Biocompatible Cationic Lipoamino Acids as Counterions for Oral Administration of API-Ionic Liquids.

PURPOSE: The use of ionic liquids (ILs) in drug delivery has focused attention on non-toxic IL counterions. Cationic lipids can be used to form ILs with weakly acidic drugs to enhance drug loading in lipid-based formulations (LBFs). However, cationic lipids are typically toxic. Here we explore the use of lipoaminoacids (LAAs) as cationic IL counterions that degrade or digest in vivo to non-toxic components. METHODS: LAAs were synthesised via esterification of amino acids with fatty alcohols to produce potentially digestible cationic LAAs. The LAAs were employed to form ILs with tolfenamic acid (Tol) and the Tol ILs loaded into LBF and examined in vitro and in vivo. RESULTS: Cationic LAAs complexed with Tol to generate lipophilic Tol ILs with high drug loading in LBFs. Assessment of the LAA under simulated digestion conditions revealed that they were susceptible to enzymatic degradation under intestinal conditions, forming biocompatible FAs and amino acids. In vitro dispersion and digestion studies of Tol ILs revealed that formulations containing digestible Tol ILs were able to maintain drug dispersion and solubilisation whilst the LAA were breaking down under digesting conditions. Finally, in vivo oral bioavailability studies demonstrated that oral delivery of a LBF containing a Tol IL comprising a digestible cationic lipid counterion was able to successfully support effective oral delivery of Tol. CONCLUSIONS: Digestible LAA cationic lipids are potential IL counterions for weakly acidic drug molecules and digest in situ to form non-toxic breakdown products.

Computational and Experimental Models of Type III Lipid-Based Formulations of Loratadine Containing Complex Nonionic Surfactants.

Type III lipid-based formulations (LBFs) combine poorly water-soluble drugs with oils, surfactants, and cosolvents to deliver the drugs into the systemic circulation. However, the solubility of the drug can be influenced by the colloidal phases formed in the gastrointestinal tract as the formulation is dispersed and makes contact with bile and other materials present within the GI tract. Thus, an understanding of the phase behavior of LBFs in the gut is critical for designing efficient LBFs. Molecular dynamics (MD) simulation is a powerful tool for the study of colloidal systems. In this study, we modeled the internal structures of five type III LBFs of loratadine containing poly(ethylene oxide) nonionic surfactants polysorbate 80 and polyoxyl hydrogenated castor oil (Kolliphor RH40) using long-timescale MD simulations (0.4-1.7 µs). We also conducted experimental investigations (dilution of formulations with water) including commercial Claritin liquid softgel capsules. The simulations show that LBFs form continuous phase, water-swollen reverse micelles, and bicontinuous and phase-separated systems at different dilutions, which correlate with the experimental observations. This study supports the use of MD simulation as a predictive tool to determine the fate of LBFs composed of medium-chain lipids, polyethylene oxide surfactants, and polymers.

Molecular Dynamics Simulations and Experimental Results Provide Insight into Clinical Performance Differences between Sandimmune® and Neoral® Lipid-Based Formulations.

OBJECTIVE: Molecular dynamics (MD) simulations provide an in silico method to study the structure of lipid-based formulations (LBFs) and the incorporation of poorly water-soluble drugs within such formulations. In order to validate the ability of MD to effectively model the properties of LBFs, this work investigates the well-known cyclosporine A formulations, Sandimmune® and Neoral®. Sandimmune® exhibits poor dispersibility and its absorption from the gastrointestinal tract is enhanced when administered after food, whereas Neoral® disperses comparatively well and shows no food effect. METHODS: MD simulations were performed of both LBFs to investigate the differences observed in fasted and fed conditions. These conditions were also tested using an in vitro experimental model of dispersion and digestion. RESULTS: These MD simulations were able to show that the food effect observed for Sandimmune® can be explained by large changes in drug solubilization on addition of bile. In contrast, Neoral® is well dispersed in water or in simulated fasted conditions, and this dispersion is relatively unchanged on moving to fed conditions. These differences were confirmed using dispersion and digestion in vitro experimental model. CONCLUSIONS: The current data suggests that MD simulations are a potential method to model the fate of LBFs in the gastrointestinal tract, predict their dispersion and digestion, investigate behaviour of APIs within the formulations, and provide insights into the clinical performance of LBFs.

Lipophilic Salts and Lipid-Based Formulations: Enhancing the Oral Delivery of Octreotide.

PURPOSE: Successful oral peptide delivery faces two major hurdles: low enzymatic stability in the gastro-intestinal lumen and poor intestinal membrane permeability. While lipid-based formulations (LBF) have the potential to overcome these barriers, effective formulation of peptides remains challenging. Lipophilic salt (LS) technology can increase the apparent lipophilicity of peptides, making them more suitable for LBF. METHODS: As a model therapeutic peptide, octreotide (OCT) was converted to the docusate LS (OCT.DoS2), and compared to the commercial acetate salt (OCT.OAc2) in oral absorption studies and related in vitro studies, including parallel artificial membrane permeability assay (PAMPA), Caco-2, in situ intestine perfusion, and simulated digestion in vitro models. The in vivo oral absorption of OCT.DoS2 and OCT.OAc2 formulated in self-emulsifying drug delivery systems (SEDDS) was studied in rats. RESULTS: LS formulation improved the solubility and loading of OCT in LBF excipients and OCT.DoS2 in combination with SEDDS showed higher OCT absorption than the acetate comparator in the in vivo studies in rats. The Caco-2 and in situ intestine perfusion models indicated no increases in permeability for OCT.DoS2. However, the in vitro digestion studies showed reduced enzymatic degradation of OCT.DoS2 when formulated in the SEDDS formulations. Further in vitro dissociation and release studies suggest that the enhanced bioavailability of OCT from SEDDS-incorporating OCT.DoS2 is likely a result of higher partitioning into and prolonged retention within lipid colloid structures. CONCLUSION: The combination of LS and LBF enhanced the in vivo oral absorption of OCT primarily via the protective effect of LBF sheltering the peptide from gastrointestinal degradation.

Stabilising disproportionation of lipophilic ionic liquid salts in lipid-based formulations.

Lipid based formulations (LBFs) can enhance oral bioavailability, however, their utility may be restricted by low drug loading in the formulation. Converting drugs to drug-ionic liquids (drug-ILs) or lipophilic salts can significantly increase lipid solubility but this approach is complicated in some cases by salt disproportionation, leading to a reduction in solubility and physical instability. Here we explore the physical stability of the weakly basic model drug, cinnarizine (CIN), when paired with a decanoate counterion (Dec) to form the drug-IL, cinnarizine decanoate (CIN.Dec). Consistent with published studies of salt disproportionation in aqueous solution, weakly acidic counterions such as Dec lead to the generation of drug-IL lipid solutions with pHs below pHmax. This leads to CIN deprotonation to the less soluble free base and precipitation. Subsequent studies however, show that these effects can be reversed by acidification of the formulation (either with excess decanoic acid or other lipid soluble acids), stimulating a pH shift to the salt plateau of CIN.Dec and the formation of stable lipid solutions of CIN.Dec. Altering formulation pH to more acidic conditions, therefore stabilises drug-ILs formed using weakly acidic lipophilic counterions, and is a viable method to promote formulation stability via inhibition of disproportionation of some drug-ILs.

Aqueous phase behavior of the PEO-containing non-ionic surfactant C12E6: A molecular dynamics simulation study.

HYPOTHESIS: Non-ionic surfactants containing polyethylene oxide (PEO) chains are widely used in drug formulations, cosmetics, paints, textiles and detergents. High quality molecular dynamics models for PEO surfactants can give us detailed, atomic-scale information about the behavior of surfactant/water mixtures. SIMULATIONS: We used two molecular dynamics force fields (FFs), 2016H66 and 53A6DBW, to model the simple non-ionic PEO surfactant, hexaoxyethylene dodecyl ether (C12E6). We investigated surfactant/water mixtures that span the phase diagram of starting from randomly distributed arrangements. In some cases, we also started with prebuilt, approximate models. The simulations results were compared with the experimentally observed phase behavior. FINDINGS: Overall, this study shows that the spontaneous self-assembly of PEO non-ionic surfactants into different colloidal structures can be accurately modeled with MD simulations using the 2016H66 FF although transitions to well-formed hexagonal phase are slow. Of the two FFs investigated, the 2016H66 FF better reproduces the experimental phase behavior across all regions of the C12E6/water phase diagram.

API ionic liquids: probing the effect of counterion structure on physical form and lipid solubility.

Lipid based formulations (LBFs) are extensively utilised as an enabling technology in drug delivery. The use of ionic liquids (ILs) or lipophilic salts (LS) in drug delivery has also garnered considerable interest due to unique solubility properties. Conversion of active pharmaceutical ingredients (API) to ILs by pairing with an appropriately lipophilic counterion has been shown to decrease melting point of the salt complex and improve solubility in LBFs. However, the relationship between the structure of the counterion, the physicochemical properties of the resulting salts and solubility in LBFs has not been systematically explored. This study investigates the relationship between alkyl sulfate counterion structure and melting temperature (T m or T g) in addition to LBF solubility, utilizing cinnarizine and lumefantrine as model weakly basic APIs. Three series of structurally diverse alkyl sulfate counterions were chosen to probe this relationship. Pairing cinnarizine and lumefantrine with a majority of these alkyl sulfate counterions resulted in a reduction in melting temperature and enhanced solubility in model medium chain and long chain LBFs. The chain length of the alkyl sulfate plays a crucial role in performance, and consistently branched alkyl sulfate counterions perform better than straight chain alkyl sulfate counterions, as predicted. Most interestingly, trends in counterion performance were found to be consistent across two APIs with disparate chemical structures. The findings from this study will facilitate the design of counterions which enhance solubility of ionisable drugs and unlock the potential to develop compounds previously restrained by poor solubility.

Comparison of In Vitro and In Vivo Results Using the GastroDuo and the Salivary Tracer Technique: Immediate Release Dosage Forms under Fasting Conditions.

The fasted state administration of immediate release (IR) dosage forms is often regarded as uncritical since physiological aspects seem to play a minor role for disintegration and drug release. However, recent in vivo studies in humans have highlighted that fasted state conditions are in fact highly dynamic. It was therefore the aim of this study to investigate the disintegration and drug release behavior of four different IR formulations of the probe drug caffeine under physiologically relevant conditions with the aid of the GastroDuo. One film-coated tablet and three different capsule formulations based on capsule shells either made from hard gelatin or hydroxypropylmethyl cellulose (HPMC) were tested in six different test programs. To evaluate the relevance of the data generated, the four IR formulations were also studied in a four-way cross-over study in 14 healthy volunteers by using the salivary tracer technique (STT). It could be shown that the IR formulations behaved differently in the in vitro test programs. Thereby, the simulated parameters affected the disintegration and dissolution behavior of the four IR formulations in different ways. Whereas drug release from the tablet started early and was barely affected by temperature, pH or motility, the different capsule formulations showed a longer lag time and were sensitive to specific parameters. However, once drug release was initiated, it typically progressed with a higher rate for the capsules compared to the tablet. Interestingly, the results obtained with the STT were not always in line with the in vitro data. This observation was due to the fact that the probability of the different test programs was not equal and that certain scenarios were rather unlikely to occur under the controlled and standardized conditions of clinical studies. Nonetheless, the in vitro data are still valuable as they allowed to discriminate between different formulations.

Ionic Liquid Forms of the Antimalarial Lumefantrine in Combination with LFCS Type IIIB Lipid-Based Formulations Preferentially Increase Lipid Solubility, In Vitro Solubilization Behavior and In Vivo Exposure.

Lipid based formulations (LBFs) are commonly employed to enhance the absorption of highly lipophilic, poorly water-soluble drugs. However, the utility of LBFs can be limited by low drug solubility in the formulation. Isolation of ionizable drugs as low melting, lipophilic salts or ionic liquids (ILs) provides one means to enhance drug solubility in LBFs. However, whether different ILs benefit from formulation in different LBFs is largely unknown. In the current studies, lumefantrine was isolated as a number of different lipophilic salt/ionic liquid forms and performance was assessed after formulation in a range of LBFs. The solubility of lumefantrine in LBF was enhanced 2- to 80-fold by isolation as the lumefantrine docusate IL when compared to lumefantrine free base. The increase in drug loading subsequently enhanced concentrations in the aqueous phase of model intestinal fluids during in vitro dispersion and digestion testing of the LBF. To assess in vivo performance, the systemic exposure of lumefantrine docusate after administration in Type II-MCF, IIIB-MCF, IIIB-LCF, and IV formulations was evaluated after oral administration to rats. In vivo exposure was compared to control lipid and aqueous suspension formulations of lumefantrine free base. Lumefantrine docusate in the Type IIIB-LCF showed significantly higher plasma exposure compared to all other formulations (up to 35-fold higher). The data suggest that isolation of a lipid-soluble IL, coupled with an appropriate formulation, is a viable means to increase drug dose in an oral formulation and to enhance exposure of lumefantrine in vivo.

In vivo characterization of enTRinsic™ drug delivery technology capsule after intake in fed state: A cross-validation approach using salivary tracer technique in comparison to MRI.

The instability of various small molecules, vaccines and peptides in the human stomach is a complex challenge for oral drug delivery. Recently, a novel gastro-resistant capsule - the enTRinsic™ Drug Delivery Technology capsule - has been developed. In this work, the salivary tracer technique based on caffeine has been applied to study the in vivo disintegration of enTRinsic™ capsules in 16 healthy volunteers. In addition, magnetic resonance imaging (MRI) was used to visualize GI transit and to verify the disintegration times determined by using the salivary tracer technique. The enTRinsic™ capsules filled with 50mg of caffeine and 5mg of black iron oxide were administered in the fed state, i.e. 30min after a light meal (500kcal). In the first hour after capsule intake, the subjects were placed in supine position in the MRI scanner and scans were performed in short time intervals. After 1h, the subjects could leave the MRI scanner in between the MRI measurements, which were performed every 15min until disintegration of the capsule was confirmed (maximum observation time: 8h). Saliva samples were obtained simultaneously with MR imaging. Caffeine concentrations in saliva were determined by LC/MS-MS. The starting point of capsule disintegration was determined visually by inspection of the MR images as well as by the onset of salivary caffeine concentrations. In 14 out of 16 subjects, the capsule disintegrated in the small intestine. In one subject, the enTRinsic™ capsule was not emptied from the stomach within the observation time. In another subject, disintegration occurred during gastric emptying in the antropyloric region. In this study, we demonstrated that the enTRinsic™ capsules are also gastro resistant when taken under fed state conditions. Furthermore, we demonstrated the feasibility of using low dose caffeine as a salivary tracer for the determination of the disintegration of an enteric formulation.

Unlocking the full potential of lipid-based formulations using lipophilic salt/ionic liquid forms.

Lipid-based formulations (LBF) are widely used by industry and accepted by the regulatory authorities for oral drug delivery in the pharmaceutical and consumer healthcare market. Innovation in the LBF field is however needed in order to meet the demands of modern drugs, their more challenging problem statements and growing needs for achieving optimal pharmacokinetics (i.e., no food-effects, low variability) on approval. This review describes a new lipophilic salt / ionic liquid approach in combination with LBF, and how this salt strategy can be used to better tailor the properties of a drug to LBFs. The potential advantages of lipophilic salts are discussed in the context of dose escalation studies during toxicological evaluation, reducing the pill burden, increasing drug absorption of new drugs and in life-cycle management. Commentary on lipophilic salt synthesis, scale-up, LBF design and the regulatory aspects are also provided. These topics are discussed in the broad context of bringing the widely recognized advantages of LBFs to a broader spectrum of drugs.

Characterization of the gastrointestinal transit and disintegration behavior of floating and sinking acid-resistant capsules using a novel MRI labeling technique.

The application areas of hard capsules are currently widened by the introduction of acid-resistant capsule shells. In this study, the gastrointestinal behavior of acid-resistant hard capsule formulations as well as the influence of their density on the gastric residence time were characterized using magnetic resonance imaging (MRI). As labeling material for a reliable identification of the capsules in the MR images, small pieces of dried pineapple were used as they provide a high T1 signal. Tested products were DRcaps™ as capsule in capsule (Cap-in-Cap) system (outer capsule size 00). For the investigation of the influence of the capsule density on the gastric residence time, a floating low-density Cap-in-Cap capsule formulation and a sinking high-density Cap-in-Cap capsule formulation were investigated. The study was performed in eight healthy human subjects under fasting conditions. Besides the transit data of the capsule systems, the intraluminal fluid volume kinetics were determined using T2 weighted sequences. The gastric emptying times of the systems did not differ, with mean values of 45 ±â€¯35 min for floating DRcaps™ and 36 ±â€¯18 min for the sinking DRcaps™. The difference in density had no remarkable influence on gastric emptying. Thus, the concept of floating capabilities for gastroretentive dosage forms seems rather implausible. Furthermore, this assures transferability of common knowledge about dosage form transit for estimation of the performance of acid-resistant capsule shells, which most typically float. The mean disintegration times amounted to 139 ±â€¯35 min for the floating DRcaps™ Cap-in-Cap and 163 ±â€¯55 min for the sinking DRcaps™ Cap-in-Cap. In only one case, a sinking DRcaps™ Cap-in-Cap system disintegrated during gastric emptying, but all other capsules disintegrated in the small intestine, irrespective of their gastric residence time. The use of dried pineapple as labeling material could be successfully demonstrated as a reliable and easy method for the tracking of the transit and disintegration behavior of orally administered drug delivery systems, leading to a thorough understanding of their in vivo performance.

A Nonionic Polyethylene Oxide (PEO) Surfactant Model: Experimental and Molecular Dynamics Studies of Kolliphor EL.

Polyethoxylated, nonionic surfactants are important constituents of many drug formulations, including lipid-based formulations. In an effort to better understand the behavior of formulation excipients at the molecular level, we have developed molecular dynamics (MD) models for the widely used surfactant Kolliphor EL (KOL), a triricinoleate ester of ethoxylated glycerol. In this work, we have developed models based on a single, representative molecular component modeled with 2 force field variations based on the GROMOS 53A6DBW and 2016H66 force field parameters for polyethoxylate chains. To compare the computational models to experimental measurements, we investigated the phase behavior of KOL using nephelometry, dynamic light scattering, cross-polarized microscopy, small-angle X-ray scattering, and cryogenic transmission electron microscopy. The potential for digestion of KOL was also evaluated using an in vitro digestion experiment. We found that the size and spherical morphology of the KOL colloids at low concentrations was reproduced by the MD models as well as the growing interactions between the aggregates to from rod-like structures at high concentrations. We believe that this model reproduces the phase behavior of KOL relevant to drug absorption and that it can be used in whole formulation simulations to accelerate the formulation development.

Location of Solvated Probe Molecules Within Nonionic Surfactant Micelles Using Molecular Dynamics.

An iconic textbook that pharmaceutical scientists encounter in undergraduate courses is "Martin's Physical Pharmacy and Pharmaceutical Sciences." Within the chapter on Colloids, a figure indicates the location of solubilization of molecules within spherical, nonionic surfactant micelles. The surfactant consists of polyethylene glycol (PEG) hydrophilic headgroups and alkane chains for the hydrophobic tail. The figure shows benzene and toluene within the alkane core, salicylic acid (2-hydroxybenzoic acid) at the interface between the core and PEG chains, and then para-hydroxybenzoic acid (4-hydroxybenzoic acid) located between the PEG chains. Molecular dynamics simulations of octaethylene glycol monododecyl ether micelles were performed with a series of probe molecules, including those within the Martin's figure, to determine their solubilization location. Relative placement of molecules within the micelle was correct; however, some specifics were different. In particular, benzene and toluene are excluded from the core, and 4-hydroxybenzoic acid prefers to maintain contact with the core. A series of molecules containing 6 carbon atoms were also studied to determine the effects of cyclization (moves out of core), polar functionalization (anchored to interface), and aromatization (excluded from central core). Molecular dynamics was found to be a useful tool for gaining insight into interactions important in solubilization of molecules.

Improvement in the Predicted Partitioning of Alcohol and Polyethylene Oxide Groups Between Water and Octanol (logP) in Molecular Dynamics Simulations.

Molecular dynamics simulations can be applied to explore the complex liquid phase behavior of lipid-based formulations and the gastrointestinal tract lumen. In order for the results from these simulations to be of value, the manner in which molecules interact with both aqueous and oil phases present needs to be as correct as possible. An existing molecular dynamics force field, GROMOS 53a6, was demonstrated to poorly reproduce the partitioning of straight-chain alcohol and short-chain polyethylene glycol (PEG) molecules between octanol and water phase (logP), with the molecules too hydrophobic. Force field parameters for Lennard-Jones interactions between CH2 and CH3 with water oxygen were adjusted to reproduce the experimental octanol logP, with all other Lennard-Jones and force field parameters left untouched. This parameter set, called 53a6DBW, was subsequently used to recalculate straight-chain alcohol and short-chain PEG molecules, with significant improvement in the values obtained. Simulations of a nonionic surfactant in water, octaethylene glycol monocaprylate, were also performed to observe the aggregation behavior. 53a6DBW demonstrated significant improvements in water interactions with the PEG chains, well hydrating the PEG groups, and allowing the formation of micelles. Further improvements and evaluation of the improved parameter set are ongoing.

Enhancing the Oral Absorption of Kinase Inhibitors Using Lipophilic Salts and Lipid-Based Formulations.

The absolute bioavailability of many small molecule kinase inhibitors (smKIs) is low. The reasons for low bioavailability are multifaceted and include constraints due to first pass metabolism and poor absorption. For smKIs where absorption limits oral bioavailability, low aqueous solubility and high lipophilicity, often in combination with high-dose requirements have been implicated in low and variable absorption, food-effects, and absorption-related drug-drug interactions. The current study has evaluated whether preparation of smKIs as lipophilic salts/ionic liquids in combination with coadministration with lipid-based formulations is able to enhance absorption for examples of this compound class. Lipophilic (docusate) salt forms of erlotinib, gefitinib, ceritinib, and cabozantinib (as example smKIs demonstrating low aqueous solubility and high lipophilicity) were prepared and isolated as workable powder solids. In each case, the lipophilic salt exhibited high and significantly enhanced solubility in lipidic excipients (>100 mg/g) when compared to the free base or commercial salt form. Isolation as the lipophilic salt facilitated smKI loading in model lipid-based formulations at high concentration, increased in vitro solubilization at gastric and intestinal pH and in some cases increased oral absorption (∼2-fold for cabozantinib formulations in rats). Application of a lipophilic salt approach can therefore facilitate the use of lipid-based formulations for examples of the smKI compound class where low solubility limits absorption and is a risk factor for increased variability due to food-effects.

Transformation of Biopharmaceutical Classification System Class I and III Drugs Into Ionic Liquids and Lipophilic Salts for Enhanced Developability Using Lipid Formulations.

Higher lipid solubility of lipophilic salt forms creates new product development opportunities for high-dose liquid-filled capsules. The purpose of this study is to determine if lipophilic salts of Biopharmaceutical Classification System (BCS) Class I amlodipine and BCS Class III fexofenadine, ranitidine, and metformin were better lipid formulation candidates than existing commercial salts. Lipophilic salts were prepared from lipophilic anions and commercial HCl or besylate salt forms, as verified by 1H-NMR. Thermal properties were assessed by differential scanning calorimetry and hot-stage microscopy. X-ray diffraction and polarized light microscopy were used to confirm the salt's physical form. All lipophilic salt forms were substantially more lipid-soluble (typically >10-fold) when compared to commercial salts. For example, amlodipine concentrations in lipidic excipients were limited to <5-10 mg/g when using the besylate salt but could be increased to >100 mg/g when using the docusate salt. Higher lipid solubility of the lipophilic salts of each drug translated to higher drug loadings in lipid formulations. In vitro tests showed that lipophilic salts solubilized in a lipid formulation resulted in dispersion behavior that was at least as rapid as the dissolution rates of conventional salts. This study confirmed the applicability of forming lipophilic salts of BCS I and III drugs to promote the utility of lipid-based delivery systems.

Computational Models of the Intestinal Environment. 3. The Impact of Cholesterol Content and pH on Mixed Micelle Colloids.

In this study, we use molecular dynamics (MD) and experimental techniques (nephelometry and dynamic light scattering) to investigate the influence of cholesterol content and pH on the colloidal structures that form in the gastrointestinal (GI) tract upon lipid digestion. We demonstrate that the ionization state of the molecular species is a primary driver for the self-assembly of aggregates formed by model bile and therefore should be considered when performing in silico modeling of colloidal drug delivery systems. Additionally, the incorporation of physiological concentrations of cholesterol within the model systems does not affect size, number, shape, or dynamics of the aggregates to a significant degree. The MD data shows a reduction in aggregate size with increasing pH, a preference for glycodeoxycholate (GDX) to occupy the aggregate surface, and that the mixed micellar aggregates are oblate spheroids (disc-like). The results obtained assist in understanding the process by which pH and cholesterol influence self-assembly of mixed micelles within the GI tract. The MD approach provides a platform for investigation of interactions of drugs and formulation excipients with the endogenous contents of the GI tract.

Computational Models of the Gastrointestinal Environment. 1. The Effect of Digestion on the Phase Behavior of Intestinal Fluids.

Improved models of the gastrointestinal environment have great potential to assist the complex process of drug formulation. Molecular dynamics (MD) is a powerful method for investigating phase behavior at a molecular level. In this study we use multiple MD simulations to calculate phase diagrams for bile before and after digestion. In these computational models, undigested bile is represented by mixtures of palmitoyl-oleoylphosphatidylcholine (POPC), sodium glycodeoxycholate (GDX), and water. Digested bile is modeled using a 1:1 mixture of oleic acid and palmitoylphosphatidylcholine (lysophosphatidylcholine, LPC), GDX, and water. The computational phase diagrams of undigested and digested bile are compared, and we describe the typical intermolecular interactions that occur between phospholipids and bile salts. The diffusion coefficients measured from MD simulation are compared to experimental diffusion data measured by DOSY-NMR, where we observe good qualitative agreement. In an additional set of simulations, the effect of different ionization states of oleic acid on micelle formation is investigated.

Computational Models of the Gastrointestinal Environment. 2. Phase Behavior and Drug Solubilization Capacity of a Type I Lipid-Based Drug Formulation after Digestion.

Lipid-based drug formulations can greatly enhance the bioavailability of poorly water-soluble drugs. Following the oral administration of formulations containing tri- or diglycerides, the digestive processes occurring within the gastrointestinal (GI) tract hydrolyze the glycerides to mixtures of free fatty acids and monoglycerides that are, in turn, solubilized by bile. The behavior of drugs within the resulting colloidal mixtures is currently not well characterized. This work presents matched in vitro experimental and molecular dynamics (MD) theoretical models of the GI microenvironment containing a digested triglyceride-based (Type I) drug formulation. Both the experimental and theoretical models consist of molecular species representing bile (glycodeoxycholic acid), digested triglyceride (1:2 glyceryl-1-monooleate and oleic acid), and water. We have characterized the phase behavior of the physical system using nephelometry, dynamic light scattering, and polarizing light microscopy and compared these measurements to phase behavior observed in multiple MD simulations. Using this model microenvironment, we have investigated the dissolution of the poorly water-soluble drug danazol experimentally using LC-MS and theoretically by MD simulation. The results show how the formulation lipids alter the environment of the GI tract and improve the solubility of danazol. The MD simulations successfully reproduce the experimental results showing the utility of MD in modeling the fate of drugs after digestion of lipid-based formulations within the intestinal lumen.