ABSTRACT
Lipid based formulations (LBF) have shown to overcome food dependent bioavailability for some poorly water-soluble drugs. However, the utility of LBFs can be limited by low dose loading due to a low drug solubility in LBF vehicles. This study investigated the solubility and drug loading increases in LBFs using lipophilic counterions to form lipophilic salts of venetoclax. Venetoclax docusate was formed from venetoclax free base and verified by 1H NMR. Formation of stable venetoclax-fatty acid associations with either oleic acid or decanoic acid were attempted, however, the molecular associations were less consistent based on 1H NMR. Venetoclax docusate displayed a up to 6.2-fold higher solubility in self-emulsifying drug delivery systems (SEDDS) when compared to the venetoclax free base solubility resulting in a higher dose loading. A subsequent bioavailability study in landrace pigs demonstrated a 2.5-fold higher bioavailability for the lipophilic salt containing long chain SEDDS compared to the commercially available solid dispersion Venclyxto® in the fasted state. The bioavailability of all lipophilic salt SEDDS in the fasted state was similar to Venclyxto® in the fed state. This study confirmed that lipophilic drug salts increase the dose loading in LBFs and showed that lipophilic salt-SEDDS combinations may be able to overcome bioavailability limitations of drugs with low inherent dose loading in lipid vehicles. Furthermore, the present study demonstrated the utility of a LBF approach, in combination with lipophilic salts, to overcome food dependent variable oral bioavailability of drugs.
Subject(s)
Lipids , Salts , Administration, Oral , Animals , Biological Availability , Bridged Bicyclo Compounds, Heterocyclic , Drug Compounding/methods , Drug Delivery Systems/methods , Emulsions , Lipids/chemistry , Salts/chemistry , Solubility , Sulfonamides , SwineABSTRACT
PURPOSE: To investigate the compatibility between hard gelatin and HPMC capsules with a range of different isotropic lipid based formulations containing multiple excipients. METHODS: The miscibility was investigated for 350 systems applying five different oils (Labrafac ™ lipophile WL1349, Maisine® CC, Captex 300 EP/NF, olive oil, and Capmul MCM EP/NF), five different surfactans (Labrasol ® ALF, Labrafil M 2125 CS, Kolliphor ® ELP, Kolliphor ® HS 15, Tween 80) and three different cosolvents (propylene glycol, polyethylene glycol 400, and Transcutol ® HP). For the isotropic systems capsule compatibility was investigated in both gelatin and HPMC capsules at 25°C at 40% and 60% relative humidity by examining physical damages to the capsules and weight changes after storage. RESULTS: The miscibility of lipid based vehicles was best when the formulation contained monoglycerides and surfactants with a hydrophilic-lipophilic balance value <12. Gelatin capsules in general resulted in a better compatibility when compared to HPMC capsules for the evaluated formulations. Addition of water to the formulation improved the capsule compatibility for both capsule types. The expected capsule mass change could partly be predicted in binary systems using the provided data of the single excipients weighted for its formulation proportion. CONCLUSIONS: The capsule compatibility was driven by the components incorporated into the formulations, where more was compatible with gelatin than HPMC capsules. Prediction of the mass change from individual excipient contributions can provide a good first estimate if a vehicle is compatible with a capsule, however, this needs to be proved experimentally.
Subject(s)
Capsules/chemistry , Gelatin/chemistry , Hypromellose Derivatives/chemistry , Lipids/chemistry , Drug Compounding , Excipients/chemistry , SolubilityABSTRACT
The pig has been increasingly used as a reliable preclinical model for assessing and predicting the in vivo bioavailability of different formulation strategies. Nevertheless, differences in the composition between porcine and human intestinal fluids, may impact on the solubility and dissolution behaviour of drugs, in particular BCS II/IV drugs. Recently, a porcine fasted simulated intestinal fluid (FaSSIFp) was developed to mimic the composition in the lumen of landrace pigs under fasted state conditions. In this work, we present the utilization of FaSSIFp to compare solubility against human FaSSIF & FeSSIF and further combine species specific in vitro testing with in silico predictive modelling. Venetoclax was chosen as a model drug, representing a BCS class IV drug, with a reported clinically significant positive food effect, where bioavailability is increased up to approximately five-fold when administered with a high-fat meal. Biorelevant species specific in vitro testing was a promising tool for integrating in vitro data into in silico models, using FaSSIFp resulted in reliable predictions of the plasma concentration profile in fasted pigs, based on a porcine physiologically based absorption model. The porcine physiologically based absorption model was used to prospectively simulate the impact of food on the bioavailability of venetoclax. The use of luminal solubility estimates in combination with dissolution data for venetoclax, measured in species specific simulated fluids, correctly predict the observed pig plasma concentration profile and food effect. Overall, integrating species specific in vitro - in silico models led to accurate prediction of in vivo absorption of venetoclax in a preclinical stage, which can support guidance in early decisions of drug product development. In addition, the study further demonstrated the utility of the pig model to predict the food effects of venetoclax in humans.
Subject(s)
Intestinal Absorption , Models, Biological , Animals , Bridged Bicyclo Compounds, Heterocyclic , Computer Simulation , Fasting , Solubility , Sulfonamides , SwineABSTRACT
The concept of using precipitation inhibitors (PIs) to sustain supersaturation is well established for amorphous formulations but less in the case of lipid-based formulations (LBF). This study applied a systematic in silico-in vitro-in vivo approach to assess the merits of incorporating PIs in supersaturated LBFs (sLBF) using the model drug venetoclax. sLBFs containing hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), polyvinylpyrrolidone (PVP), PVP-co-vinyl acetate (PVP/VA), Pluronic F108, and Eudragit EPO were assessed in silico calculating a drug-excipient mixing enthalpy, in vitro using a PI solvent shift test, and finally, bioavailability was assessed in vivo in landrace pigs. The estimation of pure interaction enthalpies of the drug and the excipient was deemed useful in determining the most promising PIs for venetoclax. The sLBF alone (i.e., no PI present) displayed a high initial drug concentration in the aqueous phase during in vitro screening. sLBF with Pluronic F108 displayed the highest venetoclax concentration in the aqueous phase and sLBF with Eudragit EPO the lowest. In vivo, the sLBF alone showed the highest bioavailability of 26.3 ± 14.2%. Interestingly, a trend toward a decreasing bioavailability was observed for sLBF containing PIs, with PVP/VA being significantly lower compared to sLBF alone. In conclusion, the ability of a sLBF to generate supersaturated concentrations of venetoclax in vitro was translated into increased absorption in vivo. While in silico and in vitro PI screening suggested benefits in terms of prolonged supersaturation, the addition of a PI did not increase in vivo bioavailability. The findings of this study are of particular relevance to pre-clinical drug development, where the high in vivo exposure of venetoclax was achieved using a sLBF approach, and despite the perceived risk of drug precipitation from a sLBF, including a PI may not be merited in all cases.
Subject(s)
Bridged Bicyclo Compounds, Heterocyclic/chemistry , Drug Compounding/methods , Excipients/chemistry , Lipids/chemistry , Sulfonamides/chemistry , Administration, Oral , Animals , Biological Availability , Chemical Precipitation , Chemistry, Pharmaceutical , Computer Simulation , Drug Development , Male , Models, Animal , Models, Chemical , Solubility , Sus scrofaABSTRACT
Validation and characterisation of in vitro and pre-clinical animal models to support bio-enabling formulation development is of paramount importance. In this work, post-mortem gastric and small intestinal fluids were collected in the fasted, fed state and at five sample-points post administration of a placebo Self-Emulsifying Drug Delivery System (SEDDS) in the fasted state to pigs. Cryo-TEM and Negative Stain-TEM were used for ultrastructure characterisation. Ex vivo solubility of fenofibrate was determined in the fasted-state, fed-state and post-SEDDS administration. Highest observed ex vivo drug solubility in intestinal fluids after SEDDS administration was used for optimising the biorelevant in vitro conditions to determine maximum solubility. Under microscopic evaluation, fasted, fed and SEDDS fluids resulted in different colloidal structures. Drug solubility appeared highest 1 hour post SEDDS administration, corresponding with presence of SEDDS lipid droplets. A 1:200 dispersion of SEDDS in biorelevant media matched the highest observed ex vivo solubility upon SEDDS administration. Overall, impacts of this study include increasing evidence for the pig preclinical model to mimic drug solubility in humans, observations that SEDDS administration may poorly mimic colloidal structures observed under fed state, while microscopic and solubility porcine assessments provided a framework for increasingly bio-predictive in vitro tools.
Subject(s)
Drug Delivery Systems , Fenofibrate , Administration, Oral , Animals , Biological Availability , Emulsions , Solubility , SwineABSTRACT
Computational approaches are increasingly utilised in development of bio-enabling formulations, including self-emulsifying drug delivery systems (SEDDS), facilitating early indicators of success. This study investigated if in silico predictions of drug solubility gain i.e. solubility ratios (SR), after dispersion of a SEDDS in biorelevant media could be predicted from drug properties. Apparent solubility upon dispersion of two SEDDS in FaSSIF was measured for 30 structurally diverse poorly water soluble drugs. Increased drug solubility upon SEDDS dispersion was observed in all cases, with higher SRs observed for cationic and neutral versus anionic drugs at pH 6.5. Molecular descriptors and solid-state properties were used as inputs during partial least squares (PLS) modelling resulting in predictive models for SRMC (r2 = 0.81) and SRLC (r2 = 0.77). Multiple linear regression (MLR) facilitated generation of simplified SR equations with high predictivity (SRMC r2 = 0.74; SRLC r2 = 0.69), requiring only three drug properties; partition coefficient at pH 6.5 (logD6.5), melting point (Tm) and aromatic bonds as fraction of total bonds (F-AromB). Through using the equations to inform developability classification system (DCS) classes for drugs that have already been licensed as lipid-based formulations, merits for development with SEDDS was predicted for 2/3 drugs.
Subject(s)
Drug Delivery Systems , Lipids , Biological Availability , Drug Compounding , Emulsions , SolubilityABSTRACT
Within preclinical research, the pig has become an important model in regulatory toxicology and pharmacokinetics, to assess oral dosage forms and to compare different formulation strategies. In addition, there are emerging application of the pig model to asses clinical dosing conditions in the fasted and fed state. In this study, the gastrointestinal transit conditions in male landrace pigs were studied with a telemetric motility capsule under fasted and postprandial conditions. The whole gut transit time (WGTT) was determined by administering a SmartPill® capsule to four landrace pigs, under both fasted and fed state conditions in a cross-over study design. Overall, this study found that small intestinal transit in landrace pigs ranged from 2.3 - 4.0 h, and was broadly similar to reported human estimates and was not affected by the intake conditions. Gastric emptying was highly variable and prolonged in landrace pigs ranging from 20 - 233 h and up to 264 h in one specific case. Under dynamic conditions pigs have a low gastric pH comparable to humans, however a high variability under fasted conditions could be observed. The comparison of the data from this study with a recent similar study in beagle dogs revealed major differences between gastric maximum pressures observed in landrace pigs and dogs. In the porcine stomach maximum pressures of up to 402 mbar were observed, which are comparable to reported human data. Intestinal maximum pressures in landrace pigs were in the same range as in humans. Overall, the study provides new insights of gastrointestinal conditions in landrace pigs, which can lead to more accurate interpretation of in vivo results obtained of pharmacokinetic studies in preclinical models. While small intestinal transit conditions, GI pH and pressures were similar to humans, the prolonged gastric emptying observed in pigs need to be considered in assessing the suitability of the pig model for assessing in vivo performance of large non-disintegrated oral drug products.
Subject(s)
Gastric Emptying , Gastrointestinal Transit , Animals , Cross-Over Studies , Digestion , Dogs , Gastrointestinal Motility , Male , Swine , TelemetryABSTRACT
The absence of an intestinal absorption sink is a significant weakness of standard in vitro lipolysis methods, potentially leading to poor prediction of in vivo performance and an overestimation of drug precipitation. In addition, the majority of the described lipolysis methods only attempt to simulate intestinal conditions, thus overlooking any supersaturation or precipitation of ionizable drugs as they transition from the acidic gastric environment to the more neutral conditions of the intestine. The aim of this study was to develop a novel lipolysis method incorporating a two-stage gastric-to-intestinal transition and an absorptive compartment to reliably predict in vivo performance of lipid-based formulations (LBFs). Drug absorption was mimicked by in situ quantification of drug partitioning into a decanol layer. The method was used to characterize LBFs from four studies described in the literature, involving three model drugs (i.e., nilotinib, fenofibrate, and danazol) where in vivo bioavailability data have previously been reported. The results from the novel biphasic lipolysis method were compared to those of the standard pH-stat method in terms of reliability for predicting the in vivo performance. For three of the studies, the novel biphasic lipolysis method more reliably predicted the in vivo bioavailability compared to the standard pH-stat method. In contrast, the standard pH-stat method was found to produce more predictive results for one study involving a series of LBFs composed of the soybean oil, glyceryl monolinoleate (Maisine CC), Kolliphor EL, and ethanol. This result was surprising and could reflect that increasing concentrations of ethanol (as a cosolvent) in the formulations may have resulted in greater partitioning of the drug into the decanol absorptive compartment. In addition to the improved predictivity for most of the investigated systems, this biphasic lipolysis method also uses in situ analysis and avoids time- and resource-intensive sample analysis steps, thereby facilitating a higher throughput capacity and biorelevant approach for characterization of LBFs.
Subject(s)
Lipids/chemistry , Lipolysis/physiology , Pharmaceutical Preparations/chemistry , Pharmaceutical Preparations/metabolism , Biological Availability , Chemistry, Pharmaceutical/methods , Humans , Intestinal Absorption/physiology , Reproducibility of Results , Solubility/drug effects , Soybean Oil/chemistryABSTRACT
The scientific rationale for selection of the surfactant type during oral formulation development requires an in-depth understanding of the interplay between surfactant characteristics and biopharmaceutical factors. Currently, however, there is a lack of comprehensive knowledge of how surfactant properties, such as hydrophilic-lipophilic balance (HLB), digestibility, and fatty acid (FA) chain length, translate into in vivo performance. In the present study, the relationship between surfactant properties, in vitro characteristics, and in vivo bioavailability was systematically evaluated. An in vitro lipolysis model was used to study the digestibility of a variety of nonionic surfactants. Eight surfactants and one surfactant mixture were selected for further analysis using the model poorly water-soluble drug nilotinib. In vitro lipolysis of all nilotinib formulations was performed, followed by an in vivo pharmacokinetic evaluation in rats. The in vitro lipolysis studies showed that medium-chain FA-based surfactants were more readily digested compared to long-chain surfactants. The in vivo study demonstrated that a Tween 20 formulation significantly enhanced the absolute bioavailability of nilotinib up to 5.2-fold relative to an aqueous suspension. In general, surfactants that were highly digestible in vitro tended to display higher bioavailability of nilotinib in vivo. The bioavailability may additionally be related to the FA chain length of digestible surfactants with an improved exposure in the case of medium-chain FA-based surfactants. There was no apparent relationship between the HLB value of surfactants and the in vivo bioavailability of nilotinib. The impact of this study's findings suggests that when designing surfactant-based formulations to enhance oral bioavailability of the poorly water-soluble drug nilotinib, highly digestible, medium chain-based surfactants are preferred. Additionally, for low-permeability drugs such as nilotinib, which is subject to efflux by intestinal P-glycoprotein, the biopharmaceutical effects of surfactants merit further consideration.
Subject(s)
Digestion/drug effects , Pyrimidines/metabolism , Surface-Active Agents/metabolism , Administration, Oral , Animals , Biological Availability , Chemistry, Pharmaceutical/methods , Excipients/metabolism , Fatty Acids/metabolism , Hydrophobic and Hydrophilic Interactions , Lipolysis/drug effects , Male , Rats , Rats, Sprague-Dawley , Solubility/drug effects , Suspensions/metabolismABSTRACT
PURPOSE: Lipid-based formulations (LBF) have shown oral bioavailability enhancement of lipophilic drugs, but not necessarily in the case of hydrophobic drugs. This study explored the potential of lipid vehicles to improve the bioavailability of the hydrophobic drug nilotinib comparing a chase dosing approach and lipid suspensions. METHODS: Nilotinib in vivo bioavailability in rats was determined after administering an aqueous suspension chase dosed with blank olive oil, Captex 1000, Peceol or Capmul MCM, respectively. Absolute bioavailability was determined (relative to an intravenous formulation). Pharmacokinetic parameters were compared to lipid suspensions. RESULTS: Compared to the lipid suspensions, the chase dosed lipids showed a 2- to 7-fold higher bioavailability. Both long chain chase dosed excipients also significantly increased the bioavailability up to 2-fold compared to the aqueous suspension. Deconvolution of the pharmacokinetic data indicated that chase dosing of nilotinib resulted in prolonged absorption compared to the aqueous suspension. CONCLUSION: Chase dosed LBF enhanced the in vivo bioavailability of nilotinib. Long chain lipids showed superior performance compared to medium chain lipids. Chase dosing appeared to prolong the absorption phase of the drug. Therefore, chase dosing of LBF is favourable compared to lipid suspensions for 'brick dust' molecules such as nilotinib. Graphical Abstract The potential of bio-enabling lipid vehicles, administered via chase dosing and lipid suspensions, has been evaluated as an approach to enhance oral bioavailability of nilotinib.
Subject(s)
Lipids/chemistry , Liposomes/chemistry , Pyrimidines/chemistry , Animals , Biological Availability , Chemistry, Pharmaceutical , Diglycerides/chemistry , Dose-Response Relationship, Drug , Excipients/chemistry , Hydrophobic and Hydrophilic Interactions , Male , Monoglycerides/chemistry , Oleic Acids/chemistry , Olive Oil/chemistry , Pyrimidines/pharmacokinetics , Rats , Rats, Sprague-Dawley , Solubility , Sorafenib/chemistry , Sorafenib/pharmacokinetics , Suspensions/chemistry , WaterABSTRACT
Simulated human intestinal media, have proved to be a useful biopharmaceutics tool as a dissolution media for predicting in vivo dissolution and pharmacokinetic profile in humans. During drug product development preclinical animal models are also required to assess drug product performance, and there is a need to develop species specific intestinal media to similarly predict in vivo pharmacokinetic profiles in each preclinical model. Pigs, are increasingly being used in preclinical drug development, however to date there is a lack of quantitative information about the composition of porcine gastrointestinal (GI) fluids. As a result, a porcine biorelevant medium has not yet been developed, which is essential to improve interpretation and forecast of preclinical results using biorelevant in vitro dissolution studies. GI fluid samples, were collected from landrace pigs, and characterized. Fasted State Simulated Intestinal Fluid of pigs (FaSSIFp) was developed based on the physiological composition of the GI fluids in terms of pH, buffer capacity, osmolality, surface tension, as well as the bile salt, phospholipid and free fatty acid content. This study demonstrated that FaSSIFp was superior at predicting the solubility of the six model drugs in porcine intestinal fluids (PIF). A markedly high correlation (r2 0.98) was observed between the solubility obtained in PIF and FaSSIFp, whereas poor correlation (r2 0.12) was found for the solubility of the model drugs between human FaSSIF and PIF. This confirms that species specific biorelevant intestinal media are crucial to provide more accurate predictions of pharmacokinetic studies in preclinical models. Additionally, the availability of a species specific intestinal medium offers the potential to improve in vitro-in silico approaches to predict in vivo absorption and to reduce the overall number of animals needed in oral drug product development testing.
Subject(s)
Bile Acids and Salts/chemistry , Biological Products/chemistry , Drug Development/methods , Gastric Acid/chemistry , Gastric Mucosa/chemistry , Intestine, Small/chemistry , Animals , Bile Acids and Salts/metabolism , Biological Products/metabolism , Body Fluids/chemistry , Body Fluids/drug effects , Body Fluids/metabolism , Celecoxib/pharmacokinetics , Drug Evaluation, Preclinical/methods , Gastric Acid/metabolism , Gastric Mucosa/drug effects , Gastric Mucosa/metabolism , Humans , Hydrogen-Ion Concentration , Intestinal Absorption/drug effects , Intestinal Absorption/physiology , Intestine, Small/drug effects , Intestine, Small/metabolism , Ketoconazole/pharmacokinetics , Osmolar Concentration , SwineABSTRACT
Increasing numbers of beyond Rule-of-Five drugs are emerging from discovery pipelines, generating a need for bio-enabling formulation approaches, such as lipid-based formulations (LBF), to ensure maximal in vivo exposure. However, many drug candidates display insufficient lipid solubility, leading to dose-loading limitations in LBFs. The aim of this study was to explore the potential of supersaturated LBFs (sLBF) for the beyond Rule-of-Five drug venetoclax. Temperature-induced sLBFs of venetoclax were obtained in olive oil, Captex® 1000, Peceol® and Capmul MCM®, respectively. A Peceol®-based sLBF displayed the highest drug loading and was therefore evaluated further. In vitro lipolysis demonstrated that the Peceol®-based sLBF was able to generate higher venetoclax concentrations in the aqueous phase compared to a Peceol®-based suspension and an aqueous suspension. A subsequent bioavailability study in pigs demonstrated for sLBF a 3.8-fold and 2.1-fold higher bioavailability compared to the drug powder and Peceol®-based suspension, respectively. In conclusion, sLBF is a promising bio-enabling formulation approach to enhance in vivo exposure of beyond Rule-of-Five drugs, such as venetoclax. The in vitro lipolysis results correctly predicted a higher exposure of the sLBF in vivo. The findings of this study are of particular relevance to pre-clinical drug development, where maximum exposure is required.
ABSTRACT
A preclinical porcine model that reliably predicts human food effect of fenofibrate was developed. Fenofibrate was administered to pigs as model compound with a positive food effect. Two different types of fed conditions were explored: a FDA style breakfast and a standard pig pellet feed. In order to assess if complete stomach emptying had been achieved under the employed fasting protocol, the amount of gastric and intestinal content was evaluated post-mortem. In addition, the protocol was designed to evaluate gastric emptying in the pre- and postprandial state using paracetamol as a marker. The study confirmed that micronized fenofibrate displayed a positive food effect with a similar fold difference to humans in FDA style fed state. Post-mortem assessment of stomach and intestinal content confirmed significantly lower content in the fasted compared to the pig pellet fed state. In the case of paracetamol, a delayed gastric emptying in the fed state was not observed, which may suggest that the Magenstrasse phenomena reported in humans, may also occur in landrace pigs. The study demonstrated the utility of a food effect protocol in landrace pigs as a pre-clinical approach to predict human food effects and provided new insights into gastric emptying in pigs.
ABSTRACT
PURPOSE: Lipid suspensions have been shown to be a suitable bio-enabling formulation approach for highly lipophilic or 'grease ball' drug molecules, but studies on 'brick dust' drugs are lacking. This study explored the utility of lipid suspensions for enhancing oral bioavailability of the rather hydrophobic drug nilotinib in vivo in rats. METHODS: Four lipid suspensions were developed containing long chain triglycerides, medium chain triglyceride, long chain monoglycerides and medium chain monoglycerides and in vivo bioavailability was compared to an aqueous suspension. Additionally, in vitro lipolysis and wettability tests were conducted. RESULTS: Nilotinib lipid suspensions did not show a bioavailability increase compared to an aqueous suspension. The bioavailability was lower for triglyceride suspensions, relative to both monoglyceride and an aqueous suspension. The long chain monoglyceride displayed a significantly higher bioavailability relative to triglycerides. In vitro lipolysis results suggested entrapment of nilotinib crystals within poorly dispersible triglycerides, leading to slower nilotinib release and absorption. This was further supported by higher wettability of nilotinib by lipids. CONCLUSION: Monoglycerides improved oral bioavailability of nilotinib in rats, relative to triglycerides. For 'brick dust' drugs formulated as lipid suspensions, poorly dispersible formulations may delay the release of drug crystals from the formulation leading to reduced absorption. Graphical Abstract An aqueous and four lipid suspensions have been evaluated in in vitro and in vivo to gain insights into the potential benefits and limitations of lipid suspensions.
Subject(s)
Antineoplastic Agents/pharmacokinetics , Excipients/chemistry , Monoglycerides/chemistry , Protein-Tyrosine Kinases/pharmacokinetics , Pyrimidines/pharmacokinetics , Triglycerides/chemistry , Administration, Oral , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/chemistry , Biological Availability , Chemistry, Pharmaceutical/methods , Drug Compounding , Gastrointestinal Absorption , Hydrophobic and Hydrophilic Interactions , Lipolysis , Male , Pharmaceutical Solutions , Protein-Tyrosine Kinases/administration & dosage , Protein-Tyrosine Kinases/chemistry , Pyrimidines/administration & dosage , Pyrimidines/chemistry , Rats, Sprague-Dawley , Suspensions , WettabilityABSTRACT
OBJECTIVES: In pharmaceutical drug development, preclinical tests in animal models are essential to demonstrate whether the new drug is orally bioavailable and to gain a first insight into in vivo pharmacokinetic parameters that can subsequently be used to predict human values. Despite significant advances in the development of bio-predictive in vitro models and increasing ethical expectations for reducing the number of animals used for research purposes, there is still a need for appropriately selected pre-clinical in vivo testing to provide guidance on the decision to progress to testing in humans. The selection of the appropriate animal models is essential both to maximise the learning that can be obtained from such experiments and to avoid unnecessary testing in a range of species. KEY FINDINGS: The present review, provides an insight into the suitability of the pig model for predicting oral bioavailability in humans, by comparing the conditions in the GIT. It also contains a comparison between the bioavailability of compounds dosed to both humans and pigs, to provide an insight into the relative correlation and examples on why a lack of correlation may be observed. SUMMARY: While there is a general trend towards predicting human bioavailability from pig data, there is considerable variability in the data set, most likely reflecting species specific differences in individual drug metabolism. Nonetheless, the correlation between pigs vs. humans was comparable to that reported for dogs vs. humans. The presented data demonstrate the suitability of the pig as a preclinical model to predict bioavailability in human.
Subject(s)
Drug Development/methods , Drug Evaluation, Preclinical/methods , Models, Animal , Administration, Oral , Animals , Biological Availability , Dogs , Humans , Pharmaceutical Preparations/administration & dosage , Pharmaceutical Preparations/metabolism , Species Specificity , SwineABSTRACT
OBJECTIVES: Supersaturating formulations hold great promise for delivery of poorly soluble active pharmaceutical ingredients (APIs). To profit from supersaturating formulations, precipitation is hindered with precipitation inhibitors (PIs), maintaining drug concentrations for as long as possible. This review provides a brief overview of supersaturation and precipitation, focusing on precipitation inhibition. Trial-and-error PI selection will be examined alongside established PI screening techniques. Primarily, however, this review will focus on recent advances that utilise advanced analytical techniques to increase mechanistic understanding of PI action and systematic PI selection. KEY FINDINGS: Advances in mechanistic understanding have been made possible by the use of analytical tools such as spectroscopy, microscopy and mathematical and molecular modelling, which have been reviewed herein. Using these techniques, PI selection can be guided by molecular rationale. However, more work is required to see widespread application of such an approach for PI selection. SUMMARY: Precipitation inhibitors are becoming increasingly important in enabling formulations. Trial-and-error approaches have seen success thus far. However, it is essential to learn more about the mode of action of PIs if the most optimal formulations are to be realised. Robust analytical tools, and the knowledge of where and how they can be applied, will be essential in this endeavour.
Subject(s)
Chemical Precipitation/drug effects , Drug Delivery Systems , Pharmaceutical Preparations/administration & dosage , Chemistry, Pharmaceutical/methods , Drug Compounding/methods , Humans , Models, Molecular , Pharmaceutical Preparations/chemistry , Solubility , Technology, Pharmaceutical/methodsABSTRACT
OBJECTIVES: Solubility parameters have been used for decades in various scientific fields including pharmaceutics. It is, however, still a field of active research both on a conceptual and experimental level. This work addresses the need to review solubility parameter applications in pharmaceutics of poorly water-soluble drugs. KEY FINDINGS: An overview of the different experimental and calculation methods to determine solubility parameters is provided, which covers from classical to modern approaches. In the pharmaceutical field, solubility parameters are primarily used to guide organic solvent selection, cocrystals and salt screening, lipid-based delivery, solid dispersions and nano- or microparticulate drug delivery systems. Solubility parameters have been applied for a quantitative assessment of mixtures, or they are simply used to rank excipients for a given drug. SUMMARY: In particular, partial solubility parameters hold great promise for aiding the development of poorly soluble drug delivery systems. This is particularly true in early-stage development, where compound availability and resources are limited. The experimental determination of solubility parameters has its merits despite being rather labour-intensive because further data can be used to continuously improve in silico predictions. Such improvements will ensure that solubility parameters will also in future guide scientists in finding suitable drug formulations.