Direct Delivery of ANA-TA9, a Peptide Capable of Aß Hydrolysis, to the Brain by Intranasal Administration.

We have recently reported Catalytides (Catalytic peptides) JAL-TA9 (YKGSGFRMI) and ANA-TA9 (SKGQAYRMI), which are the first Catalytides found to cleave Aß42. Although the Catalytides must be delivered to the brain parenchyma to treat Alzheimer's disease, the blood-brain barrier (BBB) limits their entry into the brain from the systemic circulation. To avoid the BBB, the direct route from the nasal cavity to the brain was used in this study. The animal studies using rats and mice clarified that the plasma clearance of ANA-TA9 was more rapid than in vitro degradation in the plasma, whole blood, and the cerebrospinal fluid (CSF). The brain concentrations of ANA-TA9 were higher after nasal administration than those after intraperitoneal administration, despite a much lower plasma concentration after nasal administration, suggesting the direct delivery of ANA-TA9 to the brain from the nasal cavity. Similar findings were observed for its transport to CSF after nasal and intravenous administration. The concentration of ANA-TA9 in the olfactory bulb reached the peak at 5 min, whereas those in the frontal and occipital brains was 30 min, suggesting the sequential backward translocation of ANA-TA9 in the brain. In conclusion, ANA-TA9 was efficiently delivered to the brain by nasal application, as compared to other routes.

Spray Dried Formulations for Inhalation-Meaningful Characterisation of Powder Properties.

Spray drying as a particle engineering technique is of increasing interest in the field of inhalation and is already being utilised e.g., for the PulmoSphereTM products. As spray dried particles tend to agglomerate and are mechanically instable, low dose filling processes can be difficult. This study correlates powder flowability tests of spray dried formulations with filling processes with drum and dosator systems. Four pulmonary and four nasal powders with different characteristics in terms of shape, composition, and surface polarity were prepared and characterised for powder flowability according to Ph. Eur. and by powder rheometry. All formulations were filled with a manual drum TT and a dosator system. The classical flowability tests according to the Ph. Eur. showed a bad flow behaviour for hydrophilic pulmonary powders (x50 ~ 3 µm), whereas hydrophobic pulmonary particles and nasal particles (x50 ~ 25 µm) showed a better flowing behaviour. Powder rheometry supports this finding but can better differentiate flow behaviours.

Intranasal breast milk for premature infants with severe intraventricular hemorrhage-an observation.

For nasal application of neurotrophins and mesenchymal stem cells, successful delivery to the brain and therapeutic effects are known from experimental data in animals. Human breast milk contains neurotrophins and stem cells, but gavage tube feeding in preterm infants bypasses the naso-oropharynx. This is a first exploration on additional nasal breast milk and neuromorphological outcome after severe neonatal brain injury. We present a retrospective summary of 31 very low birth weight preterm infants with intraventricular hemorrhage °3/4 from one third-level neonatal center. All were breast milk fed. Sixteen infants additionally received nasal drops of fresh breast milk daily with informed parental consent for at least 28 days. Cerebral ultrasound courses were reviewed by a pediatric radiologist blinded to the intervention. The main outcome measure was severity of porencephalic defects before discharge. Clinical covariates were comparable in both groups. With nasal breast milk, a trend to a lower incidence for severe porencephalic defects (21% vs. 58%) was detected. Incidences were lower for progressive ventricular dilatation (71% vs. 91%) and surgery for posthemorrhagic hydrocephalus (50% vs. 67%).Conclusion: The hypothesis is generated that early intranasal application of breast milk could have a beneficial effect on neurodevelopment in preterm infants. Controlled investigation is needed. What is Known: • Successful delivery to the brain and therapeutic effects are known for nasal application of neurotrophins and mesenchymal stem cells from experimental data in animal studies. • Human breast milk contains neurotrophins and stem cells, but gavage tube feeding in preterm infants bypasses the naso-oropharynx. What is New: • This is the first report on additional nasal breast milk application in very low birth weight preterm infants with severe brain injury observing a trend for less severe porencephalic defects. • The hypothesis is generated that nasal breast milk might exert neuroprotective effects in preterm infants.

In vitro characterization of insulin containing thiomeric microparticles as nasal drug delivery system.

This study focused on a novel two step preparation method for the generation of insulin containing thiomer microparticles. The first step utilized the interpolymer complexation between poly(vinyl pyrrolidone) (PVP) and poly(acrylic acid) (PAA) or poly(acrylic acid)-cysteine (PAA-Cys), respectively, in the presence of insulin. Thereafter lyophilized coprecipitates were micronized via air jet mill. Particles were evaluated regarding size, morphology, insulin release and the effect on ciliary beat frequency of human nasal epithelial cells in vitro. Results displayed mean particle sizes of 2.6±1.6µm and 2.8±1.7µm for PAA/PVP/insulin and PAA-Cys/PVP/insulin microparticles, respectively, in a range where volitional impaction of particles on nasal epithelium takes place. Multi unit dosage forms showed in addition release for the incorporated insulin and nasal safety as to results of ciliary beat frequency studies (CBF). The introduced jet milled microparticles might in conclusion display a safe nasal insulin drug delivery system leading to improved absorption.

Nasal Application of the Galantamine Pro-drug Memogain Slows Down Plaque Deposition and Ameliorates Behavior in 5X Familial Alzheimer's Disease Mice.

The plant alkaloid galantamine is an established symptomatic drug treatment for Alzheimer's disease (AD), providing cognitive and global relief in human patients. However, as an acetylcholinesterase inhibitor, gastrointestinal side effects limit the dosage and duration of treatment. Memogain (Gln-1062), a pro-drug, liberates galantamine on cleavage by a carboxyesterase in the brain. The possibility to deliver Memogain intranasally may further circumvent side effects, allowing higher dosing compared to galantamine. In this study, the 5X Familial Alzheimer's Disease (5XFAD) mouse model was used to investigate the effect of chronic Memogain treatment on behavior and amyloid-ß (Aß) plaque deposition in the brain. Chronic intranasal dosage of 6 mg/kg body weight twice daily was tolerated well, whereas the double dose caused body weight loss in males and was less effective in some behavioral tests. 8 weeks of chronic treatment resulted in improved performance in behavioral tests, such as open field and light-dark avoidance, and in fear conditioning already at mildly affected stages at the age of 18 weeks compared to untreated controls. Furthermore, after treatment a significantly lower plaque density in the brain, i.e., in the entorhinal cortex (reduction 20% females, 40% males) and the hippocampus (19% females, 31% males) at the age of 18 weeks was observed. These results show that nasal application of Memogain effectively delivers the drug to the brain with the potential to retard plaque deposition and improve behavioral symptoms in AD similar to the approved galantamine.