| 1. |
- Ansari, Shaquib Rahman, 1993-, et al.
(författare)
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Hyperthermia-Induced In Situ Drug Amorphization by Superparamagnetic Nanoparticles in Oral Dosage Forms
- 2022
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Ingår i: ACS Applied Materials and Interfaces. - : American Chemical Society (ACS). - 1944-8244 .- 1944-8252. ; 14:19, s. 21978-21988
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Tidskriftsartikel (refereegranskat)abstract
- Superparamagnetic iron oxide nanoparticles (SPIONs) generate heat upon exposure to an alternating magnetic field (AMF), which has been studied for hyperthermia treatment and triggered drug release. This study introduces a novel application of magnetic hyperthermia to induce amorphization of a poorly aqueous soluble drug, celecoxib, in situ in tablets for oral administration. Poor aqueous solubility of many drug candidates is a major hurdle in oral drug development. A novel approach to overcome this challenge is in situ amorphization of crystalline drugs. This method facilitates amorphization by molecular dispersion of the drug in a polymeric network inside a tablet, circumventing the physical instability encountered during the manufacturing and storage of conventional amorphous solid dispersions. However, the current shortcomings of this approach include low drug loading, toxicity of excipients, and drug degradation. Here, doped SPIONs produced by flame spray pyrolysis are compacted with polyvinylpyrrolidone and celecoxib and exposed to an AMF in solid state. A design of experiments approach was used to investigate the effects of SPION composition (Zn0.5Fe2.5O4 and Mn0.5Fe2.5O4), doped SPION content (10–20 wt %), drug load (30–50 wt %), and duration of AMF (3–15 min) on the degree of drug amorphization. The degree of amorphization is strongly linked to the maximum tablet temperature achieved during the AMF exposure (r = 0.96), which depends on the SPION composition and content in the tablets. Complete amorphization is achieved with 20 wt % Mn0.5Fe2.5O4 and 30 wt % celecoxib in the tablets that reached the maximum temperature of 165.2 °C after 15 min of AMF exposure. Furthermore, manganese ferrite exhibits no toxicity in human intestinal Caco-2 cell lines. The resulting maximum solubility of in situ amorphized celecoxib is 5 times higher than that of crystalline celecoxib in biorelevant intestinal fluid. This demonstrates the promising capability of SPIONs as enabling excipients to magnetically induce amorphization in situ in oral dosage forms.
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| 2. |
- Hempel, Nele-Johanna, et al.
(författare)
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The Effect of the Molecular Weight of Polyvinylpyrrolidone and the Model Drug on Laser-Induced In Situ Amorphization
- 2021
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Ingår i: Molecules. - : MDPI. - 1431-5157 .- 1420-3049. ; 26:13
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Tidskriftsartikel (refereegranskat)abstract
- Laser radiation has been shown to be a promising approach for in situ amorphization, i.e., drug amorphization inside the final dosage form. Upon exposure to laser radiation, elevated temperatures in the compacts are obtained. At temperatures above the glass transition temperature (T-g) of the polymer, the drug dissolves into the mobile polymer. Hence, the dissolution kinetics are dependent on the viscosity of the polymer, indirectly determined by the molecular weight (M-w) of the polymer, the solubility of the drug in the polymer, the particle size of the drug and the molecular size of the drug. Using compacts containing 30 wt% of the drug celecoxib (CCX), 69.25 wt% of three different M-w of polyvinylpyrrolidone (PVP: PVP12, PVP17 or PVP25), 0.25 wt% plasmonic nanoaggregates (PNs) and 0.5 wt% lubricant, the effect of the polymer M-w on the dissolution kinetics upon exposure to laser radiation was investigated. Furthermore, the effect of the model drug on the dissolution kinetics was investigated using compacts containing 30 wt% of three different drugs (CCX, indomethacin (IND) and naproxen (NAP)), 69.25 wt% PVP12, 0.25 wt% PN and 0.5 wt% lubricant. In perfect correlation to the Noyes-Whitney equation, this study showed that the use of PVP with the lowest viscosity, i.e., the lowest M-w (here PVP12), led to the fastest rate of amorphization compared to PVP17 and PVP25. Furthermore, NAP showed the fastest rate of amorphization, followed by IND and CCX in PVP12 due to its high solubility and small molecular size.
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| 3. |
- Hempel, Nele-Johanna, et al.
(författare)
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The Influence of Drug-Polymer Solubility on Laser-Induced In Situ Drug Amorphization Using Photothermal Plasmonic Nanoparticles
- 2021
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Ingår i: Pharmaceutics. - : MDPI. - 1999-4923 .- 1999-4923. ; 13:6
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Tidskriftsartikel (refereegranskat)abstract
- In this study, laser-induced in situ amorphization (i.e., amorphization inside the final dosage form) of the model drug celecoxib (CCX) with six different polymers was investigated. The drug-polymer combinations were studied with regard to the influence of (i) the physicochemical properties of the polymer, e.g., the glass transition temperature (T-g) and (ii) the drug-polymer solubility on the rate and degree of in situ drug amorphization. Compacts were prepared containing 30 wt% CCX, 69.25 wt% polymer, 0.5 wt% lubricant, and 0.25 wt% plasmonic nanoparticles (PNs) and exposed to near-infrared laser radiation. Upon exposure to laser radiation, the PNs generated heat, which allowed drug dissolution into the polymer at temperatures above its T-g, yielding an amorphous solid dispersion. It was found that in situ drug amorphization was possible for drug-polymer combinations, where the temperature reached during exposure to laser radiation was above the onset temperature for a dissolution process of the drug into the polymer, i.e., T-DStart. The findings of this study showed that the concept of laser-induced in situ drug amorphization is applicable to a range of polymers if the drug is soluble in the polymer and temperatures during the process are above T-DStart.
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| 4. |
- Hempel, Nele-Johanna, et al.
(författare)
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Utilizing Laser Activation of Photothermal Plasmonic Nanoparticles to Induce On-Demand Drug Amorphization inside a Tablet
- 2021
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Ingår i: Molecular Pharmaceutics. - : American Chemical Society (ACS). - 1543-8384 .- 1543-8392. ; 18:6, s. 2254-2262
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Tidskriftsartikel (refereegranskat)abstract
- Poor aqueous drug solubility represents a major challenge in oral drug delivery. A novel approach to overcome this challenge is drug amorphization inside a tablet, that is, on-demand drug amorphization. The amorphous form is a thermodynamically instable, disordered solid-state with increased dissolution rate and solubility compared to its crystalline counterpart. During on-demand drug amorphization, the drug molecularly disperses into a polymer to form an amorphous solid at elevated temperatures inside a tablet. This study investigates, for the first time, the utilization of photothermal plasmonic nanoparticles for on-demand drug amorphization as a new pharmaceutical application. For this, near-IR photothermal plasmonic nanoparticles were tableted together with a crystalline drug (celecoxib) and a polymer (polyvinylpyrrolidone). The tablets were subjected to a near-IR laser at different intensities and durations to study the rate of drug amorphization under each condition. During laser irradiation, the plasmonic nanoparticles homogeneously heated the tablet. The temperature was directly related to the rate and degree of amorphization. Exposure times as low as 180 s at 1.12 W cm(-2) laser intensity with only 0.25 wt % plasmonic nanoparticles and up to 50 wt % drug load resulted in complete drug amorphization. Therefore, near-IR photothermal plasmonic nanoparticles are promising excipients for on-demand drug amorphization with laser irradiation.
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| 5. |
- Kabedev, Aleksei, et al.
(författare)
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Stabilizing Mechanisms of β-Lactoglobulin in Amorphous Solid Dispersions of Indomethacin
- 2022
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Ingår i: Molecular Pharmaceutics. - : American Chemical Society (ACS). - 1543-8384 .- 1543-8392. ; 19:11, s. 3922-3933
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Tidskriftsartikel (refereegranskat)abstract
- Proteins, and in particular whey proteins, have recently been introduced as a promising excipient class for stabilizing amorphous solid dispersions. However, despite the efficacy of the approach, the molecular mechanisms behind the stabilization of the drug in the amorphous form are not yet understood. To investigate these, we used experimental and computational techniques to study the impact of drug loading on the stability of protein-stabilized amorphous formulations. β-Lactoglobulin, a major component of whey, was chosen as a model protein and indomethacin as a model drug. Samples, prepared by either ball milling or spray drying, formed single-phase amorphous solid dispersions with one glass transition temperature at drug loadings lower than 40–50%; however, a second glass transition temperature appeared at drug loadings higher than 40–50%. Using molecular dynamics simulations, we found that a drug-rich phase occurred at a loading of 40–50% and higher, in agreement with the experimental data. The simulations revealed that the mechanisms of the indomethacin stabilization by β-lactoglobulin were a combination of (a) reduced mobility of the drug molecules in the first drug shell and (b) hydrogen-bond networks. These networks, formed mostly by glutamic and aspartic acids, are situated at the β-lactoglobulin surface, and dependent on the drug loading (>40%), propagated into the second and subsequent drug layers. The simulations indicate that the reduced mobility dominates at low (<40%) drug loadings, whereas hydrogen-bond networks dominate at loadings up to 75%. The computer simulation results agreed with the experimental physical stability data, which showed a significant stabilization effect up to a drug fraction of 70% under dry storage. However, under humid conditions, stabilization was only sufficient for drug loadings up to 50%, confirming the detrimental effect of humidity on the stability of protein-stabilized amorphous formulations.
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| 6. |
- Larsen, Bjarke Strom, et al.
(författare)
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Using dextran of different molecular weights to achieve faster eeze-drying and improved storage stability of lactate dehydrogenase
- 2019
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Ingår i: Pharmaceutical development and technology (Print). - : Taylor & Francis. - 1083-7450 .- 1097-9867. ; 24:3, s. 323-328
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Tidskriftsartikel (refereegranskat)abstract
- Freeze-drying of protein formulations is frequently used to maintain otein activity during storage. The freeze-drying process usually quires long primary drying times because the highest acceptable drying mperature to obtain acceptable products is dependent on the glass ansition temperature of the maximally freeze-concentrated solution -g). On the other hand, retaining protein activity during storage is lated to the glass transition temperature (T-g) of the final eeze-dried product. In this study, dextrans with different molecular ight (1 and 40kDa) and mixtures thereof at the ratio 3:1, 1:1, and 1:3 /w) were used as cryo-/lyoprotectant and their impact on the stability the model protein lactate dehydrogenase (LDH) was investigated at evated temperatures (40 degrees C and 60 degrees C). The dextran rmulations were then compared to formulations containing sucrose as yo-/lyoprotectant. Because of the higher T-g values of the dextrans, e primary drying times could be reduced compared to freeze-drying with crose. Similarly, the higher T-g and T-g of dextrans relative to crose led to benefits during storage which was shown through improved otection of LDH activity.
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| 7. |
- Löbmann, Korbinian, et al.
(författare)
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Cellulose Nanopaper and Nanofoam for Patient-Tailored Drug Delivery
- 2017
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Ingår i: Advanced Materials Interfaces. - : Wiley-VCH Verlagsgesellschaft. - 2196-7350. ; 4:9
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Tidskriftsartikel (refereegranskat)abstract
- The development of drug delivery systems with tailored drug release can be very challenging especially in the case of problematic drugs. To address this problem, pharmaceutical scientists frequently use different formulation approaches and excipients, often involving a complex and multistep preparation. In this study, new cellulose nanofiber (CNF) based drug formulations are developed that allow controlled drug release in a facile and fast way, i.e., by simply casting drug/CNF dispersions. Altering the processing conditions and utilizing the unique inherent chemicophysical properties of cationic CNF at interfaces, it is possible to produce either drug-loaded CNF nanopapers (containing 21 or 51 wt% drug) or nanofoams (containing 21 wt% drug). The different formulations exhibit tailored release kinetics of the poorly watersoluble model drug indomethacin from immediate (nanopapers, 10-20 min) to slow release (nanofoams, approximate to 24 h). The fast release, from the nanopapers, is a result of the interplay of the molecular and supramolecular structure of indomethacin in addition to observed enhanced intrinsic dissolution of drug in the presence of CNF. The slower drug release is achieved by changing the hierarchical structure, i.e., creating a CNF based foam (porosity 99.2 wt%), and the prolonged release is mainly due to an extended drug diffusion path.
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| 8. |
- Svagan, Anna J., et al.
(författare)
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Solid cellulose nanofiber based foams – Towards facile design of sustained drug delivery systems
- 2016
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Ingår i: Journal of Controlled Release. - : Elsevier BV. - 0168-3659 .- 1873-4995. ; 244, s. 74-82
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Tidskriftsartikel (refereegranskat)abstract
- Control of drug action through formulation is a vital and very challenging topic within pharmaceutical sciences. Cellulose nanofibers (CNF) are an excipient candidate in pharmaceutical formulations that could be used to easily optimize drug delivery rates. CNF has interesting physico-chemical properties that, when combined with surfactants, can be used to create very stable air bubbles and dry foams. Utilizing this inherent property, it is possible to modify the release kinetics of the model drug riboflavin in a facile way. Wet foams were prepared using cationic CNF and a pharmaceutically acceptable surfactant (lauric acid sodium salt). The drug was suspended in the wet-stable foams followed by a drying step to obtain dry foams. Flexible cellular solid materials of different thicknesses, shapes and drug loadings (up to 50 wt%) could successfully be prepared. The drug was released from the solid foams in a diffusion-controlled, sustained manner due to the presence of intact air bubbles which imparted a tortuous diffusion path. The diffusion coefficient was assessed using Franz cells and shown to be more than one order of magnitude smaller for the cellular solids compared to the bubble-free films in the wet state. By changing the dimensions of dry foams while keeping drug load and total weight constant, the drug release kinetics could be modified, e.g. a rectangular box-shaped foam of 8 mm thickness released only 59% of the drug after 24 h whereas a thinner foam sample (0.6 mm) released 78% of its drug content within 8 h. In comparison, the drug release from films (0.009 mm, with the same total mass and an outer surface area comparable to the thinner foam) was much faster, amounting to 72% of the drug within 1 h. The entrapped air bubbles in the foam also induced positive buoyancy, which is interesting from the perspective of gastroretentive drug-delivery.
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| 9. |
- Zhuo, Xuezhi, et al.
(författare)
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Analysis of stabilization mechanisms in β-lactoglobulin-based amorphous solid dispersions by experimental and computational approaches
- 2024
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Ingår i: European Journal of Pharmaceutical Sciences. - : Elsevier. - 0928-0987 .- 1879-0720. ; 192
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Tidskriftsartikel (refereegranskat)abstract
- Our previous work shows that β-lactoglobulin-stabilized amorphous solid dispersion (ASD) loaded with 70 % indomethacin remains stable for more than 12 months. The stability is probably due to hydrogen bond networks spread throughout the ASD, facilitated by the indomethacin which has both hydrogen donors and acceptors. To investigate the stabilization mechanisms further, here we tested five other drug molecules, including two without any hydrogen bond donors. A combination of experimental techniques (differential scanning calorimetry, X-ray power diffraction) and molecular dynamics simulations was used to find the maximum drug loadings for ASDs with furosemide, griseofulvin, ibuprofen, ketoconazole and rifaximin. This approach revealed the underlying stabilization factors and the capacity of computer simulations to predict ASD stability. We searched the ASD models for crystalline patterns, and analyzed diffusivity of the drug molecules and hydrogen bond formation. ASDs loaded with rifaximin and ketoconazole remained stable for at least 12 months, even at 90 % drug loading, whereas stable drug loadings for furosemide, griseofulvin and ibuprofen were at a maximum of 70, 50 and 40 %, respectively. Steric confinement and hydrogen bonding to the proteins were the most important stabilization mechanisms at low drug loadings (≤ 40 %). Inter-drug hydrogen bond networks (including those with induced donors), ionic interactions, and a high Tg of the drug molecule were additional factors stabilizing the ASDs at drug loading greater than 40 %.
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| 10. |
- Zhuo, Xuezhi, et al.
(författare)
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Mechanisms of Drug Solubility Enhancement Induced by β-Lactoglobulin-Based Amorphous Solid Dispersions
- 2023
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Ingår i: Molecular Pharmaceutics. - : American Chemical Society (ACS). - 1543-8384 .- 1543-8392. ; 20:10, s. 5206-5213
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Tidskriftsartikel (refereegranskat)abstract
- Protein-based amorphous solid dispersions (ASDs) have emerged as a promising approach for enhancing solubility in comparison to crystalline drugs. The dissolution behavior of protein-based amorphous solid dispersions (ASDs) was investigated in various pH media. ASDs of four poorly soluble model drugs with acidic ( furosemide and indomethacin), basic (carvedilol), and neutral (celecoxib) properties were prepared by spray drying at 30 wt % drug loading with the protein ss-lactoglobulin (BLG). The effect of spray-dried BLG (SD-BLG) solubility and protein binding ability with dissolved drugs in solution were investigated to retrieve the mechanisms governing the improvement of drug solubility from the BLG-based ASDs. Powder dissolution results showed that all ASDs obtained a higher maximum concentration (C-max) compared to the respective pure crystalline drugs. It was found that the solubility increase of the drugs from the ASDs was to a large extent dependent on the solubility of the pure SD-BLG at the investigated pH values (low solubility at pH near the isoelectric point (pI) of BLG). Furthermore, drug-protein interactions in a solution were observed, in particular at pH values where the drugs were neutral. These drug-protein interactions also resulted, to some extent, in the stabilization of the drug in supersaturation.
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