Proliposomes for oral delivery of dehydrosilymarin: preparation and evaluation in vitro and in vivo

Aim:

To formulate proliposomes with a polyphase dispersed system composed of soybean phospholipids, cholesterol, isopropyl myristate and sodium cholate to improve the oral bioavailability of dehydrosilymarin, an oxidized form of herbal drug silymarin.

Methods:

Dehydrosilymarin was synthesized from air oxidation of silymarin in the presence of pyridine, and proliposomes were prepared by a film dispersion-freeze drying method. Morphological characterization of proliposomes was observed using a transmission electron microscope. Particle size and encapsulation efficiency of proliposomes were measured. The in vitro release of dehydrosilymarin from suspension and proliposomes was evaluated. The oral bioavailability of dehydrosilymarin suspension and proliposomes was investigated in rabbits.

Results:

The proliposomes prepared under the optimum conditions were spherical and smooth with a mean particle size in the range of 7 to 50 nm. Encapsulation efficiency was 81.59%±0.24%. The in vitro accumulative release percent of dehydrosilymarinloaded proliposomes was stable, which was slow in pH 1.2, and increased continuously in pH 6.8, and finally reached 86.41% at 12 h. After oral administration in rabbits, the relative bioavailability of proliposomes versus suspension in rabbits was 228.85%.

Conclusion:

Proliposomes may be a useful vehicle for oral delivery of dehydrosilymarin, a drug poorly soluble in water.     

Absolute bioavailability of imidafenacin after oral administration to healthy subjects

Aims

To investigate the absolute bioavailability of imidafenacin, a new muscarinic receptor antagonist, a single oral dose of 0.1 mg imidafenacin was compared with an intravenous (i.v.) infusion dose of 0.028 mg of the drug in healthy subjects.

Methods

Fourteen healthy male subjects, aged 21–45 years, received a single oral dose of 0.1 mg imidafenacin or an i.v. infusion dose of 0.028 mg imidafenacin over 15 min at two treatment sessions separated by a 1-week wash-out period. Plasma concentrations of imidafenacin and the major metabolites M-2 and imidafenacin-N-glucuronide (N-Glu) were determined. The urinary excretion of imidafenacin was also evaluated. Analytes in biological samples were measured by liquid chromatography tandem mass spectrometry.

Results

The absolute oral bioavailability of imidafenacin was 57.8% (95% confidence interval 54.1, 61.4) with a total clearance of 29.5 ± 6.3 l h⁻¹. The steady-state volume of distribution was 122 ± 28 l, suggesting that imidafenacin distributes to tissues. Renal clearance after i.v. infusion was 3.44 ± 1.08 l h⁻¹, demonstrating that renal clearance plays only a minor role in the elimination of imidafenacin. The ratio of AUC_t of both M-2 and N-Glu to that of imidafenacin was reduced after i.v. infusion from that seen after oral administration, suggesting that M-2 and N-Glu in plasma after oral administration were generated primarily due to first-pass metabolism. No serious adverse events were reported during the study.

Conclusions

The absolute mean oral bioavailability of imidafenacin was determined to be 57.8%. Imidafenacin was well tolerated following both oral administration and i.v. infusion.

What is already known about this subject

• The absolute bioavailability of imidafenacin in rats and dogs is 5.6% and 36.1%, respectively.
• The pharmacokinetic profiles of imidafenacin after oral administration have been revealed.
• Imidafenacin is primarily metabolized to metabolites by CYP3A4 and UGT1A4.

What this study adds

• The absolute bioavailability of imidafenacin in human is 57.8%.
• The pharmacokinetic profiles of imidafenacin after intravenous administration are revealed.
• The formation of metabolites in the plasma is caused mainly by first-pass effects.

     

Simultaneous oral therapeutic and intravenous 14C‐microdoses to determine the absolute oral bioavailability of saxagliptin and dapagliflozin

Aim

To determine the absolute oral bioavailability (F_p.o.) of saxagliptin and dapagliflozin using simultaneous intravenous ¹⁴C‐microdose/therapeutic oral dosing (i.v.micro + oraltherap).

Methods

The F_p.o. values of saxagliptin and dapagliflozin were determined in healthy subjects (n = 7 and 8, respectively) following the concomitant administration of single i.v. micro doses with unlabelled oraltherap doses. Accelerator mass spectrometry and liquid chromatography‐tandem mass spectrometry were used to quantify the labelled and unlabelled drug, respectively.

Results

The geometric mean point estimates (90% confidence interval) F_p.o. values for saxagliptin and dapagliflozin were 50% (48, 53%) and 78% (73, 83%), respectively. The i.v.micro had similar pharmacokinetics to oraltherap.

Conclusions

Simultaneous i.v.micro + oraltherap dosing is a valuable tool to assess human absolute bioavailability.     

Oral diacetylmorphine (heroin) yields greater morphine bioavailability than oral morphine: bioavailability related to dosage and prior opioid exposure

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Venosclerosis prevents many opioid addicts in heroin substitution programmes from injecting intravenously, which makes consideration of other routes of administration necessary.
• Even high doses of oral diacetylmorphine are completely converted to morphine presystemically.
• Morphine bioavailability in heroin addicts after high-dose oral diacetylmorphine administration is considerably higher than expected based on prior data obtained with relatively low oral diacetylmorphine or morphine doses in healthy subjects or patients receiving treatment for pain (64–72% vs. 20–25%).

WHAT THIS STUDY ADDS

• Morphine influx into systemic circulation is more rapid after oral diacetylmorphine than after oral morphine, resulting in earlier and more than double maximal concentrations.
• In opioid-dependent people, bioavailability of morphine from oral doses of diacetylmorphine is also 37% higher than that of oral morphine.
• Morphine bioavailability is two and 1.5 times higher in chronic users than in opioid-naive subjects after low oral doses of diacetylmorphine or morphine, respectively.
• Oral absorption of morphine from diacetylmorphine is dose dependent, i.e. bioavailability increases with diacetylmorphine dose.

AIMS

In the Swiss heroin substitution trials, patients are treated with self-administered diacetylmorphine (heroin). Intravenous administration is not possible in patients that have venosclerosis. Earlier studies have demonstrated that oral diacetylmorphine may be used, although it is completely converted to morphine presystemically. Morphine bioavailability after high-dose oral diacetylmorphine is considerably higher than would be predicted from low-dose trials. The aim was to investigate whether the unexpectedly high bioavailability is due to a difference in the drug examined, and whether it depends on previous exposure or on dose.

METHODS

Opioid-naive healthy volunteers and dependent patients from the Swiss heroin trials (n = 8 per group) received low doses of intravenous and oral deuterium-labelled morphine and diacetylmorphine, respectively. Patients also received a high oral diacetylmorphine dose.

RESULTS

The maximum plasma concentration (C_max) of morphine was twofold higher after oral diacetylmorphine than after morphine administration in both groups. However, morphine bioavailability was considerably higher in chronic users [diacetylmorphine 45.6% (95% confidence interval 40.0, 51.3), morphine 37.2% (30.1, 44.3)] than in naive subjects [diacetylmorphine 22.9% (16.4, 29.4), morphine 23.9% (16.5, 31.2)] after low oral doses (48.5 µmol) of either diacetylmorphine or morphine. Morphine clearance was similar in both groups. Moreover, oral absorption of morphine from diacetylmorphine was found to be dose dependent, with bioavailability reaching 64.2% (55.3, 73.1) for high diacetylmorphine doses (1601 µmol).

CONCLUSIONS

Oral absorption of opioids is substance-, dose- and patient collective-dependent, suggesting that there may be a saturation of first-pass processes, the exact mechanism of which is not yet understood.     

Preclinical pharmacokinetics of TPN729MA,a novel PDE5 inhibitor,and prediction of its human pharmacokinetics using a PBPK model

Aim:

TPN729MA is a novel selective PDE5 inhibitor currently under clinical development in China for the treatment of erectile dysfunction. In this study we characterized its preclinical pharmacokinetics (PK) and predict its human PK using a physiologically based pharmacokinetic (PBPK) model.

Methods:

The preclinical PK of TPN729MA was studied in rats and dogs. Human clearance (CL) values for TPN729MA were predicted from various allometric methods and from intrinsic CL determined in human liver microsomes. Human PK and plasma concentration versus time profiles of TPN729MA were predicted by using a PBPK model in GastroPlus. Considering the uncertainties in the prediction, a preliminary human study was conducted in 3 healthy male volunteers with an oral dose of 25 mg.

Results:

After a single intravenous administration of TPN729MA at a dose of 1 mg/kg in rats and 3 mg/kg in dogs, the plasma CL was 69.7 mL·min⁻¹·kg⁻¹ in rats and 26.3 mL·min⁻¹·kg⁻¹ in dogs, and the steady-state volumes of distribution (V_ss) were 7.35 L/kg in rats and 6.48 L/kg in dogs. The oral bioavailability of TPN729MA was 10% in rats and above 34% in dogs. Profiles of predicted plasma concentration versus time were similar to those observed in humans at 25 mg, and the predicted T_max, C_max and AUC values were within 2-fold of the observed values.

Conclusion:

TPN729MA demonstrates good preclinical PK. This compound is a valuable candidate for further clinical development. This study shows the benefits of using a PBPK model to predict PK in humans.     

Mixed micelles loaded with silybin-polyene phosphatidylcholine complex improve drug solubility

Aim:

To prepare a novel formulation of phosphatidylcholine (PC)-bile salts (BS)-mixed micelles (MMs) loaded with silybin (SLB)-PC complex for parenteral applications.

Methods:

SLB-PC-BS-MMs were prepared using the co-precipitation method. Differential scanning calorimetry (DSC) analysis was used to confirm the formation of the complex and several parameters were optimized to obtain a high quality formulation. The water-solubility, drug loading, particle size, zeta potential, morphology and in vivo properties of the SLB-PC-BS-MMs were determined.

Results:

The solubility of SLB in water was increased from 40.83±1.18 μg/mL to 10.14±0.36 mg/mL with a high drug loading (DL) of 14.43%±0.44% under optimized conditions. The SLB-PC-BS-MMs were observed by transmission electron microscopy (TEM) and scanning electron microscopy (SEM) and showed spherical shapes. The particle size and zeta potential, as measured by photon correlation spectroscopy (PCS), were about 30±4.8 nm and −39±5.0 mV, respectively. In vivo studies showed that incorporation of the SLB-PC complex into PC-BS-MMs led to a prolonged circulation time of the drug.

Conclusion:

This novel formulation appears to be a good candidate for drug substances that exhibit poor solubility for parenteral administration.     

Novel gastroretentive sustained-release tablet of tacrolimus based on self-microemulsifying mixture: in vitro evaluation and in vivo bioavailability test

Aim:

To develop a novel gastroretentive drug delivery system based on a self-microemulsifying (SME) lipid mixture for improving the oral absorption of the immunosuppressant tacrolimus.

Methods:

Liquid SME mixture, composed of Cremophor RH40 and monocaprylin glycerate, was blended with polyethylene oxide, chitosan, polyvinylpyrrolidone and mannitol, and then transformed into tablets via granulation, with ethanol as the wetting agent. The tablets were characterized in respect of swelling, bioadhesive and SME properties. In vitro dissolution was conducted using an HCl buffer at pH 1.2. Oral bioavailability of the tablets was examined in fasted beagle dogs.

Results:

The tablet could expand to 13.5 mm in diameter and 15 mm in thickness during the initial 20 min of contact with the HCl buffer at pH 1.2. The bioadhesive strength was as high as 0.98±0.06 N/cm². The SME gastroretentive sustained-release tablets preserved the SME capability of the liquid SME formations under transmission electron microscope. The drug-release curve was fit to the zero-order release model, which was helpful in reducing fluctuations in blood concentration. Compared with the commercially available capsules of tacrolimus, the relative bioavailability of the SME gastroretentive sustained-release tablets was 553.4%±353.8%.

Conclusion:

SME gastroretentive sustained-release tablets can enhance the oral bioavailability of tacrolimus with poor solubility and a narrow absorption window.     

Single and multiple dose intravenous and oral pharmacokinetics of the hedgehog pathway inhibitor vismodegib in healthy female subjects

AIM

Vismodegib has demonstrated clinical activity in patients with advanced basal cell carcinoma. The pharmacokinetics (PK) of vismodegib are non-linear. The objective of this study was to determine whether vismodegib PK change following repeated dosing by administering a tracer intravenous (i.v.) dose of ¹⁴C-vismodegib with single and multiple oral doses.

METHODS

Healthy post menopausal female subjects (n= 6/group) received either a single or daily 150 mg vismodegib oral dose with a ¹⁴C-labelled 10 µg i.v. bolus dose administered 2 h after the single or last oral dose (day 7). Plasma samples were assayed for vismodegib by LC-MS/MS and for ¹⁴C-vismodegib by accelerator mass spectrometry.

RESULTS

Following a single i.v. dose, mean clearance, volume of distribution and absolute bioavailability were 43.4 ml h⁻¹, 16.4 l and 31.8%, respectively. Parallel concentration–time profiles following single oral and i.v. administration of vismodegib indicated elimination rate limited PK. Following i.v. administration at steady-state, mean clearance and volume of distribution were 78.5 ml h⁻¹ and 26.8 l, respectively. Comparison of i.v. PK parameters after single and multiple oral dosing showed similar half-life, increased clearance and volume of distribution (81% and 63% higher, respectively) and decreased bioavailability (77% lower) after repeated dosing. Relative to single dose, the unbound fraction of vismodegib increased 2.4-fold with continuous daily dosing.

CONCLUSION

Vismodegib exhibited a long terminal half-life after oral and i.v. administration, moderate absolute bioavailability and non-linear PK after repeated dosing. Results from this study suggest that the non-linear PK of vismodegib result from two separate, non-linear processes, namely solubility limited absorption and high affinity, saturable plasma protein binding.     

Opposite malaria and pregnancy effect on oral bioavailability of artesunate – a population pharmacokinetic evaluation

Aim

The aim was to compare the pharmacokinetic properties of artesunate and dihydroartemisinin in the same women: i) pregnant with acute uncomplicated malaria on day 1 and 2, ii) pregnant with convalescent malaria on day 7 and iii) in a healthy state 3 months post-partum on day 1, 2 and 7.

Methods

Non-linear mixed-effects modelling was used to compare plasma concentration–time profiles of artesunate and dihydroartemisinin over 7 days of treatment following oral and intravenous artesunate administration to pregnant women with uncomplicated Plasmodium falciparum malaria during their second or third trimesters of pregnancy. The same women were restudied 3 months after delivery when fully recovered. Non-compartmental results of the same study have been published previously.

Results

Twenty pregnant patients on the Thailand-Myanmar border were studied and 15 volunteered to be restudied 3 months post-partum. Malaria and pregnancy had no effect on the pharmacokinetic properties of artesunate or dihydroartemisinin after intravenous artesunate administration. However, malaria and pregnancy had opposite effects on the absorption of orally administered artesunate. Malaria increased the absolute oral bioavailability of artesunate by 87%, presumably by inhibiting first pass effect, whereas pregnancy decreased oral bioavailability by 23%.

Conclusions

The population pharmacokinetic analysis demonstrated opposite effects of malaria and pregnancy on the bioavailability of orally administered artesunate. Lower drug exposures during the second and third trimesters of pregnancy may contribute to lower cure rates and thus the development of drug resistance. Dose optimization studies are required for artesunate containing artemisinin-based combination therapies (ACTs) in later pregnancy.     

Sublingual administration of furosemide: new application of an old drug

What is already known about this subject

• Furosemide is an effective diuretic, but its absorption may be too slow to allow oral treatment in certain patients.

What this study adds

• In healthy volunteers, sublingual administration is associated with a higher C_max, a higher bioavailability and a more accentuated initial natriuretic response than oral furosemide. Sublingual administration may offer advantages over oral administration of furosemide in certain clinical situations.

Background

In patients with decompensated heart failure, absorption of orally administered furosemide may be delayed, possibly leading to impaired pharmacodynamic effects. Sublingual administration may represent an alternative in such situations.

Methods

In a crossover study including 11 healthy men, 20 mg furosemide was administered intravenously, orally and sublingually on three different days. Pharmacokinetics and pharmacodynamics were assessed from repeated blood and urine samples.

Results

Compared with oral administration, sublingual administration was associated with 43% higher C_max[difference 215 ng ml⁻¹, 95% confidence interval (CI) 37, 392], a higher urinary recovery (8.9 vs. 7.3 mg, difference 1.6 mg, 95% CI 0.3, 2.9), an 28% higher AUC (difference 328 ng h⁻¹ ml⁻¹, 95% CI 24, 632) and a higher bioavailability of furosemide (59 vs. 47%, difference 12.0%, 95% CI −1.2, 25.2). Sodium excretion was higher after sublingual compared with oral administration (peak excretion rate 1.8 vs. 1.4 mmol min⁻¹, P < 0.05), whereas urine volume did not differ significantly between the two application modes. In comparison, intravenous administration showed the expected more rapid and intense response.

Conclusion

Sublingually administered furosemide tablets differ in certain kinetic and dynamic properties from identical tablets given orally. Sublingual administration of furosemide may offer therapeutic advantages in certain groups of patients.     

Systemic and cerebral exposure to and pharmacokinetics of flavonols and terpene lactones after dosing standardized Ginkgo biloba leaf extracts to rats via different routes of administration

BACKGROUND AND PURPOSE

Flavonols and terpene lactones are putatively responsible for the properties of Ginkgo biloba leaf extracts that relate to prevention and treatment of cardiovascular disease and cerebral insufficiency. Here, we characterized rat systemic and cerebral exposure to these ginkgo compounds after dosing, as well as the compounds’ pharmacokinetics.

EXPERIMENTAL APPROACH

Rats received single or multiple doses of ShuXueNing injection (prepared from GBE50 for intravenous administration) or GBE50 (a standardized extract of G. biloba leaves for oral administration). Brain delivery of the ginkgo compounds was assessed with microdialysis. Various rat samples were analysed using liquid chromatography/mass spectrometry.

KEY RESULTS

Slow terminal elimination features of the flavonols counterbalanced the influence of poor oral bioavailability on their systemic exposure levels, which also resulted in significant accumulation of the compounds in plasma during the subchronic treatment with ShuXueNing injection and GBE50. Unlike the flavonols, the terpene lactones had poor enterohepatic circulation due to their rapid renal excretion and unknown metabolism. The flavonol glycosides occurred as major forms in plasma after dosing with ShuXueNing injection, while the flavonol aglycone conjugates were predominant in plasma after dosing with GBE50. Cerebral exposure was negligible for the flavonols and low for the terpene lactones.

CONCLUSION AND IMPLICATIONS

Unlike the significant systemic exposure levels, the levels of cerebral exposure to the flavonols and terpene lactones are low. The elimination kinetic differences between the two classes of ginkgo compounds influence their relative systemic exposure levels. The information gained is relevant to linking ginkgo administration to the medicinal effects.     

Evaluation of doxorubicin-loaded pH-sensitive polymeric micelle release from tumor blood vessels and anticancer efficacy using a dorsal skin-fold window chamber model

Aim： To evaluation the doxorubicin （DOX）-loaded pH-sensitive polymeric micelle release from tumor blood vessels into tumor interstitium using an animal vessel visibility model, the so-called dorsal skin-fold window chamber model.
Methods： DOX-loaded pH-sensitive polyHis-b-PEG micelles and DOX-loaded pH-insensitive PLLA-b-PEG micelles were prepared. The uptake of the micelles by MDA-MB-231 breast cancer cells in vitro and in vivo was examined using flow cytometry. The pharmacokinetic parameters of the micelles were determined in SD rats after intravenous injection of a DOX dose （6 mg/kg）. The release of the micelles from tumor vasculature and the antitumor efficacy were evaluated in MDA-MB-231 breast cancer xenografted in nude mice using a dorsal skin-fold window chamber.
Results： The effective elimination half-life t1/2 of the pH-sensitive, pH-insensitive polymeric micelles and DOX-PBS in rats were 11.3 h, 9.4 h, and 2.1 h, respectively. Intravital microscopy in MDA-MB-231 breast cancer xenografted in nude mice showed that the pH-sensitive polymeric micelles rapidly extravasated from the tumor blood vessels, and DOX carried by the pH-sensitive micelles was preferentially released at the tumor site as compared to the pH-insensitive polymeric micelles. Furthermore, the pH-sensitive polymeric micelles exhibited significant greater efficacy in inhibition of tumor growth in the nude mice.
Conclusion： When DOX is loaded into pH-sensitive polymeric micelles, the acidity in tumor interstitium causes the destabilization of the micelles and triggers drug release, resulting in high local concentrations within the tumor, thus more effectively inhibiting the tumor growth in vivo.     

Effects of allisartan,a new AT1 receptor blocker,on blood pressure and end-organ damage in hypertensive animals

Aim:

To investigate the effects of allisartan, a new angiotensin II type 1 (AT₁) receptor antagonist, on blood pressure (BP) and end-organ damage (EOD) in hypertensive rats and dogs.

Methods:

First, a single dose of allisartan was given intragastrically to evaluate the BP reduction in spontaneously hypertensive rats (SHRs), two kidney-one clip (2K1C) renovascular hypertensive rats and dogs, and Beagle dogs with angiotensin II-induced hypertension. Second, allisartan was mixed in rat chow for long-term treatment. After 4 months of drug administration, rats were instrumented to determine BP and baroreflex sensitivity (BRS). Observation of morphologic changes was used to estimate EOD. Third, the acute toxicity of allisartan was compared with that of losartan in mice.

Results:

BP was significantly decreased after intragastric administration of allisartan in SHRs, 2K1C rats, 2K1C dogs and Beagle dogs with angiotensin II-induced hypertension. Compared with the control, SHRs that received long-term treatment with allisartan exhibited an improved BRS and organ protective effects. Mice who were administered allisartan experienced less acute toxicity than those treated with losartan.

Conclusion:

Allisartan is highly effective for BP reduction and organ protection with low toxicity.     

Pharmacokinetics,metabolism and bioavailability of the triazole antifungal agent voriconazole in relation to CYP2C19 genotype

AIMS

The aim was to determine the pharmacokinetics of voriconazole after a single oral dose in comparison with intravenous (i.v.) administration in healthy individuals stratified according to the cytochrome P450 (CYP) 2C19 genotype. In addition, the possible metabolic pathways and their modulation according to CYP2C19 genotype were investigated after oral and i.v. administration of voriconazole.

METHODS

In a single-centre, open-label, two-period crossover study 20 participants received single doses of 400 mg voriconazole orally and 400 mg voriconazole intravenously in randomized order. Blood and urine samples were collected up to 96 h post dose and the voriconazole and three major metabolites were quantified by high-performance liquid chromatography coupled to mass spectroscopy.

RESULTS

Absolute oral bioavailability of voriconazole was 82.6% (74.1, 91.0). It ranged from 94.4% (78.8, 109.9) in CYP2C19 poor metabolizers to 75.2% (62.9, 87.4) in extensive metabolizers. In contrast to voriconazole and its N-oxide, the plasma concentrations of both hydroxylated metabolites showed a large second peak after 24 h. Independent of the route of administration, voriconazole partial metabolic hydroxylation after i.v. administration was eightfold higher compared with N-oxidation [48.8 ml min⁻¹ (30.5, 67.1) vs. 6.1 ml min⁻¹ (4.1, 8.0)]. The formation of the metabolites was related to CYP2C19 activity.

CONCLUSIONS

Independent of the route of administration, voriconazole exposure was three times higher in CYP2C19 poor metabolizers compared with extensive metabolizers. Voriconazole has a high bioavailability with no large differences between the CYP2C19 genotypes. The hydroxylation pathway of voriconazole elimination exceeded the N-oxidation, both influenced by the CYP2C19 genotype.     

Population pharmacokinetics of clindamycin orally and intravenously administered in patients with osteomyelitis

AIMS

This study was performed to describe clindamycin, administered either orally or intravenously, concentration−time courses to patients with osteomyelitis, to study the effects of different covariates on clindamycin pharmacokinetics and to simulate an optimized administration scheme.

METHODS

Clindamycin concentrations were measured in 50 patients. A total of 122 plasma concentrations were available (58 from oral administration and 64 from i.v. infusion). A population pharmacokinetic model was developed with MONOLIX 4 software.

RESULTS

A one compartment model adequately described the data. Clindamycin clearance increased significantly with body weight (BW). The typical population estimates (interindividual variability) for clearance, volume of distribution and absorption rate constant were 16.2 l h⁻¹ (0.39), 70.2 l and 0.92 h⁻¹, respectively. The bioavailability of the oral form was estimated to be 87.6%. According to BW, theoretical doses needed to reach a C_min of 2 mg l⁻¹ were then calculated.

CONCLUSIONS

The current recommendation of 600 mg three times daily seems to be effective up to 75 kg but the dose should be raised to 900 mg three times daily thereafter. These assumptions should be prospectively confirmed.     

Methotrexate-Loaded Nanomixed Micelles: Formulation,Characterization, Bioavailability,Safety, and In Vitro Anticancer Study

Purpose

Methotrexate (MTX), a potent anticancer drug, shows low oral bioavailability due to its low aqueous solubility and permeability. Moreover, its multidrug resistance (MDR) in cancer and toxic effects restricts its clinical applications. The aim of the study was to prepare novel MTX-loaded Poloxamer 407 and Gelucire^®44/14 (GL44) mixed micelles (MTX-PGMM) to improve its oral bioavailability and cytotoxicity and to reduce its systemic toxicity.

Methods

MTX-PGMM was prepared by dialysis method, compared with blank or MTX-free blank mixed micelles (BMM) and aqueous dispersion of MTX (MTX-AD) with respect to morphology, size, zeta potential, entrapment efficiency, in vitro release, and in vitro cytotoxicity, bioavailability, and toxicity study in rats.

Results

The developed MTX-PGMM exhibited small particle size, good encapsulation efficiency, and good stability in media simulating the physiological conditions of the gastrointestinal tract. The MTX-PGMM micelles demonstrated sustained release, enhanced (6.5-fold) oral bioavailability, slow plasma elimination, and long circulation of MTX. Biocompatibility was also established as there were no signs of tissue toxicity. Moreover, MTX-PGMM produced higher in vitro cytotoxicity (GI₅₀ of 1.44?±?0.33 μg/mL) than free MTX (GI₅₀ 13.71?±?0.99 μg/mL) in human breast cancer MCF-7 cells.

Conclusion

Poloxamer 407 and Gelucire^®44/14 (GL44) mixed micelles are promising carriers for oral delivery of MTX and can be utilized for other Biopharmaceutical Classification System class IV anticancer drugs having poor oral bioavailability and multidrug resistance in cancer.

     

Effect of food on the pharmacokinetics of the oral phosphodiesterase 5 inhibitor udenafil for the treatment of erectile dysfunction

AIMS

Udenafil is a cyclic guanosine 3′,5′-monophosphate-specific phosphodiesterase type 5 (PDE5) inhibitor developed for the treatment of erectile dysfunction. The aim was to evaluate the effect of food on the pharmacokinetics of udenafil.

METHODS

An open, randomized, three-way crossover study was conducted. Fifteen healthy male volunteers received a single 200-mg oral dose of udenafil while fasting, after a low-fat meal, and after a high-fat meal separated by 7-day washout periods. Serial blood samples were taken up to 48 h after oral administration.

RESULTS

Under fasting conditions, udenafil was rapidly absorbed and t_max was observed typically 1.5 h after administration. The mean t_max values after a low-fat meal and a high-fat meal were 2.6 and 2.1 h, respectively. The ratios (90% confidence intervals) of the geometric means compared with the fasting condition for C_max and AUC_last were 0.79 (0.70, 0.90) and 0.96 (0.89, 1.03) in the low fat-fed condition, respectively, and 1.01 (0.89, 1.15) and 1.03 (0.96, 1.11), respectively, in the high fat-fed condition.

CONCLUSIONS

The t_max of udenafil was delayed under the fed conditions. However, although the C_max was reduced by approximately 21% in the low fat-fed state, overall bioavailability was not affected when taken with food.     

Synergistic enhancement of parasiticidal activity of amphotericin B using copaiba oil in nanoemulsified carrier for oral delivery: an approach for non-toxic chemotherapy

Background and Purpose

The aim of this study was to devise a nanoemulsified carrier system (CopNEC) to improve the oral delivery of amphotericin B (AmB) by increasing its oral bioavailability and synergistically enhance its antileishmanial activity with copaiba oil (Cop).

Experimental Approach

The AmB encapsulated NEC (CopNEC-AmB) comprised of Cop, d-α-tocopheryl polyethylene glycol 1000 succinate and phosphatidylcholine was prepared by high-pressure homogenization method. Stability study of CopNEC-AmB was carried out in simulated gastric fluid and simulated intestinal fluid. The CopNEC-AmB and plain AmB were compared as regards their in vitro antileishmanial activity, pharmacokinetics, organ distribution and toxicity.

Key Results

The optimal CopNEC-AmB had a small globule size, low polydispersity index, high ζ potential and encapsulation efficiency. The high resolution transmission electron microscopy illustrated spherical particle geometry with homogeny in their sizes. The optimal CopNEC-AmB was found to be stable in gastrointestinal fluids showing insignificant changes in globule size and encapsulation efficiency. The AUC_0–48 value of CopNEC-AmB in rats was significantly improved showing 7.2-fold higher oral bioavailability than free drug. The in vitro antileishmanial activity of CopNEC-AmB was significantly higher than that of the free drug as Cop synergistically enhanced the antileishmanial effect of AmB by causing drastic changes in the morphology of Leishmania parasite and rupturing its plasma membrane. The CopNEC-AmB showed significantly less haemolytic toxicity and cytotoxicity and did not change the histopathology of kidney tissues as compared with AmB alone.

Conclusions and Implications

This prototype CopNEC formulation showed improved bioavailability and had a non-toxic synergistic effect on the antileishmanial activity of AmB.     

The absolute bioavailability of racemic ketamine from a novel sublingual formulation

Aim

The principal study objective was to investigate the pharmacokinetic characteristics of a new sublingual ketamine wafer and to establish its absolute bioavailability and local tolerability.

Methods

The study was of open label, two way randomized crossover design in eight healthy male volunteers. Each participant received either a single 10 mg intravenous dose as a constant rate 30 min infusion or a 25 mg sublingual dose of ketamine wafer in two treatment periods with a 7 day wash out. Pharmacokinetic blood sampling and local tolerability and safety assessments were carried out during 24 h following both dosing occasions. Plasma concentrations were analyzed by non-compartmental methods and local tolerability was assessed using modified Likert scales.

Results

The median (90% CI lower, upper limit) absolute bioavailability of sublingual ketamine was 29% (27, 31%). The first quantifiable plasma ketamine concentration was observed within 5 min for all eight participants for both routes of administration and the median (min–max) time of the peak plasma concentration was 0.75 h (0.25–1.0 h) after sublingual administration. The ketamine wafer had very good local tolerability.

Conclusion

Sublingual administration of the ketamine wafer resulted in rapid absorption. The ketamine wafer has comparable bioavailability with other oral transmucosal formulations of ketamine but with markedly reduced inter-subject variability, warranting further evaluation as an analgesic adjunct.     

Preparation, characterization and in vivo evaluation of bergenin-phospholipid complex

Aim:

To prepare a bergenin-phospholipid complex (BPC) to increase oral bioavailability of the drug.

Methods:

In order to obtain the acceptable BPC, a spherical symmetric design-response surface methodology was used for process optimization. The influence of reaction medium, temperature, drug concentration and drug-to-phospholipid ratio on the combination percentage and content of bergenin in BPC were evaluated. BPC was then characterized by thin-layer chromatography (TLC), high-performance liquid chromatography (HPLC), ultra-violet (UV) spectroscopy, fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC) and X-ray powder diffraction. The physicochemical properties such as microscopic shape, particle size, zeta-potential, solubility, crystalline form, and hygroscopicity were tested. The pharmacokinetic characteristics and bioavailability of BPC were investigated after oral administration in rats in comparison to bergenin and the physical mixture (bergenin and phospholipids).

Results:

BPC was successfully prepared under the optimum conditions [temperature=60 °C, drug concentration=80 g/L and drug-to-phospholipids ratio=0.9 (w/w)]. The combination percentage was 100.00%±0.20%, and the content of bergenin in the complex was 45.98%±1.12%. Scanning electron microscopy and transmission electron microscopy of BPC showed spherical particles. The average particle size was 169.2±20.11 nm and the zeta-potential was -21.6±2.4 mV. The solubility of BPC in water and in n-octanol was effectively enhanced. The C_max and AUC_0→∞ of BPC were increased, and the relative bioavailability was significantly increased to 439% of bergenin.

Conclusion:

The BPC is a valuable delivery system to enhance the oral absorption of bergenin.