Infant formula as a solid lipid dose form for enhancement of the oral bioavailability of cannabidiol for paediatric patients.

Cannabinoids can save paediatric patients from harmful psychological conditions caused by epilepsy. However, the limited aqueous solubility of the drug presents a limitation to oral absorption and bioavailability. Previous studies have shown the enhancement of oral bioavailability for poorly water-soluble drugs using milk or milk-based products like infant formula as a novel lipid-based formulation, due to digestion of the lipids to enhance drug solubility. that is particularly well suited to infants and in low economy settings. Therefore, this study has investigated the in vitro solubilization enhancement of cannabidiol (CBD) in milk-based products during digestion using synchrotron small angle X-ray scattering, followed by pharmacokinetic studies to determine the relative oral bioavailability. The in vitro results, coupled with in vivo data, demonstrate a two-fold increase in the oral bioavailability of CBD in bovine milk as well as infant formula. The results of this study indicate the potential for infant formula to be considered as a novel formulation approach for CBD. Further study is encouraged for more drugs with infant formula to strengthen the correlation between the solubilization of drug and their oral bioavailability.

Evaluating human milk as a drug delivery vehicle for clofazimine to premature infants.

Human milk is proposed as a drug delivery vehicle suitable for use in neonatal patients. Clofazimine, traditionally used for the treatment of leprosy and tuberculosis, is emerging as a treatment for cryptosporidiosis in infants, however its poor aqueous solubility has led to its commercial formulation as a waxy lipid formulation in a capsule, a format that is not suitable for infants. In this study, the evaluation of pasteurised human milk for the delivery of clofazimine was investigated using an in vitro lipolysis model to simulate gastric and intestinal digestion. The total lipid composition of the human milk was characterised alongside the liberated fatty acid species following digestion for comparison to alternative lipid-based delivery systems. Small-angle X-ray scattering was used to measure the presence of crystalline clofazimine during digestion and hence the extent of drug solubilisation. High-performance liquid chromatography was used to quantify the mass of clofazimine solubilised per gram of human milk fat (drug-to-fat ratio) in digested and undigested human milk. The digestion process was essential for the solubilisation of clofazimine, with digested human milk solubilising a sufficient dose of clofazimine for treatment of a premature infant. Human milk solubilised the clofazimine to a greater extent than bovine milk and infant formula during digestion, most likely as a result of differing lipid composition and increased long-chain fatty acid concentrations. These findings show that human milk enhances the solubility of clofazimine as a model drug and may be a suitable drug delivery vehicle for infant populations requiring therapeutic treatment.

In Situ Monitoring of Drug Precipitation from Digesting Lipid Formulations Using Low-Frequency Raman Scattering Spectroscopy.

Low-frequency Raman spectroscopy (LFRS) is a valuable tool to detect the solid state of amorphous and crystalline drugs in solid dosage forms and the transformation of drugs between different polymorphic forms. It has also been applied to track the solubilisation of solid drugs as suspensions in milk and infant formula during in vitro digestion. This study reports the use of LFRS as an approach to probe drug precipitation from a lipid-based drug delivery system (medium-chain self-nanoemulsifying drug delivery system, MC-SNEDDS) during in vitro digestion. Upon lipolysis of the digestible components in MC-SNEDDS containing fenofibrate as a model drug, sharp phonon peaks appeared at the low-frequency Raman spectral region (<200 cm-1), indicating the precipitation of fenofibrate in a crystalline form from the formulation. Two multivariate data analysis approaches (principal component analysis and partial least squares discriminant analysis) and one univariate analysis approach (band ratios) were explored to track these spectral changes over time. The low-frequency Raman data produces results in good agreement with in situ small angle X-ray scattering (SAXS) measurements with all data analysis approaches used, whereas the mid-frequency Raman requires the use of PLS-DA to gain similar results. This suggests that LFRS can be used as a complementary, and potentially more accessible, technique to SAXS to determine the kinetics of drug precipitation from lipid-based formulations.

Construction of a Synthetic Colostrum Substitute and Its Protection of Intestinal Cells against Inflammation in an In Vitro Model of Necrotizing Enterocolitis.

Colostrum provides bioactive components that are essential for the colonization of microbiota in the infant gut, while preventing infectious diseases such as necrotizing enterocolitis. As colostrum is not always available from the mother, particularly for premature infants, effective and safe substitutes are keenly sought after by neonatologists. The benefits of bioactive factors in colostrum are recognized; however, there have been no accounts of human colostrum being studied during digestion of the lipid components or their self-assembly in gastrointestinal environments. Due to the weaker bile pool in infants than adults, evaluating the lipid composition of human colostrum and linking it to structural self-assembly behavior is important in these settings and thus enabling the formulation of substitutes for colostrum. This study is aimed at the rational design of an appropriate lipid component for a colostrum substitute and determining the ability of this formulation to reduce inflammation in intestinal cells. Gas chromatography was utilized to map lipid composition. The self-assembly of lipid components occurring during digestion of colostrum was monitored using small-angle X-ray scattering for comparison with substitute mixtures containing pure triglyceride lipids based on their abundance in colostrum. The digestion profiles of human colostrum and the substitute mixtures were similar. Subtle differences in lipid self-assembly were evident, with the substitute mixtures exhibiting additional non-lamellar phases, which were not seen for human colostrum. The difference is attributable to the distribution of free fatty acids released during digestion. The biological markers of necrotizing enterocolitis were modulated in cells that were treated with bifidobacteria cultured on colostrum substitute mixtures, compared to those treated with infant formula. These findings provide an insight into a colostrum substitute mixture that resembles human colostrum in terms of composition and structural behavior during digestion and potentially reduces some of the characteristics associated with necrotizing enterocolitis.

Implications of the Digestion of Milk-Based Formulations for the Solubilization of Lopinavir/Ritonavir in a Combination Therapy.

The development of formulation approaches to coadminister lopinavir and ritonavir antiretroviral drugs to children is necessary to ensure optimal treatment of human immunodeficiency virus (HIV) infection. It was previously shown that milk-based lipid formulations show promise as vehicles to deliver antimalarial drugs by enhancing their solubilization during the digestion of the milk lipids under intestinal conditions. In this study, we investigate the role of digestion of milk and infant formula on the solubilization behavior of lopinavir and ritonavir to understand the fate of drugs in the gastrointestinal (GI) tract after oral administration. Small angle X-ray scattering (SAXS) was used to probe the presence of crystalline drugs in suspension during digestion. In particular, the impact of one drug on the solubilization of the other was elucidated to reveal potential drug-drug interactions in a drug combination therapy. Our results showed that lopinavir and ritonavir affected the solubilization of each other during digestion in lipid-based formulations. While addition of ritonavir to lopinavir improved the overall solubilization of lopinavir, the impact of lopinavir was to reduce ritonavir solubilization as digestion progressed. These findings highlight the importance of assessing the solubilization of individual drugs in a combined matrix in order to dictate the state of drugs available for subsequent absorption and metabolism. Enhancement in the solubilization of lopinavir and ritonavir in a drug combination setting in vitro also supported the potential for food effects on drug exposure.

Existing and emerging mitigation strategies for the prevention of accidental overdose from oral pharmaceutical products.

Misadventure with pharmaceutical oral medication has been on the rise, with the opioid crisis playing a major part. Drug overdose related to opioids has become such an issue, that it has been labelled a worldwide crisis. This review explores the mitigation strategies currently in place to prevent accidental overdose from oral pharmaceuticals, categorising the options based on whether they are relevant before, during or after the consumption of a toxic drug dose. To prophylactically prevent an overdose before consumption, governments and medical boards provide guidelines and implement policy, such as prescription monitoring, for the use of heavily abused medication. Some opioids have also been formulated as abuse deterrent formulations (ADF) which make it difficult for an individual to tamper with the medication. However, this does not prevent accidental overdose and only a few novel formulations were found to have multi-dose preventative properties. After an overdose has occurred, the situation is usually dealt with by first responders and hospitals using antidotes or medical procedures to limit the absorption of the drug. As pharmaceutical scientists, therein lies an opportunity to produce novel formulations that could limit the chances of accidental overdose. One approach could be to harness the physiological properties within the gastrointestinal tract (GIT), especially the enzymatic degradation of macromolecular matrix formulations. The ideal formulation will deliver a therapeutic dose but prevent or limit further release from consequent dose forms if a toxic quantity of drug is consumed.

Revisiting the Dissolution of Praziquantel in Biorelevant Media and the Impact of Digestion of Milk on Drug Dissolution.

Praziquantel is a poorly water-soluble drug used to treat parasitic infections. Previous studies have suggested that its rate and extent of dissolution in milk and biorelevant media are slow and limited compared to dissolution in the pharmacopoeial-recommended medium, despite being reported as displaying a positive food effect upon administration. This study aimed to revisit the dissolution of praziquantel in biorelevant media and milk to better understand this apparent dichotomy. The context of digestion was introduced to better understand drug solubilisation under more relevant gastrointestinal conditions. The amount of praziquantel solubilised in the various media during digestion was quantified using high performance liquid chromatography (HPLC) and the kinetics of dissolution were confirmed by tracking the disappearance of solid crystalline drug using in situ small angle X-ray scattering (SAXS). For the dissolution media, where sodium lauryl sulfate (SLS) is typically included as a wetting agent, a prominent effect of SLS on drug dissolution was also apparent where >2.5 fold more drug was solubilised in SLS-containing dissolution medium compared to that without (0.1 M HCl only). In milk, significant dissolution of praziquantel was observed only during digestion and not during dispersion, hence suggesting that (1) milk can be potentially administered with praziquantel to improve oral bioavailability and (2) incorporating a digestion step into existing in vitro dissolution testing can better reflect the potential for a positive food effect when lipids are present.

Controlling drug release by introducing lipase inhibitor within a lipid formulation.

Drug overdose connected to marketed pharmaceutical products, particularly opioids, occurs at an alarming rate. Novel strategies through innovative formulation approaches that reduce the likelihood of overdose while allowing safe therapeutic outcomes are urgently required. The current study provides a proof-of-concept for a new formulation approach by co-formulating drug with a lipase inhibitor within a solid lipid formulation in order to prevent or reduce the harmful effects of taking multiple doses of an oral solid dose form. Lipase inhibitor controlled-release (LICR) formulations were created using a simple hot melt method to co-formulate the inhibitor (orlistat) and ibuprofen, as the model drug, within the lipid matrix. The digestion and drug release kinetics were determined using an in vitro lipolysis model. Above a threshold level of orlistat there was decreased digestibility of multiple doses of the LICR formulations, leading to reduced drug release. Upon administration of the formulations in capsules to rats, the LICR formulation displayed the lowest exposure of ibuprofen during the pharmacokinetic studies. This novel formulation approach shows promise in preventing accidental drug overdose after oral administration of multiple doses of formulation.

Small-volume in vitro lipid digestion measurements for assessing drug dissolution in lipid-based formulations using SAXS.

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.

Impact of pasteurization on the self-assembly of human milk lipids during digestion.

Human milk is critical for the survival and development of infants. This source of nutrition contains components that protect against infections while stimulating immune maturation. In cases where the mother's own milk is unavailable, pasteurized donor milk is the preferred option. Although pasteurization has been shown to have minimal impact on the lipid and FA composition before digestion, no correlation has been made between the impact of pasteurization on the FFA composition and the self-assembly of lipids during digestion, which could act as delivery mechanisms for poorly water-soluble components. Pooled nonpasteurized and pasteurized human milk from a single donor was used in this study. The evolving FFA composition during digestion was determined using GC coupled to a flame ionization detector. In vitro digestion coupled to small-angle X-ray scattering was utilized to investigate the influence of different calcium levels, fat content, and the presence of bile salts on the extent of digestion and structural behavior of human milk lipids. Almost complete digestion was achieved when bile salts were added to the systems containing high calcium to milk fat ratio, with similar structural behavior of lipids during digestion of both types of human milk being apparent. In contrast, differences in the colloidal structures were formed during digestion in the absence of bile salt because of a greater amount of FFAs being released from the nonpasteurized than pasteurized milks. This difference in FFAs released from both types of human milk could result in varying nutritional implications for infants.

Opportunities for milk and milk-related systems as 'new' low-cost excipient drug delivery materials.

Milk is well recognised as an amazing delivery system for essential lipids, poorly soluble nutrients, sugars, amino acids and delivery of critical biological molecules to sustain the infant and adult alike. It is also a safe and abundant resource with potential to act as a low-cost material for formulation of medicines, especially for paediatric patients and those in low economy settings. However, its use in low cost formulations has never developed beyond preclinical evaluation. Reasons for this are several-fold including variable composition and therefore regulatory challenges, as well as a lack of clear understanding around when milk or milk-related materials like infant formula could best be deployed by linking drug properties with excipient composition attributes, especially when taking digestion into account. This review collects the current understanding around these issues. It is apparent from the evolving understanding that while milk may be a bridge too far for translation as an excipient, infant formula is positioned to play a key role in the future because, as a powder-based excipient, it has the performance benefits of milk powder together with the controlled specifications during manufacture and versatility of application to function as a low cost lipid excipient to enable potential translation for the oral delivery of poorly water soluble drugs for key populations including paediatrics and low economy medicines.

Probing n-Octyl α-d-Glycosides Using Deuterated Water in the Lyotropic Phase by Deuterium NMR.

The lyotropic phase behavior of four common and easily accessible glycosides, n-octyl α-d-glycosides, namely, α-Glc-OC8, α-Man-OC8, α-Gal-OC8, and α-Xyl-OC8, was investigated. The presence of normal hexagonal (HI), bicontinuous cubic (VI), and lamellar (Lα) phases in α-Glc-OC8 and α-Man-OC8 including their phase diagrams in water reported previously was verified by deuterium nuclear magnetic resonance (2H NMR), via monitoring the D2O spectra. Additionally, the partial binary phase diagrams and the liquid crystal structures formed by α-Gal-OC8 and α-Xyl-OC8 in D2O were constructed and confirmed using small- and wide-angle X-ray scattering and 2H NMR. The average number of bound water molecules (nb) per headgroup in the Lα phase was determined by the systematic measurement of the quadrupolar splitting of D2O over a wide range of molar ratio values (glycoside/D2O), especially at high glucoside composition. The number of bound water molecules bound to the headgroup was found to be around 1.5-2.0 for glucoside, mannoside, and galactoside, all of which possesses four OH groups. In the case of xyloside, which has only three OH groups, the bound water content is ∼2.0. Our findings confirmed that the bound water content of all n-octyl α-d-glycosides studied is lower compared to the number of possible hydrogen bonding sites possibly due to the fact that most of the OH groups are involved in intralayer interaction that holds the lipid assembly together.

TAILOR-MS, a Python Package that Deciphers Complex Triacylglycerol Fatty Acyl Structures: Applications for Bovine Milk and Infant Formulas.

Liquid chromatography tandem mass spectrometry (LC/MS) and other mass spectrometric technologies have been widely applied for triacylglycerol profiling. One challenge for targeted identification of fatty acyl moieties that constitute triacylglycerol species in biological samples is the numerous combinations of 3 fatty acyl groups that can form a triacylglycerol molecule. Manual determination of triacylglycerol structures based on peak intensities and retention time can be highly inefficient and error-prone. To resolve this, we have developed TAILOR-MS, a Python (programming language) package that aims at assisting: (1) the generation of targeted LC/MS methods for triacylglycerol detection and (2) automating triacylglycerol structural determination and prediction. To assess the performance of TAILOR-MS, we conducted LC/MS triacylglycerol profiling of bovine milk and two infant formulas. Our results confirmed dissimilarities between bovine milk and infant formula triacylglycerol composition. Furthermore, we identified 247 triacylglycerol species and predicted the possible existence of another 317 in the bovine milk sample, representing one of the most comprehensive reports on the triacylglycerol composition of bovine milk thus far. Likewise, we presented here a complete infant formula triacylglycerol profile and reported >200 triacylglycerol species. TAILOR-MS dramatically shortened the time required for triacylglycerol structural identification from hours to seconds and performed decent structural predictions in the absence of some triacylglycerol constituent peaks. Taken together, TAILOR-MS is a valuable tool that can greatly save time and improve accuracy for targeted LC/MS triacylglycerol profiling.

Chemistry and Geometry of Counterions Used in Hydrophobic Ion Pairing Control Internal Liquid Crystal Phase Behavior and Thereby Drug Release.

The combination of Flash NanoPrecipitation and hydrophobic ion pairing (HIP) is a valuable approach for generating nanocarrier formulations of ionic water-soluble drugs with controllable release properties dictated by liquid crystalline structuring of the ion pairs. However, there are few examples of this in practice in the literature. This work aims to decipher the influence of the nature of the hydrophobic counterion used in HIP and its consequent impact on liquid crystalline structuring and drug release. The hypothesis of this study was that hydrophobic counterions with different head and tail groups used for FNP with HIP would give rise to different liquid crystalline structures, which in turn would result in different drug release behavior. A cationic, water-soluble antibiotic, polymixin B, was complexed with eight different hydrophobic counterions with varying head and tail groups and encapsulated into nanocarriers 100-400 nm in size prepared using FNP. Sixteen formulations were assessed for internal structure by synchrotron small-angle X-ray scattering, and drug release was measured in vitro in physiological conditions. The liquid crystalline phases formed depended on the counterion head group and tail geometry, drug:counterion charge ratio, and the ionic strength and pH of the release medium. Drug release occurred more rapidly when no liquid crystalline phases were present and more slowly when higher-ordered phases existed. Specific findings include that phosphonic acid counterions lead to the formation of lamellar structures that persisted at pH 2.0 but were not present at pH 7.3. In contrast, sulfonic acids lead to lamellar or hexagonal phases that persisted at both pH 7.3 and 2.0, while hydrophobic counterions without alkyl tails did not form internal structures. It was also clear that the lipophilicity of the counterion does not dictate drug release. These findings confirm that the liquid crystalline phase behavior of the drug:counterion complex dictates drug release and significantly improves our understanding of the types of controlled release formulations that are possible using FNP with HIP.

Internal liquid crystal structures in nanocarriers containing drug hydrophobic ion pairs dictate drug release.

HYPOTHESIS: Hydrophobic ion pairing (HIP), a solubility engineering technique in which ionic hydrophilic molecules are paired with a hydrophobic counterion, is an attractive strategy for encapsulating ionic water-soluble species into nanocarriers (NCs). Drug release from NCs containing HIP complexes is sensitive to ionic strength, pH, and drug:counterion charge ratio, but the exact mechanism for this was unknown, as was the underlying microstructure inside the NCs. We hypothesize that HIP complexes arrange into liquid crystalline structures in NC cores and that these structures are responsible for salt- and pH-dependent release. EXPERIMENT: A model hydrophobic ion pair from the cationic antimicrobial peptide polymyxin B sulfate and the anionic counterion sodium oleate is encapsulated into ~100 nm NCs formed using Flash NanoPrecipitation (FNP) and stabilized with an amphiphilic diblock copolymer, poly(caprolactone)-b-poly(ethylene glycol). Internal structures are observed using synchrotron small angle X-ray scattering (SAXS) and transmission electron microscopy (TEM) following NC formulation and are found to vary with polymyxin:oleate charge ratio. In vitro drug release is also measured with changes in pH and two charge ratio. FINDINGS: For a formulation containing a four-fold charge excess of oleate relative to polymyxin, internal structures rearranged from a lamellar phase into an inverse hexagonal phase. The hexagonal phase formation corresponds to a greatly reduced rate of polymyxin release, suggesting that the polymyxin was incorporated into the center of hexagonally-packed rods. When release tests were repeated using phosphate-buffered saline (PBS) at pH 2.0 to ensure protonation of the oleic acid, all internal structures were eliminated and release occurs much faster than at neutral pH, regardless of charge ratio. These findings shed light on the mechanism behind stimulus-responsive drug release from systems containing hydrophobic ion pairs and enable the rational design of controlled-release formulations by manipulating the formation and dynamics of liquid crystalline phases inside NCs.

Sustained absorption of delamanid from lipid-based formulations as a path to reduced frequency of administration.

Delamanid is a poorly water-soluble drug currently being used for the treatment of tuberculosis. The high frequency of dosing leads to poor adherence for patients who live in lower economic and nomadic populations. Non-digestible self-assembling lipids as a formulation approach for poorly water-soluble drugs have previously been shown to extend the window of absorption through gastric retention. We hypothesise that this approach could lead to the reduction of dosing frequency for delamanid and thereby has potential to improve adherence. Formulations of delamanid were prepared in selachyl alcohol and phytantriol as non-digestible self-assembling lipid vehicles, and their behaviour was compared with reconstituted milk powder, as a digestible lipid-based formulation, and an aqueous suspension. The self-assembly of selachyl alcohol and phytantriol in aqueous media in the presence of delamanid was studied using small angle X-ray scattering and produced the inverse hexagonal (H2) and inverse bicontinuous cubic (V2) liquid crystal structures, respectively. The times at which maximum delamanid levels in plasma were observed (Tmax) after oral administration of the phytantriol, selachyl alcohol and reconstituted milk powder formulations of delamanid to rats were 27 ± 3, 20 ± 4 and 6.5 ± 1.0 h, respectively, compared with the aqueous suspension formulation with a Tmax of 3.4 ± 1 h, which confirms the hypothesis of an extended duration of absorption after administration in non-digestible self-assembling lipids. The digestion products of the triglycerides in the milk formulation increased the solubilisation of delamanid in the gastrointestinal tract, leading to an increase in exposure compared with the aqueous suspension formulation but did not significantly extend Tmax. Overall, the non-digestible nanostructured lipid formulations extended the duration of absorption of delamanid well beyond that from milk or suspension formulations. Graphical abstract.

Emulsions containing optimum cow milk fat and canola oil mixtures replicate the lipid self-assembly of human breast milk during digestion.

HYPOTHESIS: The digestion of different milks and milk substitutes leads to the formation of a variety of self-assembled lipid structures, with the structuring of human milk being paramount for infant nutrition. It was hypothesised that mixing cow milk fat rich in medium/long-chain lipids with canola oil rich in long-chain unsaturated lipids would replicate the structuring of human milk by balancing lipid chain lengths and saturation levels. EXPERIMENTS: Emulsions of cow milk fat/canola oil mixtures were prepared in two ways - by pre-mixing ghee and canola oil before dispersing them and by dispersing canola oil directly into commercial cow milk. Small angle X-ray scattering combined with titration of the fatty acids produced during digestion allowed for the correlation of dynamic lipid self-assembly with the extent of lipid digestion. Laser light scattering was used to show that the particle sizes in the digesting mixtures were similar and coherent anti-Stokes Raman spectroscopy (CARS) microscopy was used to confirm the mixing of canola oil into cow milk fat globules. FINDINGS: As the amount of long-chain unsaturated canola oil lipids in the mixtures increased, the lipid self-assembly tended towards colloidal structures of greater interfacial curvature. When the ratio of cow milk fat to canola oil lipids was 1:1 (w/w), the digesting lipids assembled themselves into the same liquid crystalline structures as human breast milk. This observation was independent of the method used to mix the lipids, with CARS microscopy indicating uniform mixing of the canola oil into cow milk upon ultrasonication.

Synergistic and antagonistic effects of non-ionic surfactants with bile salt + phospholipid mixed micelles on the solubility of poorly water-soluble drugs.

The nature of the interaction of bile salt micelles with exogenous surfactants used in formulations and the consequent impact on drug solubilisation is not well understood. It is often assumed that addition of any surfactant will lead to an enhanced solubility of drug, which is often true in water alone. In this study we have investigated the interaction of a range of typical non-ionic formulation surfactants (Kolliphor EL, Vitamin E TPGS and a range of Pluronics) with bile salt + phospholipid (BS + PL) mixed micelles using small angle X-ray scattering. The solubility of the model poorly water-soluble drug fenofibrate was determined in the mixed micelles and compared to solubility in the presence of increasing exogenous surfactant alone. It was found that while Pluronic F68 did not appear to interact with bile salt micelles and did not impact on the solubility of the drug in the BS + PL micellar system, addition of hydrophobic surfactants led to a synergistic boost in drug solubility, while addition of more hydrophilic surfactants led to a net reduction in drug solubility. With the exception of Pluronic F68, both hydrophobic and hydrophilic surfactants swelled the bile salt mixed micelles leading to the conclusion that although the micelle size was increased, the solubilising environment was less favourable than in bile salt micelles alone. The results serve as a warning to formulators using these surfactants as solubilising agents to consider their likely interactions with endogenous colloidal structures.

Lipid Compositions in Infant Formulas Affect the Solubilization of Antimalarial Drugs Artefenomel (OZ439) and Ferroquine during Digestion.

Recent studies have shown that the solubilization of two antimalarial drug candidates, artefenomel (OZ439) and ferroquine (FQ), designed to provide a single-dose combination therapy for uncomplicated malaria can be enhanced using milk as a lipid-based formulation. However, milk as an excipient faces significant quality and regulatory hurdles. We therefore have investigated infant formula as a potential alternative formulation approach. The significance of the lipid species present in a formula with different lipid compositions upon the solubilization of OZ439 and FQ during digestion has been investigated. Synchrotron small-angle X-ray scattering was used to measure the diffraction from a dispersed drug during digestion and thereby determine the extent of drug solubilization. High-performance liquid chromatography was used to quantify the amount of drug partitioned into the digested lipid phases. Our results show that both the lipid species and the amount of lipids administered were key determinants for the solubilization of OZ439, while the solubilization of FQ was independent of the lipid composition. Infant formulas could therefore be designed and used as milk substitutes to tailor the desired level of drug solubilization while circumventing the variability of components in naturally derived milk. The enhanced solubilization of OZ439 was achieved during the digestion of medium-chain triacylglycerols (MCT), indicating the potential applicability of MCT-fortified infant formula powder as a lipid-based formulation for the oral delivery of OZ439 and FQ.

Correlating Digestion-Driven Self-Assembly in Milk and Infant Formulas with Changes in Lipid Composition.

Lipids in mammalian milks such as bovine milk and human breast milk have been shown to self-assemble into various liquid crystalline materials during digestion. In this study, the direct correlation between the composition of the lipids from three types of mammalian milk, three brands of infant formulas (IFs), and soy milk and the liquid crystalline structures that form during their digestion was investigated to link the material properties to the composition. The self-assembly behavior was assessed using in vitro digestion coupled with in situ small-angle X-ray scattering (SAXS). Lipid composition was determined during in vitro digestion using ex situ liquid chromatography-mass spectrometry. All tested milks self-assembled into ordered structures during digestion, with the majority of milks displaying nonlamellar phases. Milks that released mostly long-chain fatty acids (>95 mol % of the top 10 fatty acids released) with more than 47 mol % unsaturation predominantly formed a micellar cubic phase during digestion. Other milks released relatively more medium-chain fatty acids and medium-chain monoglycerides and produced a range of ordered liquid crystalline structures including the micellar cubic phase, the hexagonal phase, and the bicontinuous cubic phase. One infant formula did not form liquid crystalline structures at all as a consequence of differences in fatty acid distributions. The self-assembly phenomenon provides a powerful discriminator between different classes of nutrition and a roadmap for the design of human milklike systems and is anticipated to have important implications for nutrient transport and the delivery of bioactives.