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Drug supersaturation during formulation digestion, including real-time analytical approaches

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Abstract

Self-emulsifying and other lipid-based drug delivery systems have drawn considerable interest from pharmaceutical scientists for managing oral delivery of poorly water-soluble compounds. Following administration, self-emulsifying systems exhibit complex aqueous dispersion and digestion in the gastro-intestinal tract. These processes generally result in drug supersaturation, which leads to enhanced absorption or the high drug concentrations may cause precipitation with erratic and variable oral bioavailability. This review briefly outlines drug supersaturation obtained from self-emulsifying and other lipid-based formulations; recent advancements of in vitro lipolysis testing are also discussed. Further, a main focus is mechanisms by which supersaturation is triggered from gastro-intestinal processes, as well as analytical techniques that are promising from a research and development perspective. Comparatively simple approaches are presented together with more sophisticated process analytics to enable direct examination of kinetic changes. The analytical methods together with their sensor probes are discussed in detail to clarify opportunities as well as technical limitations. Some of the more sophisticated methods, including those based on synchrotron radiation, are primarily research oriented despite interesting experimental findings from an industrial viewpoint. The availability of kinetic data further opens the door to mathematical modeling of supersaturation and precipitation versus permeation, which lays the groundwork for better in vitro to in vivo correlations as well as for physiologically-based modeling of lipid-based systems.

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... To develop su-SEDDSs, it is essential to understand the basic concepts of solubility, supersaturation, and absorption. The advantages of absorption by supersaturation can be explained by the following theories [34,43,44]. Drug absorption can be assessed by Fick's First law; thus, the drug absorption via passive drug diffusion is driven by the maximum concentration in GIT: ...
... The importance of supersaturation maintenance in vivo has already been addressed in many earlier studies in the literature [18,34,[52][53][54]. The theoretical concept behind the generation and maintenance of a supersaturated state is commonly described by the "spring and parachute" theory [5,18,34,43,52,[55][56][57]. This theory is explained in a slightly modified manner for su-SEDDS as shown in Figure 3 below, considering the induction of supersaturation caused by some different factors (e.g., dispersion and digestion in GIT) in lipid-based formulations [58]. ...
... In the field of oral drug delivery, in vitro models are commonly used in the pharmaceutical development phase to estimate in vivo drug performance and optimize formulation design prior to preclinical and clinical studies [5,7,13,18,42,43,56]. To improve the accuracy of in vivo dissolution predictions using in vitro dissolution, defined dissolution media that more accurately reflect the solubilization processes in vivo need to be developed [25,52,61]. ...
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Self-emulsifying drug delivery systems (SEDDSs) are a vital strategy to enhance the bioavailability (BA) of formulations of poorly water-soluble compounds. However, these formulations have certain limitations, including in vivo drug precipitation, poor in vitro in vivo correlation due to a lack of predictive in vitro tests, issues in handling of liquid formulation, and physico-chemical instability of drug and/or vehicle components. To overcome these limitations, which restrict the potential usage of such systems, the supersaturable SEDDSs (su-SEDDSs) have gained attention based on the fact that the inclusion of precipitation inhibitors (PIs) within SEDDSs helps maintain drug supersaturation after dispersion and digestion in the gastrointestinal tract. This improves the BA of drugs and reduces the variability of exposure. In addition, the formulation of solid su-SEDDSs has helped to overcome disadvantages of liquid or capsule dosage form. This review article discusses, in detail, the current status of su-SEDDSs that overcome the limitations of conventional SEDDSs. It discusses the definition and range of su-SEDDSs, the principle mechanisms underlying precipitation inhibition and enhanced in vivo absorption, drug application cases, biorelevance in vitro digestion models, and the development of liquid su-SEDDSs to solid dosage forms. This review also describes the effects of various physiological factors and the potential interactions between PIs and lipid, lipase or lipid digested products on the in vivo performance of su-SEDDSs. In particular, several considerations relating to the properties of PIs are discussed from various perspectives.
... The spectroscopic or other analytical techniques can be implemented in a classical compendial as well as non-compendial in vitro tests. It is possible to use for example immersion probes or flow-through cells for real-time analysis of drug release and different methods were reviewed in the literature [353,354]. While ultraviolet (UV) fiber optical probes are these days widely used, other approaches such as UV imaging, Raman or Fourier transform infrared (FTIR) spectroscopy or laser scanning techniques have been used only occasionally for drug release/precipitation analysis [353,354]. ...
... It is possible to use for example immersion probes or flow-through cells for real-time analysis of drug release and different methods were reviewed in the literature [353,354]. While ultraviolet (UV) fiber optical probes are these days widely used, other approaches such as UV imaging, Raman or Fourier transform infrared (FTIR) spectroscopy or laser scanning techniques have been used only occasionally for drug release/precipitation analysis [353,354]. It is important to clarify what these analytical methods can offer to biopharmaceutical testing as well as to learn about these emerging new tools. ...
Article
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Although oral drug delivery is the preferred administration route and has been used for centuries, modern drug discovery and development pipelines challenge conventional formulation approaches and highlight the insufficient mechanistic understanding of processes critical to oral drug absorption. This review presents the opinion of UNGAP scientists on four key themes across the oral absorption landscape: (1) specific patient populations, (2) regional differences in the gastrointestinal tract, (3) advanced formulations and (4) food-drug interactions. The differences of oral absorption in pediatric and geriatric populations, the specific issues in colonic absorption, the formulation approaches for poorly water-soluble (small molecules) and poorly permeable (peptides, RNA etc.) drugs, as well as the vast realm of food effects, are some of the topics discussed in detail. The identified controversies and gaps in the current understanding of gastrointestinal absorption-related processes are used to create a roadmap for the future of oral drug absorption research.
... Self-microemulsifying drug delivery systems (SMEDDSs) are isotropic mixtures of lipids, surfactants and co-solvents, which spontaneously emulsify in gastrointestinal tract (GIT) and arguably form kinetically stable microemulsions [1][2][3] One of the recent comebacks for SMEDDSs is a game changing approach for oral delivery of hydrophilic peptides, proteins, polysaccharides and pDNA 5 . A hydrophobic ion pairing technique was developed to incorporate the hydrophilic biomacromolecules in the lipophilic phase of SMEDDSs by complexing them with oppositely charged lipophilic auxiliary agents [6][7][8] . ...
Article
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Self-microemulsifying drug delivery systems (SMEDDSs) have recently returned to the limelight of academia and industry due to their enormous potential in oral delivery of biomacromolecules. However, information on gastrointestinal lipolysis and trans-epithelial transport of SMEDDS is rare. Aggregation-caused quenching (ACQ) fluorescent probes are utilized to visualize the in vivo behaviors of SMEDDSs, because the released probes during lipolysis are quenched upon contacting water. Two SMEDDSs composed of medium chain triglyceride and different ratios of Tween-80 and PEG-400 are set as models, meanwhile Neoral® was used as a control. The SMEDDS droplets reside in the digestive tract for as long as 24 h and obey first order kinetic law of lipolysis. The increased chain length of the triglyceride decreases the lipolysis of the SMEDDSs. Ex vivo imaging of main tissues and histological examination confirm the trans-epithelial transportation of the SMEDDS droplets. Approximately 2%‒4% of the given SMEDDSs are transported via the lymph route following epithelial uptake, while liver is the main termination. Caco-2 cell lines confirm the cellular uptake and trans-epithelial transport. In conclusion, a fraction of SMEDDSs can survive the lipolysis in the gastrointestinal tract, permeate across the epithelia, translocate via the lymph, and accumulate mainly in the liver.
... Apart from the challenges to simulate these processes in vitro, it will be important to also monitor changes in a dynamic way. Sensor probes should here not only measure drug concentrations and optional supersaturation, but also structural changes should be monitored and a challenging example is digestion of LBF (Vithani et al., 2017;Kuentz, 2018). Such complex media typically exhibit relatively high turbidity that makes it hard to measure by means of any optical spectroscopy. ...
Article
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Poorly water-soluble drugs continue to be a problematic, yet important class of pharmaceutical compounds for treatment of a wide range of diseases. Their prevalence in discovery is still high, and their development is usually limited by our lack of a complete understanding of how the complex chemical, physiological and biochemical processes that occur between administration and absorption individually and together impact on bioavailability. This review defines the challenge presented by these drugs, outlines contemporary strategies to solve this challenge, and consequent in silico and in vitro evaluation of the delivery technologies for poorly water-soluble drugs. The next steps and unmet needs are proposed to present a roadmap for future studies for the field to consider enabling progress in delivery of poorly water-soluble compounds.
... Data showed a slower dissolution rate with ibuprofen sodium alone compared to dissolution rate when incorporated within the film. In each profile, it was observed that drug in its crystalline state achieved a condition of supersaturation due to the solubilizing effect of polymer combination (47,48). The dissolution profile of ibuprofen sodium showed a drug release of 59% at 15 min, while F5 had a drug release of 74%, a 1.25-fold increase (p = 0.002), and F6 of 72%, a 1.22-fold increase (p < 0.0001), resulting in an immediate-like release. ...
Article
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This study was conducted to formulate buccal films consisting of polyvinyl alcohol (PVA) and poly-N-hydroxyethyl-aspartamide (PHEA), to improve the dissolution of the drug through the oral mucosa. Ibuprofen sodium salt was used as a model drug, and the buccal film was expected to enhance its dissolution rate. Two different concentrations of PVA (5% w/v and 7.5% w/v) were used. Solvent casting was used to prepare films, where a solution consisting of drug and polymer was cast and allowed to dry. Attenuated total reflection Fourier transform infrared spectroscopy (ATR-FTIR), differential scanning calorimetry (DSC), and scanning electron microscopy (SEM) were used to investigate the properties of films. In vitro dissolution studies were also conducted to investigate drug release. SEM studies showed that films containing a higher concentration of PVA had larger particles in microrange. FTIR studies confirmed the presence of the drug in films and indicated that ibuprofen sodium did not react with polymers. DSC studies confirmed the crystalline form of ibuprofen sodium when incorporated within films. In vitro dissolution studies found that the dissolution percentage of ibuprofen sodium alone was increased when incorporated within the film from 59 to 74%. This study led to the development of solid microcrystalline dispersion as a buccal film with a faster dissolution rate than the drug alone overcoming problem of poor solubility.
... Although this assumption remains true for several drugs, for certain drugs (i.e., fenofibrate), oral absorption may still be consistent, even in light of notable drug precipitation. Accordingly, supersaturation rather than solubilization is emerging as an important drug driver flux across absorptive membranes [85,128,235,347]. ...
Article
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Approximately one third of newly discovered drug molecules show insufficient water solubility and therefore low oral bio-availability. Self-nano-emulsifying drug-delivery systems (SNEDDSs) are one of the emerging strategies developed to tackle the issues associated with their oral delivery. SNEDDSs are composed of an oil phase, surfactant, and cosurfactant or cosolvent. SNEDDSs characteristics, their ability to dissolve a drug, and in vivo considerations are determinant factors in the choice of SNEDDSs excipients. A SNEDDS formulation can be optimized through phase diagram approach or statistical design of experiments. The characterization of SNEDDSs includes multiple orthogonal methods required to fully control SNEDDS manufacture, stability, and biological fate. Encapsulating a drug in SNEDDSs can lead to increased solubilization, stability in the gastro-intestinal tract, and absorption, resulting in enhanced bio-availability. The transformation of liquid SNEDDSs into solid dosage forms has been shown to increase the stability and patient compliance. Supersaturated, mucus-permeating, and targeted SNEDDSs can be developed to increase efficacy and patient compliance. Self-emulsification approach has been successful in oral drug delivery. The present review gives an insight of SNEDDSs for the oral administration of both lipophilic and hydrophilic compounds from the experimental bench to marketed products.
... Nevertheless, high in vivo apparent supersaturation ratios may also determine drug precipitation and thus negatively impact drug exposure. Indeed, it has been suggested that a modest degree of supersaturation may be Table optimal for boosting drug absorption, while balancing the risk of drug precipitation which is higher at extremes of supersaturation (Kuentz, 2019). PIs can kinetically hinder precipitation by having a "parachute" effect and therefore prolong the supersaturation state and improve drug absorption. ...
Article
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Supersaturated lipid-based drug delivery systems are increasingly being explored as a bio-enabling formulation approach, particularly in preclinical evaluation of poorly-water soluble drugs. While increasing the drug load through thermally-induced supersaturation resulted in enhanced in vivo exposure for some drugs, for others, such as cinnarizine, supersaturated lipid-based systems have not been found beneficial to increase the in vivo bioavailability. We hypothesized that incorporation of precipitation inhibitors to reduce drug precipitation may address this limitation. Therefore, pharmacokinetic profiles of cinnarizine supersaturated lipid-based drug delivery systems with or without precipitation inhibitors were compared. Five precipitation inhibitors were selected for investigation based on a high throughput screening of twenty-one excipients. In vivo results showed that addition of 5% precipitation inhibitors to long chain monoglyceride (LCM) or medium chain monoglyceride (MCM) formulations showed a general trend of increases in cinnarizine bioavailability, albeit only statistically significantly increased for Poloxamer 407 + LCM system (i.e. 2.7-fold increase in AUC0-24h compared to LCM without precipitation inhibitors). It appeared that precipitation inhibitors mitigated the risk of in vivo precipitation of cinnarizine from sLBDDS and overall, bioavailability was comparable to that previously reported for cinnarizine after dosing of non-supersaturated lipid systems. In summary, for drugs which are prone to precipitation in supersaturated lipid-based drug delivery systems, such as cinnarizine, inclusion of precipitation inhibitors mitigates this risk and provides the opportunity to maximize exposure which is ideally suited in early efficacy and toxicology evaluation.
... The main approaches to increase intestinal flux is to increase the intestinal intraluminal drug concentration by increasing the release rate in accordance with Nernst-Brunner equation (or modified Noyes-Whitney eq [23]) and by increased passive diffusion/intestinal permeation due to an increased concentration gradient in accordance with Fick's first law. The high or oversaturated intestinal intraluminal drug concentration can be achieved using different formulation strategies such as decreasing drug crystallinity and/or preparation of digestible formulations such as lipids and cyclodextrin-based systems [24][25][26][27][28]. ...
Article
Silymarin is a mixture of flavonolignans obtained from the seeds of milk thistle (Silybum marianum L. Gaertner). Silymarin behaves as a weak acid and is categorised as a class IV drug substance in accordance with biopharmaceutics drug disposition classification system, possessing low solubility, as well as low bioavailability. The scope of this study was to identify possible formulation strategies of silymarin. Then, the main aim was to manufacture silymarin solid dispersions using a solvent evaporation approach and to characterise the physicochemical and drug release properties of the two formulations containing two different porous carriers, namely Avicel® PH-102 and Syloid® XDP 3150, and different concentrations of Tween® 80. Silymarin Log P was determined to be 1.6 (±0.14) negating the possibility of bypassing first pass metabolism via lymphatic transport. Utilising alkaline titration, the apparent pKa of silymarin was found to be similar to that of the silybin pKa (5.68). The crystallinity of raw silymarin was confirmed using powder X-ray diffraction and differential scanning calorimetry, and its thermal degradation was observed at a temperature higher than 220°C (thermogravimetric analysis). Avicel® PH-102 and Syloid® XDP 3150 were characterised in terms of morphology using scanning electron microscopy, particle size distribution (laser diffraction spectroscopy), pore size distribution and intra-particle porosity using mercury intrusion porosimetry. Solid dispersions were manufactured using an organic solvent method incorporating silymarin, the carrier and optionally Tween® 80. The amorphous state of silymarin in all prepared formulations was confirmed using differential scanning calorimetry and powder X-ray diffraction. Silymarin dissolution kinetics were faster for Syloid® XDP 3150 versus Avicel® PH-102 and explained through carrier properties. The addition of Tween® 80 and increasing the concentration from 0.3 to 1.6% (w/w) significantly increased the drug release kinetics of Avicel® PH-102 formulations but had no effect on Syloid® XDP 3150 formulations. Drug release from prepared formulations was compared with Legalon® 70 using the similarity factor (F2). Syloid® XDP 3150-based formulations showed F2>50%. Tween® 80 had a negligible effect on the silymarin release from Syloid® XDP 3150-based formulations. Interestingly, the ability of Tween® 80 to inhibit gut wall efflux is well known. Thus, the inclusion of this excipient offers an opportunity to modulate the silymarin bioavailability without changing the drug release profile. A six-month stability study (at room temperature and 40% RH) confirmed that solid dispersions were still powder X-ray diffraction and differential scanning calorimetry amorphous. Acetone was used for both silymarin extraction and preparation of solid dispersions. Thus, there is an opportunity to use a single step to both load silymarin and form solid dispersions within a single-step.
... The main approaches to increase intestinal flux is to increase the intestinal intraluminal drug concentration by increasing the release rate in accordance with Nernst-Brunner equation (or modified Noyes-Whitney eq [23]) and by increased passive diffusion/intestinal permeation due to an increased concentration gradient in accordance with Fick's first law. The high or oversaturated intestinal intraluminal drug concentration can be achieved using different formulation strategies such as decreasing drug crystallinity and/or preparation of digestible formulations such as lipids and cyclodextrin-based systems [24][25][26][27][28]. ...
... One approach to circumvent the uncertainty involved in the "sample and separate" method is to study the process of solubilisation in situ. A recent review highlighted the use of ion-selective electrodes, in-line UV probes, Raman scattering spectroscopy, and synchrotron X-ray scattering, for the real time analyses of drug solubilisation and precipitation in digesting lipids (Kuentz, 2019). On a structural level, low frequency Raman scattering spectroscopy and X-ray scattering are uniquely placed to evaluate the dissolution/precipitation of crystalline drug and any polymorphic changes occurring during digestion of lipid formulations (Salim et al., 2019a;Salim et al., 2018;Salim et al., 2019c;Salim et al., 2020c;Boyd et al., 2018). ...
Article
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Lipid-based formulations improve the absorption capacity of poorly-water-soluble drugs and digestion of the formulation is a critical step in that absorption process. A recent approach to understanding the propensity for drug to dissolve in digesting lipid-based formulations couples an in vitro pH-stat lipolysis model to small-angle X-ray scattering (SAXS) by means of a flow through capillary. However, the conventional pH-stat apparatus used to measure the extent of lipid digestion during such experiments requires digest volumes of 15–30 mL and drug doses of 50–200 mg which is problematic for scarce compounds and can require excessive amounts of formulation reagents. This manuscript describes an approach to reduce the amount of material required for in vitro lipolysis experiments coupled to SAXS, for use in instances where the amount of drug or formulation medium is limited. Importantly, this was achieved while maintaining the pH stat conditions, which is critical for maintaining biorelevance and driving digestion to completion. The digestibility of infant formula with the poorly-water-soluble drugs halofantrine and clofazimine dispersed into it was measured as an exemplar paediatric-friendly lipid formulation. Halofantrine was incorporated in its powdered free base form and clofazimine was incorporated both as unformulated drug powder and as drug in nanoparticulate form prepared using flash nanoprecipitation. The fraction of triglyceride digested was found to be independent of vessel size and the incorporation of drug. The dissolution of the two forms of clofazimine during the digestion of infant formula were then measured using synchrotron SAXS, which revealed complete and partial solubilisation over 30 min of digestion for the powdered drug and nanoparticle formulations, respectively. The main challenge in reducing the volume of the measurements was in ensuring that thorough mixing was occurring in the smaller digestion vessel to provide uniform sampling of the dispersion medium.
... In case of formulations that lead to supersaturation, such as through the use of amorphous form or lipid-based formulations [11,12] the thermodynamic solubility of the compound is not altered and the permeability remains unchanged. Formulating the API in form of amorphous solid dispersion (ASD) is a possibility to improve not just its dissolution but also the bioavailability of the API [13]. ...
Article
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The work aimed to develop the Absorption Driven Drug Formulation (ADDF) concept, which is a new approach in formulation development to ensure that the drug product meets the expected absorption rate. The concept is built on the solubility-permeability interplay and the rate of supersaturation as the driving force of absorption. This paper presents the first case study using the ADDF concept where not only dissolution and solubility but also permeation of the drug is considered in every step of the formulation development. For that reason, parallel artificial membrane permeability assay (PAMPA) was used for excipient selection, small volume dissolution-permeation apparatus was used for testing amorphous solid dispersions (ASDs), and large volume dissolution-permeation tests were carried out to characterize the final dosage forms. The API-excipient interaction studies on PAMPA indicated differences when different fillers or surfactants were studied. These differences were then confirmed with small volume dissolution-permeation assays where the addition of Tween 80 to the ASDs decreased the flux dramatically. Also, the early indication of sorbitol’s advantage over mannitol by PAMPA has been confirmed in the investigation of the final dosage forms by large-scale dissolution-permeation tests. This difference between the fillers was observed in vivo as well. The presented case study demonstrated that the ADDF concept opens a new perspective in generic formulation development using fast and cost-effective flux-based screening methods in order to meet the bioequivalence criteria. Graphical Abstract
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Lipid-based formulations (LBFs) have demonstrated a great potential in enhancing the oral absorption of poorly water-soluble drugs. However, construction of in vitro and in vivo correlations (IVIVCs) for LBFs is quite challenging, owing to a complex in vivo processing of these formulations. In this paper, we start with a brief introduction on the gastrointestinal digestion of lipid/LBFs and its relation to enhanced oral drug absorption; based on the concept of IVIVCs, the current status of in vitro models to establish IVIVCs for LBFs is reviewed, while future perspectives in this field are discussed. In vitro tests, which facilitate the understanding and prediction of the in vivo performance of solid dosage forms, frequently fail to mimic the in vivo processing of LBFs, leading to inconsistent results. In vitro digestion models, which more closely simulate gastrointestinal physiology, are a more promising option. Despite some successes in IVIVC modeling, the accuracy and consistency of these models are yet to be validated, particularly for human data. A reliable IVIVC model can not only reduce the risk, time, and cost of formulation development but can also contribute to the formulation design and optimization, thus promoting the clinical translation of LBFs.
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Oral administration of chemotherapy agents, such as docetaxel (DTX), is expected to reduce side effects significantly and increase dosing frequency. However, they often suffer from poor oral bioavailability, impeding their oral application. Dietary lipids such as triglycerides favor lymphatic transport nor vein system, bypassing the first-pass metabolism. Inspired by this concept, we developed a triglyceride-like prodrug of DTX (named as OATG) and explored the effect of lipid types on the OATG oral delivery. The plasma profile in rats revealed that long chain triglyceride (LCT)-based lipid formulations (LBLF) were more promising for OATG delivery than medium chain triglyceride (MCT) ones. The OATG LBLF elicited a markedly enhanced absorption compared with oral Taxotere or DTX LBLF, resulting in relative bioavailability 6.11 or 2.47-fold higher, respectively. The coincident intestinal behaviors of lipid excipients and TG-like prodrug facilitate the oral absorption of the prodrug. The effectiveness of the prodrug formulation was also examined in beagles with absolute bioavailability up to 41.08%, in sharp contrast to that of control DTX group (8%). Besides, the OATG oral formulation could be schedule-intensively administrated with no hypersensitivity, gastrointestinal and hematological toxicity. The current strategy provides an effective lipid formulation and a promising chance for chemotherapy at home.
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New drug candidates often require bio-enabling formation technologies such as lipid-based formulations, solid dispersions, or nanosized drug formulations. Development of such more sophisticated delivery systems generally requires higher resource investment compared to a conventional oral dosage form, which might slow down clinical development. To achieve the biopharmaceutical objectives while enabling rapid cost effective development, it is imperative to identify a suitable formulation technique for a given drug candidate as early as possible. Hence many companies have developed internal decision trees based mostly on prior organizational experience, though they also contain some arbitrary elements. As part of the EU funded PEARRL project, a number of new decision trees are here proposed that reflect both the current scientific state of the art and a consensus among the industrial project partners. This commentary presents and discusses these, while also going beyond this classical expert approach with a pilot study using emerging machine learning, where the computer suggests formulation strategy based on the physicochemical and biopharmaceutical properties of a molecule. Current limitations are discussed and an outlook is provided for likely future developments in this emerging field of pharmaceutics.
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The aim of this study is to clarify absorption mechanisms after oral administration of ritonavir (RTV) from different types of lipid-based formulations (LBFs) with particular emphasis on the effect of lipid digestion and drug permeation/re-dissolution on the oral absorption. Four LBFs were prepared; three contained either long-chain (LC) or medium-chain (MC) lipids [lipid formulation classification system (LFCS) Type II-LC, Type IIIA-MC, and Type IIIB-MC] and the fourth contained only surfactant and co-solvent (Type IV). The solubility of RTV in those LBFs was determined and drug subsequently loaded at 85% w/w of the saturated solubility in the formulations. Then, each LBF containing drug was added into a model rat intestinal fluid at approximately 2.5% w/v for evaluation using an in vitro digestion model. In vitro digestion study showed the ability of Type II-LC and Type IIIA-MC to support continued solubilization of RTV, and moderate supersaturation was observed in Type IIIA-MC. In contrast, RTV partly precipitated in the Type IIIB-MC during digestion, and the Type IV formulation lost its solubilization capacity rapidly upon dispersion, leading to drastic precipitation. Oral administration of RTV as Type IIIA-MC to rats showed significantly higher area under the plasma concentration-time curve compared to control suspension, whereas it was not improved with Type II-LC administration despite complete solubilization of RTV during digestion. From the results of in vitro permeation across dialysis membrane (a molecular weight cutoff of > 1000 Da), this may be attributed to the lowered free concentration in the gastrointestinal tract owing to incorporation of RTV into the undigested LC lipid. Oral absorption drastically increased with Type IIIB-MC and Type IV despite the observed moderate and drastic precipitation, respectively. Powder X-ray diffraction analysis revealed that the precipitate was amorphous. Therefore, improved re-solubilization may partly contribute to improved absorption. The present study revealed detailed absorption mechanisms from LBFs with different compositions. Our findings may be useful for selecting appropriate excipients to design optimal LBFs for poorly water-soluble drugs.
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Poor aqueous solubility is currently a prevalent issue in the development of small molecule pharmaceuticals. Several methods are possible for improving the solubility, dissolution rate and bioavailability of Biopharmaceutics Classification System (BCS) class II and class IV drugs. Two solid state approaches, which rely on reductions in order, and can theoretically be applied to all molecules without any specific chemical prerequisites (compared with e.g. ionizable or co-former groups, or sufficient lipophilicity), are the use of the amorphous form and nanocrystals. Research involving these two approaches is relatively extensive and commercial products are now available based on these technologies. Nevertheless, their formulation remains more challenging than with conventional dosage forms. This article describes these two technologies from both theoretical and practical perspectives by briefly discussing the physicochemical backgrounds behind these approaches, as well as the resulting practical implications, both positive and negative. Case studies demonstrating the benefits and challenges of these two techniques are presented.
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Despite the increasing interest in pharmaceutical use of mesoporous silica, there is still only limited knowledge on mechanisms of pore loading and subsequent drug desorption and release. Hence the aim of this work was to address the mechanistic aspects of drug loading into the mesoporous silica pores and to minimise the risk of pore clogging. Hydrophilic solvents (polysorbate 20 and polyethylene glycol 200) with high dissolving capacity for the model drug celecoxib were studied for their surface tension as well as dynamic viscosity by considering hydration. As an innovation in liquisolid systems preparation, a rather simple drug loading method on a mesoporous carrier was introduced by using semi-volatile solvent mixtures. Fast liquid loading into the pores was achieved due to the lowered viscosity and surface tension of the whole solvent system. Drug release kinetics suggested that lipid-based formulations belonging to class IV of Lipid Formulation Classification System may exhibit a lower risk of incomplete desorption from a carrier. The utilisation of volatile solvents during preparation had no negative impact on the liquisolid systems' dissolution behaviour. All prepared formulations showed similar significantly faster dissolution profiles compared to the physical mixture. The novel approach has potential to promote liquisolid applications in pharmaceutics.
Chapter
This chapter aims to illustrate the mechanisms by which lipid‐based formulation (LBF) overcome bioavailability limitations and control drug release, rationalize the formulation design, describe methods for characterization and identification of critical quality attributes, and explore their emerging applications including modified release formulations. LBF have long been investigated for their role in enhancing the absorption of poorly water soluble drug (PWSD). The original rationale for the investigation of LBF to improve absorption of PWSD was the observation that numerous drugs showed favorable increases in oral bioavailability when co‐administered with food. The principle components governing the controlled release behavior from lipid‐based formulations are either changes in the gastric or intestinal processes involved in absorption or release of API from a lipid matrix/ formulation. A range of in vitro techniques enables prediction of the likely fate of the drug and formulation in vivo .
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This study aimed to examine the effect of colloidal structures forming and changing with dispersion and digestion of lipid-based formulation (LBF) on the permeability of exemestane (EXE), a poorly water-soluble drug. Self-nanoemulsifying drug delivery system (SNEDDS), one of the LBF, was developed using Imwitor® 988, Kolliphor® RH 40, and Labrasol® according to the solubility study and optimized using Box-Behnken Design. The EXE-loaded SNEDDS formulation has a 14.46 ± 0.23 nm droplet size with a 0.119 ± 0.053 polydispersity index. EXE was loaded into SNEDDS at 15 mg/g. In vitro digestion was conducted to investigate the EXE permeability at the digestion medium and the flux of EXE through a dialysis membrane and porcine intestinal tissue was assessed with the permeability step. In vitro digestion study revealed that the SNEDDS formulation retained the solubilization of EXE and showed moderate supersaturation. The permeation of EXE through the dialysis membrane was observed that the EXE amount on the acceptor side was similar during different digestion phase, but the permeation of EXE through porcine intestinal tissue was slightly different during different digestion phases and EXE permeability was higher at 60 min of digestion although statistically not significant. However, EXE precipitation was observed since the solvation capacity of colloidal structures was slightly decreased at 60 min of digestion. It can be explained by the fact that EXE re-dissolved and increased the free fraction, increasing permeability. This study showed that the drug precipitation in the digestion study does not always result in low permeation and minor differences could be observed more evident in the porcine intestine tissue.
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Objectives: This review highlights aspects of drug hydrophobicity and lipophilicity as determinants of different oral formulation approaches with specific focus on enabling formulation technologies. An overview is provided on appropriate formulation selection by focussing on the physicochemical properties of the drug. Key findings: Crystal lattice energy and the octanol-water partitioning behaviour of a poorly soluble drug are conventionally viewed as characteristics of hydrophobicity and lipophilicity, which matter particularly for any dissolution process during manufacturing and regarding drug release in the gastrointestinal tract. Different oral formulation strategies are discussed in the present review, including lipid-based delivery, amorphous solid dispersions, mesoporous silica, nanosuspensions and cyclodextrin formulations. Summary: Current literature suggests that selection of formulation approaches in pharmaceutics is still highly dependent on the availability of technological expertise in a company or research group. Encouraging is that, recent advancements point to more structured and scientifically based development approaches. More research is still needed to better link physicochemical drug properties to pharmaceutical formulation design.
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Lipid based formulations (LBF) are a promising formulation strategy for many poorly water soluble drugs and have been shown previously to enhance the oral exposure of CP-532,623, an oral cholesteryl ester transfer protein inhibitor. In the current study, an in vitro lipid digestion model was used to probe the relationship between drug solubilisation and supersaturation on in vitro dispersion and digestion of LBF containing long chain (LC) lipids and drug absorption in vivo. After in vitro digestion of LBF based on LC lipids, the proportion of CP-532,623 maintained in the solubilised state in the aqueous phase of the digest was highest in formulations containing Kolliphor RH 40, and in most cases outperformed equivalent formulations based on MC lipids. Subsequent administration of the LC-LBFs to beagle dogs resulted in reasonable correlation between concentrations of CP-532,623 measured in the aqueous phase of the in vitro digest after 30 min digestion and in vivo exposure (AUC); however, the LC-LBFs required greater in vitro drug solubilisation to elicit similar in vivo exposure when compared to previous studies with MC-LBF. Although post digestion solubilisation was enhanced in LC-LBF compared to MC-LBF, equilibrium solubility studies of CP-532,623 in the aqueous phase isolated from blank lipid digestion experiments revealed that equilibrium solubility was also higher, and therefore supersaturation lower. A revised correlation based on supersaturation in the digest aqueous phase and drug absorption was therefore generated. A single, linear correlation was evident for both LC- and MC-LBF containing Kolliphor RH 40, but this did not extend to formulations based on other surfactants. The data suggest that solubilisation and supersaturation are significant drivers of drug absorption in vivo, and that across formulations with similar formulation composition good correlation is evident between in vitro and in vivo measures. However, across dissimilar formulations, solubilisation and supersaturation alone are not sufficient to explain drug exposure and other factors also likely play a role.
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Self-microemulsifying drug delivery systems provide a key technology to formulate challenging drugs. These formulations are commonly screened in early development by simple in vitro dilution tests. However, there is often a lack of rationale of how these tests are performed; so this article aims to improve this situation by studying critical concentrations in the dilution of self-microemulsifying formulations. Dynamic laser light backscattering, conductivity measurements, and electron paramagnetic resonance spectroscopy were conducted. All model formulations exhibited profound changes at a similar aqueous dilution, which was interpreted as a percolation threshold of the formulation in water. It marked the change of a bicontinuous microemulsion to discrete micelles. The systems exhibited at this point maximal particle dispersion with a threshold of polydispersity. A marked change was also observed in the paramagnetic resonance spectra and with the conductivity measurements. This altered microenvironment can be relevant for solubilized drugs. Future dilution tests should include a formulation-to-water ratio of roughly 1:5 (w/w), which is in the proximity of the individual threshold concentration. Additional dilutions may be tested below and clearly above this value to reflect the physiological dilution process.