Osteotomies around the knee alter alignment of the ankle and hindfoot: a systematic review of biomechanical and clinical studies

Purpose: Emerging reports suggest an important involvement of the ankle/hindfoot alignment in the outcome of knee osteotomy; however, a comprehensive overview is currently not available. Therefore, we systematically reviewed all studies investigating biomechanical and clinical outcomes related to the ankle/hindfoot following knee osteotomies. Methods: A systematic literature search was conducted on PubMed, Web of Science, EMBASE and Cochrane Library according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and registered on international prospective register of systematic reviews (PROSPERO) (CRD42021277189). Combining knee osteotomy and ankle/hindfoot alignment, all biomechanical and clinical studies were included. Studies investigating knee osteotomy in conjunction with total knee arthroplasty and case reports were excluded. The QUality Appraisal for Cadaveric Studies (QUACS) scale and Methodological Index for Non-Randomized Studies (MINORS) scores were used for quality assessment. Results: Out of 3554 hits, 18 studies were confirmed eligible, including 770 subjects. The minority of studies (n = 3) assessed both high tibial- and distal femoral osteotomy. Following knee osteotomy, the mean tibiotalar contact pressure decreased (n = 4) except in the presence of a rigid subtalar joint (n = 1) or a talar tilt deformity (n = 1). Patient symptoms and/or radiographic alignment at the level of the ankle/hindfoot improved after knee osteotomy (n = 13). However, factors interfering with an optimal outcome were a small preoperative lateral distal tibia angle, a small hip–knee–ankle axis (HKA) angle, a large HKA correction (>14.5°) and a preexistent hindfoot deformity (>15.9°). Conclusions: Osteotomies to correct knee deformity alter biomechanical and clinical outcomes at the level of the ankle/hindfoot. In general, these changes were beneficial, but several parameters were identified in association with deterioration of ankle/hindfoot symptoms following knee osteotomy

Exploring gastrointestinal variables affecting drug and formulation behavior: methodologies, challenges and opportunities

Various gastrointestinal (GI) factors affect drug and formulation behavior after oral administration, including GI transfer, motility, pH and GI fluid volume and composition. An in-depth understanding of these physiological and anatomical variables is critical for a continued progress in oral drug development. In this review, different methodologies (invasive versus non-invasive) to explore the impact of physiological variables on formulation behavior in the human GI tract are presented, revealing their strengths and limitations. The techniques mentioned allow for an improved understanding of the role of following GI variables: gastric emptying (magnetic resonance imaging (MRI), scintigraphy, acetaminophen absorption technique, ultrasonography, breath test, intraluminal sampling and telemetry), motility (MRI, small intestinal/colonic manometry and telemetry), GI volume changes (MRI and ultrasonography), temperature (telemetry) and intraluminal pH (intraluminal sampling and telemetry)

Biorelevant in vitro evaluation of gastrointestinal drug supersaturation

Estimates are that around 70% of today s drug candidates are handicapped by poor aqueous solubility. As gastrointestinal dissolution is a prerequisite for absorption, it is evident that the exposure of these drug candidates will be little to zero after oral administration as such. However, experience with a variety of formulation approaches, so called supersaturating drug delivery systems (SDDS), has shown that intraluminal concentrations of a drug are not necessarily limited by their thermodynamicsolubility in gastrointestinal fluids. Drugs may be in solution at a concentration exceeding the solubility, i.e., in a state of supersaturation. However, the supersaturated state is thermodynamically unstable and, on itself, the driving force for precipitation. As long as supersaturated drugs do not precipitate from this thermodynamic unstable condition, intestinal absorption may be enabled. Considering the vast potential of the supersaturation concept for oral delivery of poorly water soluble drug candidates, industry and academia show a growing interest in studying both induction of supersaturation and subsequent precipitation. Since the added value of gastrointestinal supersaturation will depend on its stability in vivo , efficient exploitation of this strategy requires in vitro evaluation procedures predictive for the behavior of supersaturation inducing formulations in vivo . However, the current knowledge onthe effects of gastrointestinal physiology (including the composition of gastrointestinal fluids, gastrointestinal transit, hydrodynamics and transepithelial transport rate) on drug supersaturation/precipitation is extremely limited, hampering the implementation of biorelevant supersaturation assays in drug and formulation development. The research performed in the framework of this thesis therefore investigated the impact of different biorelevant aspects on drug supersaturation and precipitation to provide the insights needed to advance the biorelevance of the current supersaturation evaluation. As it is extremely difficult to demonstrate drug supersaturation in situ in the intraluminal environment, in a first step, human gastric and intestinal fluids representative for fastedand fed state conditions, were aspirated from healthy volunteers, to serve as biorelevant in vitro test medium for exploring the potential of supersaturation. As such, the supersaturation/precipitation behavior of various poorly soluble drugs (itraconazole, etravirine, loviride, danazol, ritonavir, fenofibrate and glibenclamide) was evaluated in vitro in human gastrointestinal aspirates. The results clearly illustrated that supersaturation of drug compounds with different physicochemical characteristics can be created and maintained up to a certain degree in human gastrointestinal fluids representing different nutritional states, validating the potential of supersaturating drug delivery systems, in vivo . The stability of the induced supersaturation proved to be compound- and medium-dependent. Comparison of the supersaturation stability in human gastric fluids versus fasted state human intestinal fluids indicated inferior supersaturation stability in human gastric fluids. Regarding the effect of food on supersaturation behavior, it was illustrated for allcompounds, except for itraconazole, that supersaturation stability was reduced in postprandial conditions. In addition to the studies performedin human gastrointestinal aspirates, commonly used gastric and intestinal simulation media and simple buffer solutions were benchmarked for their predictive value in a supersaturation/precipitation context. The supersaturation/precipitation behavior in human gastric fluids was adequately predicted using fasted state simulated gastric fluids (FaSSGF). In contrast, SGF overestimated supersaturation stability in 3 out of 5 cases suggesting that the use of FaSSGF is to be preferred for the biorelevant evaluation of drug precipitation in a gastric environment. To predict precipitation kinetics in the intestinal environment, simple aqueous buffer solutions at pH 6.5 should be avoided as they significantly overestimate the stability of supersaturation. The commonly used FaSSIF performs reasonably well in predicting the precipitation behavior in fasted state human fluids. For the fed state, in contrast, fed state simulated intestinal fluid (FeSSIF) may significantly underestimate precipitation. In a second step, the potential of various excipients to inhibit drug precipitation was evaluated in human gastrointestinal aspirates and compared to the excipient mediated precipitation inhibition obtained commonly used artificial media. The extent to which precipitation inhibition could be obtained appeared to be medium, compound and excipientdependent. Experiments using human intestinal fluids from volunteers inthe fasted or fed state evidenced that the nutritional state did not significantly affect the extent of excipient-mediated precipitation inhibition. Achieving substantial excipient-mediated precipitation inhibition in human gastric fluids or FaSSGF proved to be difficult with only modest effects of Eudragit® E PO and HPMC-E5 and no effect of PVP K25. Takinginto account the limited supersaturation stability in human gastric fluids and the modest capacity of excipients to slow down gastric precipitation, one could argue that supersaturation should be targeted to the small intestine. Precipitation inhibition studies performed in human intestinal fluids provide evidence that cellulosic polymers posses the potential to decelerate drug precipitation, possibly resulting in enhanced absorption of low solubility compounds. The usefulness of simple aqueous buffers or simulated intestinal fluids representative for the fasted or fed state as solvent systems to predict excipient-mediated precipitationinhibition in human intestinal fluids appeared to be limited, illustrating the need for further evaluation of media for supersaturation screening. However, since lack of supersaturation stabilization by a given excipient in aqueous buffer or simulated intestinal fluids was always confirmed in human intestinal fluids, elimination of excipients based on screening tests in simple media appears feasible. Since in the intestinal tract, absorption might serve as an alternative for precipitation of supersaturated drug molecules, precipitation kinetics might be altered in an absorption environment compared to a non-absorption environment. Therefore, in a last step, the impact of supersaturation/precipitation on transepithelial transport and vice versa was investigated. The interplaybetween absorption and supersaturation was investigated by comparing classic precipitation assessment in a non-absorption environment with precipitation/permeation assessment in an absorption environment for the poorly soluble drug loviride. While absorption was clearly enhanced when supersaturation was induced, subsequent precipitation also proved to limitthe absorption enhancement. Through comparison of precipitation in absorption versus non-absorption setups, this study explicitly revealed, forthe first time, that, loviride precipitation is overestimated in a non-absorption environment. Consequently, the added value of precipitation inhibitors was also overestimated in a non-absorption setup. These results confirm the hypothesis that absorption in vivo could serve as an alternative for drug precipitation. As such, ignoring permeation is detrimental for accurate prediction of the impact of supersaturation on absorption. Implementing transepithelial permeation into in vitro precipitation assays will therefore be crucial for the efficient development of supersaturating drug delivery systems. In conclusion, this dissertation research has demonstrated that, although very complex, supersaturation and excipient mediated precipitation inhibition are feasible in human gastrointestinal fluids and provides a better understanding of intraluminal supersaturation under biorelevant conditions. Different artificial media were validated for their predictive capacity towards human gastrointestinal fluid and absorption was identified as a precipitation altering factor. Integration of the obtained knowledge in non-clinical evaluation procedures will improve their biorelevance and contribute to the successful exploitation of the supersaturation concept as absorption-enhancing strategy in the future .status: publishe

Excipient-mediated supersaturation stabilization in human intestinal fluids

It was the purpose of this study to investigate excipient-mediated precipitation inhibition upon induction of supersaturation of poorly water-soluble drugs in aspirated human intestinal fluids (HIF) representing both the fasted and fed state. Etravirine, ritonavir, loviride, danazol and fenofibrate were selected as model compounds. For comparative purposes, precipitation inhibition was also evaluated in simple aqueous buffer, and in intestinal simulation media representative for the fasted and fed state (FaSSIF and FeSSIF, respectively). Supersaturation was induced in the test media containing predissolved excipient (HPMC-AS, HPMC-E5, HPMC-E50, HPMC-E4M, HPMC-P and PVP) at a defined degree of supersaturation (DS = 20) using the solvent shift method. The results illustrate that cellulosic polymers can reduce the precipitation rate and stabilize supersaturation in HIF. The extent of stabilization was compound and excipient dependent but independent of the nutritional state. Whenever excipient effects were observed, the predictive value of simple buffer or FaSSIF/FeSSIF was rather limited. In general, excipient-mediated precipitation inhibition was less pronounced in HIF compared to simple aqueous buffer or FaSSIF/FeSSIF. However, excipients showing no effect in simple aqueous buffer or FaSSIF/FeSSIF also proved to be ineffective in HIF, indicating the value of these simulation media in the elimination of excipients during formulation development.status: publishe

Drug precipitation-permeation interplay: Supersaturation in an absorptive environment

PURPOSE: The present study investigated the interplay between supersaturation, absorption, precipitation, and excipient-mediated precipitation inhibition by comparing classic precipitation assessment in a non-absorption environment with precipitation/permeation assessment in an absorption environment. Loviride and HPMC-E5 were selected as poorly soluble model drug and precipitation inhibitor, respectively. METHOD: To investigate supersaturation in an absorptive environment, supersaturation was induced at different degrees (DS), using a solvent shift method, in shaken Caco-2 Transwell® inserts containing fasted state simulated intestinal fluid (FaSSIF); to simulate a non-absorption environment, the inserts were parafilm-sealed and did not contain a cell monolayer. Donor and acceptor compartments were sampled as a function of time to determine precipitation kinetics and transport, respectively. RESULTS: In absence of precipitation, loviride transport increased proportionally with the initial DS; however, precipitation limited the supersaturation-induced transport enhancement. Loviride precipitation was found to be less extensive in an absorption environment compared to a non-absorption environment. As a result, the optimal DS obtained in a non-absorption environment (highest amount maintained in solution) did not correlate with the highest transport in an absorption environment. In addition, the impact of HPMC-E5 on loviride transport was inferior to its precipitation inhibitory capacity observed in a non-absorption environment. CONCLUSION: For the first time, the present study explicitly demonstrated that implementation of permeation in precipitation assays is critical to predict the impact of supersaturation, precipitation, and precipitation inhibition on the absorption of poorly soluble drugs.status: publishe

Supersaturation in human gastric fluids

PURPOSE: The current study reports on supersaturation, precipitation and excipient mediated precipitation inhibition of five poorly soluble drugs (loviride, glibenclamide, itraconazole, danazol, and etravirine) in human and simulated gastric fluids. METHOD: Upon induction of supersaturation in human gastric fluids (HGFs), simulated gastric fluid (SGF), and fasted state simulated gastric fluid (FaSSGF) using a solvent shift method, supersaturation and precipitation were assessed as a function of time. In addition, the precipitation inhibitory capacity of three polymers (Eudragit® E PO, HPMC-E5, and PVP K25) was investigated. RESULTS: Supersaturation in human gastric fluids was observed for all model compounds, but proved to be relatively unstable (fast precipitation), except for itraconazole. Only modest excipient-mediated stabilizing effects on supersaturation were observed using HPMC-E5 and Eudragit® E PO whereas PVP K25 exerted no effect. In contrast to SGF, the observed precipitation behavior in FaSSGF was similar to the behavior in human gastric fluids. CONCLUSION: The present study demonstrates that supersaturation stability of drugs in human gastric fluids is in general inferior to supersaturation stability in intestinal fluids. As the potential for excipient mediated precipitation inhibition in gastric fluids was only limited, our data suggest that supersaturation should preferably be targeted to the intestine.status: publishe

Evaluation of gastrointestinal drug supersaturation and precipitation: Strategies and issues

Supersaturating drug delivery systems (SDDS) hold the promise of enabling intestinal absorption for difficult-to-formulate, poorly soluble drug candidates based on a design approach that includes (1) converting the drug into a high energy or rapidly dissolving system which presents a supersaturated solution to the gastrointestinal environment and (2) dosage form components that act to stabilize the formed metastable drug solution through nucleation and/or crystal growth inhibition. The appropriate development and study of SDDS require that useful and biorelevant supersaturation and precipitation assays are available. This review summarizes different methodological aspects of currently available in vitro assays, including the generation of supersaturation (solvent shift, pH shift or formulation-induced), the quantification of supersaturation and the detection of precipitation. Also down-scaled approaches, including 96-well plate setups, are described and situated in the pharmaceutical development cycle based on their consumption of API as well as time requirements. Subsequently, the ability to extrapolate in vitro supersaturation assessment to the in vivo situation is discussed as are direct and indirect clinical tools that can shed light on SDDS. By emphasizing multiple variables that affect the predictive power of in vitro assays (e.g. the nature of the test media, hydrodynamics, temperature and sink versus non-sink conditions), this review finally highlights the need for further harmonization and biorelevance improvement of currently available in vitro procedures for supersaturation and precipitation evaluation.status: publishe