8 research outputs found
Interactions of artefenomel (OZ-439) with milk during digestion:insights into digestion-driven solubilization and polymorphic transformations
Milk
has been used as a vehicle for the delivery of antimalarial
drugs during clinical trials to test for a food effect and artefenomel
(OZ439) showed enhanced oral bioavailability with milk. However, the
nature of the interaction between milk and OZ439 in the gastrointestinal
tract remains poorly understood. To understand the role of milk digestion
on the solubilization of OZ439 and polymorphism, we conducted real-time
monitoring of crystalline drug in suspension during in vitro intestinal
lipolysis of milk containing OZ439 using synchrotron X-ray scattering.
OZ439 formed an unstable solid-state intermediate free base form (OZ439-FB
form 1) at intestinal pH and was partially solubilized by milk fat
globules prior to lipolysis. Dissolution of the free base form 1 and
recrystallization of OZ439 in a more stable polymorphic form (OZ439-FB
form 2) occurred during in vitro lipolysis in milk. Simply stirring
the milk/drug suspension in the absence of lipase or addition of lipase
to OZ439 in a lipid-free buffer did not induce this polymorphic transformation.
The formation of OZ439-FB form 2 was therefore accelerated by the
solubilization of OZ439-FB form 1 during the digestion of milk. Our
findings confirmed that although crystalline precipitates of OZ439-FB
form 2 could still be detected after in vitro digestion, milk-based
lipid formulations provided a significant reduction in crystalline
OZ439 compared to lipid-free formulations, which we attribute to the
formation of colloidal structures by the digested milk lipids. Milk
may therefore be particularly suited as a form of lipid-based formulation
(LBF) for coadministration with OZ439, from which both an enhancement
in OZ439 oral bioavailability and the delivery of essential nutrients
should result
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Spray drying OZ439 nanoparticles to form stable, water-dispersible powders for oral malaria therapy
Abstract Background OZ439 is a new chemical entity which is active against drug-resistant malaria and shows potential as a single-dose cure. However, development of an oral formulation with desired exposure has proved problematic, as OZ439 is poorly soluble (BCS Class II drug). In order to be feasible for low and middle income countries (LMICs), any process to create or formulate such a therapeutic must be inexpensive at scale, and the resulting formulation must survive without refrigeration even in hot, humid climates. We here demonstrate the scalability and stability of a nanoparticle (NP) formulation of OZ439. Previously, we applied a combination of hydrophobic ion pairing and Flash NanoPrecipitation (FNP) to formulate OZ439 NPs 150 nm in diameter using the inexpensive stabilizer hydroxypropyl methylcellulose acetate succinate (HPMCAS). Lyophilization was used to process the NPs into a dry form, and the powder’s in vitro solubilization was over tenfold higher than unprocessed OZ439. Methods In this study, we optimize our previous formulation using a large-scale multi-inlet vortex mixer (MIVM). Spray drying is a more scalable and less expensive operation than lyophilization and is, therefore, optimized to produce dry powders. The spray dried powders are then subjected to a series of accelerated aging stability trials at high temperature and humidity conditions. Results The spray dried OZ439 powder’s dissolution kinetics are superior to those of lyophilized NPs. The powder’s OZ439 solubilization profile remains constant after 1 month in uncapped vials in an oven at 50 °C and 75% RH, and for 6 months in capped vials at 40 °C and 75% RH. In fasted-state intestinal fluid, spray dried NPs achieved 80–85% OZ439 dissolution, to a concentration of 430 µg/mL, within 3 h. In fed-state intestinal fluid, 95–100% OZ439 dissolution is achieved within 1 h, to a concentration of 535 µg/mL. X-ray powder diffraction and differential scanning calorimetry profiles similarly remain constant over these periods. Conclusions The combined nanofabrication and drying process described herein, which utilizes two continuous unit operations that can be operated at scale, is an important step toward an industrially-relevant method of formulating the antimalarial OZ439 into a single-dose oral form with good stability against humidity and temperature
Impact of Ferroquine on the Solubilization of Artefenomel (OZ439) during <i>in Vitro</i> Lipolysis in Milk and Implications for Oral Combination Therapy for Malaria
Milk
is an attractive lipid-based formulation for the delivery
of poorly water-soluble drugs to pediatric populations. We recently
observed that solubilization of artefenomel (OZ439) during in vitro intestinal lipolysis was driven by digestion of
triglycerides in full-cream bovine milk, reflecting the ability of
milk to act as an enabling formulation in the clinic. However, when
OZ439 was co-administered with a second antimalarial drug, ferroquine
(FQ) the exposure of OZ439 was reduced. The current study therefore
aimed to understand the impact of the presence of FQ on the solubilization
of OZ439 in milk during in vitro intestinal digestion.
Synchrotron small-angle X-ray scattering was used for in situ monitoring of drug solubilization (inferred via decreases in the
intensity of drug diffraction peaks) and polymorphic transformations
that occurred during the course of digestion. Quantification of the
amount of each drug solubilized over time and analysis of their distributions
across the separated phases of digested milk were determined using
high-performance liquid chromatography. The results show that FQ reduced
the solubilization of OZ439 during milk digestion, which may be due
to competitive binding of FQ to the digested milk products. Interactions
between the protonated FQ-H+ and ionized liberated free
fatty acids resulted in the formation of amorphous salts, which removes
the low-energy crystalline state as a barrier to dissolution of FQ,
while inhibiting the solubilization of OZ439. We conclude that although
milk could enhance the solubilization of poorly water-soluble OZ439
during in vitro digestion principally due to the
formation of fatty acids, the solubilization efficiency was reduced
by the presence of FQ by competition for the available fatty acids.
Assessment of the solubilization of both drugs during digestion of
fixed-dose combination lipid formulations (such as milk) is important
and may rationalize changes in bioavailability when compared to that
of the individual drugs in the same formulation
Partnering to fight malaria in India: Past, present and future
The global fight against malaria requires continual development of new tools. Collaborations in India have played a key role in MMV’s partnerships to discover, develop and deliver new medicines. Over the last decade, India has become a focal point of global medicinal chemistry, and combined with investments in basic science, this has led to the discovery of new potential drugs. India also brings significant experience to drug development, in clinical trials, but also in formulation and manufacturing. Finally, innovative new approaches in case management have streamlined impact at the level of communities and the patients
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Encapsulation of OZ439 into Nanoparticles for Supersaturated Drug Release in Oral Malaria Therapy
Malaria
poses a major burden on human health and is becoming increasingly
difficult to treat due to the development of antimalarial drug resistance.
The resistance issue is further exacerbated by a lack of patient adherence
to multi-day dosing regimens. This situation motivates the development
of new antimalarial treatments that are less susceptible to the development
of resistance. We have applied Flash NanoPrecipitation (FNP), a polymer-directed
self-assembly process, to form stable, water-dispersible nanoparticles
(NPs) of 50–400 nm in size containing OZ439, a poorly orally
bioavailable but promising candidate for single-dose malaria treatment
developed by Medicines for Malaria Venture (MMV). During the FNP process,
a hydrophobic OZ439 oleate ion paired complex was formed and was encapsulated
into NPs. Lyophilization conditions for the NP suspension were optimized
to produce a dry powder. The <i>in vitro</i> release rates
of OZ439 encapsulated in this powder were determined in biorelevant
media and compared with the release rates of the unencapsulated drug.
The OZ439 NPs exhibit a sustained release profile and several-fold
higher release concentrations compared to that of the unencapsulated
drug. In addition, XRD suggests the drug was stabilized into an amorphous
form within the NPs, which may explain the improvement in dissolution
kinetics. Formulating OZ439 into NPs in this way may be an important
step toward developing a single-dose oral malaria therapeutic, and
offers the possibility of reducing the amount of drug required per
patient, lowering delivery costs, and improving dosing compliance
Injectable anti-malarials revisited:discovery and development of new agents to protect against malaria
Over the last 15Â years, the majority of malaria drug discovery and development efforts have focused on new molecules and regimens to treat patients with uncomplicated or severe disease. In addition, a number of new molecular scaffolds have been discovered which block the replication of the parasite in the liver, offering the possibility of new tools for oral prophylaxis or chemoprotection, potentially with once-weekly dosing. However, an intervention which requires less frequent administration than this would be a key tool for the control and elimination of malaria. Recent progress in HIV drug discovery has shown that small molecules can be formulated for injections as native molecules or pro-drugs which provide protection for at least 2Â months. Advances in antibody engineering offer an alternative approach whereby a single injection could potentially provide protection for several months. Building on earlier profiles for uncomplicated and severe malaria, a target product profile is proposed here for an injectable medicine providing long-term protection from this disease. As with all of such profiles, factors such as efficacy, cost, safety and tolerability are key, but with the changing disease landscape in Africa, new clinical and regulatory approaches are required to develop prophylactic/chemoprotective medicines. An overall framework for these approaches is suggested here