ABSTRACT
INTRODUCTION: The craniofacial asymmetry seen in unilateral lambdoid craniosynostosis may not be effectively treated by posterior cranial vault remodeling, endoscopic suturectomy, and helmet therapy, or suturectomy and distraction osteogenesis alone due to limitations in soft-tissue envelope expansion and relapse of the deformity. The authors report a series of unilateral lambdoid craniosynostosis patients treated with a posterior rotational cranial-flap technique using internal distraction osteogenesis. METHODS: Posterior cranial vault reconstruction combined with internal distraction was used, aided by preoperative virtual surgical planning. An in situ posterior rotational flap osteotomy was utilized to maximize dural preservation. Primary outcome measures included age-adjusted volume change and age-adjusted percent volume change per mm distraction. Distraction characteristics and perioperative characteristics were also assessed. RESULTS: A total of 5 patients were identified. Mean predistraction intracranial volume was 1087.5 cc (SDâ =â202.3 cc) and mean postdistraction included intracranial volume was 1266.1cc (SDâ =â131.8cc). Mean age-adjusted percent included intracranial volume change was 14.1% (SDâ =â9.6%), and mean percent intracranial volume change per mm distraction was 0.43%/mm distraction (SDâ =â0.37%/mm distraction). One patient developed a distractor site infection postoperatively that was treated successfully with oral antibiotics. All patients had a Whitaker score of 1 at one year follow up. CONCLUSIONS: Posterior cranial vault remodeling using osteogenesis and a rotational cranial flap technique with dural preservation can be effectively used to maximize bone flap viability and limit postoperative relapse in patients with unilateral lambdoid craniosynostosis. Long term analysis as well as comparison to open techniques will need to be interrogated.
Subject(s)
Craniosynostoses , Osteogenesis, Distraction , Craniosynostoses/surgery , Humans , Infant , Osteotomy , Skull/surgery , Surgical FlapsABSTRACT
Nasal deposition studies can demonstrate whether nasal sprays treating allergic rhinitis and polyposis reach the ciliated posterior nasal cavity, where turbinate inflammation and other pathology occurs. However, quantifying nasal deposition is challenging, because in vitro tests do not correlate to human nasal deposition; gamma scintigraphy studies are thus used. For valid data, the radiolabel must distribute, as the drug, into different-sized droplets, remain associated with the drug in the formulation after administration, and not alter its deposition. Some nasal deposition studies have demonstrated this using homogenous solutions. However, most commercial nasal sprays are heterogeneous suspensions. Using mometasone furoate nasal suspension (MFS), we developed a technique to validate radiolabel deposition as a surrogate for nasal cavity drug deposition and characterized regional deposition and nasal clearance in humans. Mometasone furoate (MF) formulation was spiked with diethylene triamine pentacaetic acid. Both unlabeled and radiolabeled formulations (n = 3) were sprayed into a regionally divided nasal cast. Drug deposition was quantified by high pressure liquid chromatography within each region; radiolabel deposition was determined by gamma camera. Healthy subjects (n = 12) were dosed and imaged for six hours. Scintigraphic images were coregistered with magnetic resonance imaging scans to quantify anterior and posterior nasal cavity deposition and mucociliary clearance. The ratio of radiolabel to unlabeled drug was 1.05 in the nasal cast and regionally appeared to match, indicating that in vivo radiolabel deposition could represent drug deposition. In humans, MFS delivered 86% (9.2) of metered dose to the nasal cavity, approximately 60% (9.1) of metered dose to the posterior nasal cavity. After 15 minutes, mucociliary clearance removed 59% of the initial radiolabel in the nasal cavity, consistent with clearance rates from the ciliated posterior surface. MFS deposited significant drug into the posterior nasal cavity. Both nasal cast validation and mucociliary clearance confirm the radiolabel deposition distribution method accurately represented corticosteroid nasal deposition.
Subject(s)
Anti-Allergic Agents/administration & dosage , Anti-Allergic Agents/pharmacokinetics , Nasal Sprays , Pregnadienediols/administration & dosage , Pregnadienediols/pharmacokinetics , Adult , Anti-Allergic Agents/adverse effects , Anti-Allergic Agents/chemistry , Chemistry, Pharmaceutical , Female , Humans , Isotope Labeling , Magnetic Resonance Imaging , Male , Middle Aged , Mometasone Furoate , Mucociliary Clearance , Pregnadienediols/adverse effects , Pregnadienediols/chemistry , Radionuclide Imaging , Young AdultABSTRACT
PURPOSE: To optimize a controlled release (CR) matrix formulation with two goals: (1) effectively deliver a prodrug to a preferred absorption region of the upper GI tract, and (2) afford a PK profile similar to a "reference" CR formulation. METHODS: A pharmacoscintigraphic clinical study was conducted using a flexible formulation design space. A six-arm, three-prototype study was employed to cover the formulation design space and assess performance against the reference formulation. Pharmacokinetic and scintigraphic data from the first three dosing arms were used to select prototypes to be dosed in subsequent arms. RESULTS: Of three prototypes tested, the third prototype had an optimal release rate. The in vivo erosion rate was observed via scintigraphy to reach 90% in 3 h. The AUC ratio relative to the reference for the prodrug was 1.25, while the C(max) ratio was 1.07. The ratios for the active moiety were 1.31 (AUC) and 1.01 (C(max)). CONCLUSIONS: A single pharmacoscintigraphic study efficiently investigated a wide formulation design space and precisely optimized the release rate with few formulation iterations. The selected formulation provided the desired exposure at a 30% lower dose. The approach is beneficial when drug absorption is limited to a region of the GI tract.
Subject(s)
Benzenesulfonates/chemistry , Excitatory Amino Acid Antagonists/chemistry , Prodrugs/chemistry , Absorption , Adult , Area Under Curve , Benzenesulfonates/administration & dosage , Benzenesulfonates/pharmacokinetics , Chemistry, Pharmaceutical/methods , Delayed-Action Preparations , Excitatory Amino Acid Antagonists/administration & dosage , Excitatory Amino Acid Antagonists/pharmacokinetics , Gastrointestinal Tract/metabolism , Humans , Male , Prodrugs/administration & dosage , Prodrugs/pharmacokinetics , Receptors, Glutamate/metabolism , Tablets/chemistry , Young AdultABSTRACT
Reducing the maximum plasma concentration whilst maintaining the exposure was shown to ameliorate adverse events following the oral administration of 6-hydroxybuspirone. This observation, along with a desire to provide for once daily dosing of this compound, provided the basis for the development of an extended release formulation. Hydrophilic matrix tablets based on hydroxypropyl methylcellulose and containing citric acid to provide for an acid microenvironment were prepared and evaluated by in vitro drug release studies and in vivo pharmacokinetic and scintigraphic studies using samarium oxide (¹5³Sm) labelled dosage forms. The dosage forms were found to release the contained drug by a predominantly diffusion mechanism and the release rate was relatively independent of environmental pH. Following administration of the extended release formulations to volunteers, comparative pharmacokinetic data indicated that the extended release formulations provided for a reduction in the maximum plasma concentration of 64-70% relative to that provided by the same dose given as an oral solution, whilst maintaining exposure relative to the oral solution. By examination of absorption curves derived by Wagner-Nelson analysis of pharmacokinetic data it was noted that drug release in vivo correlated well with drug release observed in vitro and no marked change in rate of absorption was noted when dosage forms were located in and releasing drug in the colon. The robust control of drug release seen in vitro translated to a good in vivo performance.
Subject(s)
Buspirone/analogs & derivatives , Administration, Oral , Adolescent , Adult , Buspirone/administration & dosage , Buspirone/blood , Buspirone/pharmacokinetics , Citric Acid/chemistry , Cross-Over Studies , Delayed-Action Preparations/administration & dosage , Delayed-Action Preparations/pharmacokinetics , Humans , Hypromellose Derivatives , Male , Methylcellulose/analogs & derivatives , Methylcellulose/chemistry , Middle Aged , Tablets , Young AdultABSTRACT
Danoprevir, a potent, selective inhibitor of HCV NS3/4A protease, has a short half-life in humans. Therefore, the feasibility of a controlled release (CR) formulation to allow less frequent dosing was investigated using experimental approaches and physiological modeling to examine whether danoprevir is absorbed in the colon. Danoprevir absorption was studied in portal-vein-cannulated monkeys and in monkeys surgically modified to make intraduodenal, intrajejunal, intracolonic and oral administration possible. In portal-vein-cannulated monkeys, absorption was apparent up to 24 h after administration. The observed relative bioavailability from intracolonic delivery in the monkey was approximately 30% relative to oral administration, consistent with the model prediction of 40%. Human relative bioavailability for a tablet delivered to the colon compared with an immediate release (IR) formulation was predicted to be 4-28%. Preclinical data and modeling suggested that CR development would be challenging for this Biopharmaceutics Classification System Class IV compound. Therefore, a confirmative study in healthy volunteers was conducted to investigate the relative bioavailability of danoprevir in various regions of the gastrointestinal tract. In a randomized, open-label, crossover study, subjects received 100 mg danoprevir IR soft gel capsule, 100 mg danoprevir solution delivered to the distal small bowel and colon via an Enterion™ capsule (a remotely activated capsule for regional drug delivery) and 100 mg danoprevir powder to the colon via an Enterion™ capsule. The relative bioavailability of danoprevir (compared with IR) delivered to the colon was 6.5% for a solution and 0.6% for a powder formulation, indicating that a CR formulation is not feasible.
Subject(s)
Antiviral Agents/pharmacokinetics , Intestinal Absorption , Lactams/pharmacokinetics , Models, Biological , Sulfonamides/pharmacokinetics , Administration, Oral , Adult , Animals , Antiviral Agents/administration & dosage , Biological Availability , Cross-Over Studies , Cyclopropanes , Delayed-Action Preparations , Feasibility Studies , Humans , Isoindoles , Lactams/administration & dosage , Lactams, Macrocyclic , Macaca fascicularis , Male , Proline/analogs & derivatives , Sulfonamides/administration & dosage , Young AdultABSTRACT
Semaglutide, a glucagon-like peptide-1 (GLP-1) analogue, has been coformulated in a tablet with the absorption enhancer, sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC). We investigated tablet erosion and the pharmacokinetics of oral semaglutide administered with 2 different water volumes and evaluated the relationships between these parameters. In a randomized, single-center (Quotient Sciences, UK), open-label, 2-period crossover trial, 26 healthy men received single doses of 10 mg oral semaglutide with 50 or 240 mL water while fasting. Tablet erosion and gastrointestinal transit were assessed by gamma scintigraphy. Semaglutide and SNAC plasma concentrations were measured until 24 and 6 hours, respectively, after administration. Complete tablet erosion (CTE) occurred in the stomach irrespective of water volume administered with the tablet (primary end point). Mean time to CTE was 85 versus 57 minutes with 50 versus 240 mL water (ratio 50/240 mL, 1.51; 95% confidence interval, 0.96-2.37; P = .072). Area under the semaglutide concentration-time curve from 0 to 24 hours (AUC0-24h,semaglutide ) and maximum semaglutide concentration (Cmax,semaglutide ) were â¼70% higher with 50 versus 240 mL water (P = .056 and P = .048, respectively). Median time to maximum semaglutide concentration (tmax,semaglutide ) was 1.5 hours independent of water volume with dosing. Higher AUC0-24h,semaglutide and Cmax,semaglutide and longer tmax,semaglutide were significantly correlated with longer time to CTE and later gastric emptying of tablet and water (all P < .05). The safety profile was as expected for the GLP-1 receptor agonist drug class. In conclusion, the oral semaglutide tablet erodes in the stomach irrespective of water volume with dosing. Slower tablet erosion in the stomach results in higher semaglutide plasma exposure.
Subject(s)
Caprylates/chemistry , Glucagon-Like Peptides/administration & dosage , Hypoglycemic Agents/administration & dosage , Administration, Oral , Adult , Area Under Curve , Cross-Over Studies , Fasting , Glucagon-Like Peptide-1 Receptor/agonists , Glucagon-Like Peptides/pharmacokinetics , Humans , Hypoglycemic Agents/pharmacokinetics , Male , Middle Aged , Radionuclide Imaging , Tablets , Water/chemistryABSTRACT
Bevirimat is a first in class, orally active, potent and selective inhibitor of HIV-1. It may have utility for the treatment of HIV-1-infected patients who are failing current regimens because of the development of drug resistance. In earlier studies in HIV-1-infected patients, an immediate-release tablet formulation exhibited a relative bioavailability (F(rel)) of 50% or greater and a higher intersubject variability than an oral solution. The purpose of this study was to determine whether this pharmacokinetic profile is attributable to a narrow permeability-dependent absorption window within the gastrointestinal tract. Three groups of subjects completed an open-label, 2-way crossover, randomized pharmacoscintigraphic study. Subjects received a 25-mg bevirimat oral immediate-release solution plus 25 mg bevirimat solution delivered to the proximal small bowel, distal small bowel, or colon via the Enterion capsule. The results indicate that the permeability of bevirimat throughout the small intestine was excellent and suggest that the variability observed for the immediate release tablet was not related to the presence of an absorption window in the small intestine.
Subject(s)
Anti-HIV Agents/pharmacokinetics , Intestinal Absorption , Succinates/pharmacokinetics , Triterpenes/pharmacokinetics , Adult , Anti-HIV Agents/administration & dosage , Biological Availability , Capsules , Colon/metabolism , Cross-Over Studies , Dosage Forms , Drug Administration Schedule , Female , Humans , Ileum/metabolism , Jejunum/metabolism , Male , Succinates/administration & dosage , Triterpenes/administration & dosageABSTRACT
Acipimox is an analog of nicotinic acid and is indicated for the treatment of dyslipidemia. It is also believed to improve glucose control by enhancing insulin sensitivity. The purpose of this study was to direct modified release (MR) formulation strategy by comparing the bioavailability of two forms of acipimox (free acid and sodium salt) from the distal small bowel (DSB) and colon with an immediate release formulation. Two parallel groups of healthy volunteers completed an open label, non-randomized, three-way crossover study. The rate and extent of acipimox absorption was highest following administration of the immediate release capsules, and was not influenced by the form of the drug administered. Following administration to the DSB, the relative bioavailability was approximately 52% and 30% for the salt form and free acid form, respectively. Following administration to the colon, the extent of absorption was further reduced. The data indicate that bioavailability from the DSB was limited by the solubility of the drug coupled with an absorption window, whilst absorption from the colon was limited by permeability. The study provided detailed information to support and guide the formulation strategy for a MR form of acipimox, which may improve the treatment of adult patients with type II diabetes and dyslipidemia.
Subject(s)
Hypolipidemic Agents/pharmacokinetics , Pyrazines/pharmacokinetics , Adult , Biological Availability , Colon/metabolism , Cross-Over Studies , Delayed-Action Preparations , Female , Humans , Hypolipidemic Agents/administration & dosage , Hypolipidemic Agents/chemistry , Intestine, Small/metabolism , Male , Middle Aged , Permeability , Pyrazines/administration & dosage , Pyrazines/chemistry , Salts , Solubility , Young AdultABSTRACT
PURPOSE: ME-401 is a novel selective inhibitor of phosphatidylinositol 3 kinase p110δ, an enzyme often found overexpressed and overactive in B-cell malignancies. The current study was performed to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of single ascending oral doses of ME-401 in healthy volunteers. METHODS: This analysis was an open-label, nonrandomized study in healthy male volunteers. Three sequential groups were dosed. Each group received single doses of ME-401 on two occasions; the doses tested ranged from 10 to 150 mg. Blood was drawn at various time points to analyze plasma concentrations of ME-401 and inhibition of basophil activation, a marker of phosphatidylinositol 3 kinase p110δ inhibition. FINDINGS: Fifteen subjects received a single dose of ME-401 on two occasions. Three adverse events that were considered possibly related to the study drug were reported: one event of pain, one event of headache, and one event of upper abdominal pain. ME-401 exhibited dose proportionality up to 60 mg, and supra-proportional increases in exposure were observed above doses of 60 mg. In addition, there was a dose-proportional increase in the inhibition of basophil activation up to 60 mg. Mean t1/2 ranged from 9.36 to 29.23 hours across the dose range. A 60 mg dose of ME-401 approached 90% inhibition of basophil activation, and thereafter no further increase to the percent inhibition of basophil activation was observed for higher doses. Once-daily dosing of 60 mg ME-401 was forecasted to result in trough plasma levels exceeding the concentration needed for 90% inhibition of basophil activation. IMPLICATIONS: This first-in-human study showed that ME-401 was well tolerated after single doses up to 150 mg. Pharmacologic activity was confirmed after administration of single ascending oral doses of 10 to 150 mg. ME-401 60 mg, administered once daily, was selected as the starting dose for patient studies. ClinicalTrials.gov identifier: NCT02521389.
Subject(s)
Organic Chemicals/pharmacology , Organic Chemicals/pharmacokinetics , Phosphoinositide-3 Kinase Inhibitors/pharmacology , Phosphoinositide-3 Kinase Inhibitors/pharmacokinetics , Administration, Oral , Adult , Area Under Curve , Dose-Response Relationship, Drug , Healthy Volunteers , Humans , Male , Middle Aged , Organic Chemicals/administration & dosage , Phosphoinositide-3 Kinase Inhibitors/administration & dosageABSTRACT
CORT125134 is an orally active, high-affinity, selective antagonist of the glucocorticoid receptor that is being developed for indications that may benefit from the modulation of cortisol activity. This first-in-human study was conducted to evaluate the dose-related safety, tolerability, pharmacokinetics and pharmacological effects of CORT125134 and its active metabolite CORT125201. Eighty-one healthy male or female subjects received a single dose of 5 to 500 mg CORT125134 or matching placebo across 9 cohorts; 1 cohort received 150 mg CORT125134 after a high-fat breakfast; and 46 subjects received 50 to 500 mg CORT125134 or matching placebo once daily for up to 14 days across 4 cohorts. CORT125134 was well tolerated at doses up to 250 mg per day for 14 days. CORT125134 was absorbed rapidly and eliminated with a mean half-life ranging from 11 to 19 hours. Steady state was achieved by day 7. Exposure increased in a greater than proportional manner, particularly at lower doses. Exposure to CORT125201 at steady state was less than 5% that of parent CORT125134. Evidence for the desired pharmacological effect (glucocorticoid receptor antagonism) was demonstrated by the ability of CORT125134 to prevent several effects of the glucocorticoid receptor agonist prednisone.
Subject(s)
Isoquinolines/administration & dosage , Isoquinolines/pharmacokinetics , Pyrazoles/administration & dosage , Pyrazoles/pharmacokinetics , Pyridines/administration & dosage , Pyridines/pharmacokinetics , Receptors, Glucocorticoid/antagonists & inhibitors , Small Molecule Libraries/adverse effects , Small Molecule Libraries/pharmacokinetics , Administration, Oral , Area Under Curve , Dose-Response Relationship, Drug , Double-Blind Method , Drug Administration Schedule , Female , Half-Life , Healthy Volunteers , Humans , Isoquinolines/adverse effects , Male , Pyrazoles/adverse effects , Pyridines/adverse effects , Small Molecule Libraries/administration & dosageABSTRACT
BACKGROUND: Raltegravir is an integrase strand transfer inhibitor indicated in combination with other anti-retroviral medicinal products for the treatment of HIV-1 infection, given twice daily. Although a BCS class II compound, raltegravir exhibits low colonic absorption, thus making development of modified release formulations challenging. It was hypothesized that a gastroretentive (GR) formulation would increase trough (C24 h) concentrations of raltegravir, hence being amenable to a once-daily (QD) regimen. METHODS: Iterative prototype GR formulations were developed in monolithic, bilayer, and trilayer tablet designs. Four phase I studies in healthy subjects were conducted to provide proof of formulation concept. RESULTS: Raltegravir C24 h was increased by a GR formulation with scintigraphy data supporting gastric retention. Single-dose exposures from a trilayer tablet administered in the morning with a high-fat meal resulted in acceptable C24 h values. However, C24 h values for evening dosing with a high-fat meal did not meet the success criteria for QD administration. Raltegravir C24 h and area under the curve (AUC) values after AM dosing with a low-fat meal were significantly lower than after dosing with a moderate-fat meal. Skipping, delaying, or giving a low-fat, low-calorie lunch after dosing with a high-calorie breakfast also resulted in an unacceptable decline in C24 h values. The requirements for consistent product performance under varying conditions of diet, timing of dosing, and dose were not favorable when given as GR tablets. CONCLUSIONS: The findings from these studies offer valuable insights into modifying the absorption of candidate drugs with limiting colonic permeability and solubility characteristics and the interplay between meal, dose timing, and GR formulation performance.
ABSTRACT
Two studies in healthy subjects assessed the absorption of edoxaban when delivered to specific locations within the gastrointestinal tract using Enterion capsules. In study 1 (single-dose, 4-way crossover), 8 participants received edoxaban 60 mg as immediate-release (IR) tablets (treatment A), as powder formulation delivered to the distal small bowel (treatment B) or ascending colon (treatment C), or as an aqueous suspension delivered to the ascending colon (treatment D). In study 2 (single-dose, 2-way crossover), 10 participants received edoxaban 30 mg as IR tablets (treatment E) or in granulate formulation with fumaric acid 50 mg, added to acidify the local gastrointestinal tract and enhance solubility, delivered to the ascending colon (treatment F). Peak and total exposure following targeted drug delivery to the distal gastrointestinal tract were significantly lower than with IR tablet delivery. In study 1, total exposure ratios of treatments B, C, and D compared with A were 14.9%, 7.9%, and 6.1%, respectively. In study 2, relative total exposure was 12.6% for treatment F despite the fumaric acid. Time to peak concentration was longer with higher variability for edoxaban delivered to the distal gastrointestinal tract compared with the IR tablet. These data indicate that edoxaban absorption occurs predominantly in the proximal small intestine.
Subject(s)
Factor Xa Inhibitors/administration & dosage , Factor Xa Inhibitors/pharmacokinetics , Gastrointestinal Absorption , Pyridines/administration & dosage , Pyridines/pharmacokinetics , Thiazoles/administration & dosage , Thiazoles/pharmacokinetics , Adolescent , Adult , Aged , Capsules , Colon/metabolism , Cross-Over Studies , Factor Xa Inhibitors/blood , Fumarates/administration & dosage , Fumarates/pharmacokinetics , Humans , Intestine, Small/metabolism , Male , Middle Aged , Pyridines/blood , Tablets , Thiazoles/blood , Young AdultABSTRACT
Ziprasidone, like many BCS Class II drugs with low intrinsic solubility and a strong tendency to crystallize from supersaturated solutions, presents significant technical challenges when developing an oral controlled release dosage form. In order to achieve acceptable bioavailability and prolonged exposures for once-daily dosing, good colonic absorption and a reliable controlled release (CR) technology are necessary. To this end, a novel solubilized drug form--coated crystals made by spray drying (CCSD), was formulated and progressed into human clinical studies. This report describes studies of colonic absorption for the CCSD using the Enterion™ capsule and a pharmacoscintigraphy study in which the CCSD was orally administered via a radiolabelled osmotic tablet formulation. These studies demonstrated that the probability of achieving the required drug solubilization in the colon with the CCSD concept and thereby the desired once daily pharmacokinetic profile was extremely low.
Subject(s)
Antipsychotic Agents/administration & dosage , Delayed-Action Preparations/chemistry , Piperazines/administration & dosage , Thiazoles/administration & dosage , Administration, Oral , Antipsychotic Agents/pharmacokinetics , Biological Availability , Capsules , Colon/metabolism , Humans , Intestinal Absorption , Piperazines/pharmacokinetics , Radionuclide Imaging , Solubility , Thiazoles/pharmacokineticsABSTRACT
The purposes of this study are to investigate the gastrointestinal transit and release properties of a novel, colon-targeted delivery system (CODES) administered to healthy volunteers using gamma scintigraphy and to confirm that lactulose functions to promote disintegration in the colon. Two placebo formulations were studied: one was CODES, which consisted of a lactulose containing core overcoated with both Eudragit E and Eudragit L designed to rapidly disintegrate in the colon, the other was lactulose-free reference formulation (LFRF) that consisted of lactulose-free tablet core overcoated with the same materials. Transit and disintegration of the radiolabeled formulations were followed by gamma scintigraphy. In the fasted state, scintigraphic images indicated that CODES started to disintegrate in the ascending colon in the majority of subjects at 7.11 +/- 2.01 h post-dose. Disintegration was complete within 1 h following commencement of in vivo release. In contrast, LFRF presented with prolonged in vivo disintegration properties. In the fed state, the disintegration period of CODES was almost comparable to that observed in the fasted state. Gamma scintigraphic studies clearly showed that CODES provides for rapid target site release in the colon regardless of the ingestion of food.
Subject(s)
Colon/diagnostic imaging , Colon/metabolism , Drug Delivery Systems/methods , Adult , Chemistry, Pharmaceutical , Colon/drug effects , Cross-Over Studies , Fasting/metabolism , Gamma Rays , Gastric Emptying/drug effects , Gastric Emptying/physiology , Gastrointestinal Transit/physiology , Humans , Lactulose/administration & dosage , Lactulose/pharmacokinetics , Male , Radionuclide ImagingABSTRACT
The enteric coating of HPMC capsules containing paracetamol was investigated. Two enteric polymers, Eudragit L 30 D-55 and Eudragit FS 30 D were studied, which are designed to achieve enteric properties and colonic release, respectively. The capsules were coated in an Accela Cota 10, and, as shown by optical microscopy, resulted in capsules with a uniform coating. Scanning electron microscopy of the surface of the capsules illustrate that, in contrast to gelatin, HPMC has a rough surface, which provides for good adhesion to the coating. Dissolution studies demonstrated that capsules coated with Eudragit L 30 D-55 were gastro resistant for 2 h at pH 1.2 and capsules coated with Eudragit FS 30 D were resistant for a further 1 h at pH 6.8. The product visualisation technique of gamma scintigraphy was used to establish the in vivo disintegration properties of capsules coated with 8 mg cm(-2) Eudragit L 30 D-55 and 6 mg cm(-2) Eudragit FS 30 D. For HPMC units coated with Eudragit L 30 D-55, complete disintegration occurred predominately in the small bowel in an average time of 2.4 h post dose. For HPMC capsules coated with Eudragit FS 30 D, complete disintegration did not occur until the distal small intestine and proximal colon in an average time of 6.9 h post dose.
Subject(s)
Drug Delivery Systems/methods , Intestinal Mucosa/metabolism , Intestines/drug effects , Lactose/analogs & derivatives , Lactose/administration & dosage , Methylcellulose/analogs & derivatives , Methylcellulose/administration & dosage , Capsules , Cross-Over Studies , Female , Humans , Intestines/diagnostic imaging , Lactose/pharmacokinetics , Male , Methylcellulose/pharmacokinetics , Microscopy, Electron, Scanning , Oxazines , Polymethacrylic Acids/administration & dosage , Polymethacrylic Acids/pharmacokinetics , Radionuclide Imaging , Solubility , Tablets, Enteric-CoatedABSTRACT
BACKGROUND: Sensory attributes of intranasal corticosteroids, such as rundown to the back of the throat, may influence patient treatment preferences. This study compares the nasal deposition and nasal retention of a radiolabeled solution of ciclesonide nasal aerosol (CIC-hydrofluoroalkane [HFA]) with a radiolabeled suspension of mometasone furoate monohydrate aqueous nasal spray (MFNS) in subjects with either perennial allergic rhinitis (AR) or seasonal AR. METHODS: In this open-label, single-dose, randomized, crossover scintigraphy study, 14 subjects with symptomatic AR received a single dose of radiolabeled 74-µg CIC-HFA (37 µg/spray, 1 spray/each nostril) via a nasal metered-dose inhaler or a single dose of radiolabeled 200-µg MFNS (50 µg/spray, 2 sprays/each nostril), with a minimum 5-day washout period between treatments. Initial deposition (2 minutes postdose) of radiolabeled CIC-HFA and MFNS in the nasal cavity, nasopharynx, and on nasal wipes, and retention of radioactivity in the nasal cavity and nasal run-out on nasal wipes at 2, 4, 6, 8, and 10 minutes postdose were quantified with scintigraphy. RESULTS: At 2 and 10 minutes postdose, deposition of radiolabeled CIC-HFA was significantly higher in the nasal cavity versus radiolabeled MFNS (99.42% versus 86.50% at 2 minutes, p = 0.0046; and 81.10% versus 54.31% at 10 minutes, p < 0.0001, respectively; p values unadjusted for multiplicity). Deposition of radioactivity on nasal wipes was significantly higher with MFNS versus CIC-HFA at all five time points, and posterior losses of radiolabeled formulation were significantly higher with MFNS at 6, 8, and 10 minutes postdose. CONCLUSION: In this scintigraphic study, significantly higher nasal deposition and retention of radiolabeled aerosol CIC-HFA were observed versus radiolabeled aqueous MFNS in subjects with AR.
Subject(s)
Anti-Allergic Agents/administration & dosage , Nasal Sprays , Pregnadienediols/administration & dosage , Pregnenediones/administration & dosage , Rhinitis, Allergic/drug therapy , Adolescent , Adult , Aged , Anti-Allergic Agents/adverse effects , Anti-Allergic Agents/pharmacokinetics , Feedback, Sensory/drug effects , Female , Humans , Male , Middle Aged , Mometasone Furoate , Pregnadienediols/adverse effects , Pregnadienediols/pharmacokinetics , Pregnenediones/adverse effects , Pregnenediones/pharmacokinetics , Radionuclide Imaging , Young AdultABSTRACT
Pranlukast hydrate was demonstrated in a human site-of-absorption study to have extremely poor absorption properties in the lower gastrointestinal tract. The ratios of AUC0-24 in the distal small bowel and colon compared to stomach delivery were approximately 1/7 and 1/70, respectively. As a consequence, a gastroretentive double-layered tablet formulation (gastric swelling system; GSS), consisting of a swelling layer and a drug release layer, was developed for once-daily dosing. To study the gastric retention of the optimized GSS, an in vivo gamma scintigraphic study was carried out in nine healthy volunteers. The transit profiles demonstrated that the GSS was retained in the stomach for more than 10h. The plasma profile was prolonged, especially following administration after an evening meal. The human data validated the design concept and suggest that GSS could be a promising approach for the development of sustained-release formulation for drugs with a limited absorption window in the upper small bowel.
Subject(s)
Anti-Asthmatic Agents/pharmacokinetics , Chromones/pharmacokinetics , Drug Delivery Systems , Gastric Mucosa/metabolism , Adolescent , Adult , Anti-Asthmatic Agents/blood , Anti-Asthmatic Agents/chemistry , Chromones/blood , Chromones/chemistry , Cross-Over Studies , Delayed-Action Preparations/chemistry , Delayed-Action Preparations/pharmacokinetics , Gastrointestinal Transit , Humans , Male , Middle Aged , Young AdultABSTRACT
BACKGROUND: Tacrolimus is an established immunosuppressant used for the prevention and treatment of allograft rejection in solid organ transplantation. An immediate-release oral formulation of tacrolimus has been commercially available since 1994 that is administered orally BID. To improve the compliance and quality of life of transplant patients, a once-daily modified release (MR) formulation is an attractive option. However, to be successful, the drug of interest must be sufficiently well absorbed from the distal region of the gastrointestinal tract. OBJECTIVE: To facilitate the development of an MR formulation, we investigated the absorption of tacrolimus from different regions of the human gastrointestinal tract, proximal and distal small bowels, and ascending colon. METHODS: The study was performed as an open-label, randomized, 4-way crossover design in 6 healthy white male subjects. For each subject, 1 mg (2 mg/mL) of tacrolimus solution in polyethylene glycol 400 was administered to each location in the gastrointestinal tract via a site-specific radiolabeled delivery capsule, which can release tacrolimus solution at specific sites of the gastrointestinal tract. Real-time visualization of capsule location and tacrolimus release at each target site was performed by using γ-scintigraphy. Blood samples were collected to determine tacrolimus levels in the blood. The pharmacokinetic parameters Cmax, Tmax after the capsule activation, AUC0-24, and mean residence time were determined from the concentration-time profiles. RESULTS: Ten healthy male subjects underwent dosing. Six subjects completed all 4 treatments. Three adverse events (mild headache [n = 1], small amount of blood in stool [n = 1], and mild syncopal episode [n = 1]) that were possibly study drug related were reported in 3 different subjects. Tacrolimus was absorbed from not only the small intestine but also from the colonic region of the gastrointestinal tract. Although AUC0-24 values revealed some site-specific absorption tendencies, the mean AUC0-24 values obtained were similar regardless of the location of tacrolimus release from the capsule. CONCLUSIONS: Tacrolimus was absorbed from the duodenum to the colon in these male subjects, although differences were observed in the value of AUC0-24, possibly due to variation in cytochrome P450 3A4 activity in the intestine. Although this study was conducted in small group of healthy fasting men, the present results indicate that tacrolimus is suitable for MR formulation development due to a wide absorption window throughout the intestine in humans.
Subject(s)
Colon, Ascending/metabolism , Gastric Mucosa/metabolism , Intestine, Small/metabolism , Tacrolimus/administration & dosage , Tacrolimus/pharmacokinetics , Biological Availability , Capsules , Cross-Over Studies , Drug Administration Schedule , Drug Delivery Systems , Gamma Cameras , Healthy Volunteers , Humans , Male , Tacrolimus/adverse effectsABSTRACT
Functional analyses of elopement (i.e., leaving a specific area without permission) are challenging to conduct because clients must have repeated opportunities to elope from one room (or area) to another safely. These analyses often require two or more adjoining rooms and retrieval of the client following each instance of elopement (e.g., Piazza et al., 1997). These room arrangements may be impractical in some settings, and therapist delivery of attention or demands during retrieval may confound the results. To address these issues, we evaluated the viability of conducting a functional analysis (FA) of elopement within a single room. Participants were 2 children and 2 adults with developmental disabilities who eloped from rooms at their day programs. Results of the single-room assessments were compared to those of a second FA that was conducted using methods similar to those described in previous studies. Function-based treatments were implemented for each participant. Results suggest that the single-room assessment may be a viable alternative for identifying the function of elopement.
Subject(s)
Behavior Therapy/methods , Developmental Disabilities , Outcome Assessment, Health Care , Treatment Refusal/psychology , Adult , Child , Developmental Disabilities/diagnosis , Developmental Disabilities/psychology , Developmental Disabilities/therapy , Female , Humans , Male , Reproducibility of ResultsABSTRACT
OBJECTIVES: This exploratory study in healthy volunteers investigated the effect of single doses of oxycodone on gastrointestinal (GI) transit time and the degree to which a single dose of naloxone reverses the oxycodone-induced effect. METHODS: Fifteen healthy male volunteers received: oxycodone 10 and2 0 mg, oxycodone/naloxone 10/5 and 20/10 mg (all as prolonged release tablets) and placebo. Each dose was radiolabelled and administered with a capsule containing radiolabelled resin (surrogate for GI contents). RESULTS: Scintigraphic analysis showed that 20 mg oxycodone significantly increased colon arrival time (mean 7.19 vs 5.15 h for placebo, p = 0.0159). Mean colon arrival time for oxycodone/naloxone 20/10 mg (5.16 h) was similar to placebo, although the difference between oxycodone/naloxone 20/10 mg versus oxycodone 20 mg was not significant (p = 0.0653). Colonic geometric centre analysis showed a significant increase in mean time for the resin to reach the colon following oxycodone 10 and 20 mg compared with placebo (increases of 5.3 and 8.8 h). There was no significant effect of naloxone at the lower dose; however, oxycodone/naloxone 20/10 mg significantly reduced mean colonic transit time by 2.1 h (p = 0.0376). CONCLUSION: A single dose of oxycodone 20 mg significantly prolonged GI transit time but this effect was reduced by co-administration of naloxone.