| 1. |
- Andreadis, Ioannis I., et al.
(författare)
-
Exploring the use of modified in vitro digestion assays for the evaluation of ritonavir loaded solid lipid-based formulations
- 2023
-
Ingår i: European Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0928-0987 .- 1879-0720. ; 189
-
Tidskriftsartikel (refereegranskat)abstract
- Solid lipid-based formulations (sLBFs) have the potential to increase the oral bioavailability of drugs with poor solubility in water, while counteracting some of the disadvantages of liquid LBFs. The most common experimental set-up to study the performance of LBFs in vitro is the lipolysis assay, during which the LBFs are digested by lipases in an environment mimicking the human small intestine. However, this assay has failed in many cases to correctly predict the performance of LBFs in vivo, highlighting the need for new and improved in vitro assays to evaluate LBFs at the preclinical stage. In this study, the suitability of three different in vitro digestion assays for the evaluation of sLBFs was assessed; the classic one-step intestinal digestion assay, a two-step gastrointestinal digestion assay and a bicompartmental assay permitting the simultaneous monitoring of digestion and permeation of the active pharmaceutical ingredient (API) across an artificial membrane (Lecithin in Dodecane - LiDo). Three sLBFs (M1-M3) with varied composition and ritonavir as model drug were prepared and examined. When comparing the ability of these formulations to keep the drug solubilized in the aqueous phase, all three assays show that M1 performs better, while M3 presents poor performance. However, the classic in vitro intestinal digestion assay fails to provide a clear ranking of the three formulations, something that is more evident when using the two modified and more physiologically relevant assays. Also, the two modified assays provide additional information about the performance of the formulations including the performance in the gastric environment and intestinal flux of the drug. These modified in vitro digestion assays are valuable tools for the development and evaluation of sLBFs to make better informed decisions of which formulations to pursue for in vivo studies.
|
|
| 2. |
|
|
| 3. |
- Lenhart, Vincent, et al.
(författare)
-
Fibrillated Cellulose via High Pressure Homogenization : Analysis and Application for Orodispersible Films
- 2019
-
Ingår i: AAPS PharmSciTech. - : SPRINGER. - 1530-9932. ; 21:1
-
Tidskriftsartikel (refereegranskat)abstract
- Powdered cellulose (PC) and microcrystalline cellulose (MCC) are common excipients in pharmaceuticals. Recent investigations imply that particle size is the most critical parameter for the different performance in many processes. High-pressure homogenization (HPH) was used to reduce fiber size of both grades. The effect of the homogenization parameters on suspension viscosity, particle size, and mechanical properties of casted films was investigated. PC suspensions showed higher apparent viscosities and yield stresses under the same process conditions than MCC. SLS reduced shear viscosity and thixotropic behavior of both cellulose grades probably due to increased electrostatic repulsion. Homogenization reduced cellulose particle sizes, but re-agglomeration was too strong to analyze the particle size correctly. MCC films showed a tensile strength of up to 16.0 MPa and PC films up to 4.1 MPa. PC films disintegrated within 30 s whereas MCC films did not. Mixtures of MCC and PC led to more stable films than PC alone, but these films did not disintegrate anymore. Diclofenac sodium was incorporated in therapeutic dose with drug load of 47% into orodispersible PC films. The content uniformity of these films fulfilled requirements of Ph.Eur and the films disintegrated in 12 s. In summary, PC and MCC showed comparable results after HPH and most differences could be explained by the smaller particle size of MCC suspensions. These results confirm the hypothesis that mainly the fiber size during processing is responsible for the existing differences of MCC and PC in pharmaceutical process, e.g., wet-extrusion/spheronization.
|
|
| 4. |
- Levine, Valerie, 1996-, et al.
(författare)
-
Geometry impact on fundamental properties of theophylline-containing SLS printed pharmaceutical tablets
- 2024
-
Ingår i: Frontiers in Drug Delivery. - 2674-0850. ; 4
-
Tidskriftsartikel (refereegranskat)abstract
- Selective Laser Sintering (SLS) has the potential to offer a more accurate alternative to current-practice manipulation of oral dosage forms for pediatric, geriatric, and dysphagia-suffering patient groups. In order to create the best possible dosage forms for these patient groups, an in-depth look into how a dosage forms geometry impacts the overall properties is essential. In this study, the impact of geometry on SLS manufactured oral dosage forms on the tablet’s microstructure, actual-to-theoretical volume, mass deviation, disintegration, and dissolution was investigated. Three different shapes; cylinder, hollow cylinder, and conical frustum with similar surface area (SA), as well as three cylinders with different diameters, were investigated. The results indicate that the geometry has an impact on the mass uniformity, resultant volume, disintegration, and dissolution properties of the tablets. The mass uniformity analysis of the tablets provided the most variation between tablets of different sizes, with more uniformity for tablets with similar SA-to-volume ratio (SA/V). When examining the actual-to-theoretical volume of the tablets, a greater variance between the actual and theoretical volumes for shapes with higher overall SA was observed. The values found are approximately 1.05 for the three differently sized cylinders, 1.23 for the conical frustum, and 1.44 for the hollow cylinder, following this trend. Disintegration data supported a link between SA/V and average disintegration time, observed with the tablet of the highest SA/V disintegrating in 12 s and the tablet with the lowest SA/V disintegrating in 58 s. Dissolution results also indicated a strong dependence on SA/V. Hence, when novel ways to produce oral dosage form tablets become available by additive manufacturing, such as SLS, both geometry and SA/V must be taken into consideration in the tablet design process to ensure appropriate release kinetics and dosing standards.
|
|
| 5. |
- Levine, Valerie R., 1996-, et al.
(författare)
-
Geometry Study of Theophylline-Containing SLS Printed Pharmaceutical Tablets
- 2022
-
Konferensbidrag (refereegranskat)abstract
- Purpose: There are many challenges in the pharmaceutical industry with modifications to oral dosage forms. This is especially apparent for certain demographics, including pediatric and geriatric patients. With regards to oral dosage forms for children, fixed-dose tablets designed for adults are used and require manual manipulation. This is often due to the lack of available premade dosages in the right strength. (Kader et al., 2021) For some groups, such as pediatric oncology patients, as many as 74% need manipulation of dosage forms. (Johannesson et al., 2022) The common practice for manipulation of oral dosage forms is to cut the tablets with a knife or pill cutter, which is of low accuracy and high patient and caregiver risk. A solution to this problem would be to create customizable additive manufactured oral dosage forms. Pharmaceutical tablets created with additive manufacturing technologies are developing in many print styles, including powder printing. While technologies like Fused Deposition Modelling (FDM) have come to a level of maturation for their own specific applications in pharmaceutical printing, Selective Laser Sintering (SLS) is still developing for pharmaceutical applications. This style of printing allows for a variable shape and an aesthetic similar to a traditionally pressed tablet. Many of the features of these printed tablets, however, are still unknown, as this technology is still rather new. The impact of the geometry of the tablets is one such area that is still not sufficiently explored, which is an essential analysis for the path to adoption of this technology for pharmaceutical application. Employing SLS technology, surface area and surface area to volume ratio impacts were analyzed to determine the effects of these variables.Methods: For this study, theophylline was used as the API (active pharmaceutical ingredient), Kollidon VA 64 was used as the polymer, Aerosil was used as the excipient, and activated carbon was used as the colorant. The composition of the powder material used for printing was 10% API (theophylline), 88.5% polymer (Kollidon VA 64), 0.5% excipient (Aerosil), and 1% colorant (activated carbon). For the comparison of the impact of surface area on tablets, three different shapes were chosen as a comparison: a cylinder, a hollow cylinder, and a conical frustum. Dimensions of these shapes were chosen to have similar surface areas, so an impact comparison could be achieved. The basis for the surface area of the shapes was a cylinder with a height of 4 mm and a radius of 5 mm. For the comparison of surface area to volume, different size cylinders were printed, since this is the simplest shape, thus creating different surface area to volume ratios. Radii of 3 mm, 5 mm, and 7 mm were chosen for comparison (surface area to volume ratios of 1.17, 0.9, and 0.79, respectively), all with a height of 4 mm for the tablets. Fusion 360 modelling software was employed to design the tablets and a Sintratec Kit printer was used to print the tablets, all with the same print settings. After printing, characterization was done and differences between the tablets were investigated.Results: On examination of the tablet masses, a consistency of the print quality can be observed, which is a promising result for the SLS print method, since all geometries were printed with the same settings. The geometries are consistent in that the average mass deviations are within the requirement for European Pharmacopoeia standards for tablets in their weight ranges. (2.9.5. Uniformity of Mass of Single-Dose Preparations, 2020) DSC analysis showed a partial crystallinity of the tablets, while dissolution data showed clear trends.Conclusion: The geometries of tablets are important for the further development of SLS additive manufacturing technology for pharmaceutical application. Consideration into the shape, surface area, and volume are key for oral dosage forms created with this technology. An understanding of this may lead to better future application for select patient groups, such as the pediatric population.
|
|
| 6. |
- Levine, Valerie R., 1996-, et al.
(författare)
-
Investigation of Polymers for SLS 3D-Printing of Solid Oral Dosage Forms
- 2022
-
Konferensbidrag (refereegranskat)abstract
- Purpose: Selective laser sintering (SLS) for oral dosage forms is a new field still in its infancy (Fina et al., 2017). This method does, however, show promise for the application of printing oral dosage forms, particularly for small-batch scenarios or for dosages in pediatric populations, where standard medications are often not suitable due to the different size and treatment requirements of children (Ivanovska et al., 2014). In addition, 3D printing technology provides a great opportunity to speed-up clinical trials and therefore shorten development timelines. SLS printing of oral dosage forms requires specific formulation design, which includes polymers often adapted for conventional pharmaceutical usage. Current commercially available polymers are often not specifically designed for SLS printing. Therefore, there is a high need to generate application data on how to optimally print these dosage forms as well as the need for dedicated polymers suitable for this application. The development of dedicated polymers with optimized properties includes the evaluation of amphiphilic PVA grades. A direct comparison of PVA 3-82, PVA 5-74 and PVA 4-88 with other commonly used polymers is presented here. This study aims to elaborate the print parameters for a host of common pharmaceutical polymers, as well as the new PVA polymers, with regards to print temperature and laser scan speed. Additionally, this study aims to follow as closely as possible to relevant Pharmacopeia standards for tablets to show the viability of SLS as a method and find print conditions for realistic oral dosage forms.Methods: For this study PVA 3-82, PVA 5-74 and PVA 4-88 (Parteck® MXP), PVP-VA(1) (Kollidon® VA 64), PVP-VA(2) (Plasdone™) were examined. These polymers were used in formulations of 88.5% polymer, 10% API (indomethacin), 0.5% flow regulation agent (silicon dioxide colloidal), and 1% colorant (silica-based pigment, Candurin® NXT Ruby Red). A tablet design was created using Fusion 360 modelling software and translated to an STL file. A Sintratec Kit printer (2.3 W diode, λ=455 nm) was utilized to print 36 tablets per each batch, each with the same overall settings (i.e. layer height of 150 µm, 3 perimeters, hatch spacing of 50 µm). For each different polymer tested, three different temperatures and three different laser scan speeds were chosen to find optimal print conditions for each formulation; 75 ℃, 100 ℃, and 125 ℃ & 200 mm/s, 300 mm/s, and 400 mm/s, respectively. Some of the polymers, however, could not withstand the 125 ℃ print temperature, so a temperature of 112.5 ℃ was chosen instead as the upper temperature limit. After completion of printing of the tablets, characterization occurred via XRD, DSC, friability testing, mass and size analysis, HPLC, as well as dissolution.Results: During printing of the tablets, it was found that the materials PVP-VA(1) and PVP-VA(2) showed signs of the material melting together in the powder bed at 125 ℃. Therefore, the temperature of upper limit for these formulations was 112.5 ℃. Upon evaluation, the most robust tablets per batch were generally printed at higher temperature (without exceeding the appropriate temperature window for each polymer) and lower laser scan speed. These tablets generally appeared better sintered together, had less signs of crystallinity with XRD and DSC analysis, and performed better in friability testing. The mass deviations for these samples also passed mass criteria of Pharmacopeia standards in several cases. Dissolution studies showed a strong solubility enhancement of PVA based formulation compared to the crystalline drug compound.Conclusion: The print ranges for these polymers commonly used in the pharmaceutical industry, as well as the newly developed PVA grades PVA 3-82 and PVA 5-74, could be individually defined based on variations in temperature and laser scan speed. Generally, trends of higher temperatures within the print range and lower laser scan speeds showed the best results upon characterization and visual inspection. These tablets were less powdery on the surface, more fitting to the desired shape of the intended tablet (i.e. less shifting between layers), and darker in color (implying a more complete sintering). The application of SLS printing in the area of solubility enhancement is a great step into further advancing the technology and allowing the development of patient-centered medication.
|
|
| 7. |
|
|
| 8. |
- Schulzen, Arne, et al.
(författare)
-
Development and characterization of solid lipid-based formulations (sLBFs) of ritonavir utilizing a lipolysis and permeation assay
- 2024
-
Ingår i: European Journal of Pharmaceutical Sciences. - : Elsevier. - 0928-0987 .- 1879-0720. ; 196
-
Tidskriftsartikel (refereegranskat)abstract
- As a high number of active pharmaceutical ingredients (APIs) under development belong to BCS classes II and IV, the need for improving bioavailability is critical. A powerful approach is the use of lipid-based formulations (LBFs) that usually consist of a combination of liquid lipids, cosolvents, and surfactants. In this study, ritonavir loaded solid LBFs (sLBFs) were prepared using solid lipid excipients to investigate whether sLBFs are also capable of improving solubility and permeability. Additionally, the influence of polymeric precipitation inhibitors (PVPVA and HPMC-AS) on lipolysis triggered supersaturation and precipitation was investigated. One step intestinal digestion and bicompartmental permeation studies using an artificial lecithin-in-dodecane (LiDo) membrane were performed for each formulation. All formulations presented significantly higher solubility (5 to >20-fold higher) during lipolysis and permeation studies compared to pure ritonavir. In the combined lipolysispermeation studies, the formulated ritonavir concentration increased 15 -fold in the donor compartment and the flux increased up to 71 % as compared to non-formulated ritonavir. The formulation with the highest surfactant concentration showed significantly higher ritonavir solubility compared to the formulation with the highest amount of lipids. However, the precipitation rates were comparable. The addition of precipitation inhibitors did not influence the lipolytic process and showed no significant benefit over the initial formulations with regards to precipitation. While all tested sLBFs increased the permeation rate, no statistically significant difference was noted between the formulations regardless of composition. To conclude, the different release profiles of the formulations were not correlated to the resulting flux through a permeation membrane, further supporting the importance of matring use of combined lipolysis-permeation assays when exploring LBFs.
|
|
| 9. |
- Tikhomirov, Evgenii, et al.
(författare)
-
Impact of polymer chemistry on critical quality attributes of selective laser sintering 3D printed solid oral dosage forms
- 2023
-
Ingår i: International Journal of Pharmaceutics. - : Elsevier. - 2590-1567. ; 6
-
Tidskriftsartikel (refereegranskat)abstract
- The aim of this study is to investigate the influence of polymer chemistry on the properties of oral dosage forms produced using selective laser sintering (SLS). The dosage forms were printed using different grades of polyvinyl alcohol or copovidone in combination with indomethacin as the active pharmaceutical ingredient. The properties of the printed structures were assessed according to European Pharmacopoeia guidelines at different printing temperatures and laser scanning speeds in order to determine the suitable printing parameters.The results of the study indicate that the chemical properties of the polymers, such as dynamic viscosity, degree of hydrolyzation, and molecular weight, have significant impact on drug release and kinetics. Drug release rate and supersaturation can be modulated by selecting the appropriate polymer type. Furthermore, the physical properties of the dosage forms printed under the same settings are influenced by the selected polymer type, which determines the ideal manufacturing settings.This study demonstrates how the chemical properties of the polymer can determine the appropriate choice of manufacturing settings and the final properties of oral dosage forms produced using SLS.
|
|
| 10. |
- Tikhomirov, Evgenii, et al.
(författare)
-
Selective laser sintering additive manufacturing of dosage forms : Effect of powder formulation and process parameters on the physical properties of printed tablets
- 2023
-
Ingår i: International Journal of Pharmaceutics. - : Elsevier. - 0378-5173 .- 1873-3476. ; 635
-
Tidskriftsartikel (refereegranskat)abstract
- Large batches of placebo and drug-loaded solid dosage forms were successfully fabricated using selective laser sintering (SLS) 3D printing in this study. The tablet batches were prepared using either copovidone (N-vinyl-2-pyrrolidone and vinyl acetate, PVP/VA) or polyvinyl alcohol (PVA) and activated carbon (AC) as radiation absorbent, which was added to improve the sintering of the polymer. The physical properties of the dosage forms were evaluated at different pigment concentrations (i.e., 0.5 and 1.0 wt%) and at different laser energy inputs. The mass, hardness, and friability of the tablets were found to be tunable and structures with greater mass and mechanical strength were obtained with increasing carbon concentration and energy input. Amorphization of the active pharmaceutical ingredient in the drug-loaded batches, containing 10 wt% naproxen and 1 wt% AC, was achieved in-situ during printing. Thus, amorphous solid dispersions were prepared in a single-step process and produced tablets with mass losses below 1 wt%. These findings show how the properties of dosage forms can be tuned by careful selection of the process parameters and the powder formulation. SLS 3D printing can therefore be considered to be an interesting and promising technique for the fabrication of personalized medicines.
|
|
