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Colonic delivery of metronidazole-loaded capsules for local treatment of bacterial infections: A clinical pharmacoscintigraphy study.
Preisig, D, Varum, F, Bravo, R, Hartig, C, Spleiss, J, Abbes, S, Caobelli, F, Wild, D, Puchkov, M, Huwyler, J, et al
European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V. 2021;:22-30
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Abstract
Drug delivery to the colon offers great promise for local treatment of colonic diseases as it allows bypassing systemic absorption in the small intestine, thereby increasing luminal drug concentrations in the colon. The primary objective of this in vivo pharmaco-scintigraphy study was to assess the colon drug targeting accuracy of a metronidazole benzoate colonic drug delivery system intended for local treatment of Clostridioides difficile infections. Additionally, it was assessed if the concept of mucoadhesion would increase colonic residence time and promote higher drug bioavailability. Two different capsule formulations were designed and tested in healthy human subjects. Capsules contained either non-mucoadhesive (NM) or mucoadhesive (M) microgranules, both loaded with 100 mg metronidazole benzoate (antibiotic prodrug) and 5 mg samarium oxide (scintigraphy tracer). Filled capsules were coated with a colonic-targeting technology consisting of two functional layers, which allow for accelerated drug release mediated by the intestinal pH in combination with colonic bacteria. Coated capsules were neutron-activated to yield the radioisotope 153Sm prior to administration to 18 healthy subjects. Gamma-scintigraphy imaging was combined with the measurement of drug plasma levels. Formulation NM showed high colon-targeting accuracy. Initial capsule disintegration within the targeted ileocolonic region was observed in 8 out of 9 subjects (89%) with colonic arrival times in the range of 3.5-12 h and reduced systemic exposure. In contrast, the mucoadhesive formulation M showed some inconsistency regarding the site of initial capsule disintegration (targeting accuracy 56%). Variability of drug release was attributed to self-adhesion and agglomeration of the mucoadhesive microparticles within the capsule. Accurate ileocolonic delivery of metronidazole-loaded microgranules was achieved following oral administration of colonic-targeted capsules. Delayed drug release from NM microparticles in the colon leads to a reduced systemic exposure compared to immediate-release data from literature and presumably elevated drug concentrations in the colonic lumen. This approach offers promising options for the local treatment of colonic diseases.
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In vivo characterization of enTRinsic™ drug delivery technology capsule after intake in fed state: A cross-validation approach using salivary tracer technique in comparison to MRI.
Sager, M, Grimm, M, Aude, P, Schick, P, Merdivan, S, Hasan, M, Kromrey, ML, Sivert, A, Benameur, H, Koziolek, M, et al
Journal of controlled release : official journal of the Controlled Release Society. 2019;:24-32
Abstract
The instability of various small molecules, vaccines and peptides in the human stomach is a complex challenge for oral drug delivery. Recently, a novel gastro-resistant capsule - the enTRinsic™ Drug Delivery Technology capsule - has been developed. In this work, the salivary tracer technique based on caffeine has been applied to study the in vivo disintegration of enTRinsic™ capsules in 16 healthy volunteers. In addition, magnetic resonance imaging (MRI) was used to visualize GI transit and to verify the disintegration times determined by using the salivary tracer technique. The enTRinsic™ capsules filled with 50mg of caffeine and 5mg of black iron oxide were administered in the fed state, i.e. 30min after a light meal (500kcal). In the first hour after capsule intake, the subjects were placed in supine position in the MRI scanner and scans were performed in short time intervals. After 1h, the subjects could leave the MRI scanner in between the MRI measurements, which were performed every 15min until disintegration of the capsule was confirmed (maximum observation time: 8h). Saliva samples were obtained simultaneously with MR imaging. Caffeine concentrations in saliva were determined by LC/MS-MS. The starting point of capsule disintegration was determined visually by inspection of the MR images as well as by the onset of salivary caffeine concentrations. In 14 out of 16 subjects, the capsule disintegrated in the small intestine. In one subject, the enTRinsic™ capsule was not emptied from the stomach within the observation time. In another subject, disintegration occurred during gastric emptying in the antropyloric region. In this study, we demonstrated that the enTRinsic™ capsules are also gastro resistant when taken under fed state conditions. Furthermore, we demonstrated the feasibility of using low dose caffeine as a salivary tracer for the determination of the disintegration of an enteric formulation.
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A phase I dose escalation study of NK012, an SN-38 incorporating macromolecular polymeric micelle.
Burris, HA, Infante, JR, Anthony Greco, F, Thompson, DS, Barton, JH, Bendell, JC, Nambu, Y, Watanabe, N, Jones, SF
Cancer chemotherapy and pharmacology. 2016;(5):1079-86
Abstract
PURPOSE This study evaluated the safety, tolerability, pharmacokinetics, and maximum tolerated dose (MTD) and recommended phase II dose (RD) of NK012, a macromolecular polymeric micelle formulation of SN-38 (the active metabolite of irinotecan). PATIENTS AND METHODS Patients with previously treated advanced solid tumors and acceptable organ function were administered NK012 as a 30-min infusion every 21 or 28 days without premedications. Patients were screened for UGT1A1 *28 polymorphism prior to enrollment. Patients homozygous for UGT1A1*28 allele (*28/*28 genotype patients) were treated at a reduced dose level with the potential for dose escalation based on toxicities. Pharmacokinetic samples were obtained during cycles 1 and 2. RESULTS Thirty-nine patients were enrolled, and thirty-eight patients were treated with NK012. NK012 was escalated from 9 to 37 mg/m(2) in patients with UGT1A1*28 allele genotype of wt/wt and wt/*28. The MTD/RD of a Q21D regimen was determined to be 28 mg/m(2) where the dose-limiting toxicity is myelosuppression, which appears to be cumulative and limits timely subsequent dosing. Based on delayed neutrophil recovery, the NK012 dose of 28 mg/m(2) administered on an every 28 days schedule was confirmed as the RD. Gastrointestinal toxicities were mild, with no grade 3 diarrhea reported. The T1/2z value of polymer-unbound SN-38 was significantly prolonged compared to that of SN-38 metabolized from CPT-11, indicating a sustained high systemic SN-38 concentration. Six patients had confirmed partial responses. Eighteen additional patients had stable disease as their best response to treatment. CONCLUSIONS The recommended phase II dose of NK012 for UGT1A1 wt/wt and wt/*28 genotype patients is 28 mg/m(2) every 28 days. Additional clinical development as a single agent in specific patient populations or in combination with other chemotherapy agents is warranted.
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Nanoparticle albumin-bound paclitaxel for second-line treatment of metastatic urothelial carcinoma: a single group, multicentre, phase 2 study.
Ko, YJ, Canil, CM, Mukherjee, SD, Winquist, E, Elser, C, Eisen, A, Reaume, MN, Zhang, L, Sridhar, SS
The Lancet. Oncology. 2013;(8):769-76
Abstract
BACKGROUND No standard treatment exists for patients with platinum-refractory urothelial cancer. Taxanes and vinflunine are commonly used, but response is less than 20% with no survival benefit. In this phase 2 study, we assessed efficacy and tolerability of nanoparticle albumin-bound (nab) paclitaxel in platinum-refractory urothelial cancer. METHODS We did an open-label, single-group, two-stage study at five centres in Canada. We enrolled patients aged at least 18 years with histologically confirmed, locally advanced, or metastatic measurable urothelial cancer, with documented progression on or within 12 months of treatment with one previous platinum-containing regimen. Patients received nab-paclitaxel at 260 mg/m(2) intravenously every 3 weeks. Treatment continued until disease progression or occurrence of unacceptable toxic effects. The primary endpoint was objective tumour response, defined by a complete response (CR) or partial response (PR) according to Response Evaluation Criteria In Solid Tumors (version 1.0) criteria. Tumour response and safety were assessed in all patients who received at least one cycle of nab-paclitaxel. This study is registered with ClinicalTrials.gov, number NCT00683059. FINDINGS We enrolled 48 patients between Oct 16, 2008, and June 23, 2010. Patients received a median of six cycles (range one to 15). 47 patients were evaluable; one (2·1%) had a CR and 12 (25·5%) had PRs, resulting in an overall response of 27·7% (95% CI 17·3-44·4). The most frequently recorded adverse events of any grade were fatigue (38 of 48; 79%), pain (37 of 48; 77%), alopecia (34 of 48; 71%), and neuropathy (30 of 48; 77%). The most frequently recorded adverse events of grade 3 or higher were pain (11 of 48; 23%), fatigue (five of 48; 23%), hypertension (three of 48; 6%), neuropathy (three of 48, 6%), and joint stiffness or pain (two of 48; 4%). INTERPRETATION Nab-paclitaxel was well tolerated in this population of patients with pretreated advanced urothelial cancer with an encouraging tumour response. These results warrant further study of nab-paclitaxel in second-line treatment of urothelial cancer. FUNDING Abraxis Bioscience, Celgene.
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The disintegration behaviour of capsules in fed subjects: a comparison of hypromellose (carrageenan) capsules and standard gelatin capsules.
Jones, BE, Basit, AW, Tuleu, C
International journal of pharmaceutics. 2012;(1-2):40-3
Abstract
Two-piece hard shell capsules made from hypromellose (or hydroxypropyl methylcellulose, HPMC) containing carrageenan as a gelling agent have been proposed as an alternative to conventional gelatin capsules for oral drug delivery. We have previously compared the disintegration of hypromellose(carrageenan) (Quali-V(®)) and gelatin capsules (Qualicaps) in fasted human subjects using the technique of gamma scintigraphy. This second study used the same technique with both fasted and fed human subjects. Size 0 capsules were filled with powder plugs made from lactose and did not contain croscarmellose as in the original study. The capsules were separately radiolabelled with indium-111 and technetium-99m. Both capsules were administered simultaneously with 180ml water to eight healthy male subjects following an overnight fast. Each volunteer was positioned in front of the gamma camera and sequential 60s images were acquired in a continuous manner for 30min. The mean (±S.D.) disintegration time in the fasted state for the hypromellose(carrageenan) capsules was 8±2min and for gelatin 7±3min. These results were not statistically different from the data in the original study and show that the removal of the croscarmellose had no effect on the results. The mean (±S.D.) disintegration time in the fed state for the hypromellose(carrageenan) capsules was 16±5min and for the gelatin capsules was 12±4min. There was no statistical difference between the hypromellose(carrageenan) and gelatin capsules in either the fed or fasted state.
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Hyaluronan-Irinotecan improves progression-free survival in 5-fluorouracil refractory patients with metastatic colorectal cancer: a randomized phase II trial.
Gibbs, P, Clingan, PR, Ganju, V, Strickland, AH, Wong, SS, Tebbutt, NC, Underhill, CR, Fox, RM, Clavant, SP, Leung, J, et al
Cancer chemotherapy and pharmacology. 2011;(1):153-63
Abstract
PURPOSE The objective of this study was to conduct a randomised phase II study in second-line metastatic colorectal cancer with the purpose of confirming preliminary clinical data indicating that the formulation of irinotecan with the drug carrier, hyaluronan (HA) reduced toxicity of the drug. METHODS Irinotecan-naïve patients were randomized to receive either irinotecan (350 mg/m(2)) or HA-Irinotecan (HA 1,000 mg/m(2) and irinotecan at 350 mg/m(2)) every 3 weeks for a maximum of eight cycles. RESULTS Seventy-six patients (41 HA-Irinotecan and 35 irinotecan-alone) were enrolled. There was no significant difference in any individual, or overall, grade 3 or 4 toxicity. There was a trend for increased diarrhea in the HA-Irinotecan-treated patients (20 versus 9%; P = 21), potentially explained by a disproportionate number of baseline toxicity-associated risk factors in this treatment group. The median number of cycles completed was six for HA-Irinotecan patients and two for irinotecan-alone patients (P = 0.005). When compared to the control arm, HA-Irinotecan patients had a significantly longer median progression-free survival of 5.2 versus 2.4 months (P = 0.017) and time to treatment failure (4 vs. 1.8 months; P = 0.007). Median overall survival was 10.1 months for HA-Irinotecan compared to 8.0 months for irinotecan patients (P = 0.196). CONCLUSION Further studies are required to define the safety of the formulation of irinotecan with HA. While this study was not adequately powered to demonstrate survival differences, these phase II data indicated HA-Irinotecan to be a promising therapy demonstrating improved efficacy compared to irinotecan-alone.
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Antibiotic-impregnated calcium sulfate use in combat-related open fractures.
Helgeson, MD, Potter, BK, Tucker, CJ, Frisch, HM, Shawen, SB
Orthopedics. 2009;(5):323
Abstract
This article presents our experience with the use of antibiotic-impregnated calcium sulfate in the management of comminuted open fractures with a bony defect caused by combat-related blast injuries and high-energy wounds. Calcium sulfate was used 19 times in 15 patients (17 fractures) as a bone graft substitute and a carrier for antibiotics. The anatomic sites of the graft were as follows: 6 calcanei, 1 midfoot, 1 metatarsal, 5 tibiae, 3 femorae, and 1 humerus. The average number of procedures prior to grafting was 6.2 (range, 2-10; median, 6) with grafting performed at an average 28 days after injury (range, 9-194 days; median, 14 days). Average radiographic follow-up of 12 fractures not requiring repeat grafting or amputation was 8.5 months (range 1-19 months; median, 7 months), and all of these fractures demonstrated clinical and radiographic evidence of fracture healing and consolidation. Four patients subsequently underwent 5 transtibial amputations: 2 for persistent infection, 1 when the patient changed his mind against limb salvage acutely, and 2 for severe neurogenic pain. Including the 2 amputations for persistent infection, 4 patients (22.2%) required further surgical management of infection. Three patients (17.6%) subsequently developed heterotopic ossification at the graft site, which required surgical excision. Antibiotic-impregnated calcium sulfate is effective in treating severe, contaminated open fractures by reducing infection and assisting with fracture union.
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Tolerability and patient acceptance of sodium phosphate tablets compared with 4-L PEG solution in colon cleansing: combined results of 2 identically designed, randomized, controlled, parallel group, multicenter phase 3 trials.
Kastenberg, D, Barish, C, Burack, H, Dalke, DD, Duckor, S, Putnam, W, Valenzuela, G, ,
Journal of clinical gastroenterology. 2007;(1):54-61
Abstract
GOALS Evaluate patient tolerance and acceptance of a sodium phosphate (NaP) tablet purgative compared with a 4-L polyethylene glycol (PEG) solution. BACKGROUND Characteristics and side effects of bowel purgatives deter patients from undergoing screening colonoscopy. Published data demonstrated comparable bowel cleansing with NaP tablets and a 4-L PEG solution in 2 phase for 3 studies. This report presents data on patient tolerability and acceptance. STUDY Two identically designed, randomized, investigator-blinded, and multicenter trials were performed. Tolerability and patient acceptance were based on purgative regimen compliance, incidence of gastrointestinal adverse events, and patient responses to questionnaires. RESULTS Eight hundred forty-five patients were assessed (420 and 425 in the tablet and PEG solution groups, respectively). Patient compliance with the tablet regimen was greater: 94% of patients took all the tablets compared with 57% completing the PEG solution regimen (P<0.0001). Nausea, vomiting, and bloating occurred significantly less often in patients taking NaP tablets (P<0.0001). Among patients taking tablets, 88.4% rated them "easy" or "slightly difficult" to take, compared with 60.6% of patients taking the PEG solution. The preparation's taste was rated "barely tolerable" or "not tolerable" by 1% of patients treated with NaP tablets and 23.6% treated with PEG solution. Drinking the required volume of clear liquid for the tablet or PEG preparation was rated "easy" or "slightly difficult" by 92.2% and 66.9% of patients, respectively. Almost all (90.7%) patients taking the tablets indicated they would take the same preparation in the future, compared with 67.1% of patients taking the PEG solution (P<0.0001 for each comparison). CONCLUSIONS Tolerability and patient acceptance of a NaP tablet purgative were superior to 4-L PEG solution.