Nano- and microcrystals of griseofulvin subcutaneously administered to rats resulted in improved bioavailability and sustained release

Griseofulvin is a commonly used antifungal agent which is administered per oral (p.o.). The oral administration route, however, shows rather low bioavailability. The aim of this study was to improve the bioavailability and to evaluate and interpret the pharmacokinetic profiles after subcutaneous (s.c.) administration of crystalline griseofulvin nano- and microsuspensions. Both formulations were injected at 5 and 500 µmol/kg to rats. For the lower concentration, the profiles were similar after s.c. injection but extended as compared to p.o. administration. For the higher concentration, injection of microsuspension resulted in a maintained plateau whereas the nanosuspension resulted in an obvious peak exposure followed by extended elimination. Both suspensions showed improved exposure with dose. The differences in peak exposures between nano- and microparticles, at the high dose, were mainly ascribed to differences in dissolution rate, experimentally determined in vitro, using spectroscopic methods. The extended appearance in the circulation may depend on the physicochemical properties of the compound and the physiological conditions at the injection site. The bioavailability was improved for both formulations compared with an orally administered nanosuspension, suggesting the s.c. route to be a preferred administration option for compounds with low oral bioavailability regarding both overall exposure and extended efficacy.     

Evaluation of exposure properties after injection of nanosuspensions and microsuspenions into the intraperitoneal space in rats

In the present paper, BA99 and AC88 were used as model compounds for intraperitoneal (i.p.) administration to Sprague-Dawley rats. A major problem for the compounds, like many others newly developed pharmaceutical drugs, is the poor solubility in water. To solve solubility related problems, development of nanosuspensions is an attractive alternative. Both compounds are suitable for nanosuspensions, using the milling approach. After 2 weeks in freezer, the nanoparticles aggregated to form particles in the 400–2000?nm interval. However, following a 20 s ultrasonication step, the original particle sizes (about 200?nm) were obtained. Adding 5% mannitol before the samples were frozen abolished aggregation. It is also possible to freeze-dry the nanosuspension in the presence of 5% mannitol and re-disperse the formulation in water. Nanosuspensions of both compounds were injected i.p. to rats at 5 and 500 µmoL/kg. At the low dose, also a microsuspension was administered. I.p. administration resulted in overall improved C_max for both AC88 and BA99 compared to s.c. and oral administration. I.p. is the preferred route of administration of tolerable drugs when a fast onset of action is desired and when a significant first passage metabolism occurs. The net charge of the active molecule appeared to affect the absorption kinetics. In the present work, the neutral molecule was favored over the negatively charged one.     

Particle size reduction for improvement of oral absorption of the poorly soluble drug UG558 in rats during early development

Background: The exposure of UG558 was not good enough using traditional microsuspensions. Aim: The aim of this study was to find out whether nanosuspensions were a better choice compared with a microsuspension, for an acidic substance with a water solubility in the order of 2 μM (pH 6.8, small intestinal pH) and no permeability limitations. Methods: UG558 was ground by a planetary ball mill. The particle size was measured by laser diffraction and the stability of the particle sizes was followed. The pharmacokinetic parameters of UG558 administered as nanosuspension have been compared with those from microsuspension using rat as in vivo specie. Both formulations were administered orally. The nanosuspension was also administered intravenously. Results: The particle size of the nanosuspensions was about 190 nm and about 12 μm for the microsuspensions. At the administered doses, solutions were no alternative (e.g. due to limited solubility). Already at the lowest dose, 5 μmol/kg (5 ml/kg), a significant difference was observed between the two suspensions. These results were further confirmed at a high dose (500 μmol/kg, 5 mL/kg). Thus, the study demonstrated a clear correlation between particle size and in vivo exposures, where the nanosuspensions provided the highest exposure. Furthermore, no adverse events were observed for the substance nor the nanosuspension formulations (i.e., the particles) in spite of the higher exposures obtained with the nanoparticles. To make it possible to calculate the bioavailability, 5 μmol/kg doses of the nanosuspensions (5 ml/kg) were also administered intravenously. No adverse events were observed. Conclusions: The nanoparticles have a larger surface, resulting in faster in vivo dissolution rate, faster absorption, and increased bioavailability, compared to microparticles. The lower overall bioavailability observed at the high dose, compared with the low dose, was due to a combination of low dissolution rate, low solubility, and a narrow intestinal absorption window for UG558.     

Co-administration of a nanosuspension of a poorly soluble basic compound and a solution of a proton pump inhibitor--the importance of gastrointestinal pH and solubility for the in vivo exposure

In Sigfridsson et al. (2011, Drug Dev Ind Pharm, 37:243-251), there was no difference in plasma concentration of BA99 when administering the drug as nanosuspension or microsuspension and analyzing the blood samples by liquid chromatography-mass spectrometry. This was related to the dissolved amount of drug in the gastric tract, which was high enough to support fast absorption when the drug reached the small intestine. One single physicochemical property (pK(a), about 3 for BA99) abolished the benefit of small particles. These results were further confirmed in the present study, where a proton pump inhibitor, AZD0865, was used to elevate the gastric pH and then drastically decreased the gastric solubility. In this way, BA99 could be considered as a model compound for a neutral substance. By increasing the gastric pH to 5-6 and 8-9, respectively, in rats, the plasma concentrations of BA99, after administering nanosuspensions, were unchanged compared with untreated (i.e. no AZD0865) animals. For microsuspensions of the test compound, on the other hand, the exposure of BA99 was 2- to 3-fold lower than for nanosuspensions at both pHs. Moreover, the blood concentrations of BA99 administered as microsuspension were also 2- to 3-fold lower compared with untreated (no AZD0865) individuals receiving both nanoparticles and microparticles of BA99. Obviously, for neutral compounds, with similar physicochemical properties as the present compound, size reduction will be crucial for increased plasma exposure. For basic compounds, with similar physicochemical properties as the present compound, the crucial step for absorption is the dissolution and solubility in the gastric tract.     

The Improvement of Ibuprofen Dissolution Rate Through Microparticles Spray Drying Processed in an Aqueous System

A study to enhance the dissolution rate of ibuprofen, a poorly water-soluble drug, was carried out through combining specific formulations and processes with the addition of a hydrophilic carrier for the preparation of microparticles. Microparticle production was performed by spray drying ibuprofen microsuspensions formulated in an aqueous system with the addition of ethanol containing Aerosil 200® and Tween 80®. We were able to consistently produce microparticles as much as 40% of the dry weight of the input microsuspension. Spray-dried microparticles were characterized by scanning electron microscopy, X-ray diffraction, differential scanning calorimetry, laser diffractometer mastersizer, and infrared spectroscopy. No modification to the crystalinity and chemical structure of ibuprofen was observed. Dissolution of ibuprofen microparticles reached 100% in 3 minutes compared with less than 10% for unmodified ibuprofen. We concluded that both by the modification of formulation and the spray drying process it is possible to increase the dissolution rate of the tested model drug.     

Thiolated polymers: evaluation of their potential as dermoadhesive excipients

The objective of this study was to evaluate and compare four different thiolated polymers regarding their dermoadhesive potential. Therefore, three hydrophilic polymers (poly(acrylic acid), Carbopol 971 and carboxymethylcellulose) and a lipophilic polymer (silicone oil) were chosen to generate thiolated polymers followed by characterization. The total work of adhesion (TWA) and the maximum detachment force (MDF) of formulations containing modified and unmodified polymers were investigated on skin obtained from pig ears using a tensile sandwich technique. The synthesis of thiolated polymers provided 564?µmol, 1079?µmol, 482?µmol and 217?µmol thiol groups per gram poly(acrylic acid), Carbopol 971, carboxymethylcellulose and silicone oil, respectively. Hydrogels containing poly(acrylic acid)-cysteine, Carbopol 971-cysteine, and carboxymethylcellulose-cysteamine exhibited a 6-fold, 25-fold and 9-fold prolonged adhesion on porcine skin than the hydrogel formulations prepared from the corresponding unmodified polymers, respectively. Furthermore, thiolation of silicone oil with thioglycolic acid led to a 5-fold improvement in adhesion compared to the unmodified silicone oil. A comparison between the four thiolated polymer formulations showed a clear correlation between the amount of coupled thiol groups and the TWA. According to these results thiomers might also be useful excipients to provide a prolonged dermal resistance time of various formulations.     

Inhalable chitosan microparticles for simultaneous delivery of isoniazid and rifabutin in lung tuberculosis treatment

The direct delivery of antibiotics to the lung has been considered an effective approach to treat pulmonary tuberculosis, which represents approximately 80% of total cases. In this sense, this work aimed at producing inhalable chitosan microparticles simultaneously associating isoniazid and rifabutin, for an application in pulmonary tuberculosis therapy. Spray-dried chitosan microparticles were obtained with adequate flow properties for deep lung delivery (aerodynamic diameter of 4?µm) and high drug association efficiencies (93% for isoniazid and 99% for rifabutin). The highest concentration of microparticles that was tested (1?mg/mL) decreased the viability of macrophage-differentiated THP-1 cells to around 60% after 24?h exposure, although no deleterious effect was observed in human alveolar epithelial (A549) cells. The release of LDH was, however, increased in both cells. Chitosan microparticles further evidenced capacity to activate macrophage-like cells, inducing cytokine secretion well above basal levels. Moreover, the propensity of macrophages to internalize microparticles was demonstrated, with uptake levels over 90%. Chitosan microparticles also inhibited bacterial growth by 96%, demonstrating that the microencapsulation preserved drug antibacterial activity in vitro. Overall, the obtained data suggest the potential of chitosan microparticles for inhalable lung tuberculosis therapy.     

Fabricating method of SU-8 photoresist conical nozzle for inkjet printhead

A novel conical nozzle fabrication method for piezoelectric inkjet printhead is proposed based on the microelectromechanical system technology. By optimizing the exposure gap, exposure dose, postexposure bake (PEB), and development time, the SU-8 conical nozzle was fabricated. After thermal bonding with an open chamber, the piezoelectric inkjet printhead chamber was formed. The results show that the optimum SU-8 conical nozzle can be fabricated by applying exposure dose of 105?mJ/cm², exposure gap of 50?µm, PEB temperature of 65°C, PEB time of 10?min, and development time of 210?s. The final size of optimum conical nozzle is the large aperture of 30.46?±?1.17?µm, small aperture of 20.34?±?1.42?µm, and nozzle height of 45.38?±?1.02?µm.     

The improvement of ibuprofen dissolution rate through microparticles spray drying processed in an aqueous system

A study to enhance the dissolution rate of ibuprofen, a poorly water-soluble drug, was carried out through combining specific formulations and processes with the addition of a hydrophilic carrier for the preparation of microparticles. Microparticle production was performed by spray drying ibuprofen microsuspensions formulated in an aqueous system with the addition of ethanol containing Aerosil 200 and Tween 80. We were able to consistently produce microparticles as much as 40% of the dry weight of the input microsuspension. Spray-dried microparticles were characterized by scanning electron microscopy, X-ray diffraction, differential scanning calorimetry, laser diffractometer mastersizer, and infrared spectroscopy. No modification to the crystalinity and chemical structure of ibuprofen was observed. Dissolution of ibuprofen microparticles reached 100% in 3 minutes compared with less than 10% for unmodified ibuprofen. We concluded that both by the modification of formulation and the spray drying process it is possible to increase the dissolution rate of the tested model drug.     

Preparation and optimization of monodisperse polymeric microparticles using modified vibrating orifice aerosol generator for controlled delivery of letrozole in breast cancer therapy

Abstract

Letrozole (LTZ) is effective for the treatment of hormone-receptor-positive breast cancer in postmenopausal women. In this work, and for the first time, using vibrating orifice aerosol generator (VOAG) technology, monodisperse poly-ε-caprolactone (PCL), and poly (D, L-Lactide) (PDLLA) LTZ-loaded microparticles were prepared and found to elicit selective high cytotoxicity against cancerous breast cells with no apparent toxicity on healthy cells in vitro. Plackett–Burman experimental design was utilized to identify the most significant factors affecting particle size distribution to optimize the prepared particles. The generated microparticles were characterized in terms of microscopic morphology, size, zeta potential, drug entrapment efficiency, and release profile over one-month period. Long-term cytotoxicity of the microparticles was also investigated using MCF-7 human breast cancer cell lines in comparison with primary mammary epithelial cells (MEC). The prepared polymeric particles were monodispersed, spherical, and apparently smooth, regardless of the polymer used or the loaded LTZ concentration. Particle size varied from 15.6 to 91.6?µm and from 22.7 to 99.6?µm with size distribution (expressed as span values) ranging from 0.22 to 1.24 and from 0.29 to 1.48 for PCL and PDLLA based microparticles, respectively. Upon optimizing the manufacture parameters, span was reduced to 0.162–0.195. Drug entrapment reached as high as 96.8%, and drug release from PDLLA and PCL followed a biphasic zero-order release using 5 or 30% w/w drug loading in the formulations. Long-term in vitro cytotoxicity studies indicated that microparticles formulations significantly inhibited the growth of MCF-7 cell line over a prolonged period of time but did not have toxic effects on the normal breast epithelial cells.     

Impact of surfactant selection on the formulation and characterization of microparticles for pulmonary drug delivery

The effect of suspension stabilizers, internal aqueous phase volume and polymer amount were investigated for the production of protein loaded poly(d,l?lactide-co-glycolide) (PLGA) microparticles suitable for pulmonary drug delivery. PLGA microparticles were produced adopting water-in-oil-in-water (W/O/W) solvent evaporation technique and were investigated for surface morphology, particle size, encapsulation efficiency (EE%) and in-vitro release profile. Porous surface morphologies with a narrow size distribution were observed when employing 0.5?ml internal aqueous phase; 23.04?µm (±0.98), 15.05?µm (±0.27) and 22.89?µm (±0.41) for PVA, Tween 80 and oleic acid. Porous microparticles exhibited increased size and reduction in EE% with increasing internal aqueous phase, with non-porous microparticles produced when adopting 2.0?ml internal aqueous phase. The selection of stabilizer influences the size of the pores formed thus offers potential for the aerodynamic properties of the microparticles to be manipulated to achieve suitable aerosolization characteristics for pulmonary delivery of proteins.     

Development of thiolated poly(acrylic acid) microparticles for the nasal administration of exenatide

The purpose of this study was to develop a microparticulate formulation for nasal delivery of exenatide utilizing a thiolated polymer. Poly(acrylic acid)-cysteine (PAA-cys) and unmodified PAA microparticles loaded with exenatide were prepared via coprecipitation of the drug and the polymer followed by micronization. Particle size, drug load and release of incorporated exenatide were evaluated. Permeation enhancing properties of the formulations were investigated on excised porcine respiratory mucosa. The viability of the mucosa was investigated by histological studies. Furthermore, ciliary beat frequency (CBF) studies were performed. Microparticles displayed a mean size of 70–80?µm. Drug encapsulation was ～80% for both thiolated and non-thiolated microparticles. Exenatide was released from both thiolated and non-thiolated particles in comparison to exenatide in buffer only within 40?min. As compared to exenatide dissolved in buffer only, non-thiolated and thiolated microparticles resulted in a 2.6- and 4.7-fold uptake, respectively. Histological studies performed before and after permeation studies showed that the mucosa is not damaged during permeation studies. CBF studies showed that the formulations were cilio-friendly. Based on these results, poly(acrylic acid)-cysteine-based microparticles seem to be a promising approach starting point for the nasal delivery of exenatide.     

Pellets for oral administration of low-molecular-weight heparin

Background: Oral absorption of low-molecular-weight heparin (LMWH) is limited by its molecular size and negative charge. It has been shown previously that orally administered polymeric nano- or microparticles containing encapsulated LMWH have led to gastrointestinal absorption of heparin in rabbits. Method: Based on these investigations, pellets containing two LMWHs, enoxaparin (MW 4500 Da) or bemiparin (MW 3600 Da), and Eudragit®RS30D (ERS), were prepared using extrusion/ spheronization technique. Uncoated or coated (ERS) pellets were evaluated in vitro and in vivo on rabbits. Results: Enoxaparin pellets showed fast in vitro release in phosphate buffer (pH 7.4) and prolonged in vivo drug absorption after a single oral dose of 600 anti-Xa IU/ kg of body weight, leading to relative bioavailabilities ranging from 9.7 ± 1.9% to 12.8 ± 2.7% and anti-Xa activity over the curative dose. Bemiparin included in matrix pellets of ERS and coated with ERS exhibited in vitro prolonged release up to 4 hours and in vivo anti-Xa activity below the therapeutic minimum value of 0.1 IU/mL. Conclusion: This study presents LMWH in a pellet dosage form, which compared to nano- or microparticles, may offer a more convenient and industrializable way of manufacture leading to an easier scale-up process.     

Evaluation of systemic exposure of nanoparticle suspensions subcutaneously administered to mice regarding stabilization,volume, location,concentration and size

Different routes of administration are likely to result in very different outcomes due to different availability or plasma profile. The objective of the present study was to evaluate the pharmacokinetic profile after different subcutaneous (s.c.) administration of nanoparticle suspensions of a lipophilic compound to mice. Pharmacokinetics of the selected test compound and the effect of drug concentration, particle size, location of administration, volume given and particle stabilizers were studied. Adding PEGylated lipids or pluronic F-127 to the negatively charged surface of the nanoparticles increased the stability of the particles and the bioavailability. The in vivo studies demonstrated linear absorption kinetics for the selected model compound up to at least 500?µmol/kg. Absorption from upper-neck resulted in different systemic exposure compared to administration in the hip. The former was preferred if a prolonged C_max was desired while the latter ensured a flat profile for approximately 24 hours. Administering the double volume (but the same dose) had no effect on the pharmacokinetics, whereas smaller particle size significantly increased the exposure.     

Dynamic electrostatic charge of lactose-salbutamol sulphate powder blends dispersed from a Cyclohaler®

Context: Electrostatic forces have been claimed to be a mechanism for aerosol deposition in the lungs. However, the extent of its influence on aerosol performance is not clear, particularly for carrier-drug formulations.

Objectives: To prepare lactose-salbutamol powder blends, varying in blend ratio, and identify any relationships between salbutamol dose, electrostatic characteristics and in vitro aerosol performance.

Methods: Decanted lactose and micronized salbutamol sulfate was mixed to produce five blends (equivalent to 50, 100, 200, 300 and 400 µg salbutamol per 33?mg of powder). 33?±?1?mg of a blend was loaded into a Cyclohaler? and dispersed into the electrical Next Generation Impactor (eNGI) at an air flow rate of 60?L/min. This was conducted in triplicate for all five lactose-salbutamol blends.

Results: Fine particle fraction increased with salbutamol dose, from 5.89?±?1.42 to 21.35?±?2.91%. Specific charge (charge divided by mass) distributions for each blend were greatest in magnitude for the 50 µg blend and similar in magnitude between all other blends. However, in eNGI Stage 1 (>8.06?µm), specific charge decreased from 100 µg (?170.4?±?45.8 pC/µg) to 400 µg (?10.0?±?9.1 pC/µg).

Conclusions: The improvement in fine particle fraction with increased salbutamol dose was indicative of fine drug binding to high and low energy sites on the lactose carrier surface. This finding was supported by electrostatic charge results, but the aerosol charge itself was not found to influence aerosol performance by electrostatic forces.     

Onychopharmacokinetics of terbinafine hydrochloride penetration from a novel topical formulation into the human nail in vitro

This study determined the onychopharmacokinetics, nail absorption, distribution, and penetration of [¹⁴C]-terbinafine HCl in a new topical formulation into/through the human finger nail using the in vitro finite dose model. This study determined the penetration rate of terbinafine HCl from multiple doses of topical formulation applied daily for 14 days. Results showed that the total dose recovery (mass balance) was almost 100%. The concentration of terbinafine HCl in the deeper nail plate (ventral/intermediate layers) and the cotton-pad nail bed samples after the 14-day treatment were 613?±?145 and (±S.D.) and 27?±?1.2 µg/cm³ (or 1.9?±?0.6 µg/cm³ daily) on average, respectively. In comparison with nail concentration data from the literature for other topical terbinatine formulations, our results show that higher amounts of terbinafine HCl reached the deep nail plate and/or the nail bed after a 14-day topical treatment with this topical formulation in vitro.     

Dry powder inhaler of colistimethate sodium for lung infections in cystic fibrosis: optimization of powder construction

Abstract

Colistimethate sodium (CMS) for treatment of lung infections in cystic fibrosis patient was transformed into a dry powder for inhalation by spray drying. Design of Experiment was applied for understanding the role of the spray-drying process parameters on the critical quality attributes of the CMS spray-dried (SD) powders and agglomerates thereof. Eleven experimental SD microparticle powders were constructed under different process conditions according to a central composite design. The SD microparticles were then agglomerated in soft pellets. Eleven physico-chemical characteristics of SD CMS microparticle powders or agglomerates thereof were selected as critical quality attributes. The yield of SD process was higher than 75%. The emitted fraction of agglomerates from RS01 inhaler was 75–84%, and the fine particle fraction (particles <5?µm) was between 58% and 62%. The quality attributes of CMS SD powders and respective agglomerates that were significantly influenced by spray-drying process parameters were residual solvent and drug content of the SD microparticles as well as bulk density and respirable dose of the agglomerates. These attributes were also affected by the combination of the process variables. The air aspiration rate was found as the most positively influential on drug and solvent content and respirable dose. The residual solvent content significantly influenced the powder bulk properties and aerodynamic behavior of the agglomerates, i.e. quality attributes that govern drug metering in the device and the particles lungs deposition. Agglomerates of CMS SD microparticles, in combination with RS01?DPI, showed satisfactory results in terms of dose emitted and fine particle fraction.     

Inhibitory effects of curcumin on activity of cytochrome P450 2C9 enzyme in human and 2C11 in rat liver microsomes

Cytochrome P450 2C9 (CYP2C9), one of the most important phase I drug metabolizing enzymes, could catalyze the reactions that convert diclofenanc into diclofenac 4′-hydroxylation. Evaluation of the inhibitory effects of compounds on CYP2C9 is clinically important because inhibition of CYP2C9 could result in serious drug–drug interactions. The objective of this work was to investigate the effects of curcumin on CYP2C9 in human and cytochrome P450 2C11 (CYP2C11) in rat liver microsomes. The results showed that curcumin inhibited CYP2C9 activity (10?µmol?L^–1 diclofenac) with half-maximal inhibition or a half-maximal inhibitory concentration (IC50) of 15.25?µmol?L^–1 and Ki?=?4.473?µmol?L^–1 in human liver microsomes. Curcumin’s mode of action on CYP2C9 activity was noncompetitive for the substrate diclofenanc and uncompetitive for the cofactor NADPH. In contrast to its potent inhibition of CYP2C9 in human, diclofenanc had lesser effects on CYP2C11 in rat, with an IC50 ≥100?µmol L^–1. The observations imply that curcumin has the inhibitory effects on CYP2C9 activity in human. These in vitro findings suggest that more attention should be paid to special clinical caution when intake of curcumin combined with other drugs in treatment.     

Effect of primary drying temperature on process efficiency and product performance of lyophilized Ertapenam sodium

Abstract

The present work aimed to investigate the impact of primary drying temperature on lyophilization process efficiency and product performance of lyophilized Ertapenam sodium (EPM). Phase behavior of EPM formulation (200?mg/mL) using differential scanning calorimetry (DSC) and freeze drying microscopy (FDM) showed Tg′ at ?28.3?°C (onset) and Tc at ?25.0?°C (onset), respectively. The formulation was freeze dried at different product temperature (Tp) during primary drying, using (a) conservative cycle (CC) where the maximum Tp (?31.9?°C) <Tg′, (b) aggressive cycle 01 (AC01) where the maximum Tp (?24.8?°C) >Tg′, and (c) AC02 where the maximum Tp (?21.0?°C) >Tc. The drying kinetics revealed that the sublimation rate was increased from 0.128?g/h/vial in CC to 0.159 and 0.182?g/h/vial in AC01 and AC02, respectively. This ultimately reduced the primary drying time of 208?min in CC to 145?min in AC01 and to 103?minutes in AC02. Morphological evaluation of cake using scanning electron microscopy (SEM) and texture analysis revealed that AC01 lead to induction of microcollapse, whereas AC02 resulted in collapsed cake. Furthermore, the microcollapsed formulations showed similar physicochemical stability to CC formulation, whereas collapsed cake showed significant degradation of EPM and increased degradation on stress stability. The study highlights that primary drying with microcollapse can be utilized to improve the process efficiency without compromising product quality of amorphous EPM.     

Pharmacokinetics and tissue distribution of amphotericin B following oral administration of three lipid-based formulations to rats

The objective of this study was to assess the pharmacokinetics and tissue distribution of amphotericin B (AmB) in rats following oral administration of three lipid-based formulations (iCo-009, iCo-010 and iCo-011). The lipid-based formulations were administered to rats at a dose of 10?mg/kg and blood samples were withdrawn at predose, 1, 2, 4, 6, 8, 10, 12, 24, 48 and 72?h, after which the animals were sacrificed and the body organs were collected for AmB quantification using a validated HPLC method. Plasma pharmacokinetics parameters were determined using non-compartmental analysis. The disappearance of AmB from plasma was the slowest following the administration of iCo-010 with MRT of 63?h followed by iCo-009 then iCo-011 (36 and 27?h). The AUC_0-24h of iCo-009 and iCo-010 was 1.5–2-fold higher than that of iCo-011. The kidney exposure was comparable between iCo-009 and iCo-010 and was higher than that of iCo-011. The lung exposure was the highest following iCo-010 administration as compared to that of iCo-009. The distribution of AmB from plasma to tissues resulted in a high accumulation of AmB overtime with slow back-distribution to plasma. The pharmacokinetics profiles varied among the three formulations, despite the similarity in lipid composition between iCo-010 and iCo-011 and the presence of Peceol® as a common component in the formulations. The administration of oral iCo-010 could lead to higher steady state concentrations in the tissues after multiple dosing, which could lead to enhanced eradication of tissue borne fungal and parasitic infections.