Drug content determination of low-dosed hot-melt extruded filaments using Raman spectroscopy.

The aim of this study was to evaluate the suitability of a non-disruptive Raman spectroscopic method to quantify drug concentrations below 5 w% within a polymer matrix produced by hot-melt extrusion (HME). For calibration, praziquantel (PZQ)-polyvinylpyrrolidone-vinylacetat-copolymer (PVP-VA) mixtures were extruded. By focusing the laser light of the Raman probe to a diameter of 1 mm and implementing a self-constructed filament holder, the signal-to-noise (S/N) ratio could be reduced considerably. The obtained Raman spectra show quite high fluorescence, which is likely to be caused by dissolved pharmaceutical active ingredient (API) in the polymer matrix. For content determination, HPLC analysis was conducted as a reference method using the same filament segments. A partial least squares (PLS) model, regressing the PZQ concentrations from HPLC method analysis versus the off-line collected Raman spectra, was developed. The linear correlation for a suitable extrusion run for the production of low-dosed filaments (extrusion 1, two kneading zones) is acceptable (R2 = 0.9915) while the correlation for a extrusion set-up with low miscibility (extrusion 2; without kneading zone) is unacceptable (R2 = 0.5349). The predictive performance of the calibration model from extrusion 1 is rated by the root mean square error of estimation (RMSEE), which was 0.08%. This calibration can now be used to validate the content of low-dosed filaments during HME.

The Impact of Nasal Intubation on Feeding Outcomes in Neonates Requiring Cardiac Surgery: A Randomized Control Trial.

Neonates who require surgery for congenital heart disease (CHD) frequently have difficulty with oral feeds post-operatively and may require a feeding tube at hospital discharge. The purpose of this study was to determine the effect of oral or nasal intubation route on feeding method at hospital discharge. This was a non-blinded randomized control trial of 62 neonates who underwent surgery for CHD between 2018 and 2021. Infants in the nasal (25 patients) and oral (37 patients) groups were similar in terms of pre-operative risk factors for feeding difficulties including completed weeks of gestational age at birth (39 vs 38 weeks), birthweight (3530 vs 3100 g), pre-operative PO intake (92% vs 81%), and rate of pre-operative intubation (22% vs 28%). Surgical risk factors were also similar including Society of Thoracic Surgeons-European Association for Cardio-Thoracic Surgery category (3.9 vs 4.1), shunt placement (32% vs 41%), cardiopulmonary bypass time (181 vs 177 min), and cross-clamp time (111 vs 105 min). 96% of nasally intubated patients took full oral feeds by discharge as compared with 78% of orally intubated infants (p = 0.05). Nasally intubated infants reach full oral feeds an average of 3 days earlier than their orally intubated peers. In this cohort of patients, nasally intubated infants reach oral feeds more quickly and are less likely to require supplemental tube feeding in comparison to orally intubated peers. Intubation route is a potential modifiable risk factor for oral aversion and appears safe in neonates. The study was approved by the University of Virginia Institutional Review Board for Health Sciences Research and was retrospectively registered on clinicaltrials.gov (NCT05378685) on May 18, 2022.

3D Printed Mini-Floating-Polypill for Parkinson's Disease: Combination of Levodopa, Benserazide, and Pramipexole in Various Dosing for Personalized Therapy.

Therapy for Parkinson's disease is quite challenging. Numerous drugs are available for symptomatic treatment, and levodopa (LD), in combination with a dopa decarboxylase inhibitor (e.g., benserazide (BZ)), has been the drug of choice for years. As the disease progresses, therapy must be supplemented with a dopamine agonist (e.g., pramipexole (PDM)). Side effects increase, as do the required dose and dosing intervals. For these specific requirements of drug therapy, the 3D printing method fused deposition modelling (FDM) was applied in this study for personalized therapy. Hot melt extrusion was utilized to produce two different compositions into filaments: PDM and polyvinyl alcohol for rapid drug release and a fixed combination of LD/BZ (4:1) in an ethylene-vinyl acetate copolymer matrix for prolonged drug release. Since LD is absorbed in the upper gastrointestinal tract, a formulation that floats in gastric fluid was desired to prolong API absorption. Using the FDM 3D printing process, different polypill geometries were printed from both filaments, with variable dosages. Dosage forms with 15−180 mg LD could be printed, showing similar release rates (f2 > 50). In addition, a mini drug delivery dosage form was printed that released 75% LD/BZ within 750 min and could be used as a gastric retentive drug delivery system due to the floating properties of the composition. The floating mini-polypill was designed to accommodate patients' swallowing difficulties and to allow for individualized dosing with an API release over a longer period of time.

Quality of FDM 3D Printed Medicines for Pediatrics: Considerations for Formulation Development, Filament Extrusion, Printing Process and Printer Design.

3d printing is capable of providing dose individualization for pediatric medicines and translating the precision medicine approach into practical application. In pediatrics, dose individualization and preparation of small dosage forms is a requirement for successful therapy, which is frequently not possible due to the lack of suitable dosage forms. For precision medicine, individual characteristics of patients are considered for the selection of the best possible API in the most suitable dose with the most effective release profile to improve therapeutic outcome. 3d printing is inherently suitable for manufacturing of individualized medicines with varying dosages, sizes, release profiles and drug combinations in small batch sizes, which cannot be manufactured with traditional technologies. However, understanding of critical quality attributes and process parameters still needs to be significantly improved for this new technology. To ensure health and safety of patients, cleaning and process validation needs to be established. Additionally, adequate analytical methods for the in-process control of intermediates, regarding their printability as well as control of the final 3d printed tablets considering any risk of this new technology will be required. The PolyPrint consortium is actively working on developing novel polymers for fused deposition modeling (FDM) 3d printing, filament formulation and manufacturing development as well as optimization of the printing process, and the design of a GMP-capable FDM 3d printer. In this manuscript, the consortium shares its views on quality aspects and measures for 3d printing from drug-loaded filaments, including formulation development, the printing process, and the printed dosage forms. Additionally, engineering approaches for quality assurance during the printing process and for the final dosage form will be presented together with considerations for a GMP-capable printer design.

Pulmonary artery and conduit reintervention rates after norwood using a right ventricle to pulmonary artery conduit.

BACKGROUND: There is a high incidence of cardiovascular reinterventions in patients undergoing a Norwood procedure (NP). The goal of this study was to analyze the rate of pulmonary artery (PA) and conduit stenosis using the right ventricle (RV)-to-PA modification of the NP. METHODS: Patients who underwent a NP January 2005 to December 2009 were included. The procedure was performed with a ringed conduit sutured to a membrane to form a patch. The patch was sutured to the PA confluence, and the spatulated conduit was anastomosed to an appropriately sized right ventriculotomy. Rates of PA and conduit stenosis requiring reintervention were calculated based on cardiac catheterization data. RESULTS: Thirty-three patients with hypoplastic left heart syndrome underwent a NP. Perioperative mortality was 6% (2 of 33). Twenty-eight patients (85%) had a Glenn procedure 5 ± 1 months later, and 12 patients (36%) had a Fontan procedure 34 ± 2 months after the Glenn. Pulmonary artery stenosis occurred in 11 patients (33%), and RV-PA conduit stenosis occurred only in 2 patients (6%). One-year and 3-year actuarial survival rates were 82% and 77%, respectively. Both branch PAs showed good and symmetric growth at cardiac catheterization before Glenn. CONCLUSIONS: The NP with RV-PA conduit using a ringed graft and a pulmonary patch is a technique associated with a low rate of PA and conduit stenosis, and good outcomes.