Processing of Lipid Nanodispersions into Solid Powders by Spray Drying

Spray drying is a promising technology for drying lipid nanodispersions. These formulations can serve as carrier systems for poorly water-soluble active pharmaceutical ingredients (APIs) that are loaded into the lipid matrix to improve their bioavailability. Once the API-loaded nanocarriers have been further processed into solid dosage forms, they could be administered orally, which is usually preferred by patients. Various solid lipids as well as oils were used in this study to prepare lipid nanodispersions, and it was shown that their nanoparticulate properties could be maintained when lactose in combination with SDS was used as matrix material in the spray-drying process. In addition, for lipid nanoemulsions loaded with fenofibrate, a good redispersibility with particle sizes below 300 nm at a lipid content of 26.8 wt.% in the powders was observed. More detailed investigations on the influence of the drying temperature yielded good results when the inlet temperature of the drying air was set at 110 °C or above, enabling the lactose to form an amorphous matrix around the embedded lipid particles. A tristearin suspension was developed as a probe to measure the temperature exposure of the lipid particles during the drying process. The results with this approach indicate that the actual temperature the particles were exposed to during the drying process could be higher than the outlet temperature

Membrane interactions of ternary phospholipid/cholesterol bilayers and encapsulation efficiencies of a RIP II protein

Membrane interactions of liposomes of ternary phospholipid/cholesterol bilayers are investigated. These interactions lead to discoidal deformations and regular aggregations and are strongly enhanced by the presence of mistletoe lectin (ML), a RIP 11 type protein. The encapsulation of ML into liposomal nanocapsules is studied with a systematic variation of the lipid composition to monitor its effect on the physical properties: entrapment, mean size, morphology, and stability. Extrusion of multilamellar vesicles through filters 80 nm pore size was used for the generation of liposomes. The mean sizes of liposomes ranged between 120 and 200 nm in diameter with narrow size distributions. The increase in flow rate with pressure for three dioleoylphosphatidylcholine (DOPC/cholesterol (Chol)/dipalmitoylphosphatidylcholine (DPPC) lipid mixtures was linear and allowed to extrapolate to the minimum burst pressure of the liposomal bilayers. From the minimum pressures P(min), the bilayer lysis tensions gamma(1) were determined. The increase in P in and gamma(1) with an increasing content of a saturated phosopholipid (DPPC) indicates that DPPC increases the mechanical strength of lipid bilayers. Apparently, DPPC, like cholesterol, leads to a less compressible surface and a more cohesive membrane. After preparation, vesicle solutions were purified by gel permeation chromatography to separate encapsulated ML from free ML in the extravesicular solution. Purified liposomes were then characterized. The content of entrapped and adsorbed ML was measured using ELISA. Repetitive freezing/thawing cycles prior to extrusion significantly increased ML uptake. On the contrary, adsorption was not affected neither by lipid composition, nor concentration and preparation. Differences in experimental encapsulation efficiency only reflect the differences in the mean vesicle sizes of the different samples as is revealed by a comparison to a theoretical estimate. Cryo-transmission electron microscopy (Cryo-TEM) images show that beside spherical, single-walled liposomes, there is a considerable fraction of discoidally deformed vesicles. Based on our results and those found in the literature, we speculate that the flattening of the vesicles is a consequence of lipid phase separation and the formation of condensed complexes and areas of different bending elasticities. This phenomenon eventually leads to agglomeration of deformed liposomal structures, becoming more pronounced with the increase in the relative amount of saturated fatty acids, presumably caused by hydrophobic interaction. For the same lipid mixture aggregation correlated linearly with the ML content. Finally, tested liposomal samples were kept at 4 degrees C to examine their stability. Only slight fluctuations in diameter and the increase in polydispersity after 3 weeks of storage occurred, with no statistically significant evidence of drug leakage during a time period of 12 days, illustrating physical stability of liposomes

Stability of the metastable α-polymorph in solid triglyceride drug carrier nanoparticles.

Colloidal dispersions of crystalline nonpolar lipids are under intensive investigation as carrier systems in pharmaceutics and nutrition. In this context, the controlled preparation of particles in a metastable polymorphic state is of some interest for the delivery of active substances. In the present study, tristearin particles stabilized with three α-polymorph preserving emulsifier regimes ((I) sodium glycocholate/saturated long-chain phospholipids, (II) sodium glycocholate, (III) poly(vinyl alcohol) (PVA)) were investigated concerning the stability of the metastable α-polymorph after controlled crystallization of the particles from the melt. Upon long-term storage, the α-polymorph was preserved best in PVA-stabilized dispersions, followed by those stabilized with the glycocholate/phospholipid mixture and finally those stabilized solely with the bile salt. In particular for rapidly crystallized nanoparticles, the formation of an α-polymorph with highly reduced lamellarity was observed. According to time-/temperature-resolved synchrotron X-ray diffraction analysis with simultaneous DSC (differential scanning calorimetry) studies this less-ordered α-polymorph transformed into the common, lamellar α-form upon heating. Although the presence of the less-ordered form is probably related to the extraordinarily high stability of the metastable α-polymorph observed in some of the dispersions, it could not completely prevent the transition into the stable β-polymorph. The higher the transition temperature of the less-ordered α-form to the ordered one, the slower was the polymorphic transition to the stable β-polymorph. To estimate the polymorphic stability of the differently stabilized particles upon isothermal long-term storage, standard DSC measurements on samples stored at 23 °C for four weeks seem to be of predictive value

Etoposide-loaded nanoparticles made from glyceride lipids: Formulation, characterization, in vitro drug release, and stability evaluation

The aim of the study was to prepare etoposide-loaded nanoparticles with glyceride lipids and then characterize and evaluate the in vitro steric stability and drug release characteristics and stability. The nanoparticles were prepared by melt emulsification and homogenization followed by spray drying of nanodispersion. Spray drying created powder nanoparticles with excellent redispersibility and a minimal increase in particle size (20–40 nm). Experimental variables, such as homogenization pressure, number of homogenization cycles, and surfactant concentration, showed a profound influence on the particle size and distribution. Spray drying of Poloxamer 407-stabilized nanodispersion lead to the formation of matrix-like structures surrounding the nanoparticles, resulting in particle growth. The in vitro steric stability test revealed that the lipid nanoparticles stabilized by sodium tauroglycocholate exhibit excellent steric stability compared with Poloxamer 407. All 3 glyceride nanoparticle formulations exhibited sustained release characteristics, and the release pattern followed the Higuchi equation. The spray-dried lipid nanoparticles stored in black polypropylene containers exhibited excellent long-term stability at 25°C and room light conditions. Such stable lipid nanoparticles with in vitro steric stability can be a beneficial delivery system for intravenous administration as long circulating carriers for controlled and targeted drug delivery

Transplantation of peripheral blood stem cells as compared with bone marrow from HLA-identical siblings in adult patients with acute myeloid leukemia and acute lymphoblastic leukemia

Several studies show that allogeneic peripheral blood stem cells (PBSCs) engraft more rapidly than bone marrow (BM). However, the data are inconsistent with regard to acute and chronic graft-versus-host disease (GVHD), relapse, transplant-related mortality (TRM), and leukemia-free survival (LFS)

Allogeneic Hematopoietic Sct For Adults Aml Using I.V. Bu In The Conditioning Regimen: Outcomes And Risk Factors For The Occurrence Of Hepatic Sinusoidal Obstructive Syndrome

I.v. BU is frequently used in the conditioning regimen prior to allogeneic hematopoietic SCT (allo-HSCT); however, overall outcomes, incidence of hepatic sinusoidal obstructive syndrome (SOS) and its risk factors are not well known. With this aim, we performed a study on 257 AML adult recipients. Seattle Criteria were used for diagnosis and classification of SOS. The median age was 44 years. Donors were HLA-identical siblings in 60%, HLA-matched unrelated in 29% and HLA mismatched in 11%. Conditioning regimen was myeloablative in 84% (i.v. BU with CY was the most frequently used regimen) and it was reduced intensity in 16% (i.v. BU associated with fludarabine). Acute and chronic GVHD was observed in 28% and 44%, respectively. Two-year incidence of non-relapse mortality was 16 +/- 2% and 2-year leukemia-free survival for patients in CR1, CR2 and non remission at HSCT were 55 +/- 4%, 58 +/- 7%, and 20 +/- 5%, respectively. At 6 months, incidence of SOS was 7.8 +/- 2%; and it was severe in eight patients (3%). Factors associated with the occurrence of SOS were: HLA-mismatched donor HSCT (P = 0.002) and patients transplanted in non-remission (P = 0.002). In conclusion, outcomes of HSCT using i.v. BU are encouraging in this setting, SOS incidence is low and it is influenced by the type of donor and disease status at the time of transplant

A survey of fully haploidentical hematopoietic stem cell transplantation in adults with high-risk acute leukemia: a risk factor analysis of outcomes for patients in remission at transplantation.

Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) is an alternative treatment to patients with high-risk acute leukemia lacking a human leukocyte antigen-matched donor. We analyzed 173 adults with acute myeloid leukemia (AML) and 93 with acute lymphoblastic leukemia (ALL) who received a haplo-HSCT in Europe. All grafts were T cell-depleted peripheral blood progenitor cells from a direct family or other related donor. At transplantation, there were 25 patients with AML in CR1 (complete remission 1), 61 in more than or equal to CR2, and 87 in nonremission, and 24 with ALL in CR1, 37 in more than or equal to CR2, and 32 in nonremission. Median follow-up was 47 months in AML and 29 months in the ALL groups. Engraftment was observed in 91% of the patients. Leukemia-free survival at 2 years was 48% plus or minus 10%, 21% plus or minus 5%, and 1% for patients with AML undergoing transplantation in CR1, more than or equal to CR2, and nonremission, and 13% plus or minus 7%, 30% plus or minus 8%, and 7% plus or minus 5% in ALL patients, respectively. In conclusion, haplo-HSCT can be an alternative option for the treatment of high-risk acute leukemia patients in remission, lacking a human leukocyte antigen-matched donor