Examination of Effective Buccal Absorption of Salmon Calcitonin Using Cell-Penetrating Peptide-Conjugated Liposomal Drug Delivery System.

INTRODUCTION: The buccal route has been considered an attractive alternative delivery route for injectable formulations. Cell-penetrating peptides (CPPs) are gaining increased attention for their cellular uptake and tissue permeation effects. This study was aimed to evaluate the in vitro and ex vivo permeation-enhancing effect of penetratin-conjugated liposomes for salmon calcitonin (sCT) in TR146 human buccal cells and porcine buccal tissues. METHODS: Penetratin was conjugated to phospholipids through a maleimide-thiol reaction. Liposomes were prepared and sCT was encapsulated using a thin-film hydration method. Physical properties such as particle size, zeta potential, encapsulation efficiency, and morphological images via transmission electron microscopy were obtained. Cellular uptake studies were conducted using flow cytometry (FACS) and confocal laser scanning microscopy (CLSM). A cell permeation study was performed using a Transwell® assay, and permeation through porcine buccal tissue was evaluated. The amount of sCT permeated was quantified using an ELISA kit and was optically observed using CLSM. RESULTS: The particle size of penetratin-conjugated liposomes was approximately 123.0 nm, their zeta potential was +29.6 mV, and their calcitonin encapsulation efficiency was 18.0%. In the cellular uptake study using FACS and CLSM, stronger fluorescence was observed in penetratin-conjugated liposomes compared with the solution containing free sCT and control liposomes. Likewise, the amount of sCT permeated from penetratin-conjugated liposomes was higher than that from the free sCT solution and control liposomes by 5.8-fold across TR146 cells and 91.5-fold across porcine buccal tissues. CONCLUSION: Penetratin-conjugated liposomes are considered a good drug delivery strategy for sCT via the buccal route.

Dose Number as a Tool to Guide Lead Optimization for Orally Bioavailable Compounds in Drug Discovery.

Small molecule developability challenges have been well documented over the last two decades. One of these critical developability parameters is aqueous solubility. In general, more soluble compounds have improved oral absorption. While enabling formulation technologies exist to improve bioperformance for low solubility compounds, these are often more complex, expensive, and challenging to scale up. Therefore, to avoid these development issues, medicinal chemists need tools to rapidly profile and improve the physicochemical properties of molecules during discovery. Dose number (Do) is a simple metric to predict whether a compound will be reasonably absorbed based on solubility at an expected clinical dose and represents a valuable parameter to the medicinal chemist defining a clinical candidate. The goal of this mini-Perspective is to present the background of the Do equation and how it can be effectively used to rapidly predict oral absorption potential for molecules in the discovery space.

The pH of Smokeless Tobacco Determines Nicotine Buccal Absorption: Results of a Randomized Crossover Trial.

Nicotine absorption rate influences tobacco products' addictiveness. For smokeless tobacco, nicotine buccal absorption is associated with its free-base form; the pH of smokeless tobacco defines the proportion of free-base (i.e., unprotonated) vs. protonated nicotine. This was the first study to compare nicotine pharmacokinetics (PK) and pharmacodynamics (PD) after the use of commercial smokeless tobacco products that were experimentally manipulated to differ only in pH and percent free-base nicotine. Moist snuff users (N = 40) completed four crossover visits and used a single 2 g portion of Copenhagen Original Long Cut amended to 4 pH levels: 5.0, 7.7, 8.2, and 8.6 (free-base nicotine 0.1, 32, 60, and 79%) for 30 minutes. Nicotine PK and PD were assessed for 4 hours post-use. Nicotine PK substantially depends on its free-base proportion, with more than 4-fold increases in mean plasma nicotine maximum concentration and area under the curve over 240 minutes (3.9 to 16.7 ng/mL; 385 to 1810 ng min/mL, respectively, both P < 0.001) from pH 5.0 to 8.6. The autonomic cardiovascular effects of smokeless tobacco use reflected percent free-base nicotine, with small (albeit significant) systematic increases in heart rate and blood pressure associated with free-base nicotine. Smokeless tobacco product pH and percent free-base nicotine play a major role in the rate and extent of nicotine absorption, determining product PD effects and abuse potential. Research and regulation of smokeless tobacco products should consider both total nicotine content and product pH. Further research may address the impact of modifying pH on the addictiveness of smokeless tobacco and associated use behaviors.

Physiologically-Based Pharmacokinetic Modeling to Investigate the Effect of Maturation on Buprenorphine Pharmacokinetics in Newborns with Neonatal Opioid Withdrawal Syndrome.

Neonatal opioid withdrawal syndrome (NOWS) is a major public health concern whose incidence has paralleled the opioid epidemic in the United States. Sublingual buprenorphine is an emerging treatment for NOWS, but given concerns about long-term adverse effects of perinatal opioid exposure, precision dosing of buprenorphine is needed. Buprenorphine pharmacokinetics (PK) in newborns, however, is highly variable. To evaluate underlying sources of PK variability, a neonatal physiologically-based pharmacokinetic (PBPK) model of sublingual buprenorphine was developed using Simcyp (version 19.1). The PBPK model included metabolism by cytochrome P450 (CYP) 3A4, CYP2C8, UDP-glucuronosyltransferase (UGT) 1A1, UGT1A3, UGT2B7, and UGT2B17, with additional biliary excretion. Maturation of metabolizing enzymes was incorporated, and default CYP2C8 and UGT2B7 ontogeny profiles were updated according to recent literature. A biliary clearance developmental profile was outlined using clinical data from neonates receiving sublingual buprenorphine as NOWS treatment. Extensive PBPK model validation in adults demonstrated good predictability, with geometric mean (95% confidence interval (CI)) predicted/observed ratios (P/O ratios) of area under the curve from zero to infinity (AUC0-∞ ), peak concentration (Cmax ), and time to reach peak concentration (Tmax ) equaling 1.00 (0.74-1.33), 1.04 (0.84-1.29), and 0.95 (0.72-1.26), respectively. In neonates, the geometric mean (95% CI) P/O ratio of whole blood concentrations was 0.75 (95% CI 0.64-0.87). PBPK modeling and simulation demonstrated that variability in biliary clearance, sublingual absorption, and CYP3A4 abundance are likely important drivers of buprenorphine PK variability in neonates. The PBPK model could be used to guide development of improved buprenorphine starting dose regimens for the treatment of NOWS.

Predictivity of standardized and controlled permeation studies: Ex vivo - In vitro - In vivo correlation for sublingual absorption of propranolol.

In preclinical drug development, ex vivo and in vitro permeability studies are a decisive element for specifying subsequent development steps. In this context, reliability, physiological alignment and appropriate in vivo correlation are mandatory for predictivity regarding drug absorption. Especially in oromucosal drug delivery, these prerequisites are not adequately met, which hinders its progressive development and results in the continuous need for animal experiments. To address current limitations, an innovative, standardized, and controlled ex vivo permeation model was applied. It is based on Kerski diffusion cells embedded in automated sampling and coupled to mass spectrometric quantification under physiologically relevant conditions. This study aimed to evaluate the predictivity of the developed model using porcine mucosa (ex vivo) in relation to data of sublingual propranolol absorption (in vivo). In addition, the usefulness of biomimetic barriers (in vitro) as a replacement for porcine mucosa was investigated. Therefore, solubility and permeability studies considering microenvironmental conditions were conducted and achieved good predictivity (R2 = 0.997) for pH-dependent permeability. A multiple level C correlation (R2 ≥ 0.860) between obtained permeability and reported pharmacokinetic animal data (AUC, Cmax) was revealed. Furthermore, a point-to-point correlation was demonstrated for several sublingual formulations. The successful IVIVC confirms the standardized ex vivo model as a viable alternative to animal testing for estimating the in vivo absorption behavior of oromucosal pharmaceuticals.

Population pharmacokinetic analysis of apomorphine sublingual film or subcutaneous apomorphine in healthy subjects and patients with Parkinson's disease.

Apomorphine is an on-demand treatment of "OFF" episodes in patients with Parkinson's disease (PD). A joint parent-metabolite population pharmacokinetic (PK) model characterized apomorphine and apomorphine-sulfate following administration of apomorphine sublingual film (APL) and two formulations of subcutaneous apomorphine. Overall, 2485 samples from 87 healthy subjects and 71 patients with PD and "OFF" episodes were analyzed using nonlinear mixed-effects modeling. Apomorphine PK was adequately described by a two-compartment model with first-order transit absorption via both routes of administration and first-order metabolism to apomorphine-sulfate with one-compartment disposition and first-order elimination. Bioavailability of apomorphine sublingual film was ~ 18% relative to subcutaneous apomorphine. Among covariates tested, only body weight had a large effect on apomorphine exposure (maximum plasma concentration and area under the concentration-time curve [AUC0-∞ ]), with greater weight resulting in lower exposure. Model-predicted apomorphine exposure was similar between apomorphine sublingual film 30 mg and subcutaneous apomorphine 5 mg (median AUC0-24 , 66.7 ng•h/mL, geometric mean ratio of 0.99; 90% confidence interval [CI], 0.96-1.03) and was comparable between apomorphine sublingual film 35 mg and subcutaneous apomorphine 6 mg (median AUC0-24 , 75.4 and 80.0 ng•h/mL, respectively; geometric mean ratio of 0.94; 90% CI, 0.90-0.97) administered every 2 h for a maximum of 5 doses per day. In a typical patient with PD, predicted apomorphine exposure increased with increasing doses of apomorphine sublingual film; however, the increase was less than dose proportional. Similar apomorphine exposure was predicted in patients with mild renal impairment versus normal renal function. PK properties of apomorphine sublingual film support its administration for a wide range of patients with PD and "OFF" episodes, regardless of demographic and clinical characteristics.

Pharmacokinetics and Pharmacodynamics of 3 Doses of Oral-Mucosal Dexmedetomidine Gel for Sedative Premedication in Women Undergoing Modified Radical Mastectomy for Breast Cancer.

BACKGROUND: Buccal dexmedetomidine (DEX) produces adequate preoperative sedation and anxiolysis when used as a premedication. Formulating the drug as a gel decreases oral losses and improves the absorption of buccal DEX. We compared pharmacokinetic and pharmacodynamic properties of 3 doses of buccal DEX gel formulated in our pharmaceutical laboratory for sedative premedication in women undergoing modified radical mastectomy for breast cancer. METHODS: Thirty-six patients enrolled in 3 groups (n = 12) to receive buccal DEX gel 30 minutes before surgery at 0.5 µg/kg (DEX 0.5 group), 0.75 µg/kg (DEX 0.75 group), or 1 µg/kg (DEX 1 group). Assessments included plasma concentrations of DEX, and pharmacokinetic variables calculated with noncompartmental methods, sedative, hemodynamic and analgesic effects, and adverse effects. RESULTS: The median time to reach peak serum concentration of DEX (Tmax) was significantly shorter in patients who received 1 µg/kg (60 minutes) compared with those who received 0.5 µg/kg (120 minutes; P = .003) and 0.75 µg/kg (120 minutes; P = .004). The median (first quartile-third quartile) peak concentration of DEX (maximum plasma concentration [Cmax]) in plasma was 0.35 ng/mL (0.31-0.49), 0.37 ng/mL (0.34-0.40), and 0.54 ng/mL (0.45-0.61) in DEX 0.5, DEX 0.75, and DEX 1 groups (P = .082). The 3 doses did not produce preoperative sedation. The 1 µg/kg buccal DEX gel produced early postoperative sedation and lower intraoperative and postoperative heart rate values. Postoperative analgesia was evident in the 3 doses in a dose-dependent manner with no adverse effects. CONCLUSIONS: Provided that it is administered 60-120 minutes before surgery, sublingual administration of DEX formulated as an oral-mucosal gel may provide a safe and practical means of sedative premedication in adults.

A Physiologically Based Pharmacokinetic Model of Vismodegib: Deconvoluting the Impact of Saturable Plasma Protein Binding, pH-Dependent Solubility and Nonsink Permeation.

Vismodegib displays unique pharmacokinetic characteristics including saturable plasma protein binding to alpha-1 acid glycoprotein (AAG) and apparent time-dependent bioavailability leading to non-linear PK with dose and time, significantly faster time to steady-state and lower than predicted accumulation. Given these unique characteristics, a PBPK model was developed to explore mechanistic insights into saturable protein binding and complex oral absorption processes and de-convolute the impact of these independent non-linear processes on vismodegib exposure. Simcyp V18 was used for model development; oral absorption was characterized using the multi-layer gut wall (M-ADAM) model and mechanistic permeability model, incorporating transport across an unstirred boundary layer (UBL) between the luminal fluid and enterocyte in each segment of the gastrointestinal tract. PBPK simulations were compared with observed PK data from clinical trials in oncology patients and healthy subjects. Saturation of vismodegib protein binding to AAG led to substantially lower total drug accumulation, time to steady-state, and Csstotal. For free exposure, Cssfree and accumulation were unchanged, but time to steady-state was substantially reduced. Vismodegib oral absorption declined with both dose and dosing frequency; the concentration gradient driving vismodegib oral absorption declined with multiple doses, leading to a 32% decrease in vismodegib fa from first dose to steady-state. Fed simulations suggested that increased solubility and dissolution are partially offset by reduced permeability across the UBL due to slower diffusion of micelle-bound drug. This work demonstrates the value of PBPK modeling to simultaneously capture and de-convolute multi-faceted absorption and disposition processes and provide mechanistic insights for compounds with complex pharmacokinetics.

Allergen Stability and Immunological Reactivity during Co-dissolution and Incubation of House Dust Mite and Japanese Cedar Pollen SLIT-Tablets.

Japanese allergic subjects are commonly sensitized to both house dust mite (HDM) and Japanese cedar pollen (JCP) and combined treatment with sublingual immunotherapy (SLIT) tablets is desirable. However, mixing extracts of two non-homologous allergens may compromise allergen stability and affect the clinical outcome. Therefore, we investigated the stability of major allergens and total allergenic reactivity of HDM and JCP SLIT-tablets following dissolution in human saliva or artificial gastric juice. Two fast-dissolving freeze-dried SLIT-tablets were completely dissolved and incubated at 37 °C. Major allergen concentrations and total allergenic reactivity were measured. After mixing and co-incubation of HDM and JCP SLIT tablets in human saliva for 10 min at 37°C, there were no statistically significant changes in major allergen concentrations. In addition, no loss of allergenic reactivity of the mixed two SLIT-tablet solutions was seen. In contrast, complete loss of allergenic reactivity and detectable major allergen concentrations occurred when the two SLIT-tablets were dissolved and incubated in artificial gastric juice. These results demonstrate that HDM or JCP major allergens and the total allergenic reactivity of both SLIT-tablets measured here remain intact after dissolution and co-incubation in human saliva, supporting the possibility of a dual HDM and JCP SLIT-tablet administration regimen if clinically indicated. The complete loss of allergenic reactivity after incubation in artificial gastric juice can furthermore be taken to indicate that the immunological activity of the allergen extracts contained in the two SLIT-tablets is likely to be lost or severely compromised upon swallowing.

Factors affecting the buccal delivery of deformable nanovesicles based on insulin-phospholipid complex: an in vivo investigation.

Deformable nanovesicles (DNVs) have been used in the buccal delivery of biomacromolecules due to their ability to enhance drug penetration. However, no breakthroughs have been made until now due to limited understanding of the factors affecting in vivo buccal delivery. In this study, we designed a series of DNVs, based on an insulin-phospholipid complex (IPC-DNVs), to investigate the influence of drug dose, buccal administration methods, and key quality characteristics of IPC-DNVs for buccal delivery. IPC-DNVs showed a non-linear dose-response relationship between 8 and 12 IU. There was no significant effect of drug delivery site (sublingual mucosa/buccal mucosa) or ligation time (15 or 30 min) on buccal absorption of IPC-DNVs. However, the area above the curve of reduction in blood glucose level overtime (AAC0-6h) for oral mucosa administration was significantly higher than that for buccal mucosa administration. Increasing the drug concentration in IPC-DNVs led to a decrease in AAC0-6h. This might be due to local leakage of DNVs, while squeezing through biological barriers with high concentration of insulin, thus hindering the subsequent delivery of DNVs. IPC-DNVs, measuring 80-220 nm in size, did not significantly affect AAC0-6h. However, when the size was increased to approximately 400 nm, AAC0-6h decreased, thus suggesting that IPC-DNVs with reasonable size were more effective. Additionally, increased deformability of IPC-DNVs might cause drugs to leak easily, thus reducing the promoting effect of buccal absorption. Our results clarified the effect of characteristics of IPC-DNVs on buccal delivery in vivo and provided meaningful support for the design of dosage form of DNVs.

Nanotechnology based blended chitosan-pectin hybrid for safe and efficient consolidative antiemetic and neuro-protective effect of meclizine hydrochloride in chemotherapy induced emesis.

The aim of this study was to formulate an easily-administered, safe and effective dosage form loaded with meclizine for treatment of chemotherapy-induced nausea and vomiting (CINV) through the buccal route. CINV comprises bothersome side effects accompanying cytotoxic drugs administration in cancer patients. Meclizine was loaded in chitosan-pectin nanoparticles which were further incorporated within a buccal film. Different formulations were prepared based on a 21.31 full factorial study using Design Expert®8. The optimum formulation possessed favorable characters regarding its particle size (129 nm), entrapment efficiency (90%) and release profile. Moreover, its permeation efficiency through sheep buccal mucosa was assessed via Franz cell diffusion and confocal laser microscopy methods. Enhanced permeation was achieved compared with the free drug form. In-vivo performance was assessed using cyclophosphamide induced emesis. The proposed formulation exerted significant relief of the measured responses (reduced body weight and motor coordination, elevated emesis, anorexia, proinflammatory mediators and neurotransmitters that were also associated with scattered degenerated neurons and glial cells). The developed formulation ameliorated all behavioral, biochemical and histopathological changes induced by cyclophosphamide. The obtained data were promising suggesting that our bioadhesive formulation can offer an auspicious medication for treating distressing symptoms associated with chemotherapy for cancer patients.

How Can Biomolecules Improve Mucoadhesion of Oral Insulin? A Comprehensive Insight using Ex-Vivo, In Silico, and In Vivo Models.

Currently, insulin can only be administered through the subcutaneous route. Due to the flaws associated with this route, it is of interest to orally deliver this drug. However, insulin delivered orally has several barriers to overcome as it is degraded by the stomach's low pH, enzymatic content, and poor absorption in the gastrointestinal tract. Polymers with marine source like chitosan are commonly used in nanotechnology and drug delivery due to their biocompatibility and special features. This work focuses on the preparation and characterization of mucoadhesive insulin-loaded polymeric nanoparticles. Results showed a suitable mean size for oral administration (<600 nm by dynamic laser scattering), spherical shape, encapsulation efficiency (59.8%), and high recovery yield (80.6%). Circular dichroism spectroscopy demonstrated that protein retained its secondary structure after encapsulation. Moreover, the mucoadhesive potential of the nanoparticles was assessed in silico and the results, corroborated with ex-vivo experiments, showed that using chitosan strongly increases mucoadhesion. Besides, in vitro and in vivo safety assessment of the final formulation were performed, showing no toxicity. Lastly, the insulin-loaded nanoparticles were effective in reducing diabetic rats' glycemia. Overall, the coating of insulin-loaded nanoparticles with chitosan represents a potentially safe and promising approach to protect insulin and enhance peroral delivery.

Cell-penetrating peptide enhanced insulin buccal absorption.

Non-injectable delivery of peptides and proteins is not feasible due to the limitations of large molecular mass, high hydrophilic properties, and gastrointestinal degradation. Therefore, proposing a new method to solve this problem is a burning issue. The objective of this study was to propose a novel protein delivery strategy to overcome the poor efficacy and irritation of buccal insulin delivery. In this study, we applied a conjugate of cell-penetrating peptides (LMWP) and insulin (INS-PEG-LMWP) for buccal delivery. INS-PEG-LMWP was prepared using insulin solution and mixture as references. The transport behaviour, in vivo bioactivity, hypoglycaemic effect, and safety of INS-PEG-LMWP were systematically characterised. An in vitro study demonstrated that the uptake and transportation of INS-PEG-LMWP across buccal mucosal multilayers significantly increased. By comparing the effects of different endocytic inhibitors on INS-PEG-LMWP uptake, the conjugate might be delivered via an energy independent, electrostatically adsorbed pathway. INS-PEG-LMWP's relative pharmacological bioavailability was high and its relative bioavailability was up to 26.86%, demonstrating no visible mucosal irritation. Cell-penetrating peptides are likely to become a reliable and safe tool for overcoming insulin's low permeability through the epithelial multilayers, the major barrier to buccal delivery.

The effect of piperine on oral absorption of cannabidiol following acute vs. chronic administration.

Piperine is an alkaloid naturally found in black pepper with a myriad of pharmacological attributes. Piperine's most far reaching indication is drug absorption enhancment, with supportive data regarding its ability to inhibit first pass effect mechanisms. However, alongside these findings, the role of piperine as an absorption enhancer is undermined with publications stating an apparent effect of a metabolic inducer. The aim of this work is to investigate the effect of repeated administration of piperine in a lipid-based formulation ,on oral absorption of cannabidiol (CBD), compared to acute piperine dosing. The effect of piperine on CBD absorption was determined pre-clinically in the freely moving rat model. Results of this work demonstrated that there was no significant difference in piperine's effect, when given chronically or in a single dose regimen. Both groups resulted in approximate 2.5-fold increase in oral bioavailability of CBD compared to control group without piperine.

Estimating Efflux Transporter-Mediated Disposition of Molecules beyond the Rule of Five (bRo5) Using Transporter Gene Knockout Rats.

Transporter gene knockout models are a practical and widely used tool for pharmacokinetic studies in drug discovery. P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp) are major efflux transporters that control absorption and bioavailability, and are important when determining oral drug disposition. To the best of our knowledge, beyond the rule of five (bRo5) molecules launched on the market to date tend to be substrates for efflux transporters. The purpose of this study is to evaluate in vivo the impact of efflux transporters on the oral absorption process and systemic clearance using rats which lack P-gp and/or Bcrp expression. We administered five bRo5 substrates (asunaprevir, cyclosporine, danoprevir, ledipasvir, and simeprevir) intravenously or orally to wild-type and Mdr1a, Bcrp, and Mdr1a/Bcrp knockout rats, calculated the clearance, oral bioavailability, and absorption rate profile of each substrate, and compared the results. Systemic clearance of the substrates in knockout rats changed within approximately ±40% compared to wild-types, suggesting the efflux transporters do not have a significant influence on clearance in rats. On the other hand, the oral absorption of substrates in the knockout rats, especially those lacking Mdr1a, increased greatly-between 2- and 5-fold more than in wild-types. This suggests that rat efflux transporters, especially P-gp, greatly reduce the oral exposure of these substrates. Moreover, results on the absorption rate-time profile suggest that efflux transporters are constantly active during the absorption period in rats. Transporter knockout rats are a useful in vivo tool for estimating the transporter-mediated disposition of bRo5 molecules in drug discovery.

Inflammation, but Not the Underlying Disease or Its Location, Predicts Oral Iron Absorption Capacity in Patients With Inflammatory Bowel Disease.

BACKGROUND AND AIMS: Anaemia is common in patients with inflammatory bowel disease [IBD], its two main aetiologies being iron deficiency anaemia [IDA] and anaemia of chronic inflammation [ACI]. Impaired intestinal iron absorption due to inflammatory cytokines is thought to play a role in ACI. We undertook for the first time a controlled prospective study investigating effects of differing underlying diseases, disease locations, and types of iron deficiency or anaemia on oral iron absorption in adult IBD patients with and without inflammation. METHODS: This study was a comparative, single-centred open clinical trial in adults with IBD [n = 73] and healthy controls [n = 22]. Baseline parameters included blood count, iron status [ferritin, transferrin, transferrin saturation, soluble transferrin receptor, hepcidin, serum iron], high-sensitivity C-reactive protein [hsCRP] and interleukin-6. Iron absorption was tested using one oral, enteric-coated capsule containing 567.7 mg iron[II]-glycine-sulphate complex. Serum iron was determined 60/90/120/180/240 min after ingestion. RESULTS: Iron absorption capacity was shown to be influenced by inflammation and anaemia or iron deficiency [ID] type but not by underlying disease type or localisation. The ACI group showed a significantly lower iron absorption capacity than all others. Whereas hsCRP levels [-0.387, p < 0.001], IL-6 [-0.331, p = 0.006], ferritin [-0.531, p < 0.001], and serum hepcidin [-0.353, p = 0.003] correlated negatively with serum iron change at 2 h, transferrin showed a positive correlation at the same time point [0.379, p < 0.001]. CONCLUSIONS: Underlying disease type and localisation appear to have little effect on iron absorption capacity, whereas lack of response to oral iron correlates well with serum markers of inflammation. Iron absorption capacity is thus significantly reduced in the presence of inflammation.

Characterization of the buccal and gastric transit of orally disintegrating tablets in humans using gamma scintigraphy.

The present study characterized the buccal cavity-emptying and gastric-emptying kinetics of orally disintegrating tablets (ODTs) in fasted humans using gamma scintigraphy. 111Indium-diethylenetriaminepentaacetic acid and technetium-99 m-labeled ion exchange resin were used as a model soluble drug and insoluble pellet-type drug, respectively, and housed in ODTs. These ODTs were then administered to human subjects with or without ingestion of water, after which scintigraphic images were collected in order to characterize the buccal and gastric transit of the radioactivity. The oral disintegration of the ODTs was extremely rapid, with a mean time of ≤1 min. The buccal emptying of the radioactivity was most rapid for the ODT with a water-soluble radiolabel; however, the ODTs with water-insoluble radiolabels showed buccal emptying with median half-times of ≤2.5 min. The ODT with the soluble radiolabel in subjects without water ingestion showed the most rapid gastric emptying compared with the ODTs with the insoluble radiolabels, the gastric-emptying time of which was highly variable. Further, water ingestion did not markedly affect the gastric-emptying time of the tablets with the water-soluble model drug. The observations in the present clinical study will help clarify the in vivo performance of ODTs in humans.

Self-assembled liposome from core-sheath chitosan-based fibres for buccal delivery of carvedilol: formulation, characterization and in vitro and ex vivo buccal absorption.

OBJECTIVES: A novel drug delivery system based on self-assembled liposome from core-sheath nanofibres for buccal delivery of Carvedilol (Car) was explored. METHODS: The Car-loaded PVP/PC (phospholipids) layer was coated with chitosan-PVA (CS-PVA) or CS-PVP to increase retention period in the mouth. SEM, confocal laser scanning microscopy (CLSM), XRD and Fourier transform infrared spectroscopy were applied to characterize fibre diameter and drug state. Appearance, particle size and encapsulation efficiency of self-assembled liposome were investigated by transmission electron microscopy (TEM) and Zeta-sizer Nano. The dissolution test and permeation tests across porcine buccal mucosa and TR146 cell model also were run. KEY FINDINGS: Confocal laser scanning microscopy and XRD confirmed the core-sheath structure of coaxial fibre and non-crystalline form of Car, separately. TEM demonstrated the sphere morphology of self-assembled liposome from spun fibres after contacting water. The dissolution test implied the ratio of PC to Car had a huge impact on drug release. The permeation tests across porcine buccal mucosa and TR146 cell model showed similar result, namely our formulation having a better permeation performance than Car suspension. The indirect toxicity against TR146 cells presented 5 mg/ml (or lower) of fibre extraction was safe for cells. CONCLUSIONS: These researches exhibited this drug delivery system was promising and advantageous for Car buccal delivery.

Intestinal oligopeptide transporter PepT1-targeted polymeric micelles for further enhancing the oral absorption of water-insoluble agents.

The intestinal epithelium is the main barrier for nanocarriers to orally deliver poorly water-soluble and absorbed agents. To further improve the transmembrane transport efficiency of polymeric micelles, intestinal oligopeptide transporter PepT1-targeted polymeric micelles were fabricated by Gly-Sar-conjugated poly(ethylene glycol)-poly(d,l-lactic acid). The functionalized polymeric micelles with about 40 nm diameter, uniform spherical morphology and favorable cytocompatibility with Caco-2 cells were demonstrated to distinctly enhance the cellular uptake and transmembrane transport of the loaded agents. The results of intestinal absorption strongly evidenced the higher accumulation of the micelles inside the epithelial cells, at the apical and basolateral sides of the epithelium within the villi in mice. Furthermore, the interaction of Gly-Sar decorated polymeric micelles with PepT1 was explored to promote the internalization of the micelles through fluorescence immunoassay, and the PepT1 level on the membrane of Caco-2 cells treated with the micelles appeared to change in a distinctly time-dependent manner. Both clathrin- and caveolae-mediated pathways were involved in the transcellular transport for undecorated polymeric micelles, while the transcellular transport pathway for Gly-Sar decorated ones was changed to be mainly mediated by clathrin and lipid rafts. The colocalization of Gly-Sar decorated micelles with the organelles observed by confocal laser scanning microscopy indicated that late endosomes, lysosomes, endoplasmic reticulum and Golgi apparatus appeared to participate in the intracellular trafficking progression of the micelles. These results suggested that PepT1-targeted polymeric micelles might have a strong potential to greatly promote the oral absorption of poorly water-soluble and absorbed agents.

Justification of Biowaiver and Dissolution Rate Specifications for Piroxicam Immediate Release Products Based on Physiologically Based Pharmacokinetic Modeling: An In-Depth Analysis.

A quantitative prediction of human pharmacokinetic (PK) profiles has become an increasing demand for the reduction of the clinical failure of drug formulations. The existing in vitro and in vivo correlation (IVIVC) methodology could achieve this goal, but the development of IVIVC for immediate release (IR) products is challenging. Herein, we report that for certain weakly acidic biopharmaceutical classification system (BCS) class II molecules (piroxicam, PIRO), physiologically based PK (PBPK) modeling could be used as a tool to quantitatively predict PK in beagle dogs and to conduct an interspecies extrapolation to humans. First, robust PBPK models were constructed in beagle dogs under both fasted and fed states. Then, a Z-factor model was integrated to assess the effect of in vitro dissolution rates on the in vivo PK performance, and the results illustrated that PIRO IR products had a much wider dissolution space than was anticipated by bioequivalence. In addition, the parameter sensitivity analysis (PSA) assay showed that good oral absorption was achieved only when the particle size was below 150 µm. Finally, the combined PBPK models were extrapolated to humans to specify a quality control strategy; this extrapolation constituted an extension of a biowaiver for PIRO IR formulations. The results showed that the developed method can be utilized to quantitatively predict human PK, which would be meaningful for future scale-up or postapproval changes.