orally administered drugs are solubility and permeability, which are location-dependent and may vary along the gastrointestinal tract (GIT). The purpose of this work was to investigate segmental-dependent intestinal absorption and its role in controlled-release (CR) drug product development. The solubility/dissolution and permeability of carvedilol (vs. metoprolol) were thoroughly studied, in vitro/in vivo (Octanol-buffer distribution coefficients (Log D), parallel artificial membrane permeability assay (PAMPA), rat intestinal perfusion), focusing on location-dependent effects. Carvedilol exhibits changing solubility in different conditions throughout the GIT, attributable to its zwitterionic nature. A biorelevant pH-dilution dissolution study for carvedilol immediate release (IR) vs. CR scenario elucidates that while the IR dose (25 mg) may dissolve in the GIT luminal conditions, higher doses used in CR products would precipitate if administered at once, highlighting the advantage of CR from the solubility/dissolution point of view. Likewise, segmental-dependent permeability was evident, with higher permeability of carvedilol vs. the low/high Peff marker metoprolol throughout the GIT, confirming it as a biopharmaceutical classification system (BCS) class II drug. Theoretical analysis of relevant physicochemical properties confirmed these results as well. A CR product may shift the carvedilol&rsquo, s solubility behavior from class II to I since only a small dose portion needs to be solubilized at a given time point. The permeability of carvedilol surpasses the threshold of metoprolol jejunal permeability throughout the entire GIT, including the colon, establishing it as a suitable candidate for CR product development. Altogether, this work may serve as an analysis model in the decision process of CR formulation development and may increase our biopharmaceutical understanding of a successful CR drug product.

Bariatric surgery is an effective treatment of obesity and related comorbidities. With surgery, the stomach undergoes major anatomical/physiological changes that may affect the oral exposure of drugs, especially marginally soluble weak bases, such as lamotrigine. The aim of this work was to study the solubility/dissolution of lamotrigine in conditions simulating the stomach before vs. after bariatric surgery. Lamotrigine solubility was studied in-vitro, as well as ex-vivo in gastric content aspirated from patients before vs. after bariatric surgery. We then compared the dissolution kinetics of various marketed lamotrigine products in pre- vs. post-operative stomach conditions, different in volume, pH, agitation strength and speed. Decreased lamotrigine solubility with increasing pH (from 1.37 ± 0.09 (pH = 1) to 0.22 ± 0.03 mg/mL (pH = 7)) was obtained. Twelve-fold higher lamotrigine solubility was revealed in gastric content aspirated before vs. after surgery (8.5 ± 0.7 and 0.7 ± 0.01 mg/mL, respectively). Dissolution studies showed that only the lowest dose (25 mg) fully dissolved in the post-surgery stomach conditions, while at higher doses, lamotrigine tablet dissolution was impaired. Neither fast-dissolving tablet, nor tablet crushing, helped resolving this problem. Based on these results, and given that dissolution of the drug dose governs the subsequent absorption, close monitoring of this essential drug is advised after bariatric surgery.

Bariatric surgery may alter the absorption and overall bioavailability of oral drugs. Lamotrigine is a major antiepileptic and mood stabilizer, that its use after bariatric surgery has not yet been studied. In this article, we provide a thorough mechanistic analysis of the effects of bariatric surgery on multiple mechanisms important for the absorption, bioavailability and overall pharmacokinetics of lamotrigine. Attributable to its pharmacokinetic properties and drug characteristics, the use of lamotrigine after bariatric surgery may be challenging. The complex situation in which some mechanisms may lead to increased drug exposure (e.g., decreased metabolism, weight loss) while others to its decrease (e.g., hampered dissolution/solubility, decreased gastric volume), may result in lowered, unchanged, or enhanced lamotrigine plasma levels after the surgery. We conclude with a set of clinical recommendations for lamotrigine treatment after bariatric surgery, aiming to allow better patient care, and emphasizing the extra caution that needs to be taken with these patients.

Vitamin E TPGS (TPGS) has both surfactant and P-glycoprotein (P-gp) inhibitory effects. While surfactants were previously found to cause solubility-permeability tradeoff, TPGS P-gp inhibitory effects may change this unfavorable interplay. The purpose of this research was to investigate the solubility-permeability interplay when using TPGS vs. amorphous solid dispersions (ASD) as oral drug delivery systems for the anticancer, P-gp substrate, lipophilic drug etoposide. The concentration-dependent effects of TPGS (0-100mg/mL) vs. ASD on the solubility of etoposide, as well as the in-vitro (PAMPA) vs. in-vivo (intestinal rat perfusion) permeability of the drug were studied, and the resulting solubility-permeability interplay was analyzed. TPGS above CMC (0.3mg/mL) increased etoposide solubility linearly, and ASD allowed significant supersaturation. Etoposide in-vitro PAMPA permeability decreased markedly with increasing TPGS levels, similarly to the solubility-permeability tradeoff previously defined for surfactants. In contrast, the presence of TPGS significantly increased etoposide in-vivo rat permeability, attributable to P-gp inhibition, similarly to the effect of the potent P-gp inhibitor GF120918 (10µg/mL). High supersaturation achieved via ASD increased the drug's in-vivo permeability to the level obtained by TPGS or GF120918, supporting P-gp saturation. In conclusion, unique pattern of solubility-permeability interplay was found, involving concomitant increase of both the solubility and the permeability, as opposed to the previously reported tradeoff for solubilization methods and the unchanged permeability for supersaturation; P-gp inhibition/saturation by TPGS or by supersaturation allows simultaneous increase of both solubility and permeability, representing a significant advantage of such drug delivery approaches when suitable.

Targeting drugs to the inflamed intestinal tissue(s) represents a major advancement in the treatment of inflammatory bowel disease (IBD). In this work we present a powerful in-silico modeling approach to guide the molecular design of novel prodrugs targeting the enzyme PLA2, which is overexpressed in the inflamed tissues of IBD patients. The prodrug consists of the drug moiety bound to the sn-2 position of phospholipid (PL) through a carbonic linker, aiming to allow PLA2 to release the free drug. The linker length dictates the affinity of the PL-drug conjugate to PLA2, and the optimal linker will enable maximal PLA2-mediated activation. Thermodynamic integration and Weighted Histogram Analysis Method (WHAM)/Umbrella Sampling method were used to compute the changes in PLA2 transition state binding free energy of the prodrug molecule (∆∆Gtr) associated with decreasing/increasing linker length. The simulations revealed that 6-carbons linker is the optimal one, whereas shorter or longer linkers resulted in decreased PLA2-mediated activation. These in-silico results were shown to be in excellent correlation with experimental in-vitro data. Overall, this modern computational approach enables optimization of the molecular design of novel prodrugs, which may allow targeting the free drug specifically to the diseased intestinal tissue of IBD patients.

The enzyme phospholipase A2 (PLA2) is overexpressed in the inflamed intestine in inflammatory bowel disease (IBD) patients, and in this work we aimed to exploit PLA2 as a prodrug-activating enzyme for a novel PL-drug conjugate, thereby liberating the free drug specifically in the targeted diseased tissue(s). The proposed prodrug contains a drug moiety covalently bound through a linker to the sn-2 position of a phospholipid (PL). The NSAID diclofenac was used as model molecule, and four different linker lengths (2, 4, 6 and 8 -CH2 units) were studied. The four PL-diclofenac conjugates were synthesized and characterized by LC/MS and NMR. PLA2-mediated activation of the prodrugs was analyzed in-vitro, and the remaining intact complex and free drug liberation were assessed after incubation with PLA2. The rate and degree of PLA2-mediated activation were highly dependent on the linker length; 2- and 4-carbon linker conjugates were activated to lower extent than the 6-carbon conjugate, and longer linker again decreased the affinity towards PLA2. The 6-carbon linker conjugate was found to be the optimal and released ~95% of the free drug after incubation with PLA2, whereas only ~20% were delivered by the 2-carbon linker prodrug. The 6-carbon linker conjugate was shown to be stable in intestinal perfusate, fresh plasma, and pH4.0 and 6.8 buffers, but not at pH1.0. In conclusion, the results of this work confirm the feasibility of our general aim to exploit PLA2 as a prodrug-activating enzyme of PL-drug conjugates. This may provide a novel oral drug targeting approach in IBD therapy.

The purpose of this work was to investigate key factors dictating the success/failure of cyclodextrin-based solubility-enabling formulations for oral delivery of low-solubility drugs. We have studied the solubility, the permeability, and the solubility–permeability interplay, of the highly lipophilic drug danazol, formulated with different levels (8.5, 10, 20, and 30%) of the commonly used hydroxypropyl-β-cyclodextrin (HPβCD), accounting for the biorelevant solubilization of the drug along the gastrointestinal tract (GIT), the unstirred water layer (UWL) adjacent to the GI membrane, and the overall absorption. HPβCD significantly increased danazol solubility, and decreased the drugs’ permeability, in a concentration-dependent manner. These Peff results were in good correlation (R2 = 0.977) to literature rat AUC data of the same formulations. Unlike vehicle without HPβCD, formulations containing 8.5% HPβCD and above were shown to successfully dissolve the drug dose during the entire biorelevant dissolution...

Nowadays, prodrugs are no longer used as a last resort, rather, they are intentionally designed at the early stages of drug development. Lipidic prodrug strategy, where a drug moiety is covalently bound to a lipid carrier, was initially proposed half a century ago, yet, this approach still remains to be explored. Lipidic prodrugs can join physiological lipid metabolic pathways, and hence provide drug targeting via lymphatic transport or site-specific drug release, improve drugs’ pharmacokinetic profile, overcome obstacles originating from biological barriers and bypass hepatic first-pass metabolism. Physiological pathways of lipid processing, uses of different lipidic prodrugs and their clinical benefits are overviewed. Overall, lipidic prodrugs present a promising approach for overcoming different obstacles and fulfilling various unmet needs in drug delivery/targeting.

The lipidic prodrug approach is an emerging field for improving a number of biopharmaceutical and drug delivery aspects. Owing to their structure and nature, phospholipid (PL)-based prodrugs may join endogenous lipid processing pathways, and hence significantly improve the pharmacokinetics and/or bioavailability of the drug. Additional advantages of this approach include drug targeting by enzyme-triggered drug release, blood&ndash, brain barrier permeability, lymphatic targeting, overcoming drug resistance, or enabling appropriate formulation. The PL-prodrug design includes various structural modalities-different conjugation strategies and/or the use of linkers between the PL and the drug moiety, which considerably influence the prodrug characteristics and the consequent effects. In this article, we describe how molecular modeling can guide the structural design of PL-based prodrugs. Computational simulations can predict the extent of phospholipase A2 (PLA2)-mediated activation, and facilitate prodrug development. Several computational methods have been used to facilitate the design of the pro-drugs, which will be reviewed here, including molecular docking, the free energy perturbation method, molecular dynamics simulations, and free density functional theory. Altogether, the studies described in this article indicate that computational simulation-guided PL-based prodrug molecular design correlates well with the experimental results, allowing for more mechanistic and less empirical development. In the future, the use of molecular modeling techniques to predict the activity of PL-prodrugs should be used earlier in the development process.

In ulcerative colitis (UC), the inflammation is localized in the colon, and one of the successful strategies for colon-targeting drug delivery is the prodrug approach. In this work, we present a novel phospholipid (PL)-based prodrug approach, as a tool for colonic drug targeting in UC. We aim to use the phospholipase A2 (PLA2), an enzyme that is overexpressed in the inflamed colonic tissues of UC patients, as the PL-prodrug activating enzyme, to accomplish the liberation of the parent drug from the prodrug complex at the specific diseased tissue(s). Different linker lengths between the PL and the drug moiety can dictate the rate of activation by PLA2, and subsequently determine the amount of free drugs at the site of action. The feasibility of this approach was studied with newly synthesized PL-Fmoc (fluorenylmethyloxycarbonyl) conjugates, using Fmoc as a model compound for testing our hypothesis. In vitro incubation with bee venom PLA2 demonstrated that a 7-carbon linker between the PL and Fmoc has higher activation rate than a 5-carbon linker. 4-fold higher colonic expression of PLA2 was demonstrated in colonic mucosa of colitis-induced rats when compared to healthy animals, validating our hypothesis of a colitis-targeting prodrug approach. Next, a novel molecular dynamics (MD) simulation was developed for PL-based prodrugs containing clinically relevant drugs. PL-methotrexate conjugate with 6-carbon linker showed the highest extent of PLA2-mediated activation, whereas shorter linkers were activated to a lower extent. In conclusion, this work demonstrates that for carefully designed PL-drug conjugates, PLA2 overexpression in inflamed colonic tissues can be used as prodrug-activating enzyme and drug targeting strategy, including insights into the activation mechanisms in a PLA2 binding site.

Injectable-to-oral conversions for anticancer drugs represent an important trend. The goal of this research was to investigate the suitability of formulation approaches for anticancer oral drug delivery, aiming to reveal mechanistic insights that may guide oral chemotherapy development. TPGS vs. PEG-400 were studied as oral formulations for the anticancer drug etoposide, accounting for drug solubility, biorelevant dissolution, permeability, solubility-permeability interplay, and overall bioavailability. Increased etoposide solubility was demonstrated with both excipients. Biorelevant dissolution revealed that TPGS or PEG-400, but not aqueous suspension, allowed complete dissolution of the entire drug dose. Both TPGS and PEG-400 resulted in decreased in-vitro etoposide permeability across artificial membrane, i.e. solubility-permeability tradeoff. While PEG-400 resulted in the same solubility-permeability tradeoff also in-vivo, TPGS showed the opposite trend: the in-vivo permeability of etoposide was markedly increased in the presence of TPGS. This increased permeability was similar to the drug permeability under P-gp inhibition. Rat PK study demonstrated significantly higher etoposide bioavailability from TPGS vs. PEG-400 or suspension (AUC of 72, 41, and 26 µg·min/mL, respectively). All in all, TPGS-based delivery system allows overcoming the solubility-permeability tradeoff, increasing systemic etoposide exposure. Since poor solubility and strong efflux are common to many anticancer agents, this work can aid in the development of better oral delivery approach for chemotherapeutic drugs.

Intestinal drug permeability is position dependent and pertains to a specific point along the intestinal membrane, and the resulted segmental-dependent permeability phenomenon has been recognized as a critical factor in the overall absorption of drug following oral administration. The aim of this research was to compare segmental-dependent permeability data obtained from two different rat intestinal perfusion approaches: the single-pass intestinal perfusion (SPIP) model and the closed-loop (Doluisio) rat perfusion method. The rat intestinal permeability of 12 model drugs with different permeability characteristics (low, moderate, and high, as well as passively and actively absorbed) was assessed in three small intestinal regions: the upper jejunum, mid-small intestine, and the terminal ileum, using both the SPIP and the Doluisio experimental methods. Excellent correlation was evident between the two approaches, especially in the upper jejunum ( R 2 = 0.95). Significant regional-dependent permeability was found in half of drugs studied, illustrating the importance and relevance of segmental-dependent intestinal permeability. Despite the differences between the two methods, highly comparable results were obtained by both methods, especially in the medium-high P eff range. In conclusion, the SPIP and the Doluisio method are both equally useful in obtaining crucial segmental-dependent intestinal permeability data.

Over the last few decades, polymers have been extensively used as pharmaceutical excipients in drug delivery systems. Pharmaceutical polymers evolved from being simply used as gelatin shells comprising capsule to offering great formulation advantages including enabling controlled/slow release and specific targeting of drugs to the site(s) of action (the "magic bullets" concept), hence hold a significant clinical promise. Oral administration of solid dosage forms (e.g., tablets and capsules) is the most common and convenient route of drug administration. When formulating challenging molecules into solid oral dosage forms, polymeric pharmaceutical excipients permit masking undesired physicochemical properties of drugs and consequently, altering their pharmacokinetic profiles to improve the therapeutic effect. As a result, the number of synthetic and natural polymers available commercially as pharmaceutical excipients has increased dramatically, offering potential solutions to various difficulties. For instance, the different polymers may allow increased solubility, swellability, viscosity, biodegradability, advanced coatings, pH dependency, mucodhesion, and inhibition of crystallization. The aim of this article is to provide a wide angle prospect of the different uses of pharmaceutical polymers in solid oral dosage forms. The various types of polymeric excipients are presented, and their distinctive role in oral drug delivery is emphasized. The comprehensive know-how provided in this article may allow scientists to use these polymeric excipients rationally, to fully exploit their different features and potential influence on drug delivery, with the overall aim of making better drug products.

In inflammatory bowel disease (IBD) patients, the enzyme phospholipase A2 (PLA2) is overexpressed in the inflamed intestinal tissue, and hence may be exploited as a prodrug-activating enzyme allowing drug targeting to the site(s) of gut inflammation. The purpose of this work was to develop powerful modern computational approaches, to allow optimized a-priori design of phospholipid (PL) based prodrugs for IBD drug targeting. We performed simulations that predict the activation of PL-drug conjugates by PLA2 with both human and bee venom PLA2. The calculated results correlated well with in-vitro experimental data. In conclusion, a-priori drug design using a computational approach complements and extends experimentally derived data, and may improve resource utilization and speed drug development.

Poor aqueous solubility is a major challenge in today's biopharmaceutics. While solubility-enabling formulations can significantly increase the apparent solubility of the drug, the concomitant effect on the drug's apparent permeability has been largely overlooked. The mathematical equation to describe the membrane permeability of a drug comprises the membrane/aqueous partition coefficient, which in turn is dependent on the drug's apparent solubility in the GI milieu, suggesting that the solubility and the permeability are closely related, exhibit a certain interplay between them, and treating the one irrespectively of the other may be insufficient. In this article, an overview of this solubility-permeability interplay is provided, and the available data is analyzed in the context of the effort to maximize the overall drug exposure. Overall, depending on the type of solubility-permeability interplay, the permeability may decrease, remain unchanged, and even increase, in a way that may critically affect the formulation capability to improve the overall absorption. Therefore, an intelligent design of solubility-enabling formulation needs to consider both the solubility afforded by the formulation and the permeability in the new luminal environment resulting from the formulation.

The anatomic and physiologic changes in the gastrointestinal (GI) tract after bariatric surgery may significantly affect the pharmacokinetics of medications taken by the patients for various reasons. Unfortunately, there is little information regarding changes in drug absorption after bariatric surgeries, limiting the ability of medical professionals to produce clear recommendations on what changes should be made to the formulations and dosing regimens of drugs after bariatric surgery. In this article, we report and analyze a case of 52-year-old male patient with morbid obesity and attention-deficit/hyperactivity disorder (ADHD) who experienced lack of methylphenidate efficacy after Roux en-Y gastric bypass (RYGB), which was eventually resolved by using the transdermal patch instead of an oral product. Interestingly, in the same patient, a prior gastric band had no effect on the drug's efficacy. Especially in light of a recent case report of methylphenidate toxicity after RYGB, these 2 cases suggest that bariatric surgeries may alter the absorption of orally administered methylphenidate in an unpredictable manner; hence, it is prudent to closely monitor the therapeutic/toxic effects of methylphenidate after bariatric surgery, and to be aware of nonoral treatment options of this medication.

Biopharmaceutical classification system (BCS) class IV drugs (low-solubility low-permeability) are generally poor drug candidates, yet, ~5% of oral drugs on the market belong to this class. While solubility is often predictable, intestinal permeability is rather complicated and highly dependent on many biochemical/physiological parameters. In this work, we investigated the solubility/permeability of BCS class IV drug, furosemide, considering the complexity of the entire small intestine (SI). Furosemide solubility, physicochemical properties, and intestinal permeability were thoroughly investigated in-vitro and in-vivo throughout the SI. In addition, advanced in-silico simulations (GastroPlus&reg, ) were used to elucidate furosemide regional-dependent absorption pattern. Metoprolol was used as the low/high permeability class boundary. Furosemide was found to be a low-solubility compound. Log D of furosemide at the three pH values 6.5, 7.0, and 7.5 (representing the conditions throughout the SI) showed a downward trend. Similarly, segmental-dependent in-vivo intestinal permeability was revealed, as the intestinal region becomes progressively distal, and the pH gradually increases, the permeability of furosemide significantly decreased. The opposite trend was evident for metoprolol. Theoretical physicochemical analysis based on ionization, pKa, and partitioning predicted the same trend and confirmed the experimental results. Computational simulations clearly showed the effect of furosemide's regional-dependent permeability on its absorption, as well as the critical role of the drug&rsquo, s absorption window on the overall bioavailability. The data reveals the absorption window of furosemide in the proximal SI, allowing adequate absorption and consequent effect, despite its class IV characteristics. Nevertheless, this absorption window so early on in the SI rules out the suitability of controlled-release furosemide formulations, as confirmed by the in-silico results. The potential link between segmental-dependent intestinal permeability and adequate oral absorption of BCS Class IV drugs may aid to develop challenging drugs as successful oral products.

The purpose of this research was to investigate drug dose, solubility, permeability, and their interplay, as key factors in oral formulation development for lipophilic drugs. A PEG400-based formulation was studied for five doses of the lipophilic drug carbamazepine, accounting for biorelevant dissolution of the dose in the GIT, and in-vivo bioavailability in rats. With the three lower doses (10, 25 and 50 mg/kg), complete in-vitro dissolution was achieved and maintained throughout the experiment with this formulation, while significant precipitation was obtained with higher doses (100 and 200 mg/kg). Likewise, the studied formulation allowed complete bioavailability in-vivo with the three lower doses, while the same formulation allowed only 76% and 42% bioavailability for the 100 and 200 mg/kg doses, respectively. There was good correlation between the in-vitro and in-vivo results. In conclusion, this work demonstrates that the dose is a crucial factor in formulation development; while a given formulation may be optimal for a certain drug dose, it may no longer be optimal for higher doses of the same drug. Hence, the solubility, the permeability, and their interplay, have to be considered in light of the drug dose intended to be administered in order to achieve successful oral formulation development.

Background Bariatric surgery can lead to changes in the oral absorption of many drugs. Levothyroxine is a narrow therapeutic drug for hypothyroidism, a common condition among patients with obesity. Objective The purpose of this work was to provide a mechanistic overview of levothyroxine absorption, and to thoroughly analyze the expected effects of bariatric surgery on oral levothyroxine therapy. Methods We performed a systematic review of the relevant literature reporting the effects of bariatric surgery on oral levothyroxine absorption and postoperative thyroid function. A PubMed search for relevant keywords resulted in a total of 14 articles reporting levothyroxine status before versus after bariatric surgery. Results Different mechanisms may support opposing trends as to levothyroxine dose adjustment postsurgery. On the one hand, based on impaired drug solubility/dissolution attributable to higher gastric pH as well as reduced gastric volume, compromised levothyroxine absorption is expected. On the other hand, the great weight loss, and altered set-point of thyroid hormone homeostasis with decreased thyroid-stimulating hormone after the surgery, may result in a decreased dose requirement. Conclusions For patients after bariatric surgery, close monitoring of both the clinical presentation and plasma thyroid-stimulating hormone and T4 levels is strongly advised. Better understanding and awareness of the science presented in this article may help to avoid preventable complications and provide optimal patient care.

In the past, a prodrug design was used as a last option to improve bioavailability through controlling transport, distribution, metabolism, or other mechanisms. Prodrugs are currently used even in early stages of drug development, and a significant percentage of all drugs in the market are prodrugs. The focus of this article is lipidic prodrugs, a strategy whereby a lipid carrier is covalently bound to the drug moiety. The increased lipophilicity of the lipid-drug conjugate can improve the pharmacokinetic profile and provide meaningful advantages: increased absorption across biological barriers, prolonged circulation half-life, selective distribution profile (eg brain penetration), reduced hepatic first-pass metabolism, and overall enhanced bioavailability of the parent drug. Moreover, lipidic prodrugs may join the endogenous lipid trafficking pathways, thereby facilitate drug targeting, either by selective absorption pathway (eg lymphatic transport) or drug release at specific target site(s). The different lipid-drug conjugates (triglyceride-, fatty acids, phospholipid-, and steroid-based prodrugs), the physiological barriers that challenge the absorption of these conjugates, followed by their current utilization and potential clinical benefits are described and analyzed, and future opportunities this approach could provide are discussed. Altogether, lipidic prodrugs represent an exciting approach for improving different aspects of oral drug delivery/therapy and may provide solutions for various unmet needs; the use of this strategy is expected to grow.

The solubility-permeability interplay deals with the question: what is the concomitant effect on the drug's apparent permeability when increasing the apparent solubility with a solubility-enabling formulation? The solubility and the permeability are closely related, exhibit certain interplay between them, and ongoing research throughout the past decade shows that treating the one irrespectively of the other may be insufficient. The aim of this article is to provide an overview of the current knowledge on the solubility-permeability interplay when using solubility-enabling formulations for oral lipophilic drugs, highlighting active permeability aspects. A solubility-enabling formulation may affect the permeability in opposite directions; the passive permeability may decrease as a result of the apparent solubility increase, according to the solubility-permeability tradeoff, but at the same time, certain components of the formulation may inhibit/saturate efflux transporters (when relevant), resulting in significant apparent permeability increase. In these cases, excipients with both solubilizing and e.g. P-gp inhibitory properties may lead to concomitant increase of both the solubility and the permeability. Intelligent development of such formulation will account for the simultaneous effects of the excipients' nature/concentrations on the two arms composing the overall permeability: the passive and the active arms. Overall, thorough mechanistic understanding of the various factors involved in the solubility-permeability interplay may allow developing better solubility-enabling formulations, thereby exploiting the advantages analyzed in this article, offering oral delivery solution even for BCS class IV drugs.

The molecular information that became available over the past two decades significantly influenced the field of drug design and delivery at large, and the prodrug approach in particular. While the traditional prodrug approach was aimed at altering various physiochemical parameters, e.g., lipophilicity and charge state, the modern approach to prodrug design considers molecular/cellular factors, e.g., membrane influx/efflux transporters and cellular protein expression and distribution. This novel targeted-prodrug approach is aimed to exploit carrier-mediated transport for enhanced intestinal permeability, as well as specific enzymes to promote activation of the prodrug and liberation of the free parent drug. The purpose of this article is to provide a concise overview of this modern prodrug approach, with useful successful examples for its utilization. In the past the prodrug approach used to be viewed as a last option strategy, after all other possible solutions were exhausted; nowadays this is no longer the case, and in fact, the prodrug approach should be considered already in the very earliest development stages. Indeed, the prodrug approach becomes more and more popular and successful. A mechanistic prodrug design that aims to allow intestinal permeability by specific transporters, as well as activation by specific enzymes, may greatly improve the prodrug efficiency, and allow for novel oral treatment options.

While the solubility parameter is fairly straightforward when assigning BCS classification, the intestinal permeability (Peff) is more complex than generally recognized. In this paper we emphasize this complexity through the analysis of codeine, a commonly used antitussive/analgesic drug. Codeine was previously classified as a low-permeability compound, based on its lower LogP compared to metoprolol, a marker for the low-high permeability class boundary. In contrast, high fraction of dose absorbed (Fabs) was reported for codeine, which challenges the generally recognized Peff-Fabs correlation. The purpose of this study was to clarify this ambiguity through elucidation of codeine's BCS solubility/permeability class membership. Codeine's BCS solubility class was determined, and its intestinal permeability throughout the small intestine was investigated, both in vitro and in vivo in rats. Codeine was found to be unequivocally a high-solubility compound. All in vitro studies indicated that codeine's permeability is higher than metoprolol's. In vivo studies in rats showed similar permeability for both drugs throughout the entire small-intestine. In conclusion, codeine was found to be a BCS Class I compound. No Peff-Fabs discrepancy is involved in its absorption; rather, it reflects the risk of assigning BCS classification based on merely limited physicochemical characteristics. A thorough investigation using multiple experimental methods is prudent before assigning a BCS classification, to avoid misjudgment in various settings, e.g., drug discovery, formulation design, drug development and regulation.

The present monograph reviews data relevant to applying the biowaiver procedure for the approval of immediate-release multisource solid dosage forms containing codeine phosphate. Both biopharmaceutical and clinical data of codeine were assessed. Solubility studies revealed that codeine meets the "highly soluble" criteria according to World Health Organization (WHO), the European Medicines Agency (EMA), and the United States Food and Drug Administration (US FDA). Codeine's fraction of dose absorbed in humans was reported to be high (>90%) based on cumulative urinary excretion of drug and drug-related material following oral administration. The permeability of codeine was also assessed to be high in both Caco-2 monolayers and rat intestinal perfusion studies. The main risks associated with codeine, that is, toxicity (attributed to CYP2D6 polymorphism) and its abuse potential, are present irrespective of the dosage form, and do not need to be taken into account for bioequivalence (BE) considerations. Taken together, codeine is a class 1 drug with manageable risk and is a good candidate for waiver of in vivo BE studies.

Inflammatory bowel disease (IBD) is an exceptional scenario with regard to drug targeting, as oral administration has the potential to deliver the drug directly to the site(s) of action. Consequently, retention of the drug within the intestinal lumen and tissue, rather than systemic absorption, is frequently desirable.In this article, the traditional drug-delivery strategies used in IBD are briefly summarized. These include rectal dosage forms and oral systems that target the lower intestine/colon by pH-, time-, microflora-, and pressure-dependent mechanisms. Then, the article offers an updated overview of recently developed delivery systems aimed to achieve maximal drug concentrations in the inflamed intestinal tissues with minimal systemic side effects. These include antibodies, small molecules, Janus kinase inhibitors, particulate carrier systems, anti-inflammatory peptides, gene therapy, and transgenic bacteria. The various approaches are reviewed, and the challenges that still remain to be overcome are discussed.The molecular revolution of the past decade profoundly influenced the treatment and management of IBD. In the coming years, this trend is expected to continue. Yet, many challenges are still ahead. A strong collaborative effort by experts from different fields is encouraged and necessary to maximize our success in IBD drug targeting.

Hydrotropy refers to increasing the water solubility of otherwise poorly soluble compound by the presence of small organic molecules. While it can certainly increase the apparent solubility of a lipophilic drug, the effect of hydrotropy on the drugs' permeation through the intestinal membrane has not been studied. The purpose of this work was to investigate the solubility-permeability interplay when using hydrotropic drug solubilization. The concentration-dependent effects of the commonly used hydrotropes urea and nicotinamide, on the solubility and the permeability of the lipophilic antiepileptic drug carbamazepine were studied. Then, the solubility-permeability interplay was mathematically modeled, and was compared to the experimental data. Both hydrotropes allowed significant concentration-dependent carbamazepine solubility increase (up to ~30-fold). A concomitant permeability decrease was evident both in-vitro and in-vivo (~17-fold for nicotinamide and ~9-fold for urea), revealing a solubility-permeability tradeoff when using hydrotropic drug solubilization. A relatively simplified simulation approach based on proportional opposite correlation between the solubility increase and the permeability decrease at a given hydrotrope concentration allowed excellent prediction of the overall solubility-permeability tradeoff. In conclusion, when using hydrotropic drug solubilization it is prudent to not focus solely on solubility, but to account for the permeability as well; achieving optimal solubility-permeability balance may promote the overall goal of the formulation to maximize oral drug exposure.

Recently, we have revealed a trade-off between solubility increase and permeability decrease when solubility-enabling oral formulations are employed. We have shown this trade-off phenomenon to be ubiquitous, and to exist whenever the aqueous solubility is increased via solubilizing excipients, regardless if the mechanism involves decreased free fraction (cyclodextrins complexation, surfactant micellization) or simple cosolvent solubilization. Discovering a way to increase drug solubility without concomitant decreased permeability represents a major advancement in oral delivery of lipophilic drugs and is the goal of this work. For this purpose, we sought to elucidate the solubility-permeability interplay when increased apparent solubility is obtained via supersaturation from an amorphous solid dispersion (ASD) formulation. A spray-dried ASD of the lipophilic drug progesterone was prepared in the hydrophilic polymer hydroxypropyl methylcellulose acetate succinate (HPMC-AS), which enabled supersaturation up to 4× the crystalline drug's aqueous solubility (8 μg/mL). The apparent permeability of progesterone from the ASD in HPMC-AS was then measured as a function of increasing apparent solubility (supersaturation) in the PAMPA and rat intestinal perfusion models. In contrast to previous cases in which apparent solubility increases via cyclodextrins, surfactants, and cosolvents resulted in decreased apparent permeability, supersaturation via ASD resulted in no decrease in apparent permeability with increasing apparent solubility. As a result, overall flux increased markedly with increasing apparent solubility via ASD as compared to the other formulation approaches. This work demonstrates that supersaturation via ASDs has a subtle yet powerful advantage over other solubility-enabling formulation approaches. That is, increased apparent solubility may be achieved without the expense of apparent intestinal membrane permeability. Thus, supersaturation via ASDs presents a markedly increased opportunity to maximize overall oral drug absorption.

Guanidino-containing compounds are well-known for their important biological roles in vivo. In a rational drug design process, the guanidino group is frequently adopted to mimic the arginine residue of the endogenous substrate and secure the affinity of the drug to the target. However, due to their inherent polarity and positive charge in the gastrointestinal tract, it is difficult for guanidino-containing compounds to be orally absorbed by passive diffusion. Hence, guanidino-containing compounds are frequently associated with low oral bioavailability.In this review, we present the barriers and challenges toward the oral absorption of guanidino-containing compounds, provide an overview of the research that has been done so far in the area, and summarize recent advances and future directions in the mechanistic enhancement of the intestinal absorption of drugs containing the polar guanidino functionality. For instance, application of several different prodrug approaches, a novel recently developed ion-pairing strategy and the utilization of advanced formulations are discussed.While additional research is required to allow efficient and facile solutions to low oral bioavailability of guanidino-containing compounds, novel and exciting strategies have been developed in recent years. Although challenging, the development of a potent guanidino-containing compound into an orally administered drug is becoming an achievable target.

Nowadays, the prodrug approach is used already at the early stages of drug development. Lipidic prodrug approach is a growing field for improving a number of drug properties/delivery/therapy aspects, and can offer solutions for various unmet needs. This approach includes drug moiety bound to the lipid carrier, which can be triglyceride, fatty acids, steroid, or phospholipid (PL). The focus of this article is PL-based prodrugs, which includes a PL carrier covalently bound to the active drug moiety. An overview of relevant physiological lipid processing pathways and absorption barriers is provided, followed by drug delivery/therapeutic application of PL-drug conjugates, as well as computational modeling techniques, and a modern bioinformatics tool that can aid in the optimization of PL conjugates. PL-based prodrugs have increased lipophilicity comparing to the parent drug, and can therefore significantly improve the pharmacokinetic profile and overall bioavailability of the parent drug, join the endogenous lipid processing pathways and therefore accomplish drug targeting, e.g., by lymphatic transport, drug release at specific target site(s), or passing the blood-brain barrier. Moreover, an exciting gateway for treating inflammatory diseases and cancer is presented, by utilizing the PL sn-2 position in the prodrug design, aiming for PLA2-mediated activation. Overall, a PL-based prodrug approach shows great potential in improving different drug delivery/therapy aspects, and is expected to grow.

In the early 1990s, a collaborative research effort between academia and the U.S. Food and Drug Administration (FDA) was initiated to establish a database of human jejunal permeabilities based on a Biopharmaceutics Classification System (BCS). The BCS broadly allowed the prediction of human absorption, Fraction absorbed (Fabs) and the rate-limiting step in the intestinal absorption process of drugs following oral administration. The BCS classified compounds into one of four biopharmaceutical classes according to water solubility and membrane permeability characteristics. Today, the BCS has generated remarkable impact on the global pharmaceutical sciences arena, in drug discovery, development and regulation, and an extensive validation/discussion of the BCS is continuously published in the literature. BCS has been effectively implanted by drug regulatory agencies around the world, and widely practiced by the pharmaceutical industry. The aim of this chapter is to present the BCS and its scientific basis, to describe its impact on regulatory practice of oral drug products, and to access the BCS classification of the top drugs on the global market. Finally, current and future directions in BCS related extensions, and their impact on the pharmaceutical industry, will be discussed. Keywords: BCS; BA/BE; biowaiver; oral drug product; intestinal absorption

The purpose of this work was to study the challenges and prospects of regional-dependent absorption in a controlled-release scenario, through the oral biopharmaceutics of the sulfonylurea antidiabetic drug glipizide. The BCS solubility class of glipizide was determined, and its physicochemical properties and intestinal permeability were thoroughly investigated, both in-vitro (PAMPA and Caco-2) and in-vivo in rats. Metoprolol was used as the low/high permeability class boundary marker. Glipizide was found to be a low-solubility compound. All intestinal permeability experimental methods revealed similar trend; a mirror image small intestinal permeability with opposite regional/pH-dependency was obtained, a downward trend for glipizide, and an upward trend for metoprolol. Yet the lowest permeability of glipizide (terminal Ileum) was comparable to the lowest permeability of metoprolol (proximal jejunum). At the colon, similar permeability was evident for glipizide and metoprolol, that was higher than metoprolol's jejunal permeability. We present an analysis that identifies metoprolol's jejunal permeability as the low/high permeability class benchmark anywhere throughout the intestinal tract; we show that the permeability of both glipizide and metoprolol matches/exceeds this threshold throughout the entire intestinal tract, accounting for their success as controlled-release dosage form. This represents a key biopharmaceutical characteristic for a successful controlled-release dosage form.

Nonsteroidal anti-inflammatory drugs, including indomethacin, have been found in both epidemiological and clinical studies to reduce the prevalence and severity of Alzheimer's disease. However, long-term use of indomethacin is limited by significant gastrointestinal and renal toxicities. An indomethacin prodrug that delivers low and continuous blood levels of the drug showed a superior safety profile and similar efficacy in comparison to an equivalent dose of free indomethacin because of limited systemic exposure and preferred brain uptake. The purpose of the present investigation was to evaluate whether sustained systemic input causes an increased brain influx in comparison to rapid input of the drug. Oral indomethacin, indomethacin prodrug, or intravenous indomethacin infusion was administered to rats. The infusion was designed to mimic the plasma indomethacin levels resulting from the prodrug. The resultant blood levels and brain indomethacin uptake were evaluated. The brain indomethacin concentrations 8 h following indomethacin administration were 0.45, 0.3, and 0.31 microg/g after the oral indomethacin, oral prodrug, and intravenous infusion, respectively. The corresponding plasma concentrations were 14.1, 4.1, and 4 microg/ml. Therefore, brain versus plasma indomethacin level ratios were 2.5-fold higher after slow systemic input of indomethacin in comparison to rapid drug input. In conclusion, indomethacin brain uptake was found to be mode of administration-dependent, and a sustained input function increases the drug brain uptake. Thus, these unique results indicate that an appropriate indomethacin controlled release delivery system may induce the desirable brain-related pharmacodynamic effects, while avoiding the concentration-dependent adverse effects. These findings may contribute to improved therapy in Alzheimer's disease.

More than a decade has passed since it was unintentionally discovered that grapefruit juice interacts with certain drugs. The coadministration of these drugs with grapefruit juice can markedly elevate drug bioavailability, and can alter pharmacokinetic and pharmacodynamic parameters of the drug. The predominant mechanism for this interaction is the inhibition of cytochrome P-450 3A4 in the small intestine, resulting in a significant reduction of drug presystemic metabolism. An additional mechanism is, presumably, the inhibition of P-glycoprotein, a transporter that carries drug from the enterocyte back to the gut lumen, resulting in a further increase in the fraction of drug absorbed. Some calcium channel antagonists, benzodiazepines, HMG-CoA reductase inhibitors and cyclosporine are the most affected drugs. A single exposure to one glass of the juice can usually produce the maximal magnitude of the interaction. The data available so far, concerning this interaction and its clinical implications, are reviewed in this article. It is likely that more information regarding this interaction will accumulate in the future, and awareness of such is necessary for achieving optimal drug therapy.

BCS classification is a vital tool in the development of both generic and innovative drug products. The purpose of this work was to provisionally classify the world's top selling oral drugs according to the BCS, using in silico methods. Three different in silico methods were examined: the well-established group contribution (CLogP) and atom contribution (ALogP) methods, and a new method based solely on the molecular formula and element contribution (KLogP). Metoprolol was used as the benchmark for the low/high permeability class boundary. Solubility was estimated in silico using a thermodynamic equation that relies on the partition coefficient and melting point. The validity of each method was affirmed by comparison to reference data and literature. We then used each method to provisionally classify the orally administered, IR drug products found in the WHO Model list of Essential Medicines, and the top-selling oral drug products in the United States (US), Great Britain (GB), Spain (ES), Israel (IL), Japan (JP), and South Korea (KR). A combined list of 363 drugs was compiled from the various lists, and 257 drugs were classified using the different in silico permeability methods and literature solubility data, as well as BDDCS classification. Lastly, we calculated the solubility values for 185 drugs from the combined set using in silico approach. Permeability classification with the different in silico methods was correct for 69-72.4% of the 29 reference drugs with known human jejunal permeability, and for 84.6-92.9% of the 14 FDA reference drugs in the set. The correlations (r(2)) between experimental log P values of 154 drugs and their CLogP, ALogP and KLogP were 0.97, 0.82 and 0.71, respectively. The different in silico permeability methods produced comparable results: 30-34% of the US, GB, ES and IL top selling drugs were class 1, 27-36.4% were class 2, 22-25.5% were class 3, and 5.46-14% were class 4 drugs, while ∼8% could not be classified. The WHO list included significantly less class 1 and more class 3 drugs in comparison to the countries' lists, probably due to differences in commonly used drugs in developing vs industrial countries. BDDCS classified more drugs as class 1 compared to in silico BCS, likely due to the more lax benchmark for metabolism (70%), in comparison to the strict permeability benchmark (metoprolol). For 185 out of the 363 drugs, in silico solubility values were calculated, and successfully matched the literature solubility data. In conclusion, relatively simple in silico methods can be used to estimate both permeability and solubility. While CLogP produced the best correlation to experimental values, even KLogP, the most simplified in silico method that is based on molecular formula with no knowledge of molecular structure, produced comparable BCS classification to the sophisticated methods. This KLogP, when combined with a mean melting point and estimated dose, can be used to provisionally classify potential drugs from just molecular formula, even before synthesis. 49-59% of the world's top-selling drugs are highly soluble (class 1 and class 3), and are therefore candidates for waivers of in vivo bioequivalence studies. For these drugs, the replacement of expensive human studies with affordable in vitro dissolution tests would ensure their bioequivalence, and encourage the development and availability of generic drug products in both industrial and developing countries.

The purpose of this study was to investigate the impact of oral cyclodextrin-based formulation on both the apparent solubility and intestinal permeability of lipophilic drugs. The apparent solubility of the lipophilic drug dexamethasone was measured in the presence of various HPβCD levels. The drug's permeability was measured in the absence vs. presence of HPβCD in the rat intestinal perfusion model, and across Caco-2 cell monolayers. The role of the unstirred water layer (UWL) in dexamethasone's absorption was studied, and a simplified mass-transport analysis was developed to describe the solubility-permeability interplay. The PAMPA permeability of dexamethasone was measured in the presence of various HPβCD levels, and the correlation with the theoretical predictions was evaluated. While the solubility of dexamethasone was greatly enhanced by the presence of HPβCD (K1:1 = 2311 M(-1)), all experimental models showed that the drug's permeability was significantly reduced following the cyclodextrin complexation. The UWL was found to have no impact on the absorption of dexamethasone. A mass transport analysis was employed to describe the solubility-permeability interplay. The model enabled excellent quantitative prediction of dexamethasone's permeability as a function of the HPβCD level. This work demonstrates that when using cyclodextrins in solubility-enabling formulations, a tradeoff exists between solubility increase and permeability decrease that must not be overlooked. This tradeoff was found to be independent of the unstirred water layer. The transport model presented here can aid in striking the appropriate solubility-permeability balance in order to achieve optimal overall absorption.

The molecular revolution greatly impacted the field of drug design and delivery in general, and the utilization of the prodrug approach in particular. The increasing understanding of membrane transporters has promoted a novel 'targeted-prodrug' approach utilizing carrier-mediated transport to increase intestinal permeability, as well as specific enzymes to promote activation to the parent drug.This article provides the reader with a concise overview of this modern approach to prodrug design. Targeting the oligopeptide transporter PEPT1 for absorption and the serine hydrolase valacyclovirase for activation will be presented as examples for the successful utilization of this approach. Additionally, the use of computational approaches, such as DFT and ab initio molecular orbital methods, in modern prodrugs design will be discussed.Overall, in the coming years, more and more information will undoubtedly become available regarding intestinal transporters and potential enzymes that may be exploited for the targeted modern prodrug approach. Hence, the concept of prodrug design can no longer be viewed as merely a chemical modification to solve problems associated with parent compounds. Rather, it opens promising opportunities for precise and efficient drug delivery, as well as enhancement of treatment options and therapeutic efficacy.

The drug intestinal permeability (P(eff)) measure has been widely used as one of the main factors governing both the rate and/or extent of drug absorption (F(abs)) in humans following oral administration. In this communication we emphasize the complexity behind and the care that must be taken with this in vivo P(eff) measurement. Intestinal permeability, considering the whole of the human intestine, is more complex than generally recognized, and this can lead to misjudgment regarding F(abs) and P(eff) in various settings, e.g. drug discovery, formulation design, drug development and regulation. Setting the adequate standard for the low/high permeability class boundary, the different experimental methods for the permeability measurement, and segmental-dependent permeability throughout the human intestine due to different mechanisms are some of the main points that are discussed. Overall, the use of jejunal P(eff) as a surrogate for extent of absorption is sound and scientifically justified; a compound with high jejunal P(eff) will have high F(abs), eliminating the risk for misclassification as a BCS class I drug. Much more care should be taken, however, when jejunal P(eff) does not support a high-permeability classification; a thorough examination may reveal high-permeability after all, attributable to e.g. segmental-dependent permeability due to degree of ionization or transporter expression. In this situation, the use of multiple permeability experimental methods, including the use of metabolism, which except for luminal degradation requires absorption, is prudent and encouraged.

The Biopharmaceutics Classification System (BCS) categorizes drugs into one of four biopharmaceutical classes according to their water solubility and membrane permeability characteristics and broadly allows the prediction of the rate-limiting step in the intestinal absorption process following oral administration. Since its introduction in 1995, the BCS has generated remarkable impact on the global pharmaceutical sciences arena, in drug discovery, development, and regulation, and extensive validation/discussion/extension of the BCS is continuously published in the literature. The BCS has been effectively implanted by drug regulatory agencies around the world in setting bioavailability/bioequivalence standards for immediate-release (IR) oral drug product approval. In this review, we describe the BCS scientific framework and impact on regulatory practice of oral drug products and review the provisional BCS classification of the top drugs on the global market. The Biopharmaceutical Drug Disposition Classification System and its association with the BCS are discussed as well. One notable finding of the provisional BCS classification is that the clinical performance of the majority of approved IR oral drug products essential for human health can be assured with an in vitro dissolution test, rather than empirical in vivo human studies.

As a consequence of modern drug discovery techniques, there has been a consistent increase in the number of new pharmacologically active lipophilic compounds that are poorly water soluble. A great challenge facing the pharmaceutical scientist is making these molecules into orally administered medications with sufficient bioavailability. One of the most popular approaches to improve the oral bioavailability of these molecules is the utilization of a lipid based drug delivery system. Unfortunately, current development strategies in the area of lipid based delivery systems are mostly empirical. Hence, there is a need for a simplified in vitro method to guide the selection of a suitable lipidic vehicle composition and to rationalize the delivery system design. To address this need, a dynamic in vitro lipolysis model, which provides a very good simulation of the in vivo lipid digestion process, has been developed over the past few years. This model has been extensively used for in vitro assessment of different lipid based delivery systems, leading to enhanced understanding of the suitability of different lipids and surfactants as a delivery system for a given poorly water soluble drug candidate. A key goal in the development of the dynamic in vitro lipolysis model has been correlating the in vitro data of various drug-lipidic delivery system combinations to the resultant in vivo drug profile. In this paper, we discuss and review the need for this model, its underlying theory, practice and limitations, and the available data accumulated in the literature. Overall, the dynamic in vitro lipolysis model seems to provide highly useful initial guidelines in the development process of oral lipid based drug delivery systems for poorly water soluble drugs, and it predicts phenomena that occur in the pre-enterocyte stages of the intestinal absorption cascade.