ABSTRACT
Aqueous suspensions containing crystalline drug in the sub-micron range is a favorable platform for long-acting injectables where particle size can be used to obtain a desired plasma-concentration profile. Stabilizers are added to the suspensions and screened extensively to define the optimal formulation composition. In the initial formulation screening the amount of drug compound can be limited, necessitating milling methods for small-volume screening predictable for scale-up. Hence, adaptive focused ultrasound was investigated as a potential milling method for rapid small-volume suspensions by identifying the critical process parameters during preparation. Suspensions containing drug compounds with different mechanical properties and thereby grindability, i.e., cinnarizine, haloperidol, and indomethacin with brittle, elastic, and plastic properties, respectively, were investigated to gain an understanding of the manufacturing with adaptive focused acoustics as well as comparison to already established milling techniques. Using a DoE-design, peak incident power was identified as the most crucial process parameter impacting the milling process for all three compounds. It was possible to decrease the sizes of drug particles to micron range after one minute of focused ultrasound exposure which was superior compared to other milling techniques (e.g., non-focused ultrasound exposure). The addition of milling beads decreased the drug particle sizes even further, thus to a lower degree than other already established milling techniques such as milling by dual centrifugation. This study thereby demonstrated that adaptive focused ultrasonication was a promising method for rapid homogenization and particle size reduction to micron range for different compounds varying in grindability without altering the crystalline structure.
Subject(s)
Chemistry, Pharmaceutical , Particle Size , Suspensions , Chemistry, Pharmaceutical/methods , Drug Compounding/methods , Indomethacin/chemistry , Water/chemistry , Sonication/methods , Cinnarizine/chemistry , Ultrasonics/methods , Technology, Pharmaceutical/methods , Haloperidol/chemistry , Excipients/chemistryABSTRACT
Supersaturation and precipitation within the gastrointestinal tract can influence oral absorption of active pharmaceutical ingredients (APIs). Supersaturation of weakly basic APIs upon transfer from the stomach into the small intestine may enhance their absorption, while salt forms of poorly soluble weak acids may generate supersaturated solutions in both stomach and intestine. Likewise, APIs with solubility-limited absorption may be developed as enabling formulations intended to produce supersaturated solutions of the API in the gut. Integrating the supersaturation/precipitation characteristics of the API into the biopharmaceutical risk classification enables comprehensive mapping of potential developability risks and guides formulation selection towards optimizing oral bioavailability (BA). The refined Developability Classification System (rDCS) provides an approach for this purpose. In this work, the rDCS strategy is revisited and a stratified approach integrating the in vitro supersaturation and precipitation behavior of APIs and their formulations is proposed.
ABSTRACT
Computational approaches are increasingly explored in development of drug products, including the development of lipid-based formulations (LBFs), to assess their feasibility for achieving adequate oral absorption at an early stage. This study investigated the use of computational pharmaceutics approaches to predict solubility changes of poorly soluble drugs during dispersion and digestion in biorelevant media. Concentrations of 30 poorly water-soluble drugs were determined pre- and post-digestion with in-line UV probes using the MicroDISS Profiler™. Generally, cationic drugs displayed higher drug concentrations post-digestion, whereas for non-ionized drugs there was no discernible trend between drug concentration in dispersed and digested phase. In the case of anionic drugs there tended to be a decrease or no change in the drug concentration post-digestion. Partial least squares modelling was used to identify the molecular descriptors and drug properties which predict changes in solubility ratio in long-chain LBF pre-digestion (R2 of calibration = 0.80, Q2 of validation = 0.64) and post-digestion (R2 of calibration = 0.76, Q2 of validation = 0.72). Furthermore, multiple linear regression equations were developed to facilitate prediction of the solubility ratio pre- and post-digestion. Applying three molecular descriptors (melting point, LogD, and number of aromatic rings) these equations showed good predictivity (pre-digestion R2 = 0.70, and post-digestion R2 = 0.68). The model developed will support a computationally guided LBF strategy for emerging poorly water-soluble drugs by predicting biorelevant solubility changes during dispersion and digestion. This facilitates a more data-informed developability decision making and subsequently facilitates a more efficient use of formulation screening resources.
Subject(s)
Lipids , Solubility , Lipids/chemistry , Pharmaceutical Preparations/chemistry , Drug Compounding/methods , Chemistry, Pharmaceutical/methods , DigestionABSTRACT
Despite the widespread use of polymers as precipitation inhibitors in supersaturating drug formulations, the current understanding of their mechanisms of action is still incomplete. Specifically, the role of hydrophobic drug interactions with polymers by considering possible supramolecular conformations in aqueous dispersion is an interesting topic. Accordingly, this study investigated the tendency of polymers to create hydrophobic domains, where lipophilic compounds may nest to support drug solubilisation and supersaturation. Fluorescence spectroscopy with the environment-sensitive probe pyrene was compared with atomistic molecular dynamics simulations of the model drug fenofibrate (FENO). Subsequently, kinetic drug supersaturation and thermodynamic solubility experiments were conducted. As a result, the different polymers showed hydrophobic domain formation to a varying degree and the molecular simulations supported interpretation of fluorescence spectroscopy data. Molecular insights were gained into the conformational structure of how the polymers interacted with FENO in solution phase, which apart from nucleation and crystal growth effects, determined drug concentrations in solution. Notable was that even at the lowest polymer concentration of 0.01 %, w/v, there were polymer-specific solubilisation effects of FENO observed and the resulting reduction in apparent drug supersaturation provided relevant knowledge both from a mechanistic and practical perspective.
Subject(s)
Fenofibrate , Hydrophobic and Hydrophilic Interactions , Molecular Dynamics Simulation , Polymers , Solubility , Fenofibrate/chemistry , Polymers/chemistry , Chemical Precipitation , Water/chemistry , Solutions , ThermodynamicsABSTRACT
The present study investigated the feasibility of fabricating self-assembled liposomes, LeciPlex®, a phospholipid-based vesicular nanocarrier using cationic, anionic, and nonionic stabilizers. The phospholipid investigated was soy phosphatidylcholine and the nano-precipitation method based on solvent diffusion was applied as the fabrication technique of liposomes in this study. The effects of various formulation variables, such as lipid and stabilizer concentration, total solid concentration, and solvent type on the self-assembly of vesicles were studied for physical characterization including particle size analysis, differential scanning calorimetry, viscosity, optical transmittance, transmission electron microscopy, and small angle neutron scattering. All three LeciPlex® systems exhibited a direct relationship between particle size and phospholipid concentration. The two categoric variables, solvent, and stabilizer used to prepare LeciPlex® demonstrated a significant effect on particle size for all three LeciPlex® systems. Small angle neutron scattering, and optical transmittance confirmed the formation of micellar systems at a phospholipid: stabilizer ratio of 1:2 and vesicular systems at a ratio of 2:1 for the systems stabilized with anionic and nonionic surfactants. In contrast to this, the LeciPlex® formed with the cationic stabilizer Dioctadecyldimethylammonium bromide (DODAB), formed vesicles at both ratios. From these investigations, it was clear that the formulation space for LeciPlex® was diversified by the addition of cationic, anionic, and non-ionic stabilizers.
Subject(s)
Liposomes , Particle Size , Quaternary Ammonium Compounds , Liposomes/chemistry , Quaternary Ammonium Compounds/chemistry , Surface-Active Agents/chemistry , Viscosity , Solvents/chemistry , Phospholipids/chemistry , Chemistry, Pharmaceutical/methods , Phosphatidylcholines/chemistry , Calorimetry, Differential Scanning , Microscopy, Electron, Transmission , Drug Compounding/methods , Drug Carriers/chemistry , Scattering, Small Angle , Nanoparticles/chemistryABSTRACT
While various non-ionic surfactants at low concentrations have been shown to increase the transport of P-gp substrates in vitro, in vivo studies in rats have shown that a higher surfactant concentration is needed to increase the oral absorption of e.g. the P-gp substrates digoxin and etoposide. The aim of the present study was to investigate if intestinal digestion of surfactants could be the reason for this deviation between in vitro and in vivo data. Therefore, Kolliphor EL, Brij-L23, Labrasol and polysorbate 20 were investigated for their ability to inhibit P-gp and increase digoxin absorption in vitro. Transport studies were performed in Caco-2 cells, while P-gp inhibition and cell viability assays were performed in MDCKII-MDR1 cells. Polysorbate 20, Kolliphor EL and Brij-L23 increased absorptive transport and decreased secretory digoxin transport in Caco-2 cells, whereas only polysorbate 20 and Brij-L23 showed P-gp inhibiting properties in the MDCKII-MDR1 cells. Polysorbate 20 and Brij-L23 were chosen for in vitro digestion prior to transport- or P-gp inhibiting assays. Brij-L23 was not digestible, whereas polysorbate 20 reached a degree of digestion around 40%. Neither of the two surfactants showed any significant difference in their ability to affect absorptive or secretory transport of digoxin after pre-digestion. Furthermore, the P-gp inhibiting effects of polysorbate 20 were not decreased significantly. In conclusion, the mechanism behind the non-ionic surfactant mediated in vitro P-gp inhibition seemed independent of the intestinal digestion and the results presented here did not suggest it to be the cause of the observed discrepancy between in vitro and in vivo.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1 , Digoxin , Polysorbates , Surface-Active Agents , Animals , Dogs , Humans , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , ATP Binding Cassette Transporter, Subfamily B, Member 1/antagonists & inhibitors , Biological Transport/drug effects , Caco-2 Cells , Cell Survival/drug effects , Digestion/drug effects , Digoxin/pharmacokinetics , Glycerides/metabolism , Intestinal Absorption/drug effects , Madin Darby Canine Kidney Cells , Polysorbates/pharmacology , Surface-Active Agents/pharmacologyABSTRACT
Lipid-based formulations (LBFs) are an enabling-formulation approach for lipophilic poorly water-soluble compounds. In LBFs, drugs are commonly pre-dissolved in lipids, and/or surfactants/cosolvents, hereby avoiding the rate-limiting dissolution step. According to the Lipid formulation classification system, proposed by Pouton in 2006, in type II LBFs a surfactant with an HLB-value lower than 12 is added to the lipids. If high drug doses are required, e.g. for preclinical toxicity studies, supersaturated LBFs prepared at elevated temperatures may be a possibility to increase drug exposure. In the present study, the impact of digestion on drug absorption in rats was studied by pre-dosing of the lipase inhibitor orlistat. The lipid chain length of the type II LBFs was varied by administration of a medium-chain- (MC) and a long-chain (LC)-based formulation. Different drug doses, both non-supersaturated and supersaturated, were applied. Due to an inherent precipitation tendency of cinnarizine in supersaturated LBFs, the effect of the addition of the precipitation inhibitor Soluplus® was also investigated. The pharmacokinetic results were also evaluated by multiple linear regression. In most cases LC-based LBFs did not perform better in vivo, in terms of a higher area under the curve (AUC0-24 h) and maximal plasma concentration (Cmax), than MC-based LBFs. The administration of supersaturated LBFs resulted in increased AUC0-24 h (1.5 - 3.2-fold) and Cmax (1.1 - 2.6-fold)-values when compared to the non-supersaturated equivalents. Lipase inhibition led to a decreased drug exposure in most cases, especially for LC formulations (AUC0-24 h reduced to 47 - 67%, Cmax to 46 - 62%). The addition of Soluplus® showed a benefit to drug absorption from supersaturated type II LBFs (1.2 - 1.7-fold AUC0-24 h), due to an increased solubility of cinnarizine in the formulation. Upon dose-normalization of the pharmacokinetic parameters, no beneficial effect of Soluplus® could be demonstrated.
Subject(s)
Cinnarizine , Lipids , Cinnarizine/chemistry , Cinnarizine/pharmacokinetics , Cinnarizine/administration & dosage , Animals , Male , Lipids/chemistry , Solubility , Lactones/chemistry , Lactones/pharmacokinetics , Lactones/administration & dosage , Rats, Wistar , Orlistat/administration & dosage , Orlistat/pharmacokinetics , Intestinal Absorption , Rats , Polyethylene Glycols/chemistry , Polyethylene Glycols/pharmacokinetics , Lipase/antagonists & inhibitors , Polyvinyls/chemistry , Chemical Precipitation , Surface-Active Agents/chemistry , Chemistry, Pharmaceutical/methodsABSTRACT
High-pressure homogenization is a widely used and acknowledged method to reduce the particle sizes of active pharmaceutical compounds into nanosized range. Thus, the method is associated with limitations, as the compound's initial particle size, since micronized particles are often prerequired to achieve successful size reduction into nanosized range. In this work, the usage of ultrasound as a potential milling or pre-milling technique to decrease particle sizes of different drug compounds varying in deformation properties into micronized range, was investigated.
Subject(s)
Drug Compounding , Particle Size , Suspensions , Drug Compounding/methods , Nanoparticles/chemistry , Water/chemistry , Ultrasonics/methods , Pharmaceutical Preparations/chemistry , Sonication/methods , Chemistry, Pharmaceutical/methods , PressureABSTRACT
The oral bioavailability of paclitaxel is limited due to low solubility and high affinity for the P-glycoprotein (P-gp) efflux transporter. Here we hypothesized that maximizing the intestinal paclitaxel levels through apparent solubility enhancement and controlling thesimultaneous release of both paclitaxel and the P-gp inhibitor encequidar from amorphous solid dispersions (ASDs) would increase the oral bioavailability of paclitaxel. ASDs of paclitaxel and encequidar in polyvinylpyrrolidone K30 (PVP-K30), hydroxypropylmethylcellulose 5 (HPMC-5), and hydroxypropylmethylcellulose 4 K (HPMC-4K) were hence prepared by freeze-drying. In vitro dissolution studies showed that both compounds were released fastest from PVP-K30, then from HPMC-5, and slowest from HPMC-4K ASDs. The dissolution of paclitaxel from all polymers resulted in stable concentration levels above the apparent solubility. The pharmacokinetics of paclitaxel after oral administration to male Sprague-Dawley rats was investigated with or without 1 mg/kg encequidar, as amorphous solids or polymer-based ASDs. The bioavailability of paclitaxel increased 3- to 4-fold when administered as polymer-based ASDs relative to solid amorphous paclitaxel. However, when amorphous paclitaxel was co-administered with encequidar, either as an amorphous powder or as a polymer-based ASD, the bioavailability increased 2- to 4-fold, respectively. Interestingly, a noticeable increase in paclitaxel bioavailability of 24-fold was observed when paclitaxel and encequidar were co-administered as HPMC-5-based ASDs. We, therefore, suggest that controlling the dissolution rate of paclitaxel and encequidar in order to obtain simultaneous and timed release from polymer-based ASDs is a strategy to increase oral paclitaxel bioavailability.
Subject(s)
Polymers , Povidone , Rats , Male , Animals , Biological Availability , Rats, Sprague-Dawley , Hypromellose Derivatives , SolubilityABSTRACT
Enabling formulations, such as lipid-based formulations (LBFs), are means to deliver challenging-to-formulate, poorly soluble drugs. LBFs may be composed of lipids, surfactants and/or cosolvents and can be classified depending on the proportions of the components and the hydrophilicity of the surfactant according to the Lipid Formulations Classification System, ranging from type I (very lipophilic) to type IV (hydrophilic). In cases where drug solubility in LBFs does not suffice, e.g. for preclinical toxicity studies, supersaturated LBFs can be used in order to increase the drug load. However, the effect of digestion on drug absorption from supersaturated type I formulations (consisting exclusively of lipids) still remains relatively unexplored and unclear. In the present study, the impact of lipid digestion on absorption of cinnarizine-loaded supersaturated lipid-based formulations of type I was investigated in rats by pre-dosing of the lipase inhibitor orlistat. The lipid chain length and the drug dose were varied by testing medium-chain triglycerides (MCT) and long-chain triglycerides (LCT), both supersaturated and non-supersaturated. Due to the physical instability of supersaturated formulations of cinnarizine, i.e. a potential of precipitation of cinnarizine, the impact of the addition of the amphiphilic polymer Soluplus®, as a potential precipitation inhibitor, was also investigated. The supersaturated systems resulted in a 2.3 - 3.3-fold higher Area Under the Curve (AUC0-24 h, not dose-normalized) and 1.4 - 2.2-fold higher maximum plasma concentration (Cmax, not dose-normalized) than non-supersaturated formulations (statistically significant with p = 0.05), whereas the addition of Soluplus® did not reveal any benefit. Results indicated that lipase inhibition affected the in vivo performance of LBFs: Co-administration of the lipase inhibitor significantly reduced Cmax and AUC0-24 h (both to 33-39 %, not dose-normalized) for the LCT formulations and, though not significant, a similar trend was observed for the AUC0-24 h of the MCT formulations (to 53-87 %), suggesting a higher dependency on lipolysis for LCT. Also, tmax tended to decrease to 20-60 % when compared to the animals not dosed with orlistat but lacking statistical significance. Without lipase inhibition, the LCT in general lead to better absorption of cinnarizine as compared to MCT, with 1.2-1.7-fold higher AUC0-24 h and 1.4-1.8-fold higher Cmax, but without showing statistical significance. Overall, the study revealed that lipolysis plays a major role in drug absorption from supersaturated lipid-based formulations type I.
Subject(s)
Cinnarizine , Rats , Animals , Orlistat , Pharmaceutical Preparations , Triglycerides , Solubility , Surface-Active Agents , Lipase , Digestion , Administration, OralABSTRACT
Understanding the effect of digestion on oral lipid-based drug formulations is a critical step in assessing the impact of the digestive process in the intestine on intraluminal drug concentrations. The classical pH-stat in vitro lipolysis technique has traditionally been applied, however, there is a need to explore the establishment of higher throughput small-scale methods. This study explores the use of alternative lipases with the aim of selecting digestion conditions that permit in-line UV detection for the determination of real-time drug concentrations. A range of immobilised and pre-dissolved lipases were assessed for digestion of lipid-based formulations and compared to digestion with the classical source of lipase, porcine pancreatin. Palatase® 20000 L, a purified liquid lipase, displayed comparable digestion kinetics to porcine pancreatin and drug concentration determined during digestion of a fenofibrate lipid-based formulation were similar between methods. In-line UV analysis using the MicroDISS ProfilerTM demonstrated that drug concentration could be monitored during one hour of dispersion and three hours of digestion for both a medium- and long-chain lipid-based formulations with corresponding results to that obtained from the classical lipolysis method. This method offers opportunities exploring the real-time dynamic drug concentration during dispersion and digestion of lipid-based formulations in a small-scale setup avoiding artifacts as a result of extensive sample preparation.
Subject(s)
Lipids , Lipolysis , Animals , Swine , Pancreatin , Lipase , Digestion , SolubilityABSTRACT
Long-acting injectables have shown to offer a prolonged release of a drug compound up to several months, providing the opportunity to increase patient compliance for treatment of long-term and chronic conditions. Different formulation technologies have already been utilized for long-acting injectables, and especially aqueous suspensions with crystalline drug particles in the sub-micron range have sparked an interest for future development of long-acting injectables. Wet bead milling is a common top-down process used to prepare nano- and microsuspensions of crystalline drug particles with the addition of surfactants in the dispersion medium, which are working as stabilizers to prevent agglomeration or crystal growth that ultimately may influence the physical stability of nano- and microsuspensions. To examine the reproducibility of the suspensions manufactured and the behavior of their physical stability, i.e., changes in particle sizes over time, low-energy roller mill was utilized for the manufacturing of nano- and microsuspensions in the present study. Investigated formulation parameters was stabilizer type and concentration and milling parameters varied in bead size and duration of milling. The obtained results demonstrated that the physical stability of suspensions containing the two model compounds, cinnarizine and indomethacin, was highly affected by the constitution of surfactant and processing. Various size classes were obtained and accompanied by high variations between the individual samples that indicated uneven and unpredictable milling by the low-energy roller mill, limiting the possibility to prepare reproducible and physical stable suspensions. Short-term stability studies revealed clear tendencies towards reversed Ostwald ripening of suspensions stabilized with poloxamer 188 that contained cinnarizine as the drug compound, and to a smaller extent suspensions containing indomethacin. Furthermore, X-ray Powder Diffraction confirmed no alteration of the drug compounds crystal structure after roller milling for multiple days.
Subject(s)
Cinnarizine , Nanoparticles , Humans , Reproducibility of Results , Drug Compounding/methods , Excipients/chemistry , Surface-Active Agents , Indomethacin , Suspensions , Particle Size , Nanoparticles/chemistry , SolubilityABSTRACT
Aqueous nano- and microsuspensions containing poorly water-soluble, crystalline drug particles have in the recent years sparked an interest for the preparation of long-acting injectables (LAIs), which increase patient compliance for patients treated for long-term or chronic conditions. Nano- and microsuspensions are often prepared by top-down methods, such as wet bead milling, with the addition of stabilizers in the dispersion media, such as surfactants, which influence the particle sizes and physical stability of the suspension. To improve the efficacy of formulation screening for nano- and microsuspensions, dual centrifugation was utilized in this study whereby 40 samples could be manufactured simultaneously to support the formulation definition. Hence, the type and concentration of stabilizer as well as bead size and milling speed was investigated throughout the presented study, but also the ability of the method to produce consistent data was investigated. The obtained results demonstrated that the particle profile obtained after milling was very consistent from run to run and so was the observed stability data, i.e., running n = 1 experiment per combination could clearly be justified as a predictable approach for the formulation screening. The data also showed that the stabilizer, as well as its concentration highly influenced the physical stability of suspensions containing both the two investigated model compounds, i.e., both cinnarizine and indomethacin, where the biggest increase in particle sizes was observed within the first week. For short-term studies, polysorbate 20 was found to be a suitable stabilizer for suspensions of cinnarizine, whereas sodium dodecyl sulphate was more suitable for indomethacin suspensions immediately after the milling even with 1% (w/v) stabilizer solution, but not sufficient for short-term stability due to an insufficient stabilizer concentration. Smaller particles sizes could be achieved by milling the suspensions with the smallest bead sizes and at the highest speed of 1500 rpm without disrupting the crystal structure of the active pharmaceutical ingredient (API), which was confirmed by X-ray Powder Diffraction.
ABSTRACT
Artificial intelligence is a rapidly expanding area of research, with the disruptive potential to transform traditional approaches in the pharmaceutical industry, from drug discovery and development to clinical practice. Machine learning, a subfield of artificial intelligence, has fundamentally transformed in silico modelling and has the capacity to streamline clinical translation. This paper reviews data-driven modelling methodologies with a focus on drug formulation development. Despite recent advances, there is limited modelling guidance specific to drug product development and a trend towards suboptimal modelling practices, resulting in models that may not give reliable predictions in practice. There is an overwhelming focus on benchtop experimental outcomes obtained for a specific modelling aim, leaving the capabilities of data scraping or the use of combined modelling approaches yet to be fully explored. Moreover, the preference for high accuracy can lead to a reliance on black box methods over interpretable models. This further limits the widespread adoption of machine learning as black boxes yield models that cannot be easily understood for the purposes of enhancing product performance. In this review, recommendations for conducting machine learning research for drug product development to ensure trustworthiness, transparency, and reliability of the models produced are presented. Finally, possible future directions on how research in this area might develop are discussed to aim for models that provide useful and robust guidance to formulators.
Subject(s)
Artificial Intelligence , Machine Learning , Reproducibility of Results , Drug Compounding , Computer SimulationABSTRACT
Lipid-based formulations, in particular supersaturated lipid-based formulations, are important delivery approaches when formulating challenging compounds, as especially low water-soluble compounds profit from delivery in a pre-dissolved state. In this article, the classification of lipid-based formulation is described, followed by a detailed discussion of different supersaturated lipid-based formulations and the recent advances reported in the literature. The supersaturated lipid-based formulations discussed include both the in situ forming supersaturated systems as well as the thermally induced supersaturated lipid-based formulations. The in situ forming drug supersaturation by lipid-based formulations has been widely employed and numerous clinically available products are on the market. There are some scientific gaps in the field, but in general there is a good understanding of the mechanisms driving the success of these systems. For thermally induced supersaturation, the technology is not yet fully understood and developed, hence more research is required in this field to explore the formulations beyond preclinical studies and initial clinical trials.
Subject(s)
Lipids , Water , Pharmaceutical Preparations , Solubility , Drug Delivery Systems , Administration, OralABSTRACT
Dissolution limitations to oral absorption can occur if the time required for dissolution is longer than the transit time across the small intestine and/or if dissolution is slower than the drug's permeation through the gut wall. These limitations most often occur for poorly soluble drugs. A standard method for overcoming dissolution issues is to reduce the particle size of the (solid) drug. Building on the refined Developability Classification System (rDCS), this work establishes a novel set of equations with which the appropriate degree of particle size reduction needed to mitigate dissolution limitations to absorption can be calculated. According to the type of data available, the appropriate equation(s) for each situation can be applied. Three case examples are used to illustrate implementation of the equations: voriconazole, lemborexant and istradefylline. Although for voriconazole (rDCS Class I) target radius (rtarget) estimates indicate that particle size reduction is unnecessary, for lemborexant (rDCS Class I) a radius of ≤20 µm would be required to improve absorption. For istradefylline (rDCS Class IIb) the rtarget was approximately 12 µm. Results are commensurate with literature information for these three drugs, signaling that the equations are suitable for application to a wide variety of drug substances.
ABSTRACT
Due to the strong tendency towards poorly soluble drugs in modern development pipelines, enabling drug formulations such as amorphous solid dispersions, cyclodextrins, co-crystals and lipid-based formulations are frequently applied to solubilize or generate supersaturation in gastrointestinal fluids, thus enhancing oral drug absorption. Although many innovative in vitro and in silico tools have been introduced in recent years to aid development of enabling formulations, significant knowledge gaps still exist with respect to how best to implement them. As a result, the development strategy for enabling formulations varies considerably within the industry and many elements of empiricism remain. The InPharma network aims to advance a mechanistic, animal-free approach to the assessment of drug developability. This commentary focuses current status and next steps that will be taken in InPharma to identify and fully utilize 'best practice' in vitro and in silico tools for use in physiologically based biopharmaceutic models.
Subject(s)
Body Fluids , Cyclodextrins , Biopharmaceutics , Solubility , Administration, OralABSTRACT
P-glycoprotein (P-gp) inhibitors, like zosuquidar, partly increase oral bioavailability of P-gp substrates, such as etoposide. Here, it was hypothesised that co-release of etoposide and zosuquidar from amorphous solid dispersions (ASDs) may further increase oral etoposide bioavailability. This was envisioned through simultaneous co-release and subsequent spatiotemporal association of etoposide and zosuquidar in the small intestinal lumen. To further achieve this, ASDs of etoposide and zosuquidar in polyvinylpyrrolidone (PVP), hydroxypropylmethyl cellulose (HPMC) 5, and HPMC 4 k were prepared by freeze-drying. From these ASDs, etoposide release was fastest from PVP, then HPMC 5 and slowest from HPMC 4. Release from PVP and HPMC5 resulted in stable supersaturations of etoposide. In transcellular permeability studies across MDCKII-MDR1 cell monolayers, the accumulated amount of etoposide increased 3.7-4.9-fold from amorphous etoposide or when incorporated into PVP- or HPMC 5-based ASDs, compared to crystalline etoposide. In vivo, the oral bioavailability in Sprague Dawley rats increased from 1.0 to 2.4-3.4 %, when etoposide was administered as amorphous drug or in ASDs. However, when etoposide and zosuquidar were co-administered, the oral bioavailability increased further to 8.2-18 %. Interestingly, a distinct increase in oral etoposide bioavailability to 26 % was observed when etoposide and zosuquidar were co-administration in HPMC5-based ASDs. The supersaturation of etoposide as well as the simultaneous co-release of etoposide and zosuquidar in the small intestinal lumen may explain the observed bioavailability increase. Overall, this study suggested that simultaneous co-release of an amorphous P-gp substrate and inhibitor may be a novel and viable formulation strategy to increase the bioavailability P-gp substrates.
Subject(s)
Povidone , Rats , Animals , Etoposide , Biological Availability , Solubility , Rats, Sprague-Dawley , Pharmaceutical Preparations/chemistry , Povidone/chemistry , Hypromellose Derivatives/chemistryABSTRACT
The present study aimed to explore the usefulness of beagle dogs in combination with physiologically based pharmacokinetic (PBPK) modeling in the evaluation of drug exposure after oral administration to pediatric populations at an early stage of pharmaceutical product development. An exploratory, single-dose, crossover bioavailability study in six beagles was performed. A paracetamol suspension and an ibuprofen suspension were coadministered in the fasted-state conditions, under reference-meal fed-state conditions, and under infant-formula fed-state conditions. PBPK models developed with GastroPlus v9.7 were used to inform the extrapolation of beagle data to human infants and children. Beagle-based simulation outcomes were compared with published human-adult-based simulations. For paracetamol, fasted-state conditions and reference-meal fed-state conditions in beagles appeared to provide adequate information for the applied scaling approach. Fasted-state and/or reference-meal fed-state conditions in beagles appeared suitable to simulate the performance of ibuprofen suspension in pediatric populations. Contrary to human-adult-based translations, extrapolations based on beagle data collected under infant-formula fed-state conditions appeared less useful for informing simulations of plasma levels in pediatric populations. Beagle data collected under fasted and/or reference-meal fed-state conditions appeared to be useful in the investigation of pediatric product performance of the two investigated highly permeable and highly soluble drugs in the upper small intestine. The suitability of the beagle as a preclinical model to understand pediatric drug product performance under different dosing conditions deserves further evaluation with a broader spectrum of drugs and drug products and comparisons with pediatric in vivo data.