The oral bioavailability of poorly water-soluble drugs (PWSD) is often significantly enhanced by coadministration with lipids in food or lipid-based oral formulations. Coadministration with lipids ...promotes drug solubilization in intestinal mixed micelles and vesicles, however, the mechanism(s) by which PWSD are absorbed from these dispersed phases remain poorly understood. Classically, drug absorption is believed to be a product of the drug concentration in free solution and the apparent permeability across the absorptive membrane. Solubilization in colloidal phases such as mixed micelles increases dissolution rate and total solubilized drug concentrations, but does not directly enhance (and may reduce) the free drug concentration. In the absence of changes to cellular permeability (which is often high for lipophilic, PWSD), significant changes to membrane flux are therefore unexpected. Realizing that increases in effective dissolution rate may be a significant driver of increases in drug absorption for PWSD, we explore here two alternate mechanisms by which membrane flux might also be enhanced: (1) collisional drug absorption where drug is directly transferred from lipid colloidal phases to the absorptive membrane, and (2) supersaturation-enhanced drug absorption where bile mediated dilution of lipid colloidal phases leads to a transient increase in supersaturation, thermodynamic activity and absorption. In the current study, collisional uptake mechanisms did not play a significant role in the absorption of a model PWSD, cinnarizine, from lipid colloidal phases. In contrast, bile-mediated dilution of model intestinal mixed micelles and vesicles led to drug supersaturation. For colloids that were principally micellar, supersaturation was maintained for a period sufficient to promote absorption. In contrast, for primarily vesicular systems, supersaturation resulted in rapid drug precipitation and no increase in drug absorption. This work suggests that ongoing dilution by bile in the gastrointestinal tract may invoke supersaturation in intestinal colloids and promote absorption, and thus presents a new mechanism by which lipids may enhance the oral absorption of PWSD.
Display omitted
We report on the successful incorporation of the antimalarial drug, halofantrine, into laboratory based soybean oil emulsions which were designed to mimic the commercially available ...parenteral fat emulsion, Intralipid®. A high pH (minimum of pH 9, preferable pH of 11) was required for the drug laden emulsion to remain stable on storage and also to resist breaking under various stresses. Ageing of lecithin samples on storage was noted to result in degradation and a decrease in pH. We argue that this is the main reason for a similar decrease in pH for lecithin based emulsions and subsequent instability in drug laden emulsions. As expected, incorporation of the drug (halofantrine) resulted in lower stability. The (intensity weighted) particle size increased from 281nm for the drug free emulsion to 550nm following a loading of 1gL−1 of halofantrine, indicative of a lowering in stability and this was reflected in a shorter shelf life. Interestingly, incorporation of even higher concentrations of drug then resulted in better stability albeit never as stable as the drug free emulsion. We also report on unusual and complex surface tension behaviour for fresh lecithin where multiple critical concentration points were observed.
To investigate the impact of lipidic formulation type on in vitro dispersion and digestion properties and the relationship to oral bioavailability, using danazol as a model lipophilic poorly ...water-soluble drug.
Three lipid-based danazol formulations a long-chain triglyceride solution (LCT-solution) and self-microemulsifying drug delivery systems (SMEDDS) based on long-chain (C18) lipids (LC-SMEDDS) and medium-chain (C8-C10) lipids (MC-SMEDDS) were administered to fasted beagle dogs and compared with a micronized danazol formulation administered postprandially and in the fasted state. In vitro dispersion and particle size data for the two SMEDDS were compared, and the distribution/solubilization patterns of danazol across the various phases produced during in vitro digestion quantified.
The LCT-solution and LC-SMEDDS formulations significantly enhanced the oral bioavailability of danazol when compared to fasted administration of the powder formulation. In contrast, and despite displaying excellent dispersion properties, the MC-SMEDDS resulted in little enhancement in danazol bioavailability. In support of the in vivo findings, in vitro digestion of the medium-chain formulation resulted in significant drug precipitation when compared with the long-chain lipid formulations.
Digestion of microemulsion preconcentrate formulations based on medium-chain lipids may limit in vivo utility when compared with similar formulations based on long chain lipids.
To investigate the impact of a change in the proportions of lipid, surfactant and co-solvent on the solubilisation capacity of self-emulsifying formulations of danazol during in vitro dispersion and ...digestion studies and correlation with in vivo bioavailability in beagle dogs.
Formulations from within the phase diagram of the pseudo-ternary system composed of soybean oil:maisine 35-1 (1:1 w/w), Cremophor EL and ethanol were assessed in vitro on dispersion and digestion. The relative bioavailability of danazol after administration of a series of these formulations was also determined.
All formulations formed microemulsions in the presence of water and no drug precipitation was observed on dispersion. In contrast, drug solubilisation was markedly affected by lipase-mediated digestion and a reduction in lipid (and increase in surfactant) content resulted in increased drug precipitation. Consistent with these data, the bioavailability of danazol decreased significantly when the lipid content in the formulations was reduced.
A rank-order correlation was observed between the patterns of solubilisation obtained during in vitro digestion and the in vivo performance of self-emulsifying formulations of danazol. In general a decrease in the lipid content and an increase in the proportions of surfactant and co-solvent resulted in reduced danazol bioavailability.
The structure and stereochemistry of the cyclohexane substituents of analogues of arterolane (OZ277) had little effect on potency against Plasmodium falciparum in vitro. Weak base functional groups ...were not required for high antimalarial potency, but they were essential for high antimalarial efficacy in P. berghei-infected mice. Five new ozonides with antimalarial efficacy and ADME profiles superior or equal to that of arterolane were identified.
In recent years there has been an increase in interest in the utility of lipid based delivery systems, at least in part as a result of the effective development of lipid based products such as ...Sandimmun Neoral
® (cyclosporin), Norvir
® (ritonavir) and Fortovase
® (saquinavir). The development pathway for lipid based formulations, however, is still largely empirical, and in vitro models that are predictive of oral bioavailability enhancement are lacking. The use of modified dissolution media, reflecting the bile salt and phospholipid levels in the intestine, has met with some success in terms of the ability to predict the bioavailability of poorly water soluble drugs and the potential bioavailability enhancing effects of food. These approaches, however, do not have the flexibility or complexity to deal with the interactions inherent in the digestion, dispersion and solubilisation of a lipid based formulation and the coincident dissolution profile of a co-administered drug. In this review, the utility of modified dissolution media to predict the impact of food on the absorption of poorly water soluble, lipophilic drugs, is explored. These dissolution based systems are subsequently contrasted with the use of lipid digestion models which have found increasing application in assessment of the interaction of digestible dose forms with the gastrointestinal milieu.
ABSTRACT
Purpose
To investigate if drug solubility in pharmaceutical excipients used in lipid based formulations (LBFs) can be predicted from physicochemical properties.
Methods
Solubility was ...measured for 30 structurally diverse drug molecules in soybean oil (SBO, long-chain triglyceride; TG
LC
), Captex355 (medium-chain triglyceride; TG
MC
), polysorbate 80 (PS80; surfactant) and PEG400 co-solvent and used as responses during PLS model development. Melting point and calculated molecular descriptors were used as variables and the PLS models were validated with test sets and permutation tests.
Results
Solvation capacity of SBO and Captex355 was equal on a mol per mol scale (
R
2
= 0.98). A strong correlation was also found between PS80 and PEG400 (
R
2
= 0.85), identifying the significant contribution of the ethoxylation for the solvation capacity of PS80.
In silico
models based on calculated descriptors were successfully developed for drug solubility in SBO (
R
2
= 0.81,
Q
2
= 0.76) and Captex355 (
R
2
= 0.84,
Q
2
= 0.80). However, solubility in PS80 and PEG400 were not possible to quantitatively predict from molecular structure.
Conclusion
Solubility measured in one excipient can be used to predict solubility in another, herein exemplified with TG
MC
versus
TG
LC
, and PS80
versus
PEG400. We also show, for the first time, that solubility in TG
MC
and TG
LC
can be predicted from rapidly calculated molecular descriptors.
Much research has focussed on the development of novel therapeutic agents to target various central nervous system disorders, however less attention has been given to determining the potential of ...such agents to permeate the blood‐brain barrier (BBB), a factor that will ultimately govern the effectiveness of these agents in man. In order to assess the potential for novel compounds to permeate the BBB, various in‐vitro, in‐vivo and in‐silico methods may be employed. Although in‐vitro models (such as primary cell culture and immortalized cell lines) are useful as a screening method and can appropriately rank compounds in order of BBB permeability, they often correlate poorly to in‐vivo brain uptake due to down‐regulation of some BBB‐specific transporters. In‐vivo models (such as the internal carotid artery single injection or perfusion, intravenous bolus injection, brain efflux index and intracerebral microdialysis) provide more accurate information regarding brain uptake, and these can be complemented with novel imaging techniques (such as magnetic resonance imaging and positron emission tomography), although such methods are not suited to high‐throughput permeability assessment. This paper reviews current methods used for assessing BBB permeability and highlights the particular advantages and disadvantages associated with each method, with a particular focus on methods suitable for moderate‐ to high‐throughput screening.
A lipophilic prodrug approach has been used to promote the delivery of a model immunomodulator, mycophenolic acid (MPA), to the lymphatic system after oral administration. Lymphatic transport was ...employed to facilitate enhanced drug uptake into lymphocytes, as recent studies demonstrate that targeted drug delivery to lymph resident lymphocytes may enhance immunomodulatory effects. Two classes of lymph-directing prodrugs were synthesised. Alkyl chain derivatives (octyl mycophenolate, MPA-C8E; octadecyl mycophenolate, MPA-C18E; and octadecyl mycophenolamide, MPA-C18AM), to promote passive partitioning into lipids in lymphatic transport pathways, and a triglyceride mimetic prodrug (1,3-dipalmitoyl-2-mycophenoloyl glycerol, 2-MPA-TG) to facilitate metabolic integration into triglyceride deacylation–reacylation pathways. Lymphatic transport, lymphocyte uptake and plasma pharmacokinetics were assessed in mesenteric lymph and carotid artery cannulated rats following intraduodenal infusion of lipid-based formulations containing MPA or MPA prodrugs. Patterns of prodrug hydrolysis in rat digestive fluid, and cellular re-esterification in vivo, were evaluated to examine the mechanisms responsible for lymphatic transport. Poor enzyme stability and low absorption appeared to limit lymphatic transport of the alkyl derivatives, although two of the three alkyl chain prodrugs — MPA-C18AM (6-fold) and MPA-C18E (13-fold) still increased lymphatic drug transport when compared to MPA. In contrast, 2-MPA-TG markedly increased lymphatic drug transport (80-fold) and drug concentrations in lymphocytes (103-fold), and this was achieved via biochemical incorporation into triglyceride deacylation–reacylation pathways. The prodrug was hydrolysed rapidly to 2-mycophenoloyl glycerol (2-MPA-MG) in the presence of rat digestive fluid, and 2-MPA-MG was subsequently re-esterified in the enterocyte with oleic acid (most likely originating from the co-administered formulation) prior to accessing the lymphatics and lymphocytes. Importantly, after administration of 2-MPA-TG, the concentrations of free MPA in the mesenteric lymph nodes were significantly enhanced (up to 28 fold) when compared to animals administered equimolar quantities of MPA, suggesting the efficient conversion of the esterified prodrug back to the pharmacologically active parent drug. The data suggest that triglyceride mimetic prodrugs have potential as a means of enhancing immunotherapy via drug targeting to lymphocytes and lymph nodes.
Triglyceride mimetic prodrugs (2-MPA-TG) integrate into dietary triglyceride (TG) lymphatic transport pathways to promote drug delivery to lymphocytes in mesenteric lymph. Aliphatic ester (MPA-C8E,C18E) and amide (MPA-C18AM) prodrugs are less effective. Display omitted
PDF
