Development and Evaluation of Self-Microemulsifying Drug Delivery System for Improving Oral Absorption of Poorly Water-Soluble Olaparib.

The purpose of this study is to develop and evaluate a self-microemulsifying drug delivery system (SMEDDS) to improve the oral absorption of poorly water-soluble olaparib. Through the solubility test of olaparib in various oils, surfactants and co-surfactants, pharmaceutical excipients were selected. Self-emulsifying regions were identified by mixing the selected materials at various ratios, and a pseudoternary phase diagram was constructed by synthesizing these results. The various physicochemical properties of microemulsion incorporating olaparib were confirmed by investigating the morphology, particle size, zeta potential, drug content and stability. In addition, the improved dissolution and absorption of olaparib were also confirmed through a dissolution test and a pharmacokinetic study. An optimal microemulsion was generated in the formulation of Capmul® MCM 10%, Labrasol® 80% and PEG 400 10%. The fabricated microemulsions were well-dispersed in aqueous solutions, and it was also confirmed that they were maintained well without any problems of physical or chemical stability. The dissolution profiles of olaparib were significantly improved compared to the value of powder. Associated with the high dissolutions of olaparib, the pharmacokinetic parameters were also greatly improved. Taken together with the results mentioned above, the microemulsion could be an effective tool as a formulation for olaparib and other similar drugs.

Recent Advances in Intranasal Liposomes for Drug, Gene, and Vaccine Delivery.

Liposomes are safe, biocompatible, and biodegradable spherical nanosized vesicles produced from cholesterol and phospholipids. Recently, liposomes have been widely administered intranasally for systemic and brain delivery. From the nasal cavity, liposome-encapsulated drugs and genes enter the systemic circulation primarily via absorption in the respiratory region, whereas they can be directly transported to the brain via the olfactory pathway. Liposomes can protect drugs and genes from enzymatic degradation, increase drug absorption across the nasal epithelium, and prolong the residence time in the nasal cavity. Intranasal liposomes are also a potential approach for vaccine delivery. Liposomes can be used as a platform to load antigens and as vaccine adjuvants to induce a robust immune response. With the recent interest in intranasal liposome formulations, this review discusses various aspects of liposomes that make them suitable for intranasal administration. We have summarized the latest advancements and applications of liposomes and evaluated their performance in the systemic and brain delivery of drugs and genes administered intranasally. We have also reviewed recent advances in intranasal liposome vaccine development and proposed perspectives on the future of intranasal liposomes.

Inhibitory effect of 20(S)-protopanaxadiol on cytochrome P450: Potential of its pharmacokinetic interactions in vivo.

20(S)-Protopanaxadiol [20(S)-PPD] is a fully deglycosylated ginsenoside metabolite produced by the gut microbiota in the gastrointestinal tract. Although diverse pharmacological effects have been reported, information on the pharmacokinetic interactions of 20(S)-PPD with cytochrome P450s (CYPs) remains limited. Therefore, the inhibitory potential of 20(S)-PPD on CYP enzymes, which mainly contribute to drug pharmacokinetics, was investigated in this study. The inhibitory effect of 20(S)-PPD was strong for CYP3A4 and moderate for CYP2B6 in human liver microsomes. 20(S)-PPD inhibited Cyp3a and Cyp2b in mouse liver microsomes with a potency similar to that in humans. The solubility of 20(S)-PPD in the artificial intestinal fluid was close to IC50 values of Cyp3a and Cyp2b in the mouse intestine. Systemic exposure to buspirone (Cyp3a specific substrate) and bupropion (Cyp2b specific substrate) increased significantly, whereas the area under the plasma concentration-time curve (AUC) ratio of metabolite to parent drug decreased significantly when co-administered with 20(S)-PPD in mice. The pharmacokinetics of felodipine, a widely used anti-hypertensive agent metabolized mainly by Cyp3a, was also altered following 20(S)-PPD treatment in mice. In conclusion, 20(S)-PPD likely affects the in vivo metabolism of CYP3A4 or CYP2B6 substrates, suggesting a need for careful attention when concomitantly administering 20(S)-PPD with other medications. This study will broaden our understanding of ginseng and products containing precursor ginsenosides of 20(S)-PPD for safer and more efficient use in humans.

Development of an LC-MS/MS Method for ARV-110, a PROTAC Molecule, and Applications to Pharmacokinetic Studies.

ARV-110, a novel proteolysis-targeting chimera (PROTAC), has been reported to show satisfactory safety and tolerability for prostate cancer therapy in phase I clinical trials. However, there is a lack of bioanalytical assays for ARV-110 determination in biological samples. In this study, we developed and validated an LC-MS/MS method for the quantitation of ARV-110 in rat and mouse plasma and applied it to pharmacokinetic studies. ARV-110 and pomalidomide (internal standard) were extracted from the plasma samples using the protein precipitation method. Sample separation was performed using a C18 column and a mobile phase of 0.1% formic acid in distilled water-0.1% formic acid in acetonitrile (30:70, v/v). Multiple reaction monitoring was used to quantify ARV-110 and pomalidomide with ion transitions at m/z 813.4 → 452.2 and 273.8 → 201.0, respectively. The developed method showed good linearity in the concentration range of 2-3000 ng/mL with acceptable accuracy, precision, matrix effect, process efficiency, and recovery. ARV-110 was stable in rat and mouse plasma under long-term storage, three freeze-thaw cycles, and in an autosampler, but unstable at room temperature and 37 °C. Furthermore, the elimination of ARV-110 via phase 1 metabolism in rat, mouse, and human hepatic microsomes was shown to be unlikely. Application of the developed method to pharmacokinetic studies revealed that the oral bioavailability of ARV-110 in rats and mice was moderate (23.83% and 37.89%, respectively). These pharmacokinetic findings are beneficial for future preclinical and clinical studies of ARV-110 and/or other PROTACs.

Pharmacokinetics and Pharmacodynamics of Intranasal Solid Lipid Nanoparticles and Nanostructured Lipid Carriers for Nose-to-Brain Delivery.

Nose-to-brain drug delivery has been of great interest for the treatment of many central nervous system (CNS) diseases and psychiatric disorders over past decades. Several nasally administered formulations have been developed to circumvent the blood-brain barrier and directly deliver drugs to the CNS through the olfactory and trigeminal pathways. However, the nasal mucosa's drug absorption is insufficient and the volume of the nasal cavity is small, which, in combination, make nose-to-brain drug delivery challenging. These problems could be minimized using formulations based on solid lipid nanoparticles (SLNs) or nanostructured lipid carriers (NLCs), which are effective nose-to-brain drug delivery systems that improve drug bioavailability by increasing drug solubility and permeation, extending drug action, and reducing enzymatic degradation. Various research groups have reported in vivo pharmacokinetics and pharmacodynamics of SLNs and NLCs nose-to-brain delivery systems. This review was undertaken to provide an overview of these studies and highlight research performed on SLN and NLC-based formulations aimed at improving the treatment of CNS diseases such neurodegenerative diseases, epilepsy, and schizophrenia. We discuss the efficacies and brain targeting efficiencies of these formulations based on considerations of their pharmacokinetic parameters and toxicities, point out some gaps in current knowledge, and propose future developmental targets.

Effects of 1α,25-dihydroxyvitamin D3 on the pharmacokinetics and biodistribution of ergothioneine, an endogenous organic cation/carnitine transporter 1 substrate, in rats.

Purpose: This study aimed to investigate the effects of 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) on the expression levels of organic cation/carnitine transporter 1 (OCTN1) as well as the pharmacokinetics and biodistribution of ergothioneine, an OCTN1 substrate, in rats. Methods: Rats pretreated with 1,25(OH)2D3 (2.56 nmol/kg/day) for four days were administered ergothioneine (2 mg/kg) intravenously. The expression levels of rat OCTN1 (rOCTN1) in organs were determined using real-time quantitative polymerase chain reaction. Ergothioneine levels in plasma, urine, and organs (with and without intravenous injection of exogenous ergothioneine) were determined using liquid chromatography-tandem mass spectrometry. Results: 1,25(OH)2D3 pretreatment resulted in a significant decrease in rOCTN1 mRNA expression levels in the kidney and brain, a significant increase in basal plasma levels of ergothioneine (from 48 h), and a significant decrease in the tissue-plasma partition coefficient (Kp) in all tissues (except the heart and lungs) and the basal urine levels of ergothioneine. After intravenous administration, the pharmacokinetic profiles of ergothioneine were consistent with the basal levels of endogenous ergothioneine, with an increase in AUC∞ by 85%, a significant decrease in total clearance by 49%, and a decrease in Vss by 32% in 1,25(OH)2D3-treated rats. The Kp value and urinary recovery of ergothioneine also decreased in the 1,25(OH)2D3-treated group. Conclusion: This study showed the effects of 1,25(OH)2D3 on the expression and function of rOCTN1 by investigating the interaction between 1,25(OH)2D3 and ergothioneine. Dose adjustment and possible changes in bioavailability should be considered before the co-administration of vitamin D or its active forms and OCTN1 substrates. Supplementary Information: The online version contains supplementary material available at 10.1007/s40005-022-00563-1.

Pharmaceutical Formulations with P-Glycoprotein Inhibitory Effect as Promising Approaches for Enhancing Oral Drug Absorption and Bioavailability.

P-glycoprotein (P-gp) is crucial in the active transport of various substrates with diverse structures out of cells, resulting in poor intestinal permeation and limited bioavailability following oral administration. P-gp inhibitors, including small molecule drugs, natural constituents, and pharmaceutically inert excipients, have been exploited to overcome P-gp efflux and enhance the oral absorption and bioavailability of many P-gp substrates. The co-administration of small molecule P-gp inhibitors with P-gp substrates can result in drug-drug interactions and increased side effects due to the pharmacological activity of these molecules. On the other hand, pharmaceutically inert excipients, including polymers, surfactants, and lipid-based excipients, are safe, pharmaceutically acceptable, and are not absorbed from the gut. Notably, they can be incorporated in pharmaceutical formulations to enhance drug solubility, absorption, and bioavailability due to the formulation itself and the P-gp inhibitory effects of the excipients. Different formulations with inherent P-gp inhibitory activity have been developed. These include micelles, emulsions, liposomes, solid lipid nanoparticles, polymeric nanoparticles, microspheres, dendrimers, and solid dispersions. They can bypass P-gp by different mechanisms related to their properties. In this review, we briefly introduce P-gp and P-gp inhibitors, and we extensively summarize the current development of oral drug delivery systems that can bypass and inhibit P-gp to improve the oral absorption and bioavailability of P-gp substrates. Since many drugs are limited by P-gp-mediated efflux, this review is helpful for designing suitable formulations of P-gp substrates to enhance their oral absorption and bioavailability.

Synthesis and anti-diabetic activity of novel biphenylsulfonamides as glucagon receptor antagonists.

Type 2 diabetes is characterized by chronic hyperglycemia. Insulin, a hormone secreted from pancreatic ß-cells, decreases blood glucose levels, and glucagon, a hormone secreted from pancreatic α-cells, increases blood glucose levels by counterregulation of insulin through stimulation of hepatic glucose production. In diabetic patients, dysregulation of glucagon secretion contributes to hyperglycemia. Thus, inhibition of the glucagon receptor is one strategy for the treatment of hyperglycemia in type 2 diabetes. In this paper, we report a series of biphenylsulfonamide derivatives that were designed, synthesized, and then evaluated by cAMP and hepatic glucose production assays as glucagon receptor antagonists. Of these, compound 7aB-3 decreased glucagon-induced cAMP production and glucagon-induced glucose production in the in vitro assays. Glucagon challenge tests and glucose tolerance tests showed that compound 7aB-3 significantly inhibited glucagon-induced glucose increases and improved glucose tolerance. These results suggest that compound 7aB-3 has therapeutic potential for the treatment of type 2 diabetes.

Development and Validation of a Bioanalytical LC-MS/MS Method for Simultaneous Determination of Sirolimus in Porcine Whole Blood and Lung Tissue and Pharmacokinetic Application with Coronary Stents.

Sirolimus is a hydrophobic macrolide compound that has been used for long-term immunosuppressive therapy, prevention of restenosis, and treatment of lymphangioleiomyomatosis. In this study, a simple and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) was developed and validated for the simultaneous determination of sirolimus in both porcine whole blood and lung tissue. Blood and lung tissue homogenates were deproteinized with acetonitrile and injected into the LC-MS/MS system for analysis using the positive electrospray ionization mode. The drug was separated on a C18 reversed phase column with a gradient mobile phase (ammonium formate buffer (5 mM) with 0.1% formic acid and acetonitrile) at 0.2 mL/min. The selected reaction monitoring transitions of m/z 931.5 → 864.4 and m/z 809.5 → 756.5 were applied for sirolimus and ascomycin (the internal standard, IS), respectively. The method was selective and linear over a concentration range of 0.5-50 ng/mL. The method was validated for sensitivity, accuracy, precision, extraction recovery, matrix effect, and stability in porcine whole blood and lung tissue homogenates, and all values were within acceptable ranges. The method was applied to a pharmacokinetic study to quantitate sirolimus levels in porcine blood and its distribution in lung tissue following the application of stents in the porcine coronary arteries. It enabled the quantification of sirolimus concentration until 2 and 14 days in blood and in lung tissue, respectively. This method would be appropriate for both routine porcine pharmacokinetic and bio-distribution studies of sirolimus formulations.

Preparation of Solid Lipid Nanoparticles and Nanostructured Lipid Carriers for Drug Delivery and the Effects of Preparation Parameters of Solvent Injection Method.

Solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) have emerged as potential drug delivery systems for various applications that are produced from physiological, biodegradable, and biocompatible lipids. The methods used to produce SLNs and NLCs have been well investigated and reviewed, but solvent injection method provides an alternative means of preparing these drug carriers. The advantages of solvent injection method include a fast production process, easiness of handling, and applicability in many laboratories without requirement of complicated instruments. The effects of formulations and process parameters of this method on the characteristics of the produced SLNs and NLCs have been investigated in several studies. This review describes the methods currently used to prepare SLNs and NLCs with focus on solvent injection method. We summarize recent development in SLNs and NLCs production using this technique. In addition, the effects of solvent injection process parameters on SLNs and NLCs characteristics are discussed.

Development of 20(S)-Protopanaxadiol-Loaded SNEDDS Preconcentrate Using Comprehensive Phase Diagram for the Enhanced Dissolution and Oral Bioavailability.

In this study, we aimed to develop a 20(S)-protopanaxadiol (PPD)-loaded self-nanoemulsifying drug delivery system (SNEDDS) preconcentrate (PSP) using comprehensive ternary phase diagrams for enhanced solubility, physical stability, dissolution, and bioavailability. Capmul MCM C8 and Capryol 90 were selected as the oil phase owing to the high solubility of PPD in these vehicles (>15%, w/w). Novel comprehensive ternary phase diagrams composed of selected oil, surfactant, and PPD were constructed, and the solubility of PPD and particle size of vehicle was indicated on them for the effective determination of PSP. PSPs were confirmed via particle size distribution, physical stability, and scanning electron microscope (SEM) with the dispersion of water. The optimized PSP (CAPRYOL90/Kolliphor EL/PPD = 54/36/10, weight%) obtained from the six possible comprehensive ternary phase diagrams showed a uniform nanoemulsion with the particle size of 125.07 ± 12.56 nm without any PPD precipitation. The PSP showed a dissolution rate of 94.69 ± 2.51% in 60 min at pH 1.2, whereas raw PPD showed negligible dissolution. In oral pharmacokinetic studies, the PSP group showed significantly higher Cmax and AUCinf values (by 1.94- and 1.81-fold, respectively) than the raw PPD group (p < 0.05). In conclusion, the PSP formulation with outstanding solubilization, dissolution, and in-vivo oral bioavailability could be suggested using effective and comprehensive ternary phase diagrams.

Determination of KD025 (SLx-2119), a Selective ROCK2 Inhibitor, in Rat Plasma by High-Performance Liquid Chromatography-Tandem Mass Spectrometry and its Pharmacokinetic Application.

KD025 (SLx-2119), the first specific Rho-associated protein kinase 2 (ROCK2) inhibitor, is a potential new drug candidate currently undergoing several phase 2 clinical trials for psoriasis, idiopathic pulmonary fibrosis, chronic graft-versus-host disease, and systemic sclerosis. In this study, a bio-analytical method was developed and fully validated for the quantification of KD025 in rat plasma and for application in pharmacokinetic studies. KD025 and GSK429286A (the internal standard) in rat plasma samples were analyzed by high-performance liquid chromatography-tandem mass spectrometry with m/z transition values of 453.10 → 366.10 and 433.00 → 178.00, respectively. The method was fully validated according to the United State Food and Drug Administration guidelines in terms of selectivity, linearity, accuracy, precision, sensitivity, matrix effects, extraction recovery, and stability. The method enabled the quantification of KD025 levels in rat plasma following oral administration of 5 mg/kg KD025 and intravenous administration of 2 mg/kg KD025 to rats, respectively. Our findings suggest that the developed method is practical and reliable for pharmacokinetic studies of KD025 in preclinical animals.

Preparation of an oil suspension containing ondansetron hydrochloride as a sustained release parenteral formulation.

Ondansetron hydrochloride (ODS) is a selective 5-hydroxytryptamine type 3 antagonist for nausea and emesis prevention in neoplastic patients. To reduce dosing frequency and side effects and improve patient compliance, a sustained release parenteral formulation of ODS was developed. Microparticles of methylcellulose (MC) and ODS were prepared using the spray-drying method and suspended in oils to form oil suspensions. The formulations were evaluated for residual moisture, drug content, size distribution, DSC, XRD, FTIR, SEM, drug release, and pharmacokinetic studies. The effects of polymers and oils on the drug release were evaluated. MC showed the most prominent sustained release effect among various polymers examined with the optimum MC/ODS ratio of 2:1 (w/w). The particle size of the produced microparticles was in the mean diameter of approximately 3 µm. Physicochemical characterization suggested that ODS existed in an amorphous matrix within the microparticles and interacted with MC via hydrogen bonds. Corn oil was selected as the appropriate oil for suspension due to the sustained release of ODS and the appropriate viscosity. The optimized sustained release formulation of ODS was the corn oil suspension of spray-dried microparticles containing MC and ODS (2:1, w/w). It showed an in vitro drug sustained release up to 120 h, while the oil suspension of ODS without any polymer released the drug within 2 h. Following subcutaneous administration in rats, the optimized formulation could prolong the drug release until 72 h with the enhanced bioavailability in comparison with the ODS solution. The oil suspension of spray-dried microparticles might be an efficient approach for prolongation of the drug effect in the management of nausea and emesis. Graphical abstract.

Data on optimization and drug release kinetics of nanostructured lipid carriers containing ondansetron hydrochloride prepared by cold high-pressure homogenization method.

Nanostructured lipid carriers (NLCs), the second generation of lipid nanoparticles could enhance the drug loading capacity and minimize the drug expulsion during storage [1,2]. They are prepared from mixtures of solid and liquid lipids [3,4]. The article described the data for the preparation, optimization, and drug release studies of NLCs loaded with ondansetron hydrochloride (OSH), a water-soluble drug. The OSH-loaded NLCs were prepared using a modified cold high-pressure homogenization method. The NLCs were optimized for various parameters of formulation and preparation process on the basis of particle size (PS), polydispersity index (PI), entrapment efficiency (EE), and drug loading (DL). The dataset presented here supports "Nanostructured lipid carriers containing ondansetron hydrochloride by cold high-pressure homogenization method: Preparation, characterization, and pharmacokinetic evaluation" [5].

Preparation of Ondansetron Hydrochloride-Loaded Nanostructured Lipid Carriers Using Solvent Injection Method for Enhancement of Pharmacokinetic Properties.

PURPOSE: This study aimed to incorporate ondansetron hydrochloride (ODS), a water-soluble drug into nanostructured lipid carriers (NLCs) to improve the pharmacokinetic properties of the drug. METHODS: NLCs were produced by solvent injection method. Various parameters of formulation and process were assessed to enhance the drug incorporation into NLCs. Physicochemical analyses, in vitro drug release, and pharmacokinetic studies were performed. RESULTS: Entrapment efficiency (EE) of ODS was considerably improved (>90%) by increasing pH of the aqueous phase. The use of an appropriate level of liquid lipid resulted in small, monodispersed NLCs with the enhanced EE and drug loading (DL). The optimized NLCs formulation exhibited particle size of 185.2 ± 1.9 nm, polydispersity index of 0.214 ± 0.006, EE of 93.2 ± 0.5%, and DL of 10.43 ± 0.05% as well as an in vitro sustained-release profile of ODS. Differential scanning calorimetry and X-ray powder diffraction suggested the amorphous state of ODS in the NLCs. The pharmacokinetic study in rats exhibited the sustained-release characteristic of the optimized ODS-loaded NLCs following subcutaneous administration with an extended Tmax and mean residence time as well as the enhanced systemic exposure compared to the ODS solution. CONCLUSIONS: The ODS-loaded NLCs appear potential for prolongation of drug action and reduction in dosing frequency.